FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Nyante, SJ Sherman, ME Pfeiffer, RM de Gonzalez, AB Brinton, LA Bowles, EJA Hoover, RN Glass, A Gierach, GL AF Nyante, Sarah J. Sherman, Mark E. Pfeiffer, Ruth M. de Gonzalez, Amy Berrington Brinton, Louise A. Bowles, Erin J. Aiello Hoover, Robert N. Glass, Andrew Gierach, Gretchen L. TI Longitudinal Change in Mammographic Density among ER-Positive Breast Cancer Patients Using Tamoxifen SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID WOMEN; RISK; DISCONTINUATION; PREVENTION; PATTERNS; THERAPY AB Tamoxifen-associated mammographic density (MD) reductions are linked to improved breast cancer survival. We evaluated MD at six time points to determine the timing of greatest reduction following tamoxifen initiation. We sampled 40 Kaiser Permanente Northwest estrogen receptor (ER)-positive breast cancer patients from a prior study of MD change, according to tamoxifen use duration and age at diagnosis: <4 years tamoxifen and <= 50 years (N = 6) or >50 years (N = 10) old; >= 4 years tamoxifen and <= 50 years (N = 13) or >50 years (N = 11) old. A single reader evaluated percent MD in the contralateral breast on baseline (pre-diagnosis) and five approximately yearly post-diagnostic (T1 to T5) mammograms. Mean MD change was calculated. Interactions with age (<= 50 and >50 years), tamoxifen duration (<4 and >= 4 years), and baseline MD (tertiles) were tested in linear regression models. Overall, the largest MD decline occurred by T1 (mean 4.5%) with little additional decline by T5. Declines differed by tertile of baseline MD (Pinteraction <0.01). In the highest tertile, the largest reduction occurred by T1 (mean 14.9%), with an additional reduction of 3.6% by T5. Changes were smaller in the middle and lowest baseline MD tertiles, with cumulative reductions of 3.0% and 0.4% from baseline to T5, respectively. There were no differences by age (Pinteraction = 0.36) or tamoxifen duration (Pinteraction = 0.42). Among ER-positive patients treated with tamoxifen and surviving >= 5 years, most of the MD reduction occurred within approximately 12 months of tamoxifen initiation, suggesting that MD measurement at a single time point following tamoxifen initiation can identify patients with substantial density declines. (C) 2015 AACR. C1 [Nyante, Sarah J.; Sherman, Mark E.; Pfeiffer, Ruth M.; de Gonzalez, Amy Berrington; Brinton, Louise A.; Hoover, Robert N.; Gierach, Gretchen L.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Sherman, Mark E.] NCI, Canc Prevent Div, Rockville, MD USA. [Bowles, Erin J. Aiello] Grp Hlth Res Inst, Seattle, WA USA. [Glass, Andrew] Kaiser Permanente Northwest Ctr Hlth Res, Portland, OR USA. RP Nyante, SJ (reprint author), Univ N Carolina, CB 7515, Chapel Hill, NC 27599 USA. EM sarah_nyante@med.unc.edu RI Gierach, Gretchen/E-1817-2016 OI Gierach, Gretchen/0000-0002-0165-5522 FU Intramural Research Program of the National Cancer Institute, NIH; National Cancer Institute federal funds [HHSN261201100441P, HHSN261200900017C/N02CP-90017, 10-312-0212208] FX This research was funded by the Intramural Research Program of the National Cancer Institute, NIH (to S.J. Nyante, M.E. Sherman, R.M. Pfeiffer, A. Berrington de Gonzalez, L.A. Brinton, R.N. Hoover, and G.L. Gierach) and National Cancer Institute federal funds awarded under contract HHSN261201100441P (to E. Aiello Bowles) and HHSN261200900017C/N02CP-90017 subcontract no. 10-312-0212208 (to A. Glass). NR 21 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JAN PY 2016 VL 25 IS 1 BP 212 EP 216 DI 10.1158/1055-9965.EPI-15-0412 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DG6DC UT WOS:000372171400028 PM 26545407 ER PT J AU Costas, L Lambert, BH Birmann, BM Moysich, KB De Roos, AJ Hofmann, JN Baris, D Wang, SS Camp, NJ Tricot, G Atanackovic, D Brennan, P Cocco, P Nieters, A Becker, N Maynadie, M Foretova, L Boffetta, P Staines, A Brown, EE De Sanjose, S AF Costas, Laura Lambert, Brice H. Birmann, Brenda M. Moysich, Kirsten B. De Roos, Anneclaire J. Hofmann, Jonathan N. Baris, Dalsu Wang, Sophia S. Camp, Nicola J. Tricot, Guido Atanackovic, Djordje Brennan, Paul Cocco, Pierluigi Nieters, Alexandra Becker, Nikolaus Maynadie, Marc Foretova, Lenka Boffetta, Paolo Staines, Anthony Brown, Elisabeth E. De Sanjose, Silvia TI A Pooled Analysis of Reproductive Factors, Exogenous Hormone Use, and Risk of Multiple Myeloma among Women in the International Multiple Myeloma Consortium SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID LYMPHOMAS; COHORT; HEALTH AB Background: Female sex hormones are known to have immunomodulatory effects. Therefore, reproductive factors and exogenous hormone use could influence the risk of multiple myeloma in women. However, the role of hormonal factors in multiple myeloma etiology remains unclear because previous investigations were underpowered to detect modest associations. Methods: We conducted a pooled analysis of seven case-control studies included in the International Multiple Myeloma Consortium, with individual data on reproductive factors and exogenous hormone use from 1,072 female cases and 3,541 female controls. Study-specific odds ratios and corresponding 95% confidence intervals (CI) were estimated using logistic regression and pooled analyses were conducted using random effects meta-analyses. Results: Multiple myeloma was not associated with reproductive factors, including ever parous [OR = 0.92; 95% confidence interval (CI), 0.68-1.25], or with hormonal contraception use (OR = 1.04; 95% CI, 0.80-1.36). Postmenopausal hormone therapy users had nonsignificantly reduced risks of multiple myeloma compared with never users, but this association differed across centers (OR = 0.65; 95% CI, 0.37-1.15, I-2 = 76.0%, P-heterogeneity = 0.01). Conclusions: These data do not support a role for reproductive factors or exogenous hormones in myelomagenesis. Impact: Incidence rates of multiple myeloma are higher in men than in women, and sex hormones could influence this pattern. Associations with reproductive factors and exogenous hormone use were inconclusive despite our large sample size, suggesting that female sex hormones may not play a significant role in multiple myeloma etiology. (C) 2015 AACR. C1 Catalan Inst Oncol, Barcelona, Spain. [Costas, Laura; De Sanjose, Silvia] Catalan Inst Oncol, IDIBELL, Canc Epidemiol Res Program, Unit Infect & Canc, Barcelona, Spain. [Costas, Laura; De Sanjose, Silvia] Univ Barcelona, Dept Med, Barcelona, Spain. [Costas, Laura; De Sanjose, Silvia] CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain. [Lambert, Brice H.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Birmann, Brenda M.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Birmann, Brenda M.] Harvard Univ, Sch Med, Boston, MA USA. [Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [De Roos, Anneclaire J.] Drexel Univ, Sch Publ Hlth, Dept Environm & Occupat Hlth, Philadelphia, PA 19104 USA. [Hofmann, Jonathan N.; Baris, Dalsu] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Dept Populat Sci, Div Canc Etiol, Duarte, CA USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. [Camp, Nicola J.; Atanackovic, Djordje] Univ Utah, Sch Med, Div Hematol & Hematol Malignancies, Salt Lake City, UT USA. [Camp, Nicola J.; Atanackovic, Djordje] Huntsman Canc Inst, Salt Lake City, UT USA. [Tricot, Guido] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. [Brennan, Paul] IARC, Lyon, France. [Cocco, Pierluigi] Univ Cagliari, Dept Publ Hlth Clin & Mol Med, Occupat Hlth Sect, Cagliari, Italy. [Nieters, Alexandra] Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, Mol Epidemiol, Freiburg, Germany. [Becker, Nikolaus] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Maynadie, Marc] Univ Hosp Dijon, CRB Ferdinand Cabanne, Biol Hematol Unit, Dijon, France. [Maynadie, Marc] Univ Burgundy, EA4184, Dijon, France. [Foretova, Lenka] Masaryk Mem Canc Inst, Canc Epidemiol & Genet, Brno, Czech Republic. [Foretova, Lenka] MF MU, Brno, Czech Republic. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA. [Staines, Anthony] Publ Hlth Univ Coll, Dublin, Ireland. [Brown, Elisabeth E.] Univ Alabama Birmingham, Ctr Comprehens Canc, Dept Pathol, Birmingham, AL 35294 USA. RP Costas, L (reprint author), Inst Catala Oncol, Barcelona, Spain. EM lcostas@iconcologia.net RI de Sanjose Llongueras, Silvia/H-6339-2014 FU Spanish Ministry of Economy and Competitiveness - Carlos III Institute of Health [Rio Hortega CM13/00232, M-AES MV15/00025, PI11/01810, PI14/01219]; University of Barcelona; Catalan Government [2014SGR756]; European Commission 5th Framework Programme [QLK4-CT-2000-00422]; European Commission 6th Framework Programme [FOOD-CT-2006-023103]; Carlos III Institute of Health [FIS PI081555, RCESP C03/09, RTICESP C03/10, RTICRD06/0020/0095]; Marato TV3 Foundation [051210]; International Agency for Research on Cancer [IARC-5111]; MH CZ - DRO (MMCI) [00209805]; RECAMO [CZ.1.05/2.1.00/03.0101]; Fondation de France [1999 008471]; Italian Association for Cancer Research (AIRC) [11855]; Italian Ministry of Education, University and Research, PRIN programme [2007WEJLZB, 20092ZELR2]; German Federal Office for Radiation Protection [StSch4261, StSch4420]; Leukemia and Lymphoma Society [6067-09]; NCI [CA152336, K07 CA115687, R01 CA127435, R01 CA149445, U54CA118948, R21CA155951, R25CA76023, R01CA186646]; University of Utah Huntsman Cancer Institute (HCI); HCI Cancer Center Support grant from the NCI [P30 CA42014]; NCI SEER program [HHSN261201000026C]; Utah State Department of Health; University of Utah; American Cancer Society [RSG-11-020-01-CNE, IRG60-001-47]; University of Alabama at Birmingham Comprehensive Cancer Center Support Grant [P30CA13148]; federal funds from the NCI, NIH [R01CA036388, R01CA077398, K05CA136967]; City of Hope Comprehensive Cancer Center Support Grant [P30CA033572]; Intramural Research Program of the NIH FX The work conducted by L. Costas was supported by grants from the Spanish Ministry of Economy and Competitiveness - Carlos III Institute of Health (Rio Hortega CM13/00232 and M-AES MV15/00025) and the University of Barcelona (Research Abroad Grant 2012). This work was partially supported by the public grants from Spanish Ministry of Economy and Competitiveness - Carlos III Institute of Health (PI11/01810, PI14/01219), and Catalan Government (2014SGR756). Epilymph was supported by European Commission 5th Framework Programme (QLK4-CT-2000-00422); 6th Framework Programme (FOOD-CT-2006-023103); Carlos III Institute of Health (FIS PI081555, RCESP C03/09, RTICESP C03/10, RTICRD06/0020/0095, CIBERESP and European Regional Development Fund-ERDF); Marato TV3 Foundation (051210); International Agency for Research on Cancer (IARC-5111); MH CZ - DRO (MMCI, 00209805), RECAMO CZ.1.05/2.1.00/03.0101; Fondation de France (1999 008471; EpiLymph-France); Italian Association for Cancer Research (AIRC, Investigator Grant 11855); Italian Ministry of Education, University and Research, PRIN programme (2007WEJLZB, 20092ZELR2); and the German Federal Office for Radiation Protection (StSch4261 and StSch4420; Epilymph Germany). Funding for the Utah study was, in part, from the Leukemia and Lymphoma Society 6067-09 (to N.J. Camp) and the NCI CA152336 (to N.J. Camp). Data collection for the Utah resource was made possible by the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR). Partial support for all datasets within the UPDB was provided by the University of Utah Huntsman Cancer Institute (HCI) and the HCI Cancer Center Support grant, P30 CA42014 from the NCI. The UCR is funded by contract HHSN261201000026C from the NCI SEER program with additional support from the Utah State Department of Health and the University of Utah. The work conducted by B.M. Birmann was supported, in part, by grants from the NCI (K07 CA115687, R01 CA127435, R01 CA149445) and the American Cancer Society (RSG-11-020-01-CNE). The work conducted by E.E. Brown was supported, in part, by grants from the NCI (U54CA118948, R21CA155951, R25CA76023, R01CA186646, and the University of Alabama at Birmingham Comprehensive Cancer Center Support Grant P30CA13148) and the American Cancer Society (IRG60-001-47). The work conducted by S.S. Wang was supported, in part, by federal funds from the NCI, NIH, under R01CA036388, R01CA077398, and K05CA136967 and by the City of Hope Comprehensive Cancer Center Support Grant P30CA033572. The NCI-Yale Myeloma Study was supported in part by the Intramural Research Program of the NIH. NR 8 TC 0 Z9 0 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JAN PY 2016 VL 25 IS 1 BP 217 EP 221 DI 10.1158/1055-9965.EPI-15-0953 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DG6DC UT WOS:000372171400029 PM 26464426 ER PT J AU Reeves, KW Tehranifar, P Crane, TE Ko, LK Cameron, C Hamilton, JG Lavigne, JA Reiter, PL Thomson, CA AF Reeves, Katherine W. Tehranifar, Parisa Crane, Tracy E. Ko, Linda K. Cameron, Carrie Hamilton, Jada G. Lavigne, Jackie A. Reiter, Paul L. Thomson, Cynthia A. TI Job Talks and Interviews: How to Stand Out and Fit In: A Report from the American Society of Preventive Oncology Junior Members Interest Group SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material C1 [Reeves, Katherine W.] Univ Massachusetts, Dept Biostat & Epidemiol, Amherst, MA 01003 USA. [Tehranifar, Parisa] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Crane, Tracy E.; Thomson, Cynthia A.] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ USA. [Ko, Linda K.] Fred Hutchinson Canc Res Ctr, Dept Canc Prevent, 1124 Columbia St, Seattle, WA 98104 USA. [Cameron, Carrie] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Hamilton, Jada G.] Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, 1275 York Ave, New York, NY 10021 USA. [Lavigne, Jackie A.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Reiter, Paul L.] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. RP Reeves, KW (reprint author), Univ Massachusetts, 411 Arnold House,715 North Pleasant St, Amherst, MA 01003 USA. EM kwreeves@schoolph.umass.edu FU NCI NIH HHS [P30 CA008748] NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JAN PY 2016 VL 25 IS 1 BP 224 EP 225 DI 10.1158/1055-9965.EPI-15-1024 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DG6DC UT WOS:000372171400032 PM 26762809 ER PT J AU Alsubai, J Matters, GL McGovern, CO Liao, JG Gilius, EL Smith, JP AF Alsubai, Jelal Matters, Gail L. McGovern, Christopher O. Liao, Jiangang Gilius, Evan L. Smith, Jill P. TI Germline Mutation of the CCK Receptor: A Novel Biomarker for Pancreas Cancer SO CLINICAL AND TRANSLATIONAL GASTROENTEROLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; HUMAN-COLON-CANCER; CELL-LINES; GASTRIN RECEPTORS; SOMATIC MUTATIONS; STIMULATES GROWTH; GNAS MUTATIONS; TUMOR-CELLS; HIGH-RISK; CHOLECYSTOKININ AB OBJECTIVES: Today, genetic biomarkers have been demonstrated to play an important role in identifying at-risk subjects for familial or inherited cancers. We have identified a single-nucleotide polymorphism (SNP) that results in missplicing of the cholecystokinin (CCK) receptor gene and expressing a larger mutated receptor in pancreatic cancer. The purpose of this study was to evaluate the significance and specificity of this SNP as a potential biomarker in patients with pancreatic cancer compared with other gastrointestinal (GI) cancers that also have CCK receptors. METHODS: DNA was isolated and genotyped for the CCK receptor SNP from frozen tumor tissue from banked specimens of patients with pancreas, gastric, or colon cancer and from human cancer cell lines. Genotype and allelic frequencies were compared between the cancer cohort and two normal control databases using Fisher's exact test and odds ratio (OR). The Kaplan-Meier method was used to estimate the survival for patients with the CCK-B receptor SNP compared with those with the wild-type genotype. Immunohistochemical staining of cancer cells was done to detect the mutated receptor. RESULTS: Colon and gastric cancer patients had similar genotype frequencies for the CCK receptor SNP as that reported in the normal population. In contrast, the prevalence of the SNP in subjects with pancreatic cancer was twice that of controls and other GI cancers. Survival was adversely affected by the presence of the SNP only in those with pancreatic cancer. Immunoreactivity for the mutated receptor was positive in pancreatic cancer tissues with the SNP but absent in other GI cancers. CONCLUSIONS: A SNP of the CCK receptor is significantly increased in patients with pancreatic cancer but not in those with other GI malignancies. Therefore, this SNP may be a potential biomarker for pancreatic cancer. C1 [Alsubai, Jelal; Smith, Jill P.] Penn State Univ, Sch Med, Dept Med, Hershey, PA USA. [Matters, Gail L.; McGovern, Christopher O.] Penn State Univ, Sch Med, Dept Biochem & Mol Biol, Hershey, PA USA. [Liao, Jiangang] Penn State Univ, Coll Med, Dept Publ Hlth Sci, Hershey, PA USA. [Gilius, Evan L.] NCI, NIH, Bethesda, MD 20892 USA. [Smith, Jill P.] Georgetown Univ, Sch Med, Dept Med Gastroenterol, Washington, DC 20007 USA. RP Smith, JP (reprint author), Georgetown Univ, 3800 Reservoir Rd NW,2 Main, Washington, DC 20007 USA. EM jps261@georgetown.edu FU NIH [R01 CA117926]; William Donner Foundation FX This work was funded by a grant NIH R01 CA117926 (to J.P.S.) and support from the William Donner Foundation (to J.P.S.). NR 49 TC 0 Z9 0 U1 0 U2 2 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 JAN PY 2016 VL 7 AR e134 DI 10.1038/ctg.2015.61 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DG5GS UT WOS:000372105700001 PM 26741064 ER PT J AU Viau, R Frank, KM Jacobs, MR Wilson, B Kaye, K Donskey, CJ Perez, F Endimiani, A Bonomo, RA AF Viau, Roberto Frank, Karen M. Jacobs, Michael R. Wilson, Brigid Kaye, Keith Donskey, Curtis J. Perez, Federico Endimiani, Andrea Bonomo, Robert A. TI Intestinal Carriage of Carbapenemase-Producing Organisms: Current Status of Surveillance Methods SO CLINICAL MICROBIOLOGY REVIEWS LA English DT Review ID KLEBSIELLA-PNEUMONIAE CARBAPENEMASE; REAL-TIME PCR; SPECTRUM-BETA-LACTAMASE; MEDIATED ISOTHERMAL AMPLIFICATION; INTENSIVE-CARE-UNIT; RESISTANT ACINETOBACTER-BAUMANNII; COMMERCIAL MULTIPLEX PCR; SCREENING AGAR PLATES; 2 CHROMOGENIC MEDIA; MODIFIED HODGE TEST AB Carbapenemases have become a significant mechanism for broad-spectrum beta-lactam resistance in Enterobacteriaceae and other Gram-negative bacteria such as Pseudomonas and Acinetobacter spp. Intestinal carriage of carbapenemase-producing organisms (CPOs) is an important source of transmission. Isolation of carriers is one strategy that can be used to limit the spread of these bacteria. In this review, we critically examine the clinical performance, advantages, and disadvantages of methods available for the detection of intestinal carriage of CPOs. Culture-based methods (Centers for Disease Control and Prevention [CDC] protocols, chromogenic media, specialized agars, and double-disk synergy tests) for detecting carriage of CPOs are convenient due to their ready availability and low cost, but their limited sensitivity and long turnaround time may not always be optimal for infection control practices. Contemporary nucleic acid amplification techniques (NAATs) such as real-time PCR, hybridization assays, loop-mediated isothermal amplification (LAMP), or a combined culture and NAAT approach may provide fast results and/or added sensitivity and specificity compared with culture-based methods. Infection control practitioners and clinical microbiologists should be aware of the strengths and limitations of available methods to determine the most suitable approach for their medical facility to fit their infection control needs. C1 [Bonomo, Robert A.] Univ Hosp Case Med Ctr, Dept Med, Div Infect Dis & HIV Med, Cleveland, OH USA. [Frank, Karen M.] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Jacobs, Michael R.] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. [Jacobs, Michael R.] Univ Hosp Case Med Ctr, Cleveland, OH USA. [Wilson, Brigid] Louis Stokes Cleveland VA Med Ctr, Ctr Geriatr Res Educ & Clin, Cleveland, OH USA. [Kaye, Keith] Wayne State Univ, Dept Med, Detroit, MI 48202 USA. [Kaye, Keith] Detroit Med Ctr, Detroit, MI USA. [Donskey, Curtis J.; Perez, Federico; Bonomo, Robert A.] Louis Stokes Cleveland Dept Vet Affairs Med Ctr, Infect Dis Sect, Med Serv, Cleveland, OH USA. [Donskey, Curtis J.; Perez, Federico; Bonomo, Robert A.] Louis Stokes Cleveland Vet Affairs Med Ctr, Res Serv, Cleveland, OH USA. [Endimiani, Andrea] Univ Bern, Fac Med, Inst Infect Dis, Bern, Switzerland. [Bonomo, Robert A.] Case Western Reserve Univ, Dept Pharmacol Mol Biol & Microbiol, Cleveland, OH 44106 USA. RP Bonomo, RA (reprint author), Univ Hosp Case Med Ctr, Dept Med, Div Infect Dis & HIV Med, Cleveland, OH USA.; Bonomo, RA (reprint author), Louis Stokes Cleveland Dept Vet Affairs Med Ctr, Infect Dis Sect, Med Serv, Cleveland, OH USA.; Bonomo, RA (reprint author), Louis Stokes Cleveland Vet Affairs Med Ctr, Res Serv, Cleveland, OH USA.; Bonomo, RA (reprint author), Case Western Reserve Univ, Dept Pharmacol Mol Biol & Microbiol, Cleveland, OH 44106 USA. EM robert.bonomo@va.gov OI Viau, Roberto/0000-0003-4982-4708; Endimiani, Andrea/0000-0003-3186-5421 FU National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) [R01AI100560, R01AI063517, R01AI072219]; NIAID DMID [100065]; NIH; Cleveland Department of Veterans Affairs, Veterans Affairs Merit Review Program Award [1I01BX001974]; Geriatric Research Education and Clinical Center VISN [10]; Swiss National Science Foundation [32003B_153377] FX Research reported in this publication was supported in part by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under award numbers R01AI100560, R01AI063517, and R01AI072219 to R.A.B.; NIAID DMID protocol 100065 to K.K.; the Intramural Research Program of the NIH, the Cleveland Department of Veterans Affairs, Veterans Affairs Merit Review Program Award 1I01BX001974, and Geriatric Research Education and Clinical Center VISN 10 to R.A.B.; and the Swiss National Science Foundation under grant number 32003B_153377 to A.E. NR 199 TC 19 Z9 20 U1 7 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0893-8512 EI 1098-6618 J9 CLIN MICROBIOL REV JI Clin. Microbiol. Rev. PD JAN PY 2016 VL 29 IS 1 BP 1 EP 27 DI 10.1128/CMR.00108-14 PG 27 WC Microbiology SC Microbiology GA DG7GB UT WOS:000372251700001 PM 26511484 ER PT J AU Moody, TW Nuche-Berenguer, B Nakamura, T Jensen, RT AF Moody, Terry W. Nuche-Berenguer, Bernardo Nakamura, Taichi Jensen, Robert T. TI EGFR Transactivation by Peptide G Protein-Coupled Receptors in Cancer SO CURRENT DRUG TARGETS LA English DT Article DE Epidermal growth factor receptor; G protein-coupled receptor; lung cancer; non-peptide receptor antagonists; peptide receptor agonists; transactivation of tyrosine kinase receptors ID EPIDERMAL-GROWTH-FACTOR; GASTRIN-RELEASING-PEPTIDE; CELL LUNG-CANCER; SMOOTH-MUSCLE-CELLS; II TYPE-1 RECEPTOR; CAUSES TYROSINE PHOSPHORYLATION; MAMMALIAN BOMBESIN RECEPTORS; SIGNAL-REGULATED KINASE; FOCAL ADHESION KINASE; SEE VOL. 31 AB Lung cancer kills approximately 1.3 million citizens in the world annually. The tyrosine kinase inhibitors (TKI) erlotinib and gefitinib are effective anti-tumor agents especially in lung cancer patients with epidermal growth factor receptor (EGFR) mutations. The goal is to increase the potency of TKI in lung cancer patients with wild type EGFR. G protein-coupled receptors (GPCR) transactivate the wild type EGFR in lung cancer cells. The GPCR can be activated by peptide agonists causing phosphatidylinositol turnover or stimulation of adenylylcyclase. Recently, nonpeptide antagonists were found to inhibit the EGFR transactivation caused by peptides. Nonpeptide antagonists for bombesin (BB), neurotensin (NTS) and cholecystokinin (CCK) inhibit lung cancer growth and increase the cytotoxicity of gefitinib. The results suggest that GPCR transactivation of the EGFR may play an important role in cancer cell proliferation. C1 NCI, US Dept HHS, Ctr Canc Res, Bethesda, MD 20892 USA. NIDDK, Digest Dis Branch, Bethesda, MD 20892 USA. RP Moody, TW (reprint author), NCI, CCR, 9609 Med Ctr Dr,Room 2W-130, Bethesda, MD 20892 USA. EM moodyt@mail.nih.gov FU NCI; NIDDK of the NIH FX Dr. D. Chan is acknowledged for helpful comments. This research is supported by the intramural programs of NCI and NIDDK of the NIH. NR 124 TC 2 Z9 2 U1 0 U2 2 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-4501 EI 1873-5592 J9 CURR DRUG TARGETS JI Curr. Drug Targets PY 2016 VL 17 IS 5 BP 520 EP 528 DI 10.2174/1389450116666150107153609 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DG4RH UT WOS:000372059600006 PM 25563590 ER PT J AU Guasch, L Zakharov, AV Tarasova, OA Poroikov, VV Liao, CZ Nicklaus, MC AF Guasch, Laura Zakharov, Alexey V. Tarasova, Olga A. Poroikov, Vladimir V. Liao, Chenzhong Nicklaus, Marc C. TI Novel HIV-1 Integrase Inhibitor Development by Virtual Screening Based on QSAR Models SO CURRENT TOPICS IN MEDICINAL CHEMISTRY LA English DT Review DE AIDS; CADD; HIV-1 integrase; QSAR; Strand transfer inhibitor; Virtual screening ID RALTEGRAVIR; PREDICTION; DISCOVERY; RESISTANCE; PROTEASE; INTASOME; DATABASE; MUTANTS; POTENCY; DOCKING AB HIV-1 integrase (IN) plays an important role in the life cycle of HIV and is responsible for integration of the virus into the human genome. We present computational approaches used to design novel HIV-1 IN inhibitors. We created an IN inhibitor database by collecting experimental data from the literature. We developed quantitative structure-activity relationship (QSAR) models of HIV-1 IN strand transfer (ST) inhibitors using this database. The prediction accuracy of these models was estimated by external 5-fold cross-validation as well as with an additional validation set of 308 structurally distinct compounds from the publicly accessible BindingDB database. The validated models were used to screen a small combinatorial library of potential synthetic candidates to identify hits, with a subsequent docking approach applied to further filter out compounds to arrive at a small set of potential HIV-1 IN inhibitors. As result, 236 compounds with good druglikeness properties and with correct docking poses were identified as potential candidates for synthesis. One of the six compounds finally chosen for synthesis was experimentally confirmed to inhibit the ST reaction with an IC50(ST) of 37 mu M. The IN inhibitor database is available for download from http://cactus.nci.nih.gov/download/iidb/. C1 [Guasch, Laura; Zakharov, Alexey V.; Nicklaus, Marc C.] NCI, CADD Grp, Biol Chem Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Tarasova, Olga A.; Poroikov, Vladimir V.] Inst Biochem Chem, Lab Struct Funct Based Drug Design, Moscow, Russia. [Liao, Chenzhong] Hefei Univ Technol, Sch Med Engn, Hefei, Peoples R China. RP Nicklaus, MC (reprint author), NCI, CADD Grp, Biol Chem Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. EM mn1@helix.nih.gov RI Tarasova, Olga/E-4318-2014; Tarasova, Olga/F-1248-2017; OI Tarasova, Olga/0000-0002-4230-3849; Tarasova, Olga/0000-0002-3723-7832; Nicklaus, Marc/0000-0002-4775-7030 FU U.S. National Institutes of Health; Russian Foundation of Basic Research [13-04-91455_NIH-a] FX This work was partially supported by the Intramural Program of the U.S. National Institutes of Health and the Russian Foundation of Basic Research (grant No. 13-04-91455_NIH-a). The content of this publication does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services, nor does mentioning of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 30 TC 0 Z9 0 U1 4 U2 20 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0266 EI 1873-5294 J9 CURR TOP MED CHEM JI Curr. Top. Med. Chem. PY 2016 VL 16 IS 4 BP 441 EP 448 DI 10.2174/1568026615666150813150433 PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA CU9WW UT WOS:000363898600008 PM 26268340 ER PT J AU Opina, ACL Strickland, M Lee, YS Tjandra, N Byrd, RA Swenson, RE Vasalatiy, O AF Opina, Ana Christina L. Strickland, Madeleine Lee, Yong-Sok Tjandra, Nico Byrd, R. Andrew Swenson, Rolf E. Vasalatiy, Olga TI Analysis of the isomer ratios of polymethylated-DOTA complexes and the implications on protein structural studies SO DALTON TRANSACTIONS LA English DT Article ID WATER EXCHANGE; LANTHANIDE(III) COMPLEXES; GADOLINIUM COMPLEXES; AQUEOUS-SOLUTION; CONTRAST AGENTS; CONFORMATIONAL MOBILITY; PSEUDOCONTACT SHIFTS; ALKYL SUBSTITUTION; NMR-SPECTROSCOPY; ACID AB A rigidified and symmetrical polymethylated 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) ligand bearing four SSSS methyl groups in both the tetraaza ring and the acetate arms (SSSS-SSSS-M4DOTMA) was prepared. The isomer ratio of SSSS-SSSS-M4DOTMA complexed with a series of lanthanide ions was carefully investigated using RP-HPLC and NMR. A square antiprismatic (SAP) configuration was exclusively observed for the early lanthanides, while the twisted square antiprismatic (TSAP) geometry was preferred as the lanthanide ion size decreases. The late lanthanides preferentially adopted the TSAP geometry. One of the pendant arms was modified with a pyridyl disulfide group (SSSS-SSSS-M8SPy) for cysteine attachment and displayed a similar isomer trend as the parent compound, Ln-SSSS-SSSS-M4DOTMA. Covalent attachment to the ubiquitin S57C mutant showed resonances whose intensities are in agreement with the isomeric population observed by RP-HPLC. Furthermore, the NOE experiments combined with quantum chemical calculations have unequivocally demonstrated that the SAP of Pr-SSSS-SSSS-M4DOTMA and Pr-SSSS-SSSS-M8SPy, as well as the TSAP of Yb-SSSS-SSSS-M8SPy are more stable than their corresponding isomers. C1 [Opina, Ana Christina L.; Swenson, Rolf E.; Vasalatiy, Olga] NHLBI, Imaging Probe Dev Ctr, NIH, Rockville, MD 20850 USA. [Strickland, Madeleine; Tjandra, Nico] NHLBI, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. [Lee, Yong-Sok] NIH, Ctr Mol Modeling, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. [Byrd, R. Andrew] NCI, Struct Biophys Lab, NIH, Frederick, MD 21702 USA. RP Opina, ACL (reprint author), NHLBI, Imaging Probe Dev Ctr, NIH, Rockville, MD 20850 USA. EM ana.opina@nih.gov OI Byrd, R. Andrew/0000-0003-3625-4232; Strickland, Madeleine/0000-0001-8160-070X FU NIH Intramural Research Program through the Center for Information Technology, NCI; NHLBI FX The quantum chemical study utilized PC/LINUX clusters at the Center for Molecular Modeling of the NIH (http://cit.nih.gov) and this research is supported by the NIH Intramural Research Program through the Center for Information Technology, NCI, and NHLBI. NR 39 TC 6 Z9 6 U1 5 U2 9 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1477-9226 EI 1477-9234 J9 DALTON T JI Dalton Trans. PY 2016 VL 45 IS 11 BP 4673 EP 4687 DI 10.1039/c5dt03210e PG 15 WC Chemistry, Inorganic & Nuclear SC Chemistry GA DG6JW UT WOS:000372191500027 PM 26857249 ER PT J AU Roche, J Ying, JF Bax, A AF Roche, Julien Ying, Jinfa Bax, Ad TI Accurate measurement of (3)J(HNH alpha) couplings in small or disordered proteins from WATERGATE-optimized TROSY spectra SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Abeta; IDP; Karplus curve; Random coil; Synuclein; Protein NMR ID AMYLOID-BETA PEPTIDES; NMR-SPECTROSCOPY; COMBINED MD/NMR; CONSTANTS; RELAXATION; COMPENSATION; PULSES; SENSITIVITY; 3JHN-ALPHA; A-BETA-42 AB Provided that care is taken in adjusting the WATERGATE element of a H-1-N-15 TROSY-HSQC experiment, such that neither the water magnetization nor the 1 Ha protons are inverted by its final 180 degrees pulse, (3)J(HNH alpha) couplings can be measured directly from splittings in the H-1 dimension of the spectrum. With band-selective H-1 decoupling, very high N-15 resolution can be achieved. A complete set of (3)J(HNH alpha) values, ranging from 3.4 to 10.1 Hz was measured for the 56-residue third domain of IgG-binding protein G (GB3). Using the H-N-Ca-Ha dihedral angles extracted from a RDC-refined structure of GB3, (3)J(HNH alpha) values predicted by a previously parameterized Karplus equation agree to within a root-mean-square deviation (rmsd) of 0.37 Hz with the experimental data. Values measured for the Alzheimer's implicated Ab 1-40 peptide fit to within an rmsd of 0.45 Hz to random coil (3)J(HNH alpha) values. C1 [Roche, Julien; Ying, Jinfa; Bax, Ad] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM bax@nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Intramural Antiviral Target Program of the Office of the Director, NIH FX We thank Dennis A. Torchia for useful discussions, and Jung Ho Lee for preparing the sample used for Fig. 4c. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and the Intramural Antiviral Target Program of the Office of the Director, NIH. NR 40 TC 2 Z9 2 U1 1 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 EI 1573-5001 J9 J BIOMOL NMR JI J. Biomol. NMR PD JAN PY 2016 VL 64 IS 1 BP 1 EP 7 DI 10.1007/s10858-015-0004-y PG 7 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA DG6BU UT WOS:000372168000001 PM 26660434 ER PT J AU Canady, K Cobb, J Deardorff, P Larson, J White, JM Boring, D AF Canady, Kristin Cobb, Johnathan Deardorff, Peter Larson, Jami White, Jonathan M. Boring, Dan TI Validation of a Stability-Indicating Method for Methylseleno-L-Cysteine (L-SeMC) SO JOURNAL OF CHROMATOGRAPHIC SCIENCE LA English DT Article ID SELENIUM-COMPOUNDS; SPECIATION; IONIZATION AB Methylseleno-L-cysteine (L-SeMC) is a naturally occurring amino acid analogue used as a general dietary supplement and is being explored as a chemopreventive agent. As a known dietary supplement, L-SeMC is not regulated as a pharmaceutical and there is a paucity of analytical methods available. To address the lack of methodology, a stability-indicating method was developed and validated to evaluate L-SeMC as both the bulk drug and formulated drug product (400 mu g Se/capsule). The analytical approach presented is a simple, nonderivatization method that utilizes HPLC with ultraviolet detection at 220 nm. AC18 column with a volatile ion-pair agent and methanol mobile phase was used for the separation. The method accuracy was 99-100% from 0.05 to 0.15 mg/mL L-SeMC for the bulk drug, and 98-99% from 0.075 to 0.15 mg/mL L-SeMC for the drug product. Method precision was <1% for the bulk drug and was 3% for the drug product. The LOQ was 0.1 mu g/mL L-SeMC or 0.002 mu g L-SeMC on column. C1 [Canady, Kristin; Cobb, Johnathan; Deardorff, Peter; Larson, Jami; White, Jonathan M.] MRIGlobal, 425 Volker Blvd, Kansas City, MO 64110 USA. [Boring, Dan] NCI, 9609 Med Ctr Dr,Room 5E536, Rockville, MD 20850 USA. RP Larson, J (reprint author), MRIGlobal, 425 Volker Blvd, Kansas City, MO 64110 USA. EM jlarson@mriglobal.org FU National Cancer Institute at the National Institutes of Health [HHSN261201100046C] FX This work was supported by the National Cancer Institute at the National Institutes of Health as part of contract HHSN261201100046C. NR 8 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 0021-9665 EI 1945-239X J9 J CHROMATOGR SCI JI J. Chromatogr. Sci. PD JAN PY 2016 VL 54 IS 1 BP 22 EP 27 DI 10.1093/chromsci/bmv100 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DG6FF UT WOS:000372177400004 PM 26199341 ER PT J AU Kwong, LS Akkaya, M Barclay, AN Hatherley, D AF Kwong, Lai Shan Akkaya, Munir Barclay, A. Neil Hatherley, Deborah TI Herpesvirus orthologues of CD200 bind host CD200R but not related activating receptors SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID NK CELL RECEPTORS; IN-VIVO; MACROPHAGE ACTIVATION; DOWN-REGULATION; NATURAL-KILLER; MAST-CELLS; HLA-C; PROTEIN; FAMILY; CYTOMEGALOVIRUS AB Several herpesviruses have acquired the gene for the CD200 membrane protein from their hosts and can downregulate myeloid activity through interaction of this viral CD200 orthologue with the host receptor for CD200, namely CD200R, which can give inhibitory signals. This receptor is a 'paired receptor', meaning proteins related to the inhibitory CD200R are present but differ in that they can give activating signals and also give a negligible interaction with CD200. We showed that the viral orthologues e127 from rat cytomegalovirus and K14 from human herpesvirus 8 do not bind the activating CD200R-like proteins from their respective species, although they do bind the inhibitory receptors. It is thought that the activating receptors have evolved in response to pathogens targeting the inhibitory receptor. In this case, the CD200 orthologue is not trapped by the activating receptor but has maintained the specificity of the host from which it was acquired, suggesting that the activating members of the CD200R family have evolved to protect against a different pathogen. C1 [Kwong, Lai Shan; Akkaya, Munir; Barclay, A. Neil; Hatherley, Deborah] Univ Oxford, Sir William Dunn Sch Pathol, S Parks Rd, Oxford OX1 3RE, England. [Kwong, Lai Shan] Oxford Biomed, Oxford OX4 4GA, Oxon, England. [Akkaya, Munir] NIAID, NIH, 12441 Parklawn Dr,Twinbrook 2 Bldg Room 213, Rockville, MD 20852 USA. [Hatherley, Deborah] Univ Oxford, Radcliffe Dept Med, Oxford OX3 9DU, England. RP Barclay, AN (reprint author), Univ Oxford, Sir William Dunn Sch Pathol, S Parks Rd, Oxford OX1 3RE, England. EM neil.barclay@path.ox.ac.uk OI AKKAYA, Munir/0000-0002-9949-9424 FU Medical Research Council [G9826026] FX This work was supported by the Medical Research Council, grant number G9826026. NR 31 TC 1 Z9 1 U1 0 U2 0 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 EI 1465-2099 J9 J GEN VIROL JI J. Gen. Virol. PD JAN PY 2016 VL 97 BP 179 EP 184 DI 10.1099/jgv.0.000335 PN 1 PG 6 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA DG4SJ UT WOS:000372062500019 PM 26538068 ER PT J AU Greaney, AJ Maier, NK Leppla, SH Moayeri, M AF Greaney, Allison J. Maier, Nolan K. Leppla, Stephen H. Moayeri, Mahtab TI Sulforaphane inhibits multiple inflammasomes through an Nrf2-independent mechanism SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE caspase-1; IL-1; NLRP1; NLRP3; inflammation ID ANTHRAX LETHAL TOXIN; INDUCED CELL-DEATH; FACTOR-KAPPA-B; NLRP3 INFLAMMASOME; BROCCOLI SPROUTS; CASPASE-1 AUTOPROTEOLYSIS; HELICOBACTER-PYLORI; MOUSE MACROPHAGE; CYTOPLASMIC DNA; GENE-EXPRESSION AB The inflammasomes are intracellular complexes that have an important role in cytosolic innate immune sensing and pathogen defense. Inflammasome sensors detect a diversity of intracellular microbial ligands and endogenous danger signals and activate caspase-1, thus initiating maturation and release of the proinflammatory cytokines interleukin-1 beta and interleukin-18. These events, although crucial to the innate immune response, have also been linked to the pathology of several inflammatory and autoimmune disorders. The natural isothiocyanate sulforaphane, present in broccoli sprouts and available as a dietary supplement, has gained attention for its antioxidant, anti-inflammatory, and chemopreventive properties. We discovered that sulforaphane inhibits caspase-1 autoproteolytic activation and interleukin-1 beta maturation and secretion downstream of the nucleotide-binding oligomerization domain-like receptor leucine-rich repeat proteins NLRP1 and NLRP3, NLR family apoptosis inhibitory protein 5/NLR family caspase-1 recruitment domain-containing protein 4 (NAIP5/NLRC4), and absent in melanoma 2 (AIM2) inflammasome receptors. Sulforaphane does not inhibit the inflammasome by direct modification of active caspase-1 and its mechanism is not dependent on protein degradation by the proteasome or de novo protein synthesis. Furthermore, sulforaphane-mediated inhibition of the inflammasomes is independent of the transcription factor nuclear factor erythroid-derived 2-like factor 2 (Nrf2) and the antioxidant response-element pathway, to which many of the antioxidant and anti-inflammatory effects of sulforaphane have been attributed. Sulforaphane was also found to inhibit cell recruitment to the peritoneum and interleukin-1 beta secretion in an in vivo peritonitis model of acute gout and to reverse NLRP1-mediated murine resistance to Bacillus anthracis spore infection. These findings demonstrate that sulforaphane inhibits the inflammasomes through a novel mechanism and contributes to our understanding of the beneficial effects of sulforaphane. C1 [Greaney, Allison J.; Maier, Nolan K.; Leppla, Stephen H.; Moayeri, Mahtab] NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, US NIH, 33 North Dr, Bethesda, MD 20814 USA. RP Moayeri, M (reprint author), NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, US NIH, 33 North Dr, Bethesda, MD 20814 USA. EM mmoayeri@niaid.nih.gov FU Intramural Research Program of the U.S. National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID) FX This work was supported by the Intramural Research Program of the U.S. National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID). We thank Dr. Russell Vance for providing the LFn-Fla protein, Dr. Alan Johnson for providing the LF protease inhibitor, Devorah Crown and Brandi Butler for performing bone marrow isolation, and Rasem Fattah for protein purification of toxins. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIAID or the NIH. NR 80 TC 4 Z9 4 U1 1 U2 7 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JAN PY 2016 VL 99 IS 1 BP 189 EP 199 DI 10.1189/jlb.3A0415-155RR PG 11 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA DG2IG UT WOS:000371890000020 PM 26269198 ER PT J AU Nagy-Smith, K Yamada, Y Schneider, JP AF Nagy-Smith, Katelyn Yamada, Yuji Schneider, Joel P. TI Protein release from highly charged peptide hydrogel networks SO JOURNAL OF MATERIALS CHEMISTRY B LA English DT Article ID MOLECULAR-STRUCTURE; DESIGNED PEPTIDE; DRUG-DELIVERY; THERAPEUTICS; CELLS; ENCAPSULATION; GELATION AB Hydrogels are useful delivery vehicles for therapeutic proteins. The ability to control the rate of protein release is paramount to a gel's utility and, in part, defines its clinical application. Electrostatic interactions made between encapsulated protein and a gel's network represents one modality in which protein motility can be controlled. For many gels this strategy works well under low ionic strength solution conditions, but dramatically less so in solutions of physiologically relevant ionic strength where electrostatic interactions are more effectively screened. Herein, we find that highly charged self-assembling peptides can be used to prepare fibrillar hydrogels of sufficient electropotential to allow electrostatic-based control over protein release under physiological buffer conditions. Rheology shows that proteins, differing significantly in their isoelectric point, can be directly encapsulated within negatively- or positively-charged peptide hydrogel networks during the peptide self-assembly event leading to gelation. Bulk adsorption studies coupled with transmission electron microscopy shows that electrostatic interactions drive the association of protein to oppositely charged fibrils in the final gel state, which in turn, dictates the diffusion and retention of these macromolecules in the hydrogel network. C1 [Nagy-Smith, Katelyn; Yamada, Yuji; Schneider, Joel P.] NCI, Biol Chem Lab, Ft Detrick, MD 21702 USA. [Nagy-Smith, Katelyn] Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA. RP Schneider, JP (reprint author), NCI, Biol Chem Lab, Ft Detrick, MD 21702 USA. EM Joel.Schneider@nih.gov FU National Cancer Institute of the National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Cancer Institute of the National Institutes of Health. NR 32 TC 1 Z9 1 U1 9 U2 24 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2050-750X EI 2050-7518 J9 J MATER CHEM B JI J. Mat. Chem. B PY 2016 VL 4 IS 11 BP 1999 EP 2007 DI 10.1039/c5tb02137e PG 9 WC Materials Science, Biomaterials SC Materials Science GA DG6YK UT WOS:000372231800009 ER PT J AU Davis, TJ Kaufman, PE Tatem, AJ Hogsette, JA Kline, DL AF Davis, Timothy J. Kaufman, Phillip E. Tatem, Andrew J. Hogsette, Jerome A. Kline, Daniel L. TI Development and Evaluation of an Attractive Self-Marking Ovitrap to Measure Dispersal and Determine Skip Oviposition in Aedes albopictus (Diptera: Culicidae) Field Populations SO JOURNAL OF MEDICAL ENTOMOLOGY LA English DT Article DE installment oviposition; egg distribution; vector surveillance; Aedes triseriatus ID RIO-DE-JANEIRO; AEGYPTI; FECUNDITY; MOSQUITOS; CONTAINER; SURVIVAL; FLORIDA; TRAPS; SIZE AB Aedes albopictus (Skuse) is a container-breeding species with considerable public health importance. To date, Ae. albopictus oviposition behavior has been assessed in outdoor conditions, but only with laboratory-reared specimens. In outdoor large-cage and field studies, we used an attractive self-marking ovipositional device to assess Ae. albopictus skip oviposition behavior. In field studies, 37 wild Ae. albopictus that visited an attractive self-marking ovisite were subsequently captured at a sticky ovitrap within a 4-d period. Because the average Ae. albopictus gonotrophic period is 4.5-6 d, the wild-caught Ae. albopictus visited at least two oviposition sites within a single gonotrophic period. This provided field-based indirect evidence of skip oviposition. The mean distance traveled (MDT) during the 20-d evaluations ranged from 58 to 78 m. The maximum observed distance traveled was 149 m, which was the outer edge of our trapping ability. As populations of Ae. albopictus increased, the MDT during the 4- and 20-d post-marking period increased significantly. Additional observations of wild-marked and captured Aedes triseriatus (Say) are discussed. C1 [Davis, Timothy J.; Kaufman, Phillip E.] Univ Florida, Dept Entomol & Nematol, POB 110620, Gainesville, FL 32611 USA. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Univ Rd, Southampton SO17 1BJ, Hants, England. [Tatem, Andrew J.] Fogarty Natl Inst Hlth, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Hogsette, Jerome A.; Kline, Daniel L.] USDA ARS, Ctr Med Agr & Vet Entomol, 1600 SW 23rd Dr, Gainesville, FL 32608 USA. RP Kaufman, PE (reprint author), Univ Florida, Dept Entomol & Nematol, POB 110620, Gainesville, FL 32611 USA. EM pkaufman@ufl.edu; pkaufman@ufl.edu; A.J.Tatem@soton.ac.uk; jerry.hogsette@ars.usda.gov; dan.kline@ars.usda.gov OI Kaufman, Phillip/0000-0001-6159-8358 FU RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX We thank James Becnel, Joyce Urban, Neil Sanscrainte, John Sivinksi, Charlie Stuhl, Chris Holderman, Emma Weeks, and Lois Wood for their contributions to this research. We thank the staff of the Evergreen Cemetery who granted access to their property to conduct research. AJT acknowledges funding support from the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Air Force, Department of Defense, or the U.S. Government. NR 34 TC 2 Z9 2 U1 2 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-2585 EI 1938-2928 J9 J MED ENTOMOL JI J. Med. Entomol. PD JAN PY 2016 VL 53 IS 1 BP 31 EP 38 DI 10.1093/jme/tjv170 PG 8 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA DG2OU UT WOS:000371907700004 PM 26534725 ER PT J AU Srivanitchapoom, P Park, JE Thirugnanasambandam, N Panyakaew, P Ramos, VFM Pandey, S Wu, TX Hallett, M AF Srivanitchapoom, Prachaya Park, Jung E. Thirugnanasambandam, Nivethida Panyakaew, Pattamon Ramos, Vesper Fe Marie Pandey, Sanjay Wu, Tianxia Hallett, Mark TI Inducing LTD-Like Effect in the Human Motor Cortex with Low Frequency and Very Short Duration Paired Associative Stimulation: An Exploratory Study SO NEURAL PLASTICITY LA English DT Article ID PLASTICITY; MODULATION; NEUROPLASTICITY; EXCITABILITY; INDUCTION AB Introduction. Paired associative stimulation (PAS) is an established technique to investigate synaptic plasticity in the human motor cortex (M1). Classically, to induce long-term depression-(LTD-) or long-term potentiation-like effects in the human M1, studies have used low frequency and long duration trains of PAS. In the present study, we explored an LTD-like effect using very short duration and low frequency of PAS(10 ms) protocols in human M1. Methods. Six protocols of low frequency PAS(10 ms) (ranging from 0.2 Hz to 1 Hz) were investigated with very short durations of 1 and 2 minutes stimulation. Six healthy volunteers were included in each protocol. We obtained motor-evoked potentials from right abductor pollicis brevis muscle before and after applying PAS(10 ms) up to 30 minutes. After we found PAS(10 ms) protocol which induced an LTD-like effect, we tested that protocol on additional 5 subjects. Results. One-way repeated-measures ANOVA showed that only the group of 1-minute stimulation of 0.25 Hz induced an LTD-like effect. When adding the additional subjects, the effect remained and lasted for 30 minutes. Conclusion. Low frequency and very short duration of PAS(10 ms) potentially induced an LTD-like effect in human M1. With further verification, this method might be useful for research relating to synaptic plasticity by reducing the duration of study and minimizing subject discomfort. C1 [Srivanitchapoom, Prachaya; Park, Jung E.; Thirugnanasambandam, Nivethida; Panyakaew, Pattamon; Ramos, Vesper Fe Marie; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Srivanitchapoom, Prachaya] Mahidol Univ, Siriraj Hosp, Fac Med, Dept Med,Div Neurol, Bangkok 10700, Thailand. [Panyakaew, Pattamon] Chulalongkorn Univ, Fac Med, Chulalongkorn Ctr Excellence Parkinsons Dis & Rel, Dept Med, Bangkok 10330, Thailand. [Panyakaew, Pattamon] King Chulalongkorn Mem Hosp, Thai Red Cross Soc, Bangkok 10330, Thailand. [Pandey, Sanjay] Govind Ballabh Pant Hosp, New Delhi 110002, India. [Wu, Tianxia] NINDS, Clin Neurosci Program, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov FU NINDS; NINDS/NIH Intramural Program; Faculty of Medicine, Siriraj Hospital, Mahidol University FX The authors are grateful to their biomedical engineer, Nguyet Dang, who provided great technical support. The Faculty of Medicine, Siriraj Hospital, Mahidol University, awarded Dr. Prachaya Srivanitchapoom a fellowship in Parkinson's disease and Movement Disorders at Human Motor Control Section (HMCS), National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, USA. The work was supported by NINDS. Funding sources for study are the following: NINDS/NIH Intramural Program. NR 24 TC 0 Z9 0 U1 1 U2 2 PU HINDAWI PUBLISHING CORP PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 2090-5904 EI 1687-5443 J9 NEURAL PLAST JI Neural. Plast. PY 2016 AR 3920298 DI 10.1155/2016/3920298 PG 8 WC Neurosciences SC Neurosciences & Neurology GA DG7BL UT WOS:000372239700001 ER PT J AU Iqbal, SA Wallach, JD Khoury, MJ Schully, SD Ioannidis, JPA AF Iqbal, Shareen A. Wallach, Joshua D. Khoury, Muin J. Schully, Sheri D. Ioannidis, John P. A. TI Reproducible Research Practices and Transparency across the Biomedical Literature SO PLOS BIOLOGY LA English DT Article ID CONFLICTS-OF-INTEREST; PRECLINICAL RESEARCH; RANDOMIZED-TRIALS; CLINICAL-TRIALS; NATIONAL-SURVEY; RAW DATA; JOURNALS; SCIENCE; AUTHORS; DISCLOSURE AB There is a growing movement to encourage reproducibility and transparency practices in the scientific community, including public access to raw data and protocols, the conduct of replication studies, systematic integration of evidence in systematic reviews, and the documentation of funding and potential conflicts of interest. In this survey, we assessed the current status of reproducibility and transparency addressing these indicators in a random sample of 441 biomedical journal articles published in 2000-2014. Only one study provided a full protocol and none made all raw data directly available. Replication studies were rare (n = 4), and only 16 studies had their data included in a subsequent systematic review or meta-analysis. The majority of studies did not mention anything about funding or conflicts of interest. The percentage of articles with no statement of conflict decreased substantially between 2000 and 2014 (94.4% in 2000 to 34.6% in 2014); the percentage of articles reporting statements of conflicts (0% in 2000, 15.4% in 2014) or no conflicts (5.6% in 2000, 50.0% in 2014) increased. Articles published in journals in the clinical medicine category versus other fields were almost twice as likely to not include any information on funding and to have private funding. This study provides baseline data to compare future progress in improving these indicators in the scientific literature. C1 [Iqbal, Shareen A.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Wallach, Joshua D.; Ioannidis, John P. A.] Stanford Sch Med, Dept Hlth Res & Policy, Palo Alto, CA USA. [Wallach, Joshua D.; Ioannidis, John P. A.] Stanford Univ, Metares Innovat Ctr Stanford, Stanford, CA 94305 USA. [Khoury, Muin J.; Schully, Sheri D.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. [Ioannidis, John P. A.] Stanford Univ, Dept Med, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Sch Humanities & Sci, Dept Stat, Stanford, CA 94305 USA. RP Ioannidis, JPA (reprint author), Stanford Sch Med, Dept Hlth Res & Policy, Palo Alto, CA USA.; Ioannidis, JPA (reprint author), Stanford Univ, Metares Innovat Ctr Stanford, Stanford, CA 94305 USA.; Ioannidis, JPA (reprint author), Stanford Univ, Dept Med, Stanford Prevent Res Ctr, Stanford, CA 94305 USA.; Ioannidis, JPA (reprint author), Stanford Univ, Sch Humanities & Sci, Dept Stat, Stanford, CA 94305 USA. EM jioannid@stanford.edu FU Laura and John Arnold Foundation FX The authors received no specific funding for this work. The Meta-Research Innovation Center at Stanford (METRICS) is supported by a grant from the Laura and John Arnold Foundation. NR 41 TC 22 Z9 22 U1 5 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD JAN PY 2016 VL 14 IS 1 AR e1002333 DI 10.1371/journal.pbio.1002333 PG 13 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA DG2FU UT WOS:000371882900003 PM 26726926 ER PT J AU Majumdar, R Tameh, AT Parent, CA AF Majumdar, Ritankar Tameh, Aidin Tavakoli Parent, Carole A. TI Exosomes Mediate LTB4 Release during Neutrophil Chemotaxis SO PLOS BIOLOGY LA English DT Article ID CELL-MIGRATION; EXTRACELLULAR VESICLES; MULTIVESICULAR BODIES; VESICULAR TRAFFICKING; ADENYLYL-CYCLASE; NUCLEAR-ENVELOPE; DENDRITIC CELLS; SIGNAL-RELAY; INFLAMMATION; RECRUITMENT AB Leukotriene B-4 (LTB4) is secreted by chemotactic neutrophils, forming a secondary gradient that amplifies the reach of primary chemoattractants. This strategy increases the recruitment range for neutrophils and is important during inflammation. Here, we show that LTB4 and its synthesizing enzymes localize to intracellular multivesicular bodies that, upon stimulation, release their content as exosomes. Purified exosomes can activate resting neutrophils and elicit chemotactic activity in a LTB4 receptor-dependent manner. Inhibition of exosome release leads to loss of directional motility with concomitant loss of LTB4 release. Our findings establish that the exosomal pool of LTB4 acts in an autocrine fashion to sensitize neutrophils towards the primary chemoattractant, and in a paracrine fashion to mediate the recruitment of neighboring neutrophils in trans. We envision that this mechanism is used by other signals to foster communication between cells in harsh extracellular environments. C1 [Majumdar, Ritankar; Tameh, Aidin Tavakoli; Parent, Carole A.] Natl Canc Inst, Lab Cellular & Mol Biol, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD USA. RP Parent, CA (reprint author), Natl Canc Inst, Lab Cellular & Mol Biol, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD USA. EM parentc@mail.nih.gov OI Majumdar, Ritankar/0000-0001-6624-0187 FU Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health FX This research was supported by the Intramural Research Program of the Center for Cancer Research, NCI, 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 55 TC 8 Z9 9 U1 3 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD JAN PY 2016 VL 14 IS 1 AR e1002336 DI 10.1371/journal.pbio.1002336 PG 28 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA DG2FU UT WOS:000371882900006 PM 26741884 ER PT J AU King, BA Patel, R Babb, SD Hartman, AM Freeman, A AF King, Brian A. Patel, Roshni Babb, Stephen D. Hartman, Anne M. Freeman, Alison TI National and state prevalence of smoke-free rules in homes with and without children and smokers: Two decades of progress SO PREVENTIVE MEDICINE LA English DT Article DE Smoking; Tobacco smoke pollution; Child; Households; Secondhand smoke ID CROSS-SECTIONAL SURVEY; SECONDHAND SMOKE; UNITED-STATES; TOBACCO USE; EXPOSURE; NONSMOKERS; BANS AB Objective. The home is the primary source of secondhand smoke (SHS) exposure for children. We assessed national and state progress in smoke-free home (SFH) rule adoption in homes with and without children and adult smokers. Methods. Data came from the 1992-1993 and 2010-2011 Tobacco Use Supplements to the Current Population Survey, a U.S. national probability household survey. Households were defined as having a SFH rule if all household respondents aged >= 18 indicated no one was allowed to smoke inside the home at any time. Households with children were those with occupants aged <18. Smokers were those who smoked >= 100 lifetime cigarettes and now smoked "everyday" or "some days". Results. From 1992-1993 to 2010-2011, SFH rule prevalence increased from 43.0% to 83.0% (p <.05). Among households with children, SFH rules increased overall (44.9% to 88.6%), in households without smokers (59.7% to 95.0%), and households with >= 1 smokers (9.7% to 61.0%) (p <.05). Among households without children, SFH rules increased overall (40.8% to 81.1%), in households without smokers (53.4% to 90.1%), and households with >= 1 smokers (6.3% to 40.9%) (p <.05). Prevalence increased in all states, irrespective of smoker or child occupancy (p <.05). In 2010-2011, among homes with smokers and children, SFH rule prevalence ranged from 36.5% (West Virginia) to 86.8% (California). Conclusions. Considerable progress has been made adopting SFH rules, but many U.S. children continue to be exposed to SHS because their homes are not smoke-free. Further efforts to promote adoption of SFH rules are essential to protect all children from this health risk. Published by Elsevier Inc. C1 [King, Brian A.; Patel, Roshni; Babb, Stephen D.] Ctr Dis Control & Prevent, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, 4770 Buford Highway,MS F-79, Atlanta, GA 30341 USA. [Hartman, Anne M.] NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Freeman, Alison] US EPA, Indoor Environm Div, Washington, DC 20460 USA. RP King, BA (reprint author), Ctr Dis Control & Prevent, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, 4770 Buford Highway,MS F-79, Atlanta, GA 30341 USA. EM baking@cdc.gov FU Intramural CDC HHS [CC999999] NR 37 TC 2 Z9 2 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD JAN PY 2016 VL 82 BP 51 EP 58 DI 10.1016/j.ypmed.2015.11.010 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DG2WY UT WOS:000371932600008 PM 26601642 ER PT J AU Nagpal, R Kumar, M Yadav, AK Hemalatha, R Yadav, H Marotta, F Yamashiro, Y AF Nagpal, R. Kumar, M. Yadav, A. K. Hemalatha, R. Yadav, H. Marotta, F. Yamashiro, Y. TI Gut microbiota in health and disease: an overview focused on metabolic inflammation SO BENEFICIAL MICROBES LA English DT Review DE intestinal microbiota; metabolic syndrome; obesity; probiotics; type 2 diabetes ID INDUCED INSULIN-RESISTANCE; PROBIOTIC FERMENTED MILK; DIET-INDUCED OBESITY; GERM-FREE MICE; INTESTINAL MICROBIOTA; BOWEL-DISEASE; LACTOBACILLUS-ACIDOPHILUS; FUNCTIONAL INTERACTIONS; HOST METABOLISM; INNATE IMMUNITY AB In concern to the continuously rising global prevalence of obesity, diabetes and associated diseases, novel preventive and therapeutic approaches are urgently required. However, to explore and develop such innovative strategies, a meticulous comprehension of the biological basis of these diseases is extremely important. Past decade has witnessed an enormous amount of research investigation and advancement in the field of obesity, diabetes and metabolic syndrome, with the gut microbiota receiving a special focus in the triangle of nutrition, health and diseases. In particular, the role of gut microbiota in health and diseases has been one of the most vigorous and intriguing field of recent research; however, much still remains to be elucidated about its precise role in host metabolism and immune functions and its implication in the onset, progression as well as in the amelioration of metabolic ailments. Recent investigations have suggested a significant contribution of the gut microbiota in the regulation and impairment of energy homeostasis, thereby causing metabolic disorders, such as metabolic endotoxemia, insulin resistance and type 2 diabetes. Numerous inflammatory biomarkers have been found to be associated with obesity, diabetes and risk of other associated adverse outcomes, thereby suggesting that a persistent low-grade inflammatory response is a potential risk factor. In this milieu, this review intends to discuss potential evidences supporting the disturbance of the gut microbiota balance and the intestinal barrier permeability as a potential triggering factor for systemic inflammation in the onset and progression of obesity, type 2 diabetes and metabolic syndrome. C1 [Nagpal, R.; Yamashiro, Y.] Juntendo Univ, Grad Sch Med, Probiot Res Lab, Tokyo 1130033, Japan. [Kumar, M.; Yadav, A. K.; Hemalatha, R.] Natl Inst Nutr, Dept Microbiol & Immunol, Hyderabad 500007, Andhra Pradesh, India. [Yadav, H.] NIDDK, Clin Res Ctr, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Marotta, F.] ReGenera Res Grp Aging Intervent, Via Moise Loira 75, I-20144 Milan, Italy. RP Kumar, M (reprint author), Natl Inst Nutr, Dept Microbiol & Immunol, Hyderabad 500007, Andhra Pradesh, India. EM manoj15micro@yahoo.co.in OI Yadav, Hariom/0000-0003-4504-1597 NR 117 TC 2 Z9 2 U1 13 U2 46 PU WAGENINGEN ACADEMIC PUBLISHERS PI WAGENINGEN PA PO BOX 220, WAGENINGEN, 6700 AE, NETHERLANDS SN 1876-2883 EI 1876-2891 J9 BENEF MICROBES JI Benef. Mirbobes PY 2016 VL 7 IS 2 BP 181 EP 194 DI 10.3920/BM2015.0062 PG 14 WC Microbiology; Nutrition & Dietetics SC Microbiology; Nutrition & Dietetics GA DG1IL UT WOS:000371819900004 PM 26645350 ER PT J AU Kensler, TW Spira, A Garber, JE Szabo, E Lee, JJ Dong, ZG Dannenberg, AJ Hait, WN Blackburn, E Davidson, NE Foti, M Lippman, SM AF Kensler, Thomas W. Spira, Ayrum Garber, Judy E. Szabo, Eva Lee, J. Jack Dong, Zigang Dannenberg, Andrew J. Hait, William N. Blackburn, Elizabeth Davidson, Nancy E. Foti, Margaret Lippman, Scott M. TI Transforming Cancer Prevention through Precision Medicine and Immune-oncology SO CANCER PREVENTION RESEARCH LA English DT Article ID COLORECTAL-CANCER; LUNG-CANCER; ASPIRIN; TUMOR; RISK AB We have entered a transformative period in cancer prevention (including early detection). Remarkable progress in precision medicine and immune-oncology, driven by extraordinary recent advances in genome-wide sequencing, big-data analytics, blood-based technologies, and deep understanding of the tumor immune microenvironment (TME), has provided unprecedented possibilities to study the biology of premalignancy. The pace of research and discovery in precision medicine and immunoprevention has been astonishing and includes the following clinical firsts reported in 2015: driver mutations detected in circulating cell-free DNA in patients with premalignant lesions (lung); clonal hematopoiesis shown to be a premalignant state; molecular selection in chemoprevention randomized controlled trial (RCT; oral); striking efficacy in RCT of combination chemoprevention targeting signaling pathway alterations mechanistically linked to germline mutation (duodenum); molecular markers for early detection validated for lung cancer and showing promise for pancreatic, liver, and ovarian cancer. Identification of HPV as the essential cause of a major global cancer burden, including HPV16 as the single driver of an epidemic of oropharyngeal cancer in men, provides unique opportunities for the dissemination and implementation of public health interventions. Important to immunoprevention beyond viral vaccines, genetic drivers of premalignant progression were associated with increasing immunosuppressive TME; and Kras vaccine efficacy in pancreas genetically engineered mouse (GEM) model required an inhibitory adjuvant (Treg depletion). In addition to developing new (e.g., epigenetic) TME regulators, recent mechanistic studies of repurposed drugs (aspirin, metformin, and tamoxifen) have identified potent immune activity. Just as precision medicine and immune-oncology are revolutionizing cancer therapy, these approaches are transforming cancer prevention. Here, we set out a brief agenda for the immediate future of cancer prevention research (including a "Pre-Cancer Genome Atlas" or " PCGA"), which will involve the inter-related fields of precision medicine and immunoprevention - pivotal elements of a broader domain of personalized public health. (C)2016 AACR. C1 [Kensler, Thomas W.] Univ Pittsburgh, Pittsburgh, PA USA. [Kensler, Thomas W.] Penn & Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Spira, Ayrum] Boston Univ, Boston, MA 02215 USA. [Garber, Judy E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Szabo, Eva] NCI, Div Canc Prevent, Rockville, MD USA. [Lee, J. Jack] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Dong, Zigang] Univ Minnesota, Hormel Inst, Minneapolis, MN USA. [Dannenberg, Andrew J.] Weill Cornell Med Coll, New York, NY USA. [Hait, William N.] Janssen Res & Dev LLC, Raritan, NJ USA. [Blackburn, Elizabeth] Salk Inst Biol Studies, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. [Davidson, Nancy E.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Foti, Margaret] Amer Assoc Canc Res, Philadelphia, PA USA. [Lippman, Scott M.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. RP Lippman, SM (reprint author), Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. EM slippman@ucsd.edu RI Kensler, Thomas/D-8686-2014 OI Kensler, Thomas/0000-0002-6676-261X FU [NIH/NCI P30 CA023100 28] FX This work was supported in part by grant NIH/NCI P30 CA023100 28. NR 101 TC 18 Z9 18 U1 14 U2 26 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD JAN PY 2016 VL 9 IS 1 BP 2 EP 10 DI 10.1158/1940-6207.CAPR-15-0406 PG 9 WC Oncology SC Oncology GA DG3XY UT WOS:000372005700002 PM 26744449 ER PT J AU Madka, V Mohammed, A Li, Q Zhang, YT Biddick, L Patlolla, JMR Lightfoot, S Towner, RA Wu, XR Steele, VE Kopelovich, L Rao, CV AF Madka, Venkateshwar Mohammed, Altaf Li, Qian Zhang, Yuting Biddick, Laura Patlolla, Jagan M. R. Lightfoot, Stan Towner, Rheal A. Wu, Xue-Ru Steele, Vernon E. Kopelovich, Levy Rao, Chinthalapally V. TI Targeting mTOR and p53 Signaling Inhibits Muscle Invasive Bladder Cancer In Vivo SO CANCER PREVENTION RESEARCH LA English DT Article ID TRANSITIONAL-CELL CARCINOMA; UROTHELIAL CARCINOMA; ANDROGEN RECEPTOR; PHASE-II; PI3K/AKT/MTOR PATHWAY; CP-31398 PREVENTS; MAMMALIAN TARGET; URINARY-BLADDER; EXPRESSION; RAPAMYCIN AB Urothelial tumors, accompanied by mutations of the tumor suppressor protein TP53 and dysregulation of mTOR signaling, are frequently associated with aggressive growth and invasiveness. We investigated whether targeting these two pathways would inhibit urothelial tumor growth and progression. Six-week-old transgenic UPII-SV40T male mice (n = 15/group) were fed control diet (AIN-76A) or experimental diets containing mTOR inhibitor (rapamycin, 8 or 16 ppm), p53 stabilizing agent [CP31398 (CP), 150 ppm], or a combination. Mice were euthanized at 40 weeks of age. Urinary bladders were collected and evaluated to determine tumor weight and histopathology. Each agent alone, and in combination, significantly inhibited tumor growth. Treatment with rapamycin alone decreased tumor weight up to 67% (P < 0.0001). Similarly, CP showed approximately 77% (P < 0.0001) suppression of tumor weight. The combi-nation of low-dose rapamycin and CP led to approximately 83% (P < 0.0001) inhibition of tumor weight. There was no significant difference in tumor weights between rapamycin and CP treatments (P > 0.05). However, there was a significant difference between 8 ppm rapamycin and the combination treatment. Tumor invasion was also significantly inhibited in 53% (P < 0.005) and 66% (P < 0.0005) mice after 8 ppm and 16 ppm rapamycin, respectively. However, tumor invasion was suppressed in 73% (P < 0.0001) mice when CP was combined with 8 ppm rapamycin. These results suggest that targeting two or more pathways achieve better treatment efficacy than a single-agent high-dose strategy that could increase the risk of side effects. A combination of CP and rapamycin may be a promising method of inhibiting muscle-invasive urothelial transitional cell carcinoma. (C) 2015 AACR. C1 [Madka, Venkateshwar; Mohammed, Altaf; Li, Qian; Zhang, Yuting; Biddick, Laura; Patlolla, Jagan M. R.; Lightfoot, Stan; Rao, Chinthalapally V.] Univ Oklahoma, Hlth Sci Ctr, Ctr Canc Prevent & Drug Dev, Stephenson Canc Ctr,Hem Onc Sect,Dept Med, Oklahoma City, OK 73104 USA. [Towner, Rheal A.] Oklahoma Med Res Fdn, Adv Magnet Resonance Ctr, 825 NE 13th St, Oklahoma City, OK 73104 USA. [Wu, Xue-Ru] NYU, Med Ctr, Dept Urol, New York, NY 10016 USA. [Steele, Vernon E.; Kopelovich, Levy] NCI, Chemoprevent Agent Dev Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. RP Rao, CV (reprint author), Univ Oklahoma, Hlth Sci Ctr OUHSC, Ctr Canc Prevent & Drug Dev, 975 NE 10th St,BRC Bldg 2,Room 1203, Oklahoma City, OK 73104 USA. EM cv-rao@ouhsc.edu FU NIH/NCI [NCI-CN53300] FX This study was funded by NCI-CN53300 (C.V. Rao) from the NIH/NCI. NR 50 TC 3 Z9 3 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD JAN PY 2016 VL 9 IS 1 BP 53 EP 62 DI 10.1158/1940-6207.CAPR-15-0199 PG 10 WC Oncology SC Oncology GA DG3XY UT WOS:000372005700008 PM 26577454 ER PT J AU Liu, ZB Chen, XY AF Liu, Zhibo Chen, Xiaoyuan TI Simple bioconjugate chemistry serves great clinical advances: albumin as a versatile platform for diagnosis and precision therapy SO CHEMICAL SOCIETY REVIEWS LA English DT Review ID HUMAN-SERUM-ALBUMIN; GLUCAGON-LIKE PEPTIDE-1; MAGNETIC-RESONANCE ANGIOGRAPHY; IRON-OXIDE NANOPARTICLES; FOLATE-BINDING-PROTEIN; POSITRON-EMISSION-TOMOGRAPHY; TARGETED DRUG-DELIVERY; MRI CONTRAST AGENTS; FATTY-ACID-BINDING; PERFORMANCE LIQUID-CHROMATOGRAPHY AB Albumin is the most abundant circulating protein in plasma and has recently emerged as a versatile protein carrier for drug targeting and for improving the pharmacokinetic profile of peptide or protein based drugs. Three drug delivery technologies related to albumin have been developed, which include the coupling of low-molecular weight drugs to exogenous or endogenous albumin, conjugating bioactive proteins by albumin fusion technology (AFT), and encapsulation of drugs into albumin nanoparticles. This review article starts with a brief introduction of human serum albumin (HSA), and then summarizes the mainstream chemical strategies of developing HSA binding molecules for coupling with drug molecules. Moreover, we also concisely condense the recent progress of the most important clinical applications of HSA-binding platforms, and specify the current challenges that need to be met for a bright future of HSA-binding. C1 [Liu, Zhibo; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Liu, ZB; Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. EM zhibo.liu@nih.gov; shawn.chen@nih.gov FU Intramural NIH HHS [Z99 EB999999, ZIA EB000073-07] NR 210 TC 11 Z9 11 U1 12 U2 41 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 0306-0012 EI 1460-4744 J9 CHEM SOC REV JI Chem. Soc. Rev. PY 2016 VL 45 IS 5 BP 1432 EP 1456 DI 10.1039/c5cs00158g PG 25 WC Chemistry, Multidisciplinary SC Chemistry GA DF8JV UT WOS:000371604800013 PM 26771036 ER PT J AU Kamal, MA Greig, NH AF Kamal, Mohammad A. Greig, Nigel H. TI Managing Strategies for Diverse Diseases: Challenges from Bench to Bedside Translation in Successful Drug Discovery and Development SO CURRENT PHARMACEUTICAL DESIGN LA English DT Editorial Material C1 [Kamal, Mohammad A.; Greig, Nigel H.] King Abdulaziz Univ, King Fahd Med Res Ctr, Fundamental & Appl Biol Grp, Metabol & Enzymol Unit, POB 80216, Jeddah 21589, Saudi Arabia. Enzymoics, 7 Peterlee Pl, Hebersham, NSW 2770, Australia. NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH,Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Kamal, MA; Greig, NH (reprint author), King Abdulaziz Univ, King Fahd Med Res Ctr, Fundamental & Appl Biol Grp, Metabol & Enzymol Unit, POB 80216, Jeddah 21589, Saudi Arabia. EM prof.makamal@lycos.com; greign@grc.nia.nih.gov OI Kamal, Mohammad Amjad/0000-0003-0088-0565 NR 10 TC 1 Z9 1 U1 0 U2 1 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 EI 1873-4286 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PY 2016 VL 22 IS 5 BP 515 EP 517 DI 10.2174/138161282205160126151535 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DG4VM UT WOS:000372071200001 PM 26825465 ER PT J AU Mushtaq, G Greig, NH Anwar, F Al-Abbasi, FA Zamzami, MA Al-Talhi, HA Kamal, MA AF Mushtaq, Gohar Greig, Nigel H. Anwar, Firoz Al-Abbasi, Fahad A. Zamzami, Mazin A. Al-Talhi, Hasan A. Kamal, Mohammad A. TI Neuroprotective Mechanisms Mediated by CDK5 Inhibition SO CURRENT PHARMACEUTICAL DESIGN LA English DT Article DE CDK5 inhibitors; neuroprotection; neurodegeneration; beta-amyloid; Alzheimer's disease; tau hyperphosphorylation; ischemic stroke; synaptic; excitotoxicity; amyotrophic lateral sclerosis ID CYCLIN-DEPENDENT KINASE-5; AMYOTROPHIC-LATERAL-SCLEROSIS; GLYCOGEN-SYNTHASE KINASE-3; ISCHEMIA-REPERFUSION INJURY; TYPE-2 DIABETES-MELLITUS; INDUCED NEURONAL DEATH; AMYLOID-BETA-PEPTIDE; ALZHEIMERS-DISEASE; CELL-DEATH; NEUROTRANSMITTER RELEASE AB Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine/threonine kinase belonging to the family of cyclin-dependent kinases. In addition to maintaining the neuronal architecture, CDK5 plays an important role in the regulation of synaptic plasticity, neurotransmitter release, neuron migration and neurite outgrowth. Although various reports have shown links between neurodegeneration and deregulation of cyclin-dependent kinases, the specific role of CDK5 inhibition in causing neuroprotection in cases of neuronal insult or in neurodegenerative diseases is not well-understood. This article discusses current evidence for the involvement of CDK5 deregulation in neurodegenerative disorders and neurodegeneration associated with stroke through various mechanisms. These include upregulation of cyclin D1 and overactivation of CDK5 mediated neuronal cell death pathways, aberrant hyperphosphorylation of human tau proteins and/or neurofilament proteins, formation of neurofibrillary lesions, excitotoxicity, cytoskeletal disruption, motor neuron death (due to abnormally high levels of CDK5/p25) and colchicine-induced apoptosis in cerebellar granule neurons. A better understanding of the role of CDK5 inhibition in neuroprotective mechanisms will help scientists and researchers to develop selective, safe and efficacious pharmacological inhibitors of CDK5 for therapeutic use against human neurodegenerative disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis and neuronal loss associated with stroke. C1 [Mushtaq, Gohar; Anwar, Firoz; Al-Abbasi, Fahad A.; Zamzami, Mazin A.; Al-Talhi, Hasan A.] King Abdulaziz Univ, Coll Sci, Dept Biochem, Jeddah 21589, Saudi Arabia. [Greig, Nigel H.] NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH,Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Kamal, Mohammad A.] King Abdulaziz Univ, King Fahd Med Res Ctr, Fundamental & Appl Biol Grp, Metabol & Enzymol Unit, POB 80216, Jeddah 21589, Saudi Arabia. [Kamal, Mohammad A.] Enzymoics, 7 Peterlee Pl, Hebersham, NSW 2770, Australia. RP Mushtaq, G (reprint author), King Abdulaziz Univ, Coll Sci, Dept Biochem, Jeddah 21589, Saudi Arabia.; Greig, NH (reprint author), NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH,Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM gmushtaq2001@gmail.com; greign@grc.nia.nih.gov RI Al-Abbasi, Fahad/H-8940-2012; Zamzami, Mazin/D-9101-2017; OI Kamal, Mohammad Amjad/0000-0003-0088-0565; Al-Talhi, Hasan/0000-0003-1441-7942 FU Department of Biochemistry, College of Science, King Abdulaziz University; KFMRC, King Abdulaziz University, Jeddah, Saudi Arabia; Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National, Institute on Aging, National Institutes of Health, USA FX The authors would like to thank the facilities provided by and support of the Department of Biochemistry, College of Science, King Abdulaziz University; KFMRC, King Abdulaziz University, Jeddah, Saudi Arabia as well as the Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National, Institute on Aging, National Institutes of Health, USA. NR 102 TC 2 Z9 2 U1 8 U2 14 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 EI 1873-4286 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PY 2016 VL 22 IS 5 BP 527 EP 534 DI 10.2174/1381612822666151124235028 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DG4VM UT WOS:000372071200003 PM 26601962 ER PT J AU Lahiri, DK Maloney, B Bayon, BL Chopra, N White, FA Greig, NH Nurnberger, JI AF Lahiri, Debomoy K. Maloney, Bryan Bayon, Baindu L. Chopra, Nipun White, Fletcher A. Greig, Nigel H. Nurnberger, John I. TI Transgenerational latent early-life associated regulation unites environment and genetics across generations SO EPIGENOMICS LA English DT Article DE aging; childhood; development; epigenetics; experiences; insult; intergenerational; late life; neurodegenerative; nutrition; post traumatic ID AUTISM SPECTRUM DISORDERS; DNA METHYLATION; ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; BIPOLAR DISORDER; PATERNAL AGE; SAPP-ALPHA; NEURODEGENERATIVE DISEASES; EPIGENETIC MODIFICATIONS; PSYCHIATRIC-DISORDERS AB The origin of idiopathic diseases is still poorly understood. The latent early-life associated regulation (LEARn) model unites environmental exposures and gene expression while providing a mechanistic underpinning for later-occurring disorders. We propose that this process can occur across generations via transgenerational LEARn (tLEARn). In tLEARn, each person is a 'unit' accumulating preclinical or subclinical 'hits' as in the original LEARn model. These changes can then be epigenomically passed along to offspring. Transgenerational accumulation of 'hits' determines a sporadic disease state. Few significant transgenerational hits would accompany conception or gestation of most people, but these may suffice to 'prime' someone to respond to later-life hits. Hits need not produce symptoms or microphenotypes to have a transgenerational effect. Testing tLEARn requires longitudinal approaches. A recently proposed longitudinal epigenome/envirome-wide association study would unite genetic sequence, epigenomic markers, environmental exposures, patient personal history taken at multiple time points and family history. C1 [Lahiri, Debomoy K.; Maloney, Bryan; Chopra, Nipun; Nurnberger, John I.] Indiana Univ Sch Med, Stark Neurosci Res Inst, Dept Psychiat, 320 West 15th St, Indianapolis, IN 46202 USA. [Lahiri, Debomoy K.; Bayon, Baindu L.; Nurnberger, John I.] Indiana Univ Sch Med, Dept Med & Mol Genet, 320 West 15th St, Indianapolis, IN 46202 USA. [White, Fletcher A.] Indiana Univ Sch Med, Dept Anesthesia, Stark Neurosci Res Inst, 320 West 15th St, Indianapolis, IN 46202 USA. [Greig, Nigel H.] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP Lahiri, DK (reprint author), Indiana Univ Sch Med, Stark Neurosci Res Inst, Dept Psychiat, 320 West 15th St, Indianapolis, IN 46202 USA.; Lahiri, DK (reprint author), Indiana Univ Sch Med, Dept Med & Mol Genet, 320 West 15th St, Indianapolis, IN 46202 USA. EM dlahiri@iupui.edu RI Bayon, Baindu/R-3097-2016; Maloney, Bryan/C-4924-2011 OI Bayon, Baindu/0000-0001-7247-8378; Nurnberger, John/0000-0002-7674-1767; Maloney, Bryan/0000-0003-2364-9649 FU National Institute on Aging, NIH [R01-AG051086, R21-AG042804]; Indiana Clinical & Translational Sciences Institute (ICTSI); Indiana Spinal Cord and Brain Injury Research Fund (ISCBIRF); Indiana Alzheimer Disease Research Center [P30 AG010133]; Purdue University [R21] FX The work was supported by grants from the National Institute on Aging, NIH R01-AG051086 and R21-AG042804; and Indiana Clinical & Translational Sciences Institute (ICTSI) and Indiana Spinal Cord and Brain Injury Research Fund (ISCBIRF); P30 AG010133 Indiana Alzheimer Disease Research Center, and R21 sub-award from Purdue University to DK Lahiri. 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 142 TC 0 Z9 0 U1 3 U2 11 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1750-1911 EI 1750-192X J9 EPIGENOMICS-UK JI Epigenomics PY 2016 VL 8 IS 3 BP 373 EP 387 DI 10.2217/epi.15.117 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA DG2MP UT WOS:000371901700007 PM 26950428 ER PT J AU Ellefsen, KN Wohlfarth, A Swortwood, MJ Diao, XX Concheiro, M Huestis, MA AF Ellefsen, Kayla N. Wohlfarth, Ariane Swortwood, Madeleine J. Diao, Xingxing Concheiro, Marta Huestis, Marilyn A. TI 4-Methoxy-alpha-PVP: in silico prediction, metabolic stability, and metabolite identification by human hepatocyte incubation and high-resolution mass spectrometry SO FORENSIC TOXICOLOGY LA English DT Article DE 4-Methoxy-alpha-PVP; Novel psychoactive substances; Synthetic cathinones; Human hepatocytes; Human liver microsomes; In silico prediction ID DRUG ALPHA-PYRROLIDINOVALEROPHENONE; DESIGNER DRUG; BATH SALTS; 3,4-METHYLENEDIOXYPYROVALERONE MDPV; TOXICOLOGICAL DETECTION; SYNTHETIC CATHINONES; MEPHEDRONE 4-METHYLMETHCATHINONE; FATAL INTOXICATIONS; HUMAN URINE; METHYLONE AB Novel psychoactive substances are continuously developed to circumvent legislative and regulatory efforts. A new synthetic cathinone, 4-methoxy-alpha-PVP, was identified for the first time in illegal products; however, the metabolism of this compound is not known. Complete metabolic profiles are needed for these novel psychoactive substances to enable identification of their intake and to link adverse effects to the causative agent. This study assessed 4-methoxy-alpha-PVP metabolic stability with human liver microsomes (HLMs) and identified its metabolites after HLM and hepatocyte incubations followed by high-resolution mass spectrometry (HRMS). A Thermo QExactive high-resolution mass spectrometer (HRMS) was used with full scan data-dependent mass spectrometry, with (1) and without (2) an inclusion list of predicted metabolite, and with full scan and all-ion fragmentation (3) to identify potential unexpected metabolites. In silico predictions were performed and compared to in vitro results. Scans were thoroughly mined with different data processing algorithms using WebMetabase (Molecular Discovery). 4-Methoxy-alpha-PVP exhibited a long half-life of 79.7 min in HLM, with an intrinsic clearance of 8.7 mu L min(-1) mg(-1). In addition, this compound is predicted to be a low-clearance drug with an estimated human hepatic clearance of 8.2 mL min(-1) kg(-1) Eleven 4-methoxy-alpha-PVP metabolites were identified, generated by O-demethylation, hydroxylation, oxidation, ketone reduction, N-dealkylation, and glucuronidation. The most dominant metabolite in HLM and human hepatocyte samples was 4-hydroxy-alpha-PVP, also predicted as the #1 in silico metabolite, and is suggested to be a suitable analytical target in addition to the parent compound. C1 [Ellefsen, Kayla N.; Wohlfarth, Ariane; Swortwood, Madeleine J.; Diao, Xingxing; Concheiro, Marta; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200,Room 05A-721, Baltimore, MD 21224 USA. [Ellefsen, Kayla N.] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. [Concheiro, Marta] CUNY John Jay Coll Criminal Justice, Dept Sci, New York, NY 10019 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program of National Institute on Drug Abuse, National Institutes of Health FX The authors would like to acknowledge Timothy Moeller from BioreclamationIVT for his assistance with the human hepatocyte incubations, and Ismael Zamora from Molecular Discovery for his help with MetaSite and WebMetabase software. This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 49 TC 13 Z9 13 U1 6 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1860-8965 EI 1860-8973 J9 FORENSIC TOXICOL JI Forensic Toxicol. PD JAN PY 2016 VL 34 IS 1 BP 61 EP 75 DI 10.1007/s11419-015-0287-4 PG 15 WC Toxicology SC Toxicology GA DF6LM UT WOS:000371467200005 ER PT J AU Scheidweiler, KB Himes, SK Desrosiers, NA Huestis, MA AF Scheidweiler, Karl B. Himes, Sarah K. Desrosiers, Nathalie A. Huestis, Marilyn A. TI In vitro stability of free and glucuronidated cannabinoids in blood and plasma collected in plastic gray-top sodium fluoride tubes following controlled smoked cannabis SO FORENSIC TOXICOLOGY LA English DT Article DE Cannabinoids; Stability; THC; Blood; Plasma ID TANDEM MASS-SPECTROMETRY; WHOLE-BLOOD; DELTA-9-TETRAHYDROCANNABINOL THC; COCAINE; METABOLITES; TETRAHYDROCANNABINOL; CARBOXYLESTERASE; URINE; TIME; DELTA(9)-TETRAHYDROCANNABINOL AB Blood and plasma cannabinoid stability is important for test interpretation and is best studied in authentic rather than fortified samples. Previous studies employed green-top (sodium heparin) tubes; however, gray-top (sodium fluoride-potassium oxalate) tubes are generally used in forensic cases. Three participants each provided three low and high blood and plasma pools after smoking a 6.8 % Delta(9)-tetrahydrocannabinol (THC) cigarette ad libitum over 10 min. THC, 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), and THCCOOH-glucuronide stabilities in samples collected via gray-top tubes were determined after 1 week at room temperature (RT), 1, 4, 12, and 26 +/- 2 weeks at 4 degrees C and 1, 4, 12, 26 +/- 2, and 52 +/- 4 weeks at -20 degrees C. Concentration changes <+/- 20 % were considered stable. In blood, THC, 11-OH-THC, and THCCOOH were stable for 1 week at RT, while THCCOOH-glucuronide decreased >47 %. In blood at 4 degrees C, THC, 11-OH-THC, THCCOOH-glucuronide, and THCCOOH were stable for 26, 26, 1, and 26 weeks, respectively, and for 26, 52, 12, and 52 weeks respectively, at -20 degrees C. In plasma, THC and 11-OH-THC were stable for 1 week at room temperature, while THCCOOH-glucuronide decreased and THCCOOH increased. In plasma at 4 degrees C, THC, 11-OH-THC, THCCOOH-glucuronide, and THCCOOH were stable for 12, 26, 1, and 4 weeks, respectively, and at -20 degrees C for 52, 52, 12, and 52 weeks, respectively. Blood and plasma specimens collected via gray-top tubes should be stored at -20 degrees C for <= 12 weeks to assure accurate quantitative results of all major and minor cannabinoid markers. C1 [Scheidweiler, Karl B.; Himes, Sarah K.; Desrosiers, Nathalie A.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, IRP, NIH,Biomed Res Ctr, 251 Bayview BoSulevard Suite 200 Room 05A-721, Baltimore, MD 21224 USA. [Himes, Sarah K.] Quest Diagnost, 14225 Newbrook Dr, Chantilly, VA 20151 USA. [Desrosiers, Nathalie A.] New York State Police Forens Invest Ctr, Toxicol Sect, 1220 Washington Ave,Bldg 30, Albany, NY 12226 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab, IRP, NIH,Biomed Res Ctr, 251 Bayview BoSulevard Suite 200 Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program of National Institute on Drug Abuse, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 29 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1860-8965 EI 1860-8973 J9 FORENSIC TOXICOL JI Forensic Toxicol. PD JAN PY 2016 VL 34 IS 1 BP 179 EP 185 DI 10.1007/s11419-015-0290-9 PG 7 WC Toxicology SC Toxicology GA DF6LM UT WOS:000371467200017 ER PT J AU Moreli, JB Santos, JH Lorenzon-Ojea, AR Correa-Silva, S Fortunato, RS Rocha, CR Rudge, MV Damasceno, DC Bevilacqua, E Calderon, IM AF Moreli, Jusciele B. Santos, Janine H. Lorenzon-Ojea, Aline Rodrigues Correa-Silva, Simone Fortunato, Rodrigo S. Rocha, Clarissa Ribeiro Rudge, Marilza V. Damasceno, Debora C. Bevilacqua, Estela Calderon, Iracema M. TI Hyperglycemia Differentially Affects Maternal and Fetal DNA Integrity and DNA Damage Response SO INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES LA English DT Article DE Diabetes; Pregnancy; DNA damage; DNA repair ID GESTATIONAL DIABETES-MELLITUS; OXIDATIVE STRESS; CIGARETTE-SMOKE; PREGNANCY; BLOOD; REPAIR; OUTCOMES; CELLS; COMPLICATIONS; LYMPHOCYTES AB Objective: Investigate the DNA damage and its cellular response in blood samples from both mother and the umbilical cord of pregnancies complicated by hyperglycemia. Methods: A total of 144 subjects were divided into 4 groups: normoglycemia (ND; 46 cases), mild gestational hyperglycemia (MGH; 30 cases), gestational diabetes mellitus (GDM; 45 cases) and type-2 diabetes mellitus (DM2; 23 cases). Peripheral blood mononuclear cell (PBMC) isolation and/or leukocytes from whole maternal and umbilical cord blood were obtained from all groups at delivery. Nuclear and mitochondrial DNA damage were measured by gene-specific quantitative PCR, and the expression of mRNA and proteins involved in the base excision repair (BER) pathway were assessed by real-time qPCR and Western blot, respectively. Apoptosis was measured in vitro experiments by caspase 3/7 activity and ATP levels. Results: GDM and DM2 groups were characterized by an increase in oxidative stress biomarkers, an increase in nuclear and mitochondrial DNA damage, and decreased expression of mRNA (APE1, POLa and FEN1) and proteins (hOGG1, APE1) involved in BER. The levels of hyperglycemia were associated with the in vitro apoptosis pathway. Blood levels of DNA damage in umbilical cord were similar among the groups. Newborns of diabetic mothers had increased expression of BER mRNA (APE1, POLa and FEN1) and proteins (hOGG1, APE1, POL beta and FEN1). A diabetes-like environment was unable to induce apoptosis in the umbilical cord blood cells. Conclusions: Our data show relevant asymmetry between maternal and fetal blood cell susceptibility to DNA damage and apoptosis induction. Maternal cells seem to be more predisposed to changes in an adverse glucose environment. This may be due to differential ability in upregulating multiple genes involved in the activation of DNA repair response, especially the BER mechanism. However if this study shows a more effective adaptive response by the fetal organism, it also calls for further studies to determine the limit of this response that definitely changes the fate of a fetus under these conditions of cellular stress. C1 [Moreli, Jusciele B.; Correa-Silva, Simone; Rudge, Marilza V.; Damasceno, Debora C.; Calderon, Iracema M.] Sao Paulo State Univ UNESP, Botucatu Med Sch, Grad Program Gynecol Obstet & Mastol, Dist Rubiao Jr S-N, BR-18618000 Botucatu, SP, Brazil. [Santos, Janine H.] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC USA. [Lorenzon-Ojea, Aline Rodrigues; Correa-Silva, Simone; Bevilacqua, Estela] Univ Sao Paulo, Inst Biomed Sci, Dept Cell & Dev Biol, BR-09500900 Sao Paulo, Brazil. [Fortunato, Rodrigo S.] Univ Fed Rio de Janeiro, Carlos Chagas Filho Biophys Inst, Lab Mol Radiobiol, Rio De Janeiro, Brazil. [Rocha, Clarissa Ribeiro] Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, DNA Repair Lab, BR-09500900 Sao Paulo, Brazil. RP Calderon, IM (reprint author), UNESP Sao Paulo State Univ, Botucatu Med Sch, Dept Obstet & Gynecol, Dist Rubiao Jr S-N, BR-18618000 Botucatu, SP, Brazil. EM juscielemoreli@gmail.com; calderon@fmb.unesp.br RI Rudge, Marilza /C-8338-2012; Lorenzon-Ojea, Aline/G-8733-2014; OI Rudge, Marilza /0000-0002-9227-832X; Lorenzon-Ojea, Aline/0000-0002-6052-6296; Fortunato, Rodrigo/0000-0003-3497-8173 FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - FAPESP [2011/18240-2, 2011/13562-1, 2012/23296-0] FX The authors would like to thank Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - FAPESP (grant number 2011/18240-2; 2011/13562-1 and 2012/23296-0) for financial support and for the fellowships of JB Moreli. Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq). Dr. Carlos Frederico Martins Menck for scientific support and Dr. Jose Eduardo Corrente for statistics support. NR 45 TC 0 Z9 0 U1 3 U2 5 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1449-2288 J9 INT J BIOL SCI JI Int. J. Biol. Sci. PY 2016 VL 12 IS 4 BP 466 EP 477 DI 10.7150/ijbs.12815 PG 12 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA DF9QN UT WOS:000371696200005 PM 27019630 ER PT J AU Kim, BW Cho, H Ylaya, K Chung, JY Hewitt, SM Kim, JH AF Kim, Bo Wook Cho, Hanbyoul Ylaya, Kris Chung, Joon-Yong Hewitt, Stephen M. Kim, Jae-Hoon TI Over-expression of BMI1 is associated with favorable prognosis in cervical cancer SO INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY LA English DT Article DE BMI; cervical cancer; prognosis ID EPITHELIAL-MESENCHYMAL TRANSITION; SELF-RENEWAL; HUMAN-PAPILLOMAVIRUS; CELL-PROLIFERATION; IMAGE-ANALYSIS; BREAST-CANCER; DNA-DAMAGE; STEM-CELLS; C-MYC; PROTEIN AB Objective: B cell-specific Moloney murine leukemia virus integration site 1 (BMI1), is a Plycomb group (PCG) protein, that is involved in the epithelial-mesenchymal transition (EMT) and induces stem cell properties, suggestive poor prognosis. In this study, we evaluated the prognostic value of BMI1 in cervical cancer. Methods: The study materials were comprised of cervical intraepithelial neoplasia (CIN, n=225), cervical cancer (n=150) and matched nonadjacent normal tissues (n=326). In order to identify BMI1 expression in the tissues, immunohistochemistry (IHC) was performed. IHC scoring was performed using digital image analysis, and the associations of BMI1 with prognosis, radiation sensitivity and human papillomavirus level were examined. Results: BMI1 compared with normal cervix and CIN lesion was highly expressed in cervical cancer. High expression of BMI1 presented better disease-free survival and overall survival than low expression according to a Kaplan-Meier survival analysis (P=0.017 and 0.035, respectively), and produced a significantly low hazard ratio for death according to a multivariate analysis (P=0.03). In CIN lesion, BMI1 was correlated with cancer stem cell (CSC) markers such as OCT4 and SOX2 (P=0.006 and 0.031, respectively), whereas in cervical cancer, no association was observed. Additionally, BMI1 expression was observed in radiation-sensitive cervical cancer, suggesting its positive prognostic indication. Conclusions: BMI1 expression is associated with favorable survival in cervical cancer, and as such, might aid the prognosis of cervical carcinoma. C1 [Kim, Bo Wook; Ylaya, Kris; Chung, Joon-Yong; Hewitt, Stephen M.] NCI, Expt Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Cho, Hanbyoul; Kim, Jae-Hoon] Yonsei Univ, Dept Obstet & Gynecol, Gangnam Severance Hosp, Coll Med, 146-92 Dogok Dong, Seoul 135720, South Korea. [Kim, Bo Wook] Kwandong Univ, Dept Obstet & Gynecol, Int St Marys Hosp, Inchon 22711, South Korea. RP Kim, JH (reprint author), Yonsei Univ, Dept Obstet & Gynecol, Gangnam Severance Hosp, Coll Med, 146-92 Dogok Dong, Seoul 135720, South Korea. EM jaehoonkim@yuhs.ac OI Hewitt, Stephen/0000-0001-8283-1788; Chung, Joon-Yong/0000-0001-5041-5982 FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research; National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2011-0005230, 2011-0010286, 2011-0007146] FX This work was supported in part by the Intramural Research Program of the NIH, the National Cancer Institute, the Center for Cancer Research and grants from the basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0005230, 2011-0010286 and 2011-0007146). NR 33 TC 0 Z9 0 U1 0 U2 1 PU E-CENTURY PUBLISHING CORP PI MADISON PA 40 WHITE OAKS LN, MADISON, WI 53711 USA SN 1936-2625 J9 INT J CLIN EXP PATHO JI Int. J. Clin. Exp. Pathol. PY 2016 VL 9 IS 2 BP 1849 EP 1857 PG 9 WC Oncology; Pathology SC Oncology; Pathology GA DG1EU UT WOS:000371809200155 ER PT J AU Alves, DA Honko, AN Kortepeter, MG Sun, M Johnson, JC Lugo-Roman, LA Hensley, LE AF Alves, Derron A. Honko, Anna N. Kortepeter, Mark G. Sun, Mei Johnson, Joshua C. Lugo-Roman, Luis A. Hensley, Lisa E. TI Necrotizing Scleritis, Conjunctivitis, and Other Pathologic Findings in the Left Eye and Brain of an Ebola Virus-Infected Rhesus Macaque (Macaca mulatta) With Apparent Recovery and a Delayed Time of Death SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola virus disease; Ebola virus; sequelae; macaque; rhesus; intramuscular; delayed death; eye; brain ID HEMORRHAGIC-FEVER; ZAIRE-EBOLAVIRUS; CONGO; KIKWIT AB A 3.5-year-old adult female rhesus macaque (Macaca mulatta) manifested swelling of the left upper eyelid and conjunctiva and a decline in clinical condition 18 days following intramuscular challenge with Ebola virus (EBOV; Kikwit-1995), after apparent clinical recovery. Histologic lesions with strong EBOV antigen staining were noted in the left eye (scleritis, conjunctivitis, and peri-optic neuritis), brain (choriomeningoencephalitis), stomach, proximal duodenum, and pancreas. Spleen, liver, and adrenal glands, common targets for acute infection, appeared histologically normal with no evidence of EBOV immunoreactivity. These findings may provide important insight for understanding sequelae seen in West African survivors of Ebola virus disease. C1 [Alves, Derron A.] Def Hlth Agcy, Def Hlth Headquarters, Vet Serv, 7700 Arlington Blvd, Falls Church, VA 22042 USA. [Honko, Anna N.; Johnson, Joshua C.; Hensley, Lisa E.] NIAID, Integrated Res Facil, NIH, Ft Detrick, MD USA. [Kortepeter, Mark G.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Sun, Mei] US Army, Med Res Inst Infect Dis, Div Pathol, Ft Detrick, MD 21702 USA. [Lugo-Roman, Luis A.] US Army, Med Res Inst Infect Dis, Vet Med Div, Ft Detrick, MD 21702 USA. RP Alves, DA (reprint author), Def Hlth Agcy, Def Hlth Headquarters, Vet Serv, 7700 Arlington Blvd, Falls Church, VA 22042 USA. EM derron.a.alves.mil@mail.mil OI Honko, Anna/0000-0001-9165-148X FU Defense Threat Reduction Agency [4.10033_07_RD_B] FX This work was supported by the Defense Threat Reduction Agency (project 4.10033_07_RD_B). NR 15 TC 3 Z9 3 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 1 PY 2016 VL 213 IS 1 BP 57 EP 60 DI 10.1093/infdis/jiv357 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DF2EG UT WOS:000371152700009 PM 26153408 ER PT J AU Dancy, BM Brockway, N Ramadasan-Nair, R Yang, Y Sedensky, MM Morgan, PG AF Dancy, Beverley M. Brockway, Nicole Ramadasan-Nair, Renjini Yang, Yoing Sedensky, Margaret M. Morgan, Philip G. TI Glutathione S-transferase mediates an ageing response to mitochondrial dysfunction SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE Hydroxynonenal; Glutathione S-transferase; Mitochondrial respiratory chain; Longevity; Reactive oxygen species; Caenorhabditis elegans ID CAENORHABDITIS-ELEGANS; LIFE-SPAN; C. ELEGANS; RESPIRATORY-CHAIN; ANESTHETIC SENSITIVITY; SUPEROXIDE DISMUTASES; ALDOSE REDUCTASE; OXIDATIVE DAMAGE; CELL-SURVIVAL; LONGEVITY AB To understand primary mitochondrial disease, we utilized a complex I-deficient Caenorhabditis elegans mutant, gas-1. These animals strongly upregulate the expression of gst-14 (encoding a glutathione S-transferase). Knockdown of gst-14 dramatically extends the lifespan of gas-1 and increases hydroxynonenal (HNE) modified mitochondrial proteins without improving complex I function. We observed no change in reactive oxygen species levels as measured by Mitosox staining, consistent with a potential role of GST-14 in HNE clearance. The upregulation of gst-14 in gas-1 animals is specific to the pharynx. These data suggest that an HNE-mediated response in the pharynx could be beneficial for lifespan extension in the context of complex I dysfunction in C. elegans. Thus, whereas HNE is typically considered damaging, our work is consistent with recent reports of its role in signaling, and that in this case, the signal is pro-longevity in a model of mitochondrial dysfunction. Published by Elsevier Ireland Ltd C1 [Dancy, Beverley M.; Brockway, Nicole; Ramadasan-Nair, Renjini; Sedensky, Margaret M.; Morgan, Philip G.] Seattle Childrens Res Inst, Ctr Dev Therapeut, 1900 9th Ave, Seattle, WA 98101 USA. [Yang, Yoing] Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA. [Sedensky, Margaret M.; Morgan, Philip G.] Univ Washington, Dept Anesthesiol & Pain Med, 1959 NE Pacific St,BB-1469, Seattle, WA 98195 USA. [Brockway, Nicole] Lewis & Clark Coll, Dept Biol, 0615 SW Palatine Hill Rd,MSC 53, Portland, OR 97313 USA. RP Dancy, BM (reprint author), NHLBI, Cardiac Energet Lab, NIH, 10 Ctr Dr,Bldg 10,Room B1D4 00,MSC 1061, Bethesda, MD 20892 USA.; Morgan, PG (reprint author), 1900 9th Ave,C9S JMB 9, Seattle, WA 98101 USA. EM beverley.m.dancy@gmail.com; nicolebrockway9@gmail.com; renjini@outlook.com; yyoing@gmail.com; sedenm@u.washington.edu; philip.morgan@seattlechildrens.org FU Northwest Mitochondrial Research Guild FX We dedicate this work to S. Serex and S. Requa and their families for sharing their stories, strength, and hope. We are deeply appreciative of Beatrice Predoi for extensive and essential technical assistance in the laboratory that made this work possible. We thank Dr. Ernst-Bernhard Kayser for valuable discussion about mitochondrial methods and the field of metabolism, Elyce Opheim for introducing B. Dancy to this project, Amy Venn for Seahorse-related data processing, and Danelle C. Hidano for helping at the bench on the subcellular fractionations. We thank the providers of WormBase and WormAtlas, online resources for Caenorhabditis researchers. We thank the Northwest Mitochondrial Research Guild for their encouragement and generous financial support for this project. This work was funded by a post-doctoral fellowship to BMD from the Northwest Mitochondrial Research Guild. The Northwest Mitochondrial Research Guild did not play any role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. NR 42 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD JAN PY 2016 VL 153 BP 14 EP 21 DI 10.1016/j.mad.2015.12.001 PG 8 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA DF9AN UT WOS:000371652700003 PM 26704446 ER PT J AU Chen, HJ Wang, GH Lang, LX Jacobson, O Kiesewetter, DO Liu, Y Ma, Y Zhang, XZ Wu, H Zhu, L Niu, G Chen, XY AF Chen, Haojun Wang, Guohao Lang, Lixin Jacobson, Orit Kiesewetter, Dale O. Liu, Yi Ma, Ying Zhang, Xianzhong Wu, Hua Zhu, Lei Niu, Gang Chen, Xiaoyuan TI Chemical Conjugation of Evans Blue Derivative: A Strategy to Develop Long-Acting Therapeutics through Albumin Binding SO THERANOSTICS LA English DT Article DE Exendin-4; Evans blue; Albumin-binding; PET; Abextide ID GLUCAGON-LIKE PEPTIDE-1; HUMAN SERUM-ALBUMIN; EXENATIDE EXENDIN-4; GLYCEMIC CONTROL; POSTPRANDIAL-GLUCOSE; TREATED PATIENTS; HUMAN INSULIN; PET; PHARMACOKINETICS; PEGYLATION AB The efficacy of therapeutic drugs is highly dependent on their optimal in vivo pharmacokinetics. Albumin conjugation is considered to be one of the most effective means of protracting the short lifespan of peptides and proteins. In this study, we proposed a novel platform for developing long lasting therapeutics by conjugating a small molecular albumin binding moiety, truncated Evans blue, to either peptides or proteins. Using the anti-diabetic peptide drug Exendin-4 as a model peptide, we synthesized a new long-acting Exendin-4 derivative (denoted as Abextide). Through complexation with albumin in situ, the biological half-life of Abextide was significantly extended. The hypoglycemic effect of Abextide was also improved remarkably over Exendin-4. Thus, Abextide has considerable potential to treat type 2 diabetes. This strategy as a general technology platform can be applied to other small molecules and biologics for the development of long-acting therapeutic drugs. C1 [Chen, Haojun; Wu, Hua] Xiamen Univ, Affiliated Hosp 1, Xiamen Canc Ctr, Dept Nucl Med, Xiamen, Peoples R China. [Chen, Haojun; Lang, Lixin; Jacobson, Orit; Kiesewetter, Dale O.; Liu, Yi; Ma, Ying; Zhang, Xianzhong; Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD USA. [Wang, Guohao; Zhu, Lei] Xiamen Univ, State Key Lab Mol Vaccinol & Mol Diagnost, Xiamen 361005, Peoples R China. [Wang, Guohao; Zhu, Lei] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. RP Wu, H (reprint author), Xiamen Univ, Affiliated Hosp 1, Xiamen Canc Ctr, Dept Nucl Med, Xiamen, Peoples R China.; Zhang, XZ; Niu, G; Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD USA.; Zhu, L (reprint author), Xiamen Univ, State Key Lab Mol Vaccinol & Mol Diagnost, Xiamen 361005, Peoples R China.; Zhu, L (reprint author), Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. EM zhangxz@xmu.edu.cn; wuhua1025@163.com; lei.zhu@xmu.edu.cn; niug@mail.nih.gov; shawn.chen@nih.gov RI Zhu, Lei/P-9786-2016; Zhang, Xianzhong/A-7754-2012 OI Zhu, Lei/0000-0002-1820-4795; Zhang, Xianzhong/0000-0002-1001-1884 FU National Natural Science Foundation of China [81471684, 81371596]; Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health; China Scholarship Council (CSC) FX The authors gratefully acknowledge the National Natural Science Foundation of China (81471684 and 81371596) and the Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. Haojun Chen was partially funded by the China Scholarship Council (CSC). NR 45 TC 2 Z9 2 U1 6 U2 13 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1838-7640 J9 THERANOSTICS JI Theranostics PY 2016 VL 6 IS 2 BP 243 EP 253 DI 10.7150/thno.14322 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DG1DY UT WOS:000371806900008 PM 26877782 ER PT J AU Wang, YB Chen, JW Yang, B Qiao, HY Gao, L Su, T Ma, S Zhang, XT Li, XJ Liu, G Cao, JB Chen, XY Chen, YD Cao, F AF Wang, Yabin Chen, Jiangwei Yang, Bo Qiao, Hongyu Gao, Lei Su, Tao Ma, Sai Zhang, Xiaotian Li, Xiujuan Liu, Gang Cao, Jianbo Chen, Xiaoyuan Chen, Yundai Cao, Feng TI In vivo MR and Fluorescence Dual-modality Imaging of Atherosclerosis Characteristics in Mice Using Profilin-1 Targeted Magnetic Nanoparticles SO THERANOSTICS LA English DT Article DE Atherosclerosis; Profilin-1; DMSA-Fe3O4-nanoparticles; Molecular imaging ID INFLAMMATION; RESONANCE; PLAQUE; LESIONS; LEADS AB Aims: This study aims to explore non-invasive imaging of atherosclerotic plaque through magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) by using profilin-1 targeted magnetic iron oxide nanoparticles (PF1-Cy5.5-DMSA-Fe3O4-NPs, denoted as PC-NPs) as multi-modality molecular imaging probe in murine model of atherosclerosis. Methods and Results: PC-NPs were constructed by conjugating polyclonal profilin-1 antibody and NHS-Cy5.5 fluorescent dye to the surface of DMSA-Fe3O4-nanoparticles via condensation reaction. Murine atherosclerosis model was induced in apoE(-/-) mice by high fat and cholesterol diet (HFD) for 16 weeks. The plaque areas in aortic artery were detected with Oil Red O staining. Immunofluorescent staining and Western blot analysis were applied respectively to investigate profilin-1 expression. CCK-8 assay and transwell migration experiment were performed to detect vascular smooth muscle cells (VSMCs) proliferation. In vivo MRI and NIRF imaging of atherosclerotic plaque were carried out before and 36 h after intravenous injection of PC-NPs. Oil Red O staining showed that the plaque area was significantly increased in HFD group (p<0.05). Immunofluorescence staining revealed that profilin-1 protein was highly abundant within plaque in HFD group and co-localized with a-smooth muscle actin. Profilin-1 siRNA intervention could inhibit VSMCs proliferation and migration elicited by ox-LDL (p<0.05). In vivo MRI and NIRF imaging revealed that PC-NPs accumulated in atherosclerotic plaque of carotid artery. There was a good correlation between the signals of MRI and ex vivo fluorescence intensities of NIRF imaging in animals with PC-NPs injection. Conclusion: PC-NPs is a promising dual modality imaging probe, which may improve molecular diagnosis of plaque characteristics and evaluation of pharmaceutical interventions for atherosclerosis. C1 [Wang, Yabin; Yang, Bo; Gao, Lei; Chen, Yundai; Cao, Feng] Chinese Peoples Liberat Army Gen Hosp, Dept Cardiol, Beijing 100853, Peoples R China. [Wang, Yabin; Chen, Jiangwei; Qiao, Hongyu; Su, Tao; Ma, Sai; Zhang, Xiaotian; Li, Xiujuan; Cao, Feng] Fourth Mil Med Univ, Xijing Hosp, Dept Cardiol, Xian 710032, Shaanxi, Peoples R China. [Liu, Gang; Cao, Jianbo] Xiamen Univ, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. [Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. RP Chen, YD; Cao, F (reprint author), Chinese Peoples Liberat Army Gen Hosp, Dept Cardiol, Beijing 100853, Peoples R China. EM cyundai@126.com; wind8828@gmail.com FU National Funds for Distinguished Young Scientists of China [81325009]; National Natural Science Foundation of China [81270168, 81530058, 81570272, 81500360, 81227901]; Innovation Team Development Grant by China Department of Education [IRT1053]; Shaanxi Province Program [2013K12-02-03]; Key Science and Technology Innovation Team in Shaanxi Province [2014KCT-20]; Beijing Natural Science Foundation [7132227] FX This work was supported by the National Funds for Distinguished Young Scientists of China (No. 81325009), and National Natural Science Foundation of China (No. 81270168, No. 81530058, 81570272, 81500360, 81227901, 81570272), Innovation Team Development Grant by China Department of Education (IRT1053), Shaanxi Province Program (2013K12-02-03), Key Science and Technology Innovation Team in Shaanxi Province (No. 2014KCT-20), and Beijing Natural Science Foundation (7132227). NR 25 TC 4 Z9 4 U1 11 U2 26 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1838-7640 J9 THERANOSTICS JI Theranostics PY 2016 VL 6 IS 2 BP 272 EP 286 DI 10.7150/thno.13350 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DG1DY UT WOS:000371806900011 PM 26877785 ER PT J AU Bridges, E McNeill, M Munro, N AF Bridges, Elizabeth McNeill, Margaret Munro, Nancy TI RESEARCH IN REVIEW: DRIVING CRITICAL CARE PRACTICE CHANGE SO AMERICAN JOURNAL OF CRITICAL CARE LA English DT Article ID FECAL MICROBIOTA TRANSPLANTATION; RANDOMIZED CLINICAL-TRIAL; ELECTROCARDIOGRAPHY LEAD WIRES; GOAL-DIRECTED RESUSCITATION; PREHOSPITAL TOURNIQUET USE; EARLY SEPTIC SHOCK; RED-BLOOD-CELLS; INTENSIVE-CARE; PERIPHERAL PERFUSION; BOSTON MARATHON AB During the past year, studies were published that will lead to practice change, address challenges at the bedside, and introduce new care strategies. This article summarizes some of this important work and considers it in the context of previous research and practice. Examples of research-based practice changes include the performance and assessment of septic shock resuscitation, and the integration of tourniquets and massive transfusions in civilian trauma. Care challenges addressed include ethical considerations in light of the Ebola epidemic, infection prevention associated with chlorhexidine bathing, bedside alarm management, evidence to enhance moral courage, and interventions to mitigate thirst in critically ill patients. Research that portends future care includes a discussion of fecal microbiota transplant for patients with refractory infection with Clostridium difficile. C1 [Bridges, Elizabeth] Univ Washington, Sch Nursing, Med Ctr, 1959 NE Pacific,Box 357266, Seattle, WA 98195 USA. [McNeill, Margaret] Frederick Reg Hlth Syst, Dept Profess & Clin Dev, Perianesthesia, Frederick, MD USA. [Munro, Nancy] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Bridges, E (reprint author), Univ Washington, Sch Nursing, Med Ctr, 1959 NE Pacific,Box 357266, Seattle, WA 98195 USA. EM ebridges@u.washington.edu NR 82 TC 0 Z9 0 U1 3 U2 8 PU AMER ASSOC CRITICAL CARE NURSES PI ALISO VIEJO PA 101 COLUMBIA, ALISO VIEJO, CA 92656 USA SN 1062-3264 EI 1937-710X J9 AM J CRIT CARE JI Am. J. Crit. Care PD JAN 1 PY 2016 VL 25 IS 1 BP 76 EP 84 DI 10.4037/ajcc2016564 PG 9 WC Critical Care Medicine; Nursing SC General & Internal Medicine; Nursing GA DF3FL UT WOS:000371229200018 PM 26724298 ER PT J AU Dastgir, J Rutkowski, A Alvarez, R Cossette, SA Yan, K Hoffmann, RG Sewry, C Hayashi, YK Goebel, HH Bonnemann, C Lawlor, MW AF Dastgir, Jahannaz Rutkowski, Anne Alvarez, Rachel Cossette, Stacy A. Yan, Ke Hoffmann, Raymond G. Sewry, Caroline Hayashi, Yukiko K. Goebel, Hans-Hilmar Bonnemann, Carsten Lawlor, Michael W. TI Common Data Elements for Muscle Biopsy Reporting SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID NEUROLOGICAL DISORDERS; NATIONAL INSTITUTE; CDE PROJECT; AGREEMENT AB Context.-There is no current standard among myopathologists for reporting muscle biopsy findings. The National Institute of Neurological Disorders and Stroke has recently launched a common data element (CDE) project to standardize neuromuscular data collected in clinical reports and to facilitate their use in research. Objective.-To develop a more-uniform, prospective reporting tool for muscle biopsies, incorporating the elements identified by the CDE project, in an effort to improve reporting and educational resources. Design.-The variation in current biopsy reporting practice was evaluated through a study of 51 muscle biopsy reports from self-reported diagnoses of genetically confirmed or undiagnosed muscle disease from the Congenital Muscle Disease International Registry. Two reviewers independently extracted data from deidentified reports and entered them into the revised CDE format to identify what was missing and whether or not information provided on the revised CDE report (complete/incomplete) could be successfully interpreted by a neuropathologist. Results.-Analysis of the data highlighted showed (1) inconsistent reporting of key clinical features from referring physicians, and (2) considerable variability in the reporting of pertinent positive and negative histologic findings by pathologists. Conclusions.-We propose a format for muscle-biopsy reporting that includes the elements in the CDE checklist and a brief narrative comment that interprets the data in support of a final interpretation. Such a format standardizes cataloging of pathologic findings across the spectrum of muscle diseases and serves emerging clinical care and research needs with the expansion of genetic-testing therapeutic trials. C1 [Dastgir, Jahannaz; Bonnemann, Carsten] NINDS, Neuromuscular & Neurogenet Disorders Childhood Se, Neurogenet Branch, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Dastgir, Jahannaz] Columbia Univ, Dept Pediat Neurol, Div Pediat Neuromuscular Med, Med Ctr, New York, NY USA. [Rutkowski, Anne; Alvarez, Rachel; Cossette, Stacy A.] Cure CMD, Olathe, KS USA. [Yan, Ke; Hoffmann, Raymond G.] Med Coll Wisconsin, Dept Pediat, Quantitat Hlth Sci Sect, Milwaukee, WI 53226 USA. [Cossette, Stacy A.; Lawlor, Michael W.] Med Coll Wisconsin, Dept Pathol & Lab Med, Div Pediat Pathol, 8701 Watertown Plank Rd,TBRC Bldg,Room C4490, Milwaukee, WI 53226 USA. [Sewry, Caroline] UCL, Dubowitz Neuromuscular Ctr, London, England. [Sewry, Caroline] UCL, Inst Child Hlth, London, England. [Sewry, Caroline] UCL, Great Ormond St Hosp, London, England. [Sewry, Caroline] RJAH Orthopaed Hosp, Wolfson Ctr Inherited Neuromuscular Dis, Oswestry, Shrops, England. [Hayashi, Yukiko K.] Tokyo Med Univ, Dept Neurophysiol, Tokyo, Japan. [Goebel, Hans-Hilmar] Johannes Gutenberg Univ Mainz, Dept Neuropathol, D-55122 Mainz, Germany. RP Lawlor, MW (reprint author), Med Coll Wisconsin, Dept Pathol & Lab Med, Div Pediat Pathol, 8701 Watertown Plank Rd,TBRC Bldg,Room C4490, Milwaukee, WI 53226 USA. EM mlawlor@mcw.edu FU US National Institutes of Health [K08 AR059750, L40 AR057721]; Cure CMD; Children's Hospital of Wisconsin Research Institute (Milwaukee) FX We thank Steve Moore MD, PhD, for his helpful comments during the course of this project. We also thank Brian Moore, MD, Med, and the American Association of Neuropathologists for distributing and/or publicizing the prospective muscle-biopsy reporting form to the neuropathology community and the numerous members of the neuropathology community who offered advice to improve the usefulness of our reporting form. This work was supported by the US National Institutes of Health [grants K08 AR059750 and L40 AR057721], Cure CMD, and the Children's Hospital of Wisconsin Research Institute (Milwaukee). NR 10 TC 5 Z9 5 U1 0 U2 0 PU COLL AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 EI 1543-2165 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD JAN PY 2016 VL 140 IS 1 BP 51 EP 65 DI 10.5858/arpa.2014-0453-OA PG 15 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA DF3EL UT WOS:000371226600009 PM 26132600 ER PT S AU Kovaleva, E Davis, DC AF Kovaleva, Elena Davis, David C. BE Murhammer, DW TI Protein Production with Recombinant Baculoviruses in Lepidopteran Larvae SO BACULOVIRUS AND INSECT CELL EXPRESSION PROTOCOLS, 3RD EDITION SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Trichoplusia ni; Cabbage looper; Baculovirus; Recombinant protein expression; Transfection of insect larvae ID TRICHOPLUSIA-NI-LARVAE; HIGH-LEVEL EXPRESSION; INSECT LARVAE; BOMBYX-MORI; MEDIATED EXPRESSION; SILKWORM; HOST; PARTICLES; INFECTION; RECEPTOR AB With an increasing need for functional analysis of proteins, there is a growing demand for fast and cost-effective production of biologically active eukaryotic proteins. The baculovirus expression vector system (BEVS) is widely used, and in the vast majority of cases cultured insect cells have been the host of choice. A low cost alternative to bioreactor-based protein production exists in the use of live insect larvae as "mini bioreactors." In this chapter we focus on Trichoplusia ni as the host insect for recombinant protein production, and explore three different methods of virus administration to the larvae. The first method is labor-intensive, as extracellular virus is injected into each larva, whereas the second lends itself to infection of large numbers of larvae via oral inoculation. While these first two methods require cultured insect cells for the generation of recombinant virus, the third relies on transfection of larvae with recombinant viral DNA and does not require cultured insect cells as an intermediate stage. We suggest that small-to mid-scale recombinant protein production (mg-g level) can be achieved in T. ni larvae with relative ease. C1 [Kovaleva, Elena] NHBLI, Harris IT Services, NIH, Bethesda, MD USA. [Davis, David C.] Frontier Agr Sci, Newark, DE USA. RP Kovaleva, E (reprint author), NHBLI, Harris IT Services, NIH, Bethesda, MD USA. NR 31 TC 0 Z9 0 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-3043-2; 978-1-4939-3042-5 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1350 BP 285 EP 297 DI 10.1007/978-1-4939-3043-2_13 D2 10.1007/978-1-4939-3043-2 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA BE3TY UT WOS:000371264800014 PM 26820863 ER PT J AU Iyer, LM Zhang, DP Aravind, L AF Iyer, Lakshminarayan M. Zhang, Dapeng Aravind, L. TI Adenine methylation in eukaryotes: Apprehending the complex evolutionary history and functional potential of an epigenetic modification SO BIOESSAYS LA English DT Review DE adenine methylation; chromatin; dioxygenases; methyltransferases; modified DNA; restriction modification; transcription regulation ID RESTRICTION-MODIFICATION SYSTEMS; RNA-POLYMERASE-II; DNA METHYLATION; ESCHERICHIA-COLI; NATURAL-HISTORY; MAMMALIAN DNA; OXIDATIVE DEMETHYLATION; MODIFICATION ENZYMES; CATALYTIC MECHANISM; REPLICATION ORIGINS AB While N-6-methyladenosine (m(6)A) is a well-known epigenetic modification inbacterial DNA, it remained largely unstudied in eukaryotes. Recent studies have brought to fore its potential epigenetic role across diverse eukaryotes with biological consequences, which are distinct and possibly even opposite to the well-studied 5-methylcytosine mark. Adenine methyltransferases appear to have been independently acquired by eukaryotes on at least 13 occasions from prokaryotic restriction-modification and counter-restriction systems. On at least four to five instances, these methyltransferases were recruited as RNA methylases. Thus, m(6)A marks in eukaryotic DNA and RNA might be more wide spread and diversified than previously believed. Several m(6)A-binding protein domains from prokaryotes were also acquired by eukaryotes, facilitating prediction of potential readers for these marks. Further, multiple lineages of the AlkB family of dioxygenases have been recruited as m(6)A demethylases. Although members of the TET/JBP family of dioxygenases have also been suggested to be m(6)A demethylases, this proposal needs more careful evaluation. C1 [Iyer, Lakshminarayan M.; Zhang, Dapeng; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM aravind@ncbi.nlm.nih.gov FU Intramural Research Program of National Library of Medicine at the National Institutes of Health, USA FX This work is supported by the funds of the Intramural Research Program of National Library of Medicine at the National Institutes of Health, USA. NR 126 TC 5 Z9 5 U1 6 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0265-9247 EI 1521-1878 J9 BIOESSAYS JI Bioessays PD JAN PY 2016 VL 38 IS 1 BP 27 EP 40 DI 10.1002/bies.201500104 PG 14 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA DF3RT UT WOS:000371265200006 PM 26660621 ER PT B AU Felsenfeld, G AF Felsenfeld, Gary BE Huang, S Litt, MD Blakey, CA TI EPIGENETIC GENE EXPRESSION AND REGULATION PREFACE SO EPIGENETIC GENE EXPRESSION AND REGULATION SE Translational Epigenetics Series LA English DT Editorial Material; Book Chapter C1 [Felsenfeld, Gary] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL ROAD, LONDON NW1 7DX, ENGLAND BN 978-0-12-800471-5; 978-0-12-799958-6 J9 TRANSL EPIGENET SER PY 2016 BP XV EP XVIII PG 4 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA BE3UM UT WOS:000371269800001 ER PT B AU Hu, GQ Zhao, KJ AF Hu, Gangqing Zhao, Keji BE Huang, S Litt, MD Blakey, CA TI Identification of intergenic long noncoding RNA by deep sequencing SO EPIGENETIC GENE EXPRESSION AND REGULATION SE Translational Epigenetics Series LA English DT Article; Book Chapter ID EMBRYONIC STEM-CELLS; GENOME-WIDE ANALYSIS; CHIP-SEQ DATA; EXPRESSION PATTERNS; GENE-EXPRESSION; CHROMATIN; REVEALS; ALIGNMENT; DIFFERENTIATION; TRANSCRIPTION C1 [Hu, Gangqing; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Hu, GQ (reprint author), NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 66 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL ROAD, LONDON NW1 7DX, ENGLAND BN 978-0-12-800471-5; 978-0-12-799958-6 J9 TRANSL EPIGENET SER PY 2016 BP 223 EP 235 DI 10.1016/B978-0-12-799958-6.00010-X PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA BE3UM UT WOS:000371269800011 ER PT J AU Sato, K Feng, XM Chen, JC Li, JG Muranski, P Desierto, MJ Keyvanfar, K Malide, D Kajigaya, S Young, NS AF Sato, Kazuya Feng, Xingmin Chen, Jichun Li, Jungang Muranski, Pawel Desierto, Marie J. Keyvanfar, Keyvan Malide, Daniela Kajigaya, Sachiko Young, Neal S. TI PPAR gamma antagonist attenuates mouse immune-mediated bone marrow failure by inhibition of T cell function SO HAEMATOLOGICA LA English DT Article ID ACTIVATED-RECEPTOR-GAMMA; COLLAGEN-INDUCED ARTHRITIS; QUANTITATIVE TRAIT LOCI; APLASTIC-ANEMIA; ETHER BADGE; ADIPOGENESIS; INFLAMMATION; ADIPOCYTES; LINE; THIAZOLIDINEDIONES AB Acquired aplastic anemia is an immune-mediated disease, in which T cells target hematopoietic cells; at presentation, the bone marrow is replaced by fat. It was reported that bone marrow adipocytes were negative regulators of hematopoietic microenvironment. To examine the role of adipocytes in bone marrow failure, we investigated peroxisomal proliferator-activated receptor gamma, a key transcription factor in adipogenesis, utilizing an antagonist of this factor called bisphenol-A-diglycidyl-ether. While bisphenol-A-diglycidyl-ether inhibited adipogenesis as expected, it also suppressed T cell infiltration of bone marrow, reduced plasma inflammatory cytokines, decreased expression of multiple inflammasome genes, and ameliorated marrow failure. In vitro, bisphenol-A-diglycidyl-ether suppressed activation and proliferation, and reduced phospholipase C gamma 1 and nuclear factor of activated T-cells 1 expression, as well as inhibiting calcium flux in T cells. The in vivo effect of bisphenol-A-diglycidyl-ether on T cells was confirmed in a second immune-mediated bone marrow failure model, using different strains and non-major histocompatibility antigen mismatched: bisphenol-A-diglycidyl-ether ameliorated marrow failure by inhibition of T cell infiltration of bone marrow. Our data indicate that peroxisomal proliferator-activated receptor gamma antagonists may attenuate murine immune-mediated bone marrow failure, at least in part, by suppression of T cell activation, which might hold implications in the application of peroxisomal proliferator-activated receptor gamma antagonists in immune-mediated pathophysiologies, both in the laboratory and in the clinic. Genetically "fatless" mice developed bone marrow failure with accumulation of marrow adipocytes in our model, even in the absence of body fat, suggesting different mechanisms of systematic and marrow adipogenesis and physiologic versus pathophysiologic fat accumulation. C1 [Sato, Kazuya; Feng, Xingmin; Chen, Jichun; Li, Jungang; Muranski, Pawel; Desierto, Marie J.; Keyvanfar, Keyvan; Kajigaya, Sachiko; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Malide, Daniela] NHLBI, Light Microscopy Core Facil, NIH, Bethesda, MD 20892 USA. RP Feng, XM (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM fengx2@nhlbi.nih.gov FU NIH FX This work was supported by NIH Intramural Research Program. NR 35 TC 1 Z9 1 U1 0 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD JAN PY 2016 VL 101 IS 1 BP 57 EP 67 DI 10.3324/haematol.2014.121632 PG 11 WC Hematology SC Hematology GA DF3CG UT WOS:000371220700020 PM 26589913 ER PT J AU Scotta, C Fanelli, G Hoong, SJ Romano, M Lamperti, EN Sukthankar, M Guggino, G Fazekasova, H Ratnasothy, K Becker, PD Afzali, B Lechler, RI Lombardi, G AF Scotta, Cristiano Fanelli, Giorgia Hoong, Sec Julie Romano, Marco Lamperti, Estefania Nova Sukthankar, Mitalee Guggino, Giuliana Fazekasova, Henrieta Ratnasothy, Kulachelvy Becker, Pablo D. Afzali, Behdad Lechler, Robert I. Lombardi, Giovanna TI Impact of immunosuppressive drugs on the therapeutic efficacy of ex vivo expanded human regulatory T cells SO HAEMATOLOGICA LA English DT Article ID RENAL-TRANSPLANT RECIPIENTS; SOLID-ORGAN TRANSPLANTATION; MYCOPHENOLIC-ACID; LIVER-TRANSPLANTATION; DENDRITIC CELLS; CYCLOSPORINE-A; IN-VIVO; CALCINEURIN INHIBITORS; MEDIATED SUPPRESSION; MULTIPLE-SCLEROSIS AB Immunosuppressive drugs in clinical transplantation are necessary to inhibit the immune response to donor antigens. Although they are effective in controlling acute rejection, they do not prevent long-term transplant loss from chronic rejection. In addition, immunosuppressive drugs have adverse side effects, including increased rate of infections and malignancies. Adoptive cell therapy with human Tregs represents a promising strategy for the induction of transplantation tolerance. Phase I/II clinical trials in transplanted patients are already underway, involving the infusion of Tregs alongside concurrent immunosuppressive drugs. However, it remains to be determined whether the presence of immunosuppressive drugs negatively impacts Treg function and stability. We tested in vitro and in vivo the effects of tacrolimus, mycophenolate and methylprednisolone (major ISDs used in transplantation) on ex vivo expanded, rapamycin-treated human Tregs. The in vitro results showed that these drugs had no effect on phenotype, function and stability of Tregs, although tacrolimus affected the expression of chemokine receptors and IL-10 production. However, viability and proliferative capacity were reduced in a dose-dependent manner by all the three drugs. The in vivo experiments using a humanized mouse model confirmed the in vitro results. However, treatment of mice with only rapamycin maintained the viability, function and proliferative ability of adoptively transferred Tregs. Taken together, our results suggest that the key functions of ex vivo expanded Tregs are not affected by a concurrent immunosuppressive therapy. However, the choice of the drug combination and their timing and dosing should be considered as an essential component to induce and maintain tolerance by Treg. C1 [Scotta, Cristiano; Fanelli, Giorgia; Hoong, Sec Julie; Romano, Marco; Lamperti, Estefania Nova; Sukthankar, Mitalee; Fazekasova, Henrieta; Ratnasothy, Kulachelvy; Becker, Pablo D.; Afzali, Behdad; Lechler, Robert I.; Lombardi, Giovanna] Kings Coll London, Guys Hosp, MRC Ctr Transplantat, Div Transplantat Immunol & Mucosal Biol,Immunoreg, London WC2R 2LS, England. [Romano, Marco] Univ Bologna, Inst Hematol L&A Seragnoli, Dept Expt Diagnost & Specialty Med, I-40126 Bologna, Italy. [Guggino, Giuliana] Univ Palermo, Dipartimento Biopatol & Biotecnol Med, I-90133 Palermo, Italy. [Afzali, Behdad] NIAMSD, Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Scotta, C (reprint author), Kings Coll London, Guys Hosp, MRC Ctr Transplantat, Div Transplantat Immunol & Mucosal Biol,Immunoreg, London WC2R 2LS, England. EM cristiano.scotta@kcl.ac.uk FU National Institute for Health Research, Medical Research Council; British Heart Foundation; Academy of Medical Sciences/Wellcome Trust; Guy's and St Thomas' Charity; European Union 7th Framework Programme (EU FP7) ONE Study; King's Health Partners Research and Development Challenge Fund [R1405170]; National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' National Health Service (NHS) Foundation Trust; King's College London FX This work was funded by grants from the National Institute for Health Research, Medical Research Council (BA, GL and RIL), British Heart Foundation (PB, KR, GL and RIL), the Academy of Medical Sciences/Wellcome Trust (BA), Guy's and St Thomas' Charity (RIL and GL), the European Union 7th Framework Programme (EU FP7) ONE Study (GL, RIL and CS) and King's Health Partners Research and Development Challenge Fund (CS; grant number R1405170), Guy's and St Thomas' Charity (CS, BA, RIL and GL). Research was also supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' National Health Service (NHS) Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. NR 50 TC 4 Z9 5 U1 1 U2 5 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD JAN PY 2016 VL 101 IS 1 BP 91 EP 100 DI 10.3324/haematol.2015.128934 PG 10 WC Hematology SC Hematology GA DF3CG UT WOS:000371220700024 PM 26471483 ER PT J AU Dunleavy, K Pittaluga, S Shovlin, M Roschewski, M Lai, C Steinberg, SM Jaffe, ES Wilson, WH AF Dunleavy, Kieron Pittaluga, Stefania Shovlin, Margaret Roschewski, Mark Lai, Catherine Steinberg, Seth M. Jaffe, Elaine S. Wilson, Wyndham H. TI Phase II trial of dose-adjusted EPOCH in untreated systemic anaplastic large cell lymphoma SO HAEMATOLOGICA LA English DT Letter DE systemic aplastic large cell lymphoma; EPOCH; dose-adjusted; phase II ID PERIPHERAL T-CELL; CLINICAL-OUTCOMES; RITUXIMAB; THERAPY; ADULTS C1 [Dunleavy, Kieron; Shovlin, Margaret; Lai, Catherine; Wilson, Wyndham H.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Roschewski, Mark; Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. RP Dunleavy, K (reprint author), NCI, Lymphoid Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM dunleavk@mail.nih.gov FU Intramural NIH HHS NR 15 TC 2 Z9 2 U1 0 U2 2 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD JAN PY 2016 VL 101 IS 1 BP E27 EP E29 DI 10.3324/haematol.2015.131151 PG 3 WC Hematology SC Hematology GA DF3CG UT WOS:000371220700008 PM 26518748 ER PT J AU Fragala, MS Alley, DE Shardell, MD Harris, TB McLean, RR Kiel, DP Cawthon, PM Dam, TTL Ferrucci, L Guralnik, JM Kritchevsky, SB Vassileva, MT Gudnason, V Eiriksdottir, G Koster, A Newman, A Siggeirsdottir, K Satterfield, S Studenski, SA Kenny, AM AF Fragala, Maren S. Alley, Dawn E. Shardell, Michelle D. Harris, Tamara B. McLean, Robert R. Kiel, Douglas P. Cawthon, Peggy M. Dam, Thuy-Tien L. Ferrucci, Luigi Guralnik, Jack M. Kritchevsky, Stephen B. Vassileva, Maria T. Gudnason, Vilmunder Eiriksdottir, Gudny Koster, Annemarie Newman, Anne Siggeirsdottir, Kristin Satterfield, Suzanne Studenski, Stephanie A. Kenny, Anne M. TI Comparison of Handgrip and Leg Extension Strength in Predicting Slow Gait Speed in Older Adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE sarcopenia; lower extremity function; walking speed ID GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK; LOWER-EXTREMITY FUNCTION; MUSCLE STRENGTH; PHYSICAL PERFORMANCE; SKELETAL-MUSCLE; GRIP STRENGTH; WALKING SPEED; MOBILITY; PEOPLE; AGE AB OBJECTIVES: To compare the relative predictive power of handgrip and leg extension strength in predicting slow walking. DESIGN: Report of correlative analysis from two epidemiological cohort studies. SETTING: Foundation of the National Institutes of Health Sarcopenia Project. PARTICIPANTS: Men and women aged 67 to 93 (N = 6,766). MEASUREMENTS: Leg strength, handgrip strength, and gait speed were measured. Strength cutpoints associated with slow gait speed were developed using classification and regression tree analyses and compared using ordinary least squares regression models. RESULTS: The cutpoints of lower extremity strength associated with slow gait speed were 154.6 N-m in men and 89.9 N-m in women for isometric leg extension strength and 94.5 N-m in men and 62.3 N-m in women for isokinetic leg extension strength. Weakness defined according to handgrip strength (odds ratios (OR) = 1.99 to 4.33, c-statistics = 0.53 to 0.67) or leg strength (ORs = 2.52 to 5.77; c-statistics = 0.61 to 0.66) was strongly related to odds of slow gait speed. Lower extremity strength contributed 1% to 16% of the variance and handgrip strength contributed 3% to 17% of the variance in the prediction of gait speed depending on sex and mode of strength assessment. CONCLUSION: Muscle weakness of the leg extensors and forearm flexors is related to slow gait speed. Leg extension strength is only a slightly better predictor of slow gait speed. Thus, handgrip and leg extension strength appear to be suitable for screening for muscle weakness in older adults. C1 [Fragala, Maren S.] Univ Cent Florida, Orlando, FL 32816 USA. [Fragala, Maren S.; Kenny, Anne M.] Univ Connecticut, Ctr Hlth, 263 Farmington Ave, Farmington, CT 06030 USA. [Alley, Dawn E.; Shardell, Michelle D.; Guralnik, Jack M.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Harris, Tamara B.; Ferrucci, Luigi] NIA, NIH, Bethesda, MD 20892 USA. [McLean, Robert R.; Kiel, Douglas P.] Hebrew Senior Life Inst Aging Res, Boston, MA USA. [McLean, Robert R.; Kiel, Douglas P.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Cawthon, Peggy M.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Dam, Thuy-Tien L.] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Vassileva, Maria T.] Fdn Natl Inst Hlth, Bethesda, MD USA. [Gudnason, Vilmunder] Univ Iceland, Reykjavik, Iceland. [Eiriksdottir, Gudny; Siggeirsdottir, Kristin] Iceland Heart Assoc, Kopavogur, Iceland. [Koster, Annemarie] Maastricht Univ, Dept Social Med, CAPHRI Sch Publ Hlth & Primary Care, NL-6200 MD Maastricht, Netherlands. [Newman, Anne] Univ Pittsburgh, Pittsburgh, PA USA. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Studenski, Stephanie A.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. RP Kenny, AM (reprint author), Univ Connecticut, Ctr Hlth, 263 Farmington Ave, Farmington, CT 06030 USA. EM Kenny@uchc.edu FU Merck Sharp Dohme; Eli Lilly; Amgen; Merck; IMS Health; GSK; National Institute on Aging [1U13AG041583, P30 AG024827]; Food and Drug Administration; FNIH; Abbott Nutrition; Novartis; Dairy Research Institute FX Dr. Kiel: Grants/Funds: Merck Sharp & Dohme, Eli Lilly, Amgen-grants to institution; Consultant: Scientific Advisory Board member consulting for Merck Sharp & Dohme, Eli Lilly, Amgen, Novartis, Ammonnet Pharma. Dr. Cawthon: Grants/Funds: Merck, Eli Lilly, IMS Health, GSK; Consultant: Eli Lilly. Dr. Ferrucci is an associate editor of the Journal of the American Geriatrics Society.; Funding support for the conference and the work of the consortium was provided by the National Institute on Aging (1U13AG041583 and P30 AG024827), the Food and Drug Administration, and through grants from the FNIH, made possible by funding from Abbott Nutrition, Amgen, Eli Lilly, Merck, Novartis, and The Dairy Research Institute. NR 38 TC 2 Z9 3 U1 3 U2 4 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 JAN PY 2016 VL 64 IS 1 BP 144 EP 150 DI 10.1111/jgs.13871 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DF2FQ UT WOS:000371157900021 PM 26782864 ER PT J AU Kent, EE Malinoff, R Rozjabek, HM Ambs, A Clauser, SB Topor, MA Yuan, GG Burroughs, J Rodgers, AB DeMichele, K AF Kent, Erin E. Malinoff, Rochelle Rozjabek, Heather M. Ambs, Anita Clauser, Steven B. Topor, Marie A. Yuan, Gigi Burroughs, James Rodgers, Anne B. DeMichele, Kimberly TI Revisiting the Surveillance Epidemiology and End Results Cancer Registry and Medicare Health Outcomes Survey (SEER-MHOS) Linked Data Resource for Patient-Reported Outcomes Research in Older Adults with Cancer SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE cancer; patient-reported outcomes; health-related quality of life; Medicare advantage; surveillance ID QUALITY-OF-LIFE; URINARY-INCONTINENCE; AMERICANS; SURVIVORS; MORTALITY; IMPACT; CARE; POPULATION AB Researchers and clinicians are increasingly recognizing the value of patient-reported outcome (PRO) data to better characterize people's health and experiences with illness and care. Considering the rising prevalence of cancer in adults aged 65 and older, PRO data are particularly relevant for older adults with cancer, who often require complex cancer care and have additional comorbid conditions. A data linkage between the Surveillance Epidemiology and End Results (SEER) cancer registry and the Medicare Health Outcomes Survey (MHOS) was created through a partnership between the National Cancer Institute and the Centers for Medicare and Medicaid Services that created the opportunity to examine PROs in Medicare Advantage enrollees with and without cancer. The December 2013 linkage of SEER-MHOS data included the linked data for 12 cohorts, bringing the number of individuals in the linked data set to 95,723 with cancer and 1,510,127 without. This article reviews the features of the resource and provides information on some descriptive characteristics of the individuals in the data set (health-related quality of life, body mass index, fall risk management, number of unhealthy days in the past month). Individuals without (n = 258,108) and with (n = 3,440) cancer (1,311 men with prostate cancer, 982 women with breast cancer, 689 with colorectal cancer, 458 with lung cancer) were included in the current descriptive analysis. Given increasing longevity, advances in effective therapies and earlier detection, and population growth, the number of individuals aged 65 and older with cancer is expected to reach more than 12 million by 2020. SEER-MHOS provides population-level, self-reported, cancer registry-linked data for person-centered surveillance research on this growing population. C1 [Kent, Erin E.] NCI, Outcomes Res Branch, Healthcare Delivery Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. [Malinoff, Rochelle; Burroughs, James] Medicare Hlth Outcomes Study, Hlth Serv Advisory Grp, Phoenix, AZ USA. [Rozjabek, Heather M.] Drexel Univ, Sch Publ Hlth, Philadelphia, PA 19104 USA. [Ambs, Anita; Rodgers, Anne B.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. [Clauser, Steven B.] Patient Ctr Outcomes Res Inst, Washington, DC USA. [Topor, Marie A.; Yuan, Gigi] Informat Management Serv Inc, Rockville, MD USA. [DeMichele, Kimberly] Ctr Medicare, Baltimore, MD USA. [Kent, Erin E.; DeMichele, Kimberly] Medicaid Serv, Baltimore, MD USA. RP Kent, EE (reprint author), 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM Erin.Kent@nih.gov NR 37 TC 0 Z9 0 U1 2 U2 4 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 JAN PY 2016 VL 64 IS 1 BP 186 EP 192 DI 10.1111/jgs.13888 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DF2FQ UT WOS:000371157900028 PM 26782871 ER PT J AU Nayor, M Wang, N Larson, MG Vasan, RS Levy, D Ho, JE AF Nayor, Matthew Wang, Na Larson, Martin G. Vasan, Ramachandran S. Levy, Daniel Ho, Jennifer E. TI Circulating Galectin-3 Is Associated With Cardiometabolic Disease in the Community SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE epidemiology; obesity; prevention ID DIET-INDUCED OBESITY; ADIPOSE-TISSUE; INSULIN-RESISTANCE; HEART-FAILURE; LEPTIN; ADIPONECTIN; FIBROSIS; GHRELIN; INDEXES; GLUCOSE AB Background-Circulating Galectin-3 (Gal-3) concentrations are associated with an increased incidence of heart failure, atrial fibrillation, chronic kidney disease, and mortality. Recent evidence suggests that Gal-3 may also be an important modulator of cardiometabolic traits such as adiposity, insulin resistance, and hyperglycemia. We examined the associations of blood Gal-3 concentrations and cardiometabolic disease traits in the Framingham Heart Study. Methods and Results-In cross-sectional analyses of 2946 Framingham Heart Study participants (mean age 59 years, 55% women), higher Gal-3 concentrations were associated with higher body mass index, waist circumference, and triglycerides (P< 0.0001 for all). Higher Gal-3 was associated with greater odds of obesity (multivariable-adjusted odds ratio 1.16 per 1-SD increase in log-Gal-3, 95% CI 1.06-1.28, P= 0.002) and hypertension (odds ratio 1.18, 95% CI 1.07-1.29, P= 0.0006). In prospective analyses, Gal-3 was associated with incident metabolic syndrome (hazard ratio 1.22, 95% CI 1.10-1.36, P= 0.0002) and diabetes (hazard ratio 1.21, 95% CI 1.04-1.41, P= 0.02), in age-and sex-adjusted, but not multivariable-adjusted models. Conclusions-In this large, community-based sample, circulating Gal-3 was associated with abdominal adiposity, dyslipidemia, and hypertension in cross-sectional analyses, but Gal-3 did not predict incident cardiometabolic disease after adjusting for cardiometabolic risk factors. Future investigations should focus on further elucidating mechanisms linking Gal-3 with cardiometabolic disease and on assessing whether modulation of the Gal-3 pathway might have positive cardiometabolic effects. C1 [Nayor, Matthew; Larson, Martin G.; Vasan, Ramachandran S.; Levy, Daniel; Ho, Jennifer E.] NHLBI, Framingham, MA USA. [Nayor, Matthew; Larson, Martin G.; Vasan, Ramachandran S.; Levy, Daniel; Ho, Jennifer E.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Nayor, Matthew] Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. [Wang, Na] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA 02118 USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [Ho, Jennifer E.] Boston Univ, Sect Cardiovasc Med, Dept Med, Boston, MA 02118 USA. [Larson, Martin G.] Boston Univ, Sect Cardiovasc Med, Dept Math & Stat, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bldg 10, Bethesda, MD 20892 USA. RP Ho, JE (reprint author), Boston Univ, Med Ctr, 88 E Newton St,C-818, Boston, MA 02118 USA. EM jenho@bu.edu OI Ho, Jennifer/0000-0002-7987-4768 FU National Heart, Lung, and Blood Institute [N01-HC-25195, HHSN268201500001I]; Boston University School of Medicine, Department of Medicine Career Investment award (Boston, MA); National Institutes of Health [T32-HL007604]; [K23-HL116780] FX This work was partially supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contracts N01-HC-25195 and HHSN268201500001I) and K23-HL116780 (Dr Ho). Dr Ho is supported by a Boston University School of Medicine, Department of Medicine Career Investment award (Boston, MA). Dr Nayor received support from National Institutes of Health grant T32-HL007604. NR 31 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 JAN PY 2016 VL 5 IS 1 AR e002347 DI 10.1161/JAHA.115.002347 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DF3XV UT WOS:000371282800030 ER PT J AU Yano, Y Ning, H Reis, JP Lewis, CE Launer, LJ Bryan, RN Yaffe, K Sidney, S Albanese, E Greenland, P Lloyd-Jones, D Liu, K AF Yano, Yuichiro Ning, Hongyan Reis, Jared P. Lewis, Cora E. Launer, Lenore J. Bryan, R. Nick Yaffe, Kristine Sidney, Stephen Albanese, Emiliano Greenland, Philip Lloyd-Jones, Donald Liu, Kiang TI Blood Pressure Reactivity to Psychological Stress in Young Adults and Cognition in Midlife: The Coronary Artery Risk Development in Young Adults (CARDIA) Study SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE blood pressure; blood pressure monitoring; cognition; stress test; young ID CARDIOVASCULAR-DISEASE; MENTAL STRESS; HEART-DISEASE; RESPONSES; HYPERTENSION; ABILITY; BRAIN AB Background-The classic view of blood pressure (BP) reactivity to psychological stress in relation to cardiovascular risks assumes that excess reactivity is worse and lower reactivity is better. Evidence addressing how stress-induced BP reactivity in young adults is associated with midlife cognitive function is sparse. Methods and Results-We assessed BP reactivity during a star tracing task and a video game in adults aged 20 to 32 years. Twenty-three years later, cognitive function was assessed with use of the Digit Symbol Substitution Test (a psychomotor speed test), the Rey Auditory Verbal Learning Test (a verbal memory test), and the modified Stroop test (an executive function test). At the time of follow-up, participants (n=3021) had a mean age of 50.2 years; 56% were women, and 44% were black. In linear regression models adjusted for demographic and clinical characteristics including baseline and follow-up resting BP, lower systolic BP (SBP) reactivity during the star tracing and video game was associated with worse Digit Symbol Substitution Test scores (beta [SE]: 0.11 [0.02] and 0.05 [0.02], respectively) and worse performance on the Stroop test (b [SE]: -0.06 [0.02] and -0.05 [0.02]; all P<0.01). SBP reactivity was more consistently associated than diastolic BP reactivity with cognitive function scores. The associations between SBP reactivity and cognitive function were mostly similar between blacks and whites. Conclusions-Lower psychological stress-induced SBP reactivity in younger adults was associated with lower cognitive function in midlife. BP reactivity to psychological stressors may have different associations with target organs in hypertension. C1 [Yano, Yuichiro; Ning, Hongyan; Greenland, Philip; Lloyd-Jones, Donald; Liu, Kiang] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, 680 North Lake Shore Dr,Suite 1400, Chicago, IL 60611 USA. [Reis, Jared P.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Lewis, Cora E.] Univ Alabama Birmingham, Dept Med, Div Prevent Med, Birmingham, AL 35294 USA. [Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Bryan, R. Nick] Univ Penn Hlth Syst, Dept Radiol, Philadelphia, PA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat Neurol & Epidemiol, San Francisco, CA 94143 USA. [Sidney, Stephen] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Albanese, Emiliano] Univ Geneva, CH-1211 Geneva 4, Switzerland. RP Yano, Y (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, 680 North Lake Shore Dr,Suite 1400, Chicago, IL 60611 USA. EM yyano@jichi.jp FU National Heart, Lung, and Blood Institute (NHLBI); CARDIA Data Analysis and Publications and Presentations Policies; University of Alabama at Birmingham [HHSN268201300025C, HHSN268201300026C]; Northwestern University [HHSN268201300027C]; University of Minnesota [HHSN268201300028C]; Kaiser Foundation Research Institute [HHSN268201300029C]; Johns Hopkins University School of Medicine [HHSN268200900041C]; National Institute on Aging (NIA); NIA; NHLBI [AG0005] FX CARDIA is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the CARDIA Data Analysis and Publications and Presentations Policies, University of Alabama at Birmingham (HHSN268201300025C and HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intraagency agreement between NIA and NHLBI (AG0005). This manuscript has been reviewed by CARDIA for scientific content. NR 38 TC 1 Z9 1 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 JAN PY 2016 VL 5 IS 1 AR e002718 DI 10.1161/JAHA.115.002718 PG 31 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DF3XV UT WOS:000371282800053 ER PT J AU Barbolosi, D Hapdey, S Battini, S Faivre, C Mancini, J Pacak, K Farman-Ara, B Taieb, D AF Barbolosi, Dominique Hapdey, Sebastien Battini, Stephanie Faivre, Christian Mancini, Julien Pacak, Karel Farman-Ara, Bardia Taieb, David TI Determination of the unmetabolised F-18-FDG fraction by using an extension of simplified kinetic analysis method: clinical evaluation in paragangliomas SO MEDICAL & BIOLOGICAL ENGINEERING & COMPUTING LA English DT Article DE Paraganglioma; Radionuclide imaging; Positron emission tomography; Mathematical modelling ID POSITRON-EMISSION-TOMOGRAPHY; PHEOCHROMOCYTOMA; PET; TUMOR; FLUORODEOXYGLUCOSE; MUTATIONS; SCANS; SDHB; SUV; FDG AB Tumours with high F-18-FDG uptake values on static late PET images do not always exhibit high proliferation indices. These discrepancies might be related to high proportion of unmetabolised F-18-FDG components in the tissues. We propose a method that enables to calculate different F-18-FDG kinetic parameters based on a new mathematical approach that integrates a measurement error model. Six patients with diagnosed non-metastatic paragangliomas (PGLs) and six control patients with different types of lesions were investigated in this pilot study using F-18-FDG PET/CT. In all cases, a whole-body acquisition was followed by four static acquisitions centred over the target lesions, associated with venous blood samplings. We used an extension of the Hunter's method to calculate the net influx rate constant (K (H)). The exact net influx rate constant and vascular volume fraction (K (i) and V, respectively) were subsequently obtained by the method of least squares. Next, we calculated the mean percentages of metabolised (PM) and unmetabolised (PUM) F-18-FDG components, and the times required to reach 80 % of the amount of metabolised F-18-FDG (T80%). A test-retest evaluation indicated that the repeatability of our approach was accurate; the coefficients of variation were below 2 % regardless of the kinetic parameters considered. We observed that the PGLs were characterised by high dispersions of the maximum standardised uptake value SUVmax (9.7 +/- A 11, coefficient of variation CV = 114 %), K (i) (0.0137 +/- A 0.0119, CV = 87 %), and V (0.292 +/- A 0.306, CV = 105 %) values. The PGLs were associated with higher PUM (p = 0.02) and T80% (p = 0.02) values and lower k (3) (p = 0.02) values compared to the malignant lesions despite the similar SUVmax values (p = 0.55). The estimations of these new kinetic parameters are more accurate than SUVmax or K (i) for in vivo metabolic assessment of PGLs at the molecular level. C1 [Barbolosi, Dominique; Battini, Stephanie; Faivre, Christian] Aix Marseille Univ, Dept Pharmacokinet, UMR INSERM CRO2 911, SMARTc,Fac Med Pharm, 27 Blvd Jean Moulin, F-13385 Marseille 5, France. [Hapdey, Sebastien] Ctr Henri Becquerel, Dept Nucl Med, F-76038 Rouen, France. [Hapdey, Sebastien] Rouen Univ Hosp, Rouen, France. [Hapdey, Sebastien] Univ Rouen, QuantIF LITIS, EA 4108, 1 Rue Amiens, F-76038 Rouen, France. [Mancini, Julien] Aix Marseille Univ, Econ & Social Hlth & Med Informat Proc SESSTIM, INSERM, UMR912,IRD, F-13273 Marseille, France. [Mancini, Julien] La Timone Univ Hosp, Dept Publ Hlth, APHM, 264 Rue St Pierre, F-13385 Marseille 5, France. [Pacak, Karel] Eunice Kennedy Shriver NICHD, Program Reprod & Adult Endocrinol, NIH, CRC, Bldg 10,Room 1E-3140,10 Ctr Dr MSC 1109, Bethesda, MD 20892 USA. [Farman-Ara, Bardia; Taieb, David] Aix Marseille Univ, Dept Nucl Med, La Timone Univ Hosp, European Ctr Res Med Imaging CERIMED, 264 Rue St Pierre, F-13385 Marseille 5, France. RP Taieb, D (reprint author), Aix Marseille Univ, Dept Nucl Med, La Timone Univ Hosp, European Ctr Res Med Imaging CERIMED, 264 Rue St Pierre, F-13385 Marseille 5, France. EM david.taieb@ap-hm.fr RI Mancini, Julien/G-6263-2011 OI Mancini, Julien/0000-0001-9500-8598 FU Rotary Club of the Tholonet, in Aix-En-Provence FX This study was partly supported by a grant from Rotary Club of the Tholonet, in Aix-En-Provence. We wish to thank the patients who agreed to participate in the present study. The authors also wish to thank the technologists in the Department of Nuclear Medicine for their help in the management of the patients for this study. We lastly gratefully acknowledge Dr. I. Buvat for their help in improving this manuscript. NR 26 TC 3 Z9 3 U1 0 U2 1 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0140-0118 EI 1741-0444 J9 MED BIOL ENG COMPUT JI Med. Biol. Eng. Comput. PD JAN PY 2016 VL 54 IS 1 BP 103 EP 111 DI 10.1007/s11517-015-1318-3 PG 9 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Mathematical & Computational Biology; Medical Informatics SC Computer Science; Engineering; Mathematical & Computational Biology; Medical Informatics GA DF6AU UT WOS:000371437900008 PM 26044552 ER PT J AU Nishihara, K Huang, RL Zhao, JH Shahane, SA Witt, KL Smith-Roe, SL Tice, RR Takeda, S Xia, MH AF Nishihara, Kana Huang, Ruili Zhao, Jinghua Shahane, Sampada A. Witt, Kristine L. Smith-Roe, Stephanie L. Tice, Raymond R. Takeda, Shunichi Xia, Menghang TI Identification of genotoxic compounds using isogenic DNA repair deficient DT40 cell lines on a quantitative high throughput screening platform SO MUTAGENESIS LA English DT Article ID DOUBLE-STRAND BREAKS; POLYMERASE-ZETA; HOMOLOGOUS RECOMBINATION; ENVIRONMENTAL CHEMICALS; CATALYTIC SUBUNIT; VERTEBRATE CELLS; TOPOISOMERASE-II; DAMAGE RESPONSE; IN-VIVO; PATHWAYS AB DNA repair pathways play a critical role in maintaining cellular homeostasis by repairing DNA damage induced by endogenous processes and xenobiotics, including environmental chemicals. Induction of DNA damage may lead to genomic instability, disruption of cellular homeostasis and potentially tumours. Isogenic chicken DT40 B-lymphocyte cell lines deficient in DNA repair pathways can be used to identify genotoxic compounds and aid in characterising the nature of the induced DNA damage. As part of the US Tox21 program, we previously optimised several different DT40 isogenic clones on a high-throughput screening platform and confirmed the utility of this approach for detecting genotoxicants by measuring differential cytotoxicity in wild-type and DNA repair-deficient clones following chemical exposure. In the study reported here, we screened the Tox21 10K compound library against two isogenic DNA repair-deficient DT40 cell lines (KU70(-/-)/RAD54(-/-) and REV3(-/-)) and the wild-type cell line using a cell viability assay that measures intracellular adenosine triphosphate levels. KU70 and RAD54 are genes associated with DNA double-strand break repair processes, and REV3 is associated with translesion DNA synthesis pathways. Active compounds identified in the primary screening included many well-known genotoxicants (e.g. adriamycin, melphalan) and several compounds previously untested for genotoxicity. A subset of compounds was further evaluated by assessing their ability to induce micronuclei and phosphorylated H2AX. Using this comprehensive approach, three compounds with previously undefined genotoxicity-2-oxiranemethanamine, AD-67 and tetraphenylolethane glycidyl ether-were identified as genotoxic. These results demonstrate the utility of this approach for identifying and prioritising compounds that may damage DNA. C1 [Nishihara, Kana] Kyoto Univ, Grad Sch Med, Radiat Genet, Sakyo Ku, Kyoto 6068501, Japan. [Nishihara, Kana; Huang, Ruili; Zhao, Jinghua; Shahane, Sampada A.; Xia, Menghang] NIH, Nat Ctr Adv Translat Sci, 9800 Med Ctr Dr,MSC 3375, Bethesda, MD 20892 USA. [Witt, Kristine L.; Smith-Roe, Stephanie L.; Tice, Raymond R.] NIEHS, Div Natl Toxicol Program, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. RP Xia, MH (reprint author), NIH, Nat Ctr Adv Translat Sci, 9800 Med Ctr Dr,MSC 3375, Bethesda, MD 20892 USA. EM mxia@mail.nih.gov FU Kyoto University Foundation; JSPS Core-to-Core Program (Advanced Research Networks); interagency agreement IAG from the National Institute of Environmental Health Sciences/Division of the National Toxicology Program [NTR 12003]; [24.5986] FX This work was supported by the Kyoto University Foundation, the Grant-in-Aid for JSPS Fellows (24.5986), JSPS Core-to-Core Program (Advanced Research Networks) and the interagency agreement IAG #NTR 12003 from the National Institute of Environmental Health Sciences/Division of the National Toxicology Program to the National Center for Advancing Translational Sciences, National Institutes of Health. NR 48 TC 1 Z9 1 U1 2 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0267-8357 EI 1464-3804 J9 MUTAGENESIS JI Mutagenesis PD JAN PY 2016 VL 31 IS 1 BP 69 EP 81 DI 10.1093/mutage/gev055 PG 13 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA DF7DI UT WOS:000371517500009 PM 26243743 ER PT J AU Acquaye, AA Lin, L Vera-Bolanos, E Gilbert, MR Armstrong, TS AF Acquaye, Alvina A. Lin, Lin Vera-Bolanos, Elizabeth Gilbert, Mark R. Armstrong, Terri S. TI Hope and mood changes throughout the primary brain tumor illness trajectory SO NEURO-ONCOLOGY LA English DT Article DE brain tumors; glioma; hope; mood changes; quality of life ID CANCER-PATIENTS; PSYCHOLOGICAL DISTRESS; PEOPLE; LIFE; UNCERTAINTY; VALIDATION; SAMPLE; FORM AB The ambiguity of defining hope impacts the level of readiness faced by health care professionals treating patients with glioma, a disease with unpredictable outcomes. This study describes the report of hope and the relationship between hope and mood in adult brain tumor patients at various points in the illness trajectory. This was a cross-sectional study with data collection including use of the Herth Hope Index (HHI), the Profile of Mood States-Short Form (POMS-SF), and clinical information. Descriptive statistics were used to report sample characteristics. Spearman's rho and Mann-Whitney tests were used to compare and differentiate scores. Eighty-two patients ranging in age from 22 to 78 years (median, 44.5 y) participated in the study. Patients were primarily male (57.3%), married (76.8%), and had a high-grade glioma (35.4%). Nearly half had recurrence, and more than 20% were on active treatment. The overall HHI total score for the sample was 41.32 (range: 13-48). Patients with recurrence had a lower HHI interconnectedness (median = 14.00) score and higher total mood disturbance (median = 14.00) compared with patients without recurrence (median = 15.00 and median = 0.00, respectively; P < .05). All negative mood states on the POMS-SF were negatively correlated with HHI subscales. Overall, patients reporting more hope also reported less overall mood disturbance As expected, patients with tumor recurrence reported lower hope and higher mood disturbance than those who were newly diagnosed or without recurrence. Targeting interventions specifically tailored to an individual's needs for improvement in quality of life throughout the disease course may include measures to address hope in order to facilitate positive coping strategies. C1 [Acquaye, Alvina A.; Armstrong, Terri S.] Univ Texas Hlth Sci Ctr Houston, Sch Nursing, Dept Family Hlth, Houston, TX 77030 USA. [Lin, Lin] Univ Calif San Francisco, Dept Family Hlth, San Francisco, CA 94143 USA. [Vera-Bolanos, Elizabeth; Armstrong, Terri S.] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. [Gilbert, Mark R.] NIH, Dept Neurooncol, Bldg 10, Bethesda, MD 20892 USA. RP Acquaye, AA (reprint author), 1400 Pressler,Unit 1414, Houston, TX 77030 USA.; Lin, L (reprint author), Univ Calif San Francisco, Dept Family Hlth Care Nursing, 2 Koret Way,N405K,Campus Mail Box 0606, San Francisco, CA 94143 USA. EM aaacquaye@mdanderson.org; lin.lin2@ucsf.edu RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 FU Collaborative Ependymoma Research Network (CERN); Dean's Research Award from University of Texas-Houston FX This study was supported by the Collaborative Ependymoma Research Network (CERN) and the Dean's Research Award from University of Texas-Houston. NR 32 TC 1 Z9 1 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JAN PY 2016 VL 18 IS 1 BP 119 EP 125 DI 10.1093/neuonc/nov101 PG 7 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DF3GU UT WOS:000371232900016 PM 26109686 ER PT J AU Shaikh, N Hoberman, A Keren, R Gotman, N Docimo, SG Mathews, R Bhatnagar, S Ivanova, A Mattoo, TK Moxey-Mims, M Carpenter, MA Pohl, HG Greenfield, S AF Shaikh, Nader Hoberman, Alejandro Keren, Ron Gotman, Nathan Docimo, Steven G. Mathews, Ranjiv Bhatnagar, Sonika Ivanova, Anastasia Mattoo, Tej K. Moxey-Mims, Marva Carpenter, Myra A. Pohl, Hans G. Greenfield, Saul TI Recurrent Urinary Tract Infections in Children With Bladder and Bowel Dysfunction SO PEDIATRICS LA English DT Article ID VESICOURETERAL REFLUX; VOIDING DYSFUNCTION; RENAL SCARS; SYMPTOMS AB BACKGROUND: Little generalizable information is available on the outcomes of children diagnosed with bladder and bowel dysfunction (BBD) after a urinary tract infection (UTI). Our objectives were to describe the clinical characteristics of children with BBD and to examine the effects of BBD on patient outcomes in children with and without vesicoureteral reflux (VUR). METHODS: We combined data from 2 longitudinal studies (Randomized Intervention for Children With Vesicoureteral Reflux and Careful Urinary Tract Infection Evaluation) in which children < 6 years of age with a first or second UTI were followed for 2 years. We compared outcomes for children with and without BBD, children with and without VUR, and children with VUR randomly assigned to prophylaxis or placebo. The outcomes examined were incidence of recurrent UTIs, renal scarring, surgical intervention, resolution of VUR, and treatment failure. RESULTS: BBD was present at baseline in 54% of the 181 toilet-trained children included; 94% of children with BBD reported daytime wetting, withholding maneuvers, or constipation. In children not on antimicrobial prophylaxis, 51% of those with both BBD and VUR experienced recurrent UTIs, compared with 20% of those with VUR alone, 35% with BBD alone, and 32% with neither BBD nor VUR. BBD was not associated with any of the other outcomes investigated. CONCLUSIONS: Among toilet-trained children, those with both BBD and VUR are at higher risk of developing recurrent UTIs than children with isolated VUR or children with isolated BBD and, accordingly, exhibit the greatest benefit from antimicrobial prophylaxis. C1 [Shaikh, Nader; Hoberman, Alejandro; Bhatnagar, Sonika] Univ Pittsburgh, Childrens Hosp Pittsburgh UPMC, Sch Med, Div Gen Acad, Pittsburgh, PA USA. [Keren, Ron] Univ Pittsburgh, Childrens Hosp Pittsburgh UPMC, Sch Med, Dept Urol, Pittsburgh, PA USA. [Gotman, Nathan; Ivanova, Anastasia; Carpenter, Myra A.] Childrens Hosp Philadelphia, Ctr Pediat Clin Effect, Div Gen Pediat, Philadelphia, PA 19104 USA. [Docimo, Steven G.] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Mathews, Ranjiv] So Illinois Univ, Sch Med, Div Urol, Springfield, IL USA. [Mattoo, Tej K.] Wayne State Univ, Childrens Hosp Michigan, Detroit, MI USA. [Moxey-Mims, Marva] NIDDK, Bethesda, MD 20892 USA. [Pohl, Hans G.] George Washington Univ, Sch Med, Childrens Natl Med Ctr, Div Urol, Washington, DC USA. [Greenfield, Saul] SUNY Buffalo, Sch Med & Biomed Sci, Div Pediat Urol, Buffalo, NY 14260 USA. RP Shaikh, N (reprint author), UPMC, Childrens Hosp Pittsburgh, One Childrens Hosp Dr,4401 Penn Ave, Pittsburgh, PA 15224 USA. EM nader.shaikh@chp.edu FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services [U01 DK074059, U01 DK074053, U01 DK074082, U01 DK074064, U01 DK074062, U01 DK074063]; National Institutes of Health (NIH) FX The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the National Institutes of Health. This research was supported by grants U01 DK074059, U01 DK074053, U01 DK074082, U01 DK074064, U01 DK074062, and U01 DK074063 from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services. Funded by the National Institutes of Health (NIH). NR 15 TC 1 Z9 1 U1 0 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD JAN PY 2016 VL 137 IS 1 DI 10.1542/peds.2015-2982 PG 7 WC Pediatrics SC Pediatrics GA DF5KJ UT WOS:000371390300044 ER PT J AU Wortham, JM Hansen, NI Schrag, SJ Hale, E Van Meurs, K Sanchez, PJ Cantey, JB Faix, R Poindexter, B Goldberg, R Bizzarro, M Frantz, I Das, A Benitz, WE Shane, AL Higgins, R Stoll, BJ AF Wortham, Jonathan M. Hansen, Nellie I. Schrag, Stephanie J. Hale, Ellen Van Meurs, Krisa Sanchez, Pablo J. Cantey, Joseph B. Faix, Roger Poindexter, Brenda Goldberg, Ronald Bizzarro, Matthew Frantz, Ivan Das, Abhik Benitz, William E. Shane, Andi L. Higgins, Rosemary Stoll, Barbara J. CA Eunice Kennedy Shriver NICHD Neona TI Chorioamnionitis and Culture-Confirmed, Early-Onset Neonatal Infections SO PEDIATRICS LA English DT Article ID B STREPTOCOCCAL DISEASE; RISK-FACTORS; SEPSIS; PREVENTION; INFANTS; CHEMOPROPHYLAXIS; GUIDELINES; MANAGEMENT; BURDEN; DEATH AB BACKGROUND: Current guidelines for prevention of neonatal group B streptococcal disease recommend diagnostic evaluations and empirical antibiotic therapy for well-appearing, chorioamnionitis-exposed newborns. Some clinicians question these recommendations, citing the decline in early-onset group B streptococcal disease rates since widespread intrapartum antibiotic prophylaxis implementation and potential antibiotic risks. We aimed to determine whether chorioamnionitis-exposed newborns with culture-confirmed, early-onset infections can be asymptomatic at birth. METHODS: Multicenter, prospective surveillance for early-onset neonatal infections was conducted during 2006-2009. Early-onset infection was defined as isolation of a pathogen from blood or cerebrospinal fluid collected <= 72 hours after birth. Maternal chorioamnionitis was defined by clinical diagnosis in the medical record or by histologic diagnosis by placental pathology. Hospital records of newborns with early-onset infections born to mothers with chorioamnionitis were reviewed retrospectively to determine symptom onset. RESULTS: Early-onset infections were diagnosed in 389 of 396 586 live births, including 232 (60%) chorioamnionitis-exposed newborns. Records for 229 were reviewed; 29 (13%) had no documented symptoms within 6 hours of birth, including 21 (9%) who remained asymptomatic at 72 hours. Intrapartum antibiotic prophylaxis exposure did not differ significantly between asymptomatic and symptomatic infants (76% vs 69%; P = .52). Assuming complete guideline implementation, we estimated that 60 to 1400 newborns would receive diagnostic evaluations and antibiotics for each infected asymptomatic newborn, depending on chorioamnionitis prevalence. CONCLUSIONS: Some infants born to mothers with chorioamnionitis may have no signs of sepsis at birth despite having culture-confirmed infections. Implementation of current clinical guidelines may result in early diagnosis, but large numbers of uninfected asymptomatic infants would be treated. C1 [Wortham, Jonathan M.] Ctr Dis Control & Prevent, Epidem Intelligence Serv, Atlanta, GA USA. [Schrag, Stephanie J.] Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. [Hansen, Nellie I.] RTI Int, Social Stat & Environm Sci, Res Triangle Pk, NC USA. [Hale, Ellen; Shane, Andi L.; Stoll, Barbara J.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA. [Hale, Ellen; Shane, Andi L.; Stoll, Barbara J.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Van Meurs, Krisa; Benitz, William E.] Stanford Univ, Sch Med, Dept Pediat, Div Neonatal & Dev Med, Palo Alto, CA 94304 USA. [Van Meurs, Krisa; Benitz, William E.] Lucile Packard Childrens Hosp, Palo Alto, CA USA. [Sanchez, Pablo J.; Cantey, Joseph B.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Faix, Roger] Univ Utah, Sch Med, Dept Pediat, Div Neonatol, Salt Lake City, UT USA. [Poindexter, Brenda] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Goldberg, Ronald] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Bizzarro, Matthew] Yale Univ, Dept Pediat, Sch Med, New Haven, CT 06520 USA. [Frantz, Ivan] Floating Hosp Children, Tufts Med Ctr, Dept Pediat, Boston, MA USA. [Higgins, Rosemary] Eunice Kennedy Shriver Natl Inst Child Hlth & Hu, Bethesda, MD USA. [Das, Abhik] RTI Int, Social Stat & Environm Sci, Rockville, MD USA. RP Wortham, JM (reprint author), Div TB Eliminat, 1600 Clifton Rd NE,Mailstop E-10, Atlanta, GA 30333 USA. EM vij5@cdc.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Centers for Disease Control and Prevention; National Institutes of Health (NIH) FX This study was supported by funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Centers for Disease Control and Prevention. Funded by the National Institutes of Health (NIH). NR 21 TC 5 Z9 5 U1 0 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD JAN PY 2016 VL 137 IS 1 AR e20152323 DI 10.1542/peds.2015-2323 PG 11 WC Pediatrics SC Pediatrics GA DF5KJ UT WOS:000371390300029 ER PT J AU Wouk, K Lara-Cinisomo, S Stuebe, AM Poole, C Petrick, JL McKenney, KM AF Wouk, Kathryn Lara-Cinisomo, Sandraluz Stuebe, Alison M. Poole, Charles Petrick, Jessica L. McKenney, Kathryn M. TI Clinical Interventions to Promote Breastfeeding by Latinas: A Meta-analysis SO PEDIATRICS LA English DT Article ID LOW-INCOME WOMEN; PRIMARY-CARE; HISPANIC MOTHERS; RANDOMIZED-TRIAL; WIC PARTICIPANTS; PUBLICATION BIAS; MINORITY WOMEN; UNITED-STATES; COST-ANALYSIS; PUERTO-RICAN AB CONTEXT: Breastfeeding duration and exclusivity among Latinas fall below recommended levels, indicating a need for targeted interventions. The effectiveness of clinical breastfeeding interventions for Latinas remains unclear. OBJECTIVE: To systematically review the documented effectiveness of clinical breastfeeding interventions on any and exclusive breastfeeding among Latinas. DATA SOURCES: English-language publications in Medline, CINAHL, and Embase were searched through May 28, 2015. STUDY SELECTION: Fourteen prospective, controlled studies describing 17 interventions met inclusion criteria. DATA EXTRACTION: Extracted study characteristics include study design, population characteristics, intervention components, timing and intensity of delivery, provider type, control procedures, and outcome measures. RESULTS: Random-effects meta-analyses estimated risk differences (RDs) between breastfeeding mothers in intervention and control arms of each study and 95% prediction intervals (PIs) within which 95% of intervals cover the true value estimated by a future study. Interventions increased any breastfeeding at 1 to 3 and 4 to 6 months (RD 0.04 [95% PI -0.15 to 0.23] and 0.08 [-0.08 to 0.25], respectively) and exclusive breastfeeding at 1 to 3 and 4 to 6 months (0.04 [-0.09 to 0.18] and 0.01 [-0.01 to 0.02]). Funnel plot asymmetry suggested publication bias for initiation and 1-to 3-month any breastfeeding. Estimates were slightly larger among interventions with prenatal and postpartum components, 3 to 6 patient contacts, and delivery by an International Board Certified Lactation Consultant or lay provider. LIMITATIONS: The published evidence for Latinas is limited, and studies have varying methodologic rigor. CONCLUSIONS: Breastfeeding interventions targeting Latinas increased any and exclusive breastfeeding compared with usual care. C1 [Wouk, Kathryn; Stuebe, Alison M.] Univ N Carolina, Gillings Sch Global Publ Hlth, Carolina Global Breastfeeding Inst, Dept Maternal & Child Hlth, CB 7445, Chapel Hill, NC 27599 USA. [Poole, Charles] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, CB 7445, Chapel Hill, NC 27599 USA. [Lara-Cinisomo, Sandraluz] Univ N Carolina, Sch Med, Dept Psychiat, CB 7445, Chapel Hill, NC 27599 USA. [Stuebe, Alison M.] Univ N Carolina, Sch Med, Dept Obstet & Gynecol, CB 7445, Chapel Hill, NC 27599 USA. [Lara-Cinisomo, Sandraluz] Univ Illinois, Coll Appl Hlth Sci, Dept Kinesiol & Community Hlth, Champaign, IL USA. [Petrick, Jessica L.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [McKenney, Kathryn M.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [McKenney, Kathryn M.] Northwestern Univ, Feinberg Sch Med, Dept Obstet & Gynecol, Chicago, IL 60611 USA. RP Wouk, K (reprint author), Univ N Carolina, Gillings Sch Global Publ Hlth, Carolina Global Breastfeeding Inst, Dept Maternal & Child Hlth, CB 7445, Chapel Hill, NC 27599 USA. EM khouk@live.unc.edu FU Carolina Global Breastfeeding Institute; National Institutes of Health [MH093315, UL1TR000083, KL2TR000084, TL1TR000085]; National Cancer Institute Intramural Research Program; Foundation of Hope for Research and Treatment of Mental Illness; North Carolina Translational and Clinical Sciences Institute; National Institutes of Health (NIH) FX This meta-analysis was supported in part by the Carolina Global Breastfeeding Institute, the National Institutes of Health (MH093315, UL1TR000083, KL2TR000084, and TL1TR000085), the National Cancer Institute Intramural Research Program, the Foundation of Hope for Research and Treatment of Mental Illness, and the North Carolina Translational and Clinical Sciences Institute. Funded by the National Institutes of Health (NIH). NR 64 TC 1 Z9 1 U1 6 U2 11 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD JAN PY 2016 VL 137 IS 1 AR e20152423 DI 10.1542/peds.2015-2423 PG 15 WC Pediatrics SC Pediatrics GA DF5KJ UT WOS:000371390300031 ER PT S AU Sechi, S AF Sechi, Salvatore BE Sechi, S TI Tools for Next Generation Quantitative Proteomics by Mass Spectrometry Preface SO QUANTITATIVE PROTEOMICS BY MASS SPECTROMETRY, 2ND EDITION SE Methods in Molecular Biology LA English DT Editorial Material; Book Chapter C1 [Sechi, Salvatore] NIDDK, NIH, Bethesda, MD 20892 USA. RP Sechi, S (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-3524-6; 978-1-4939-3522-2 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1410 BP V EP V D2 10.1007/978-1-4939-3524-6 PG 1 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BE4BX UT WOS:000371487700001 PM 27284601 ER PT S AU Whiteaker, JR Halusa, GN Hoofnagle, AN Sharma, V MacLean, B Yan, P Wrobel, JA Kennedy, J Mani, DR Zimmerman, LJ Meyer, MR Mesri, M Boja, E Carr, SA Chan, DW Chen, X Chen, J Davies, SR Ellis, MJC Fenyo, D Hiltke, T Ketchum, KA Kinsinger, C Kuhn, E Liebler, DC Liu, T Loss, M MacCoss, MJ Qian, WJ Rivers, R Rodland, KD Ruggles, KV Scott, MG Smith, RD Thomas, S Townsend, RR Whiteley, G Wu, CC Zhang, H Zhang, Z Rodriguez, H Paulovich, AG AF Whiteaker, Jeffrey R. Halusa, Goran N. Hoofnagle, Andrew N. Sharma, Vagisha MacLean, Brendan Yan, Ping Wrobel, John A. Kennedy, Jacob Mani, D. R. Zimmerman, Lisa J. Meyer, Matthew R. Mesri, Mehdi Boja, Emily Carr, Steven A. Chan, Daniel W. Chen, Xian Chen, Jing Davies, Sherri R. Ellis, Matthew J. C. Fenyoe, David Hiltke, Tara Ketchum, Karen A. Kinsinger, Chris Kuhn, Eric Liebler, Daniel C. Liu, Tao Loss, Michael MacCoss, Michael J. Qian, Wei-Jun Rivers, Robert Rodland, Karin D. Ruggles, Kelly V. Scott, Mitchell G. Smith, Richard D. Thomas, Stefani Townsend, R. Reid Whiteley, Gordon Wu, Chaochao Zhang, Hui Zhang, Zhen Rodriguez, Henry Paulovich, Amanda G. BE Sechi, S TI Using the CPTAC Assay Portal to Identify and Implement Highly Characterized Targeted Proteomics Assays SO QUANTITATIVE PROTEOMICS BY MASS SPECTROMETRY, 2ND EDITION SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Multiple reaction monitoring; Selected reaction monitoring; MRM; SRM; PRM; Quantitative proteomics; Targeted mass spectrometry; Quantitative assay database; Harmonization; Standardization ID DATABASE AB The Clinical Proteomic Tumor Analysis Consortium (CPTAC) of the National Cancer Institute (NCI) has launched an Assay Portal (http://assays.cancengov) to serve as an open-source repository of well characterized targeted proteomic assays. The portal is designed to curate and disseminate highly characterized, targeted mass spectrometry (MS)-based assays by providing detailed assay performance characterization data, standard operating procedures, and access to reagents. Assay content is accessed via the portal through queries to find assays targeting proteins associated with specific cellular pathways, protein complexes, or specific chromosomal regions. The position of the peptide analytes for which there are available assays are mapped relative to other features of interest in the protein, such as sequence domains, isoforms, single nucleotide polymorphisms, and posttranslational modifications. The overarching goals are to enable robust quantification of all human proteins and to standardize the quantification of targeted MS-based assays to ultimately enable harmonization of results over time and across laboratories. C1 [Whiteaker, Jeffrey R.; Yan, Ping; Kennedy, Jacob; Paulovich, Amanda G.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Halusa, Goran N.; Loss, Michael; Whiteley, Gordon] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [Hoofnagle, Andrew N.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Sharma, Vagisha; MacLean, Brendan; MacCoss, Michael J.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Wrobel, John A.; Chen, Xian] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill Sch Med, Chapel Hill, NC USA. [Mani, D. R.] Broad Inst, Cambridge, MA USA. [Zimmerman, Lisa J.; Liebler, Daniel C.] Vanderbilt Univ, Sch Med, Dept Biochem, Jim Ayers Inst Precancer Detect & Diag, Nashville, TN 37212 USA. [Meyer, Matthew R.; Davies, Sherri R.; Ellis, Matthew J. C.; Townsend, R. Reid] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Mesri, Mehdi; Boja, Emily; Kinsinger, Chris; Rivers, Robert; Rodriguez, Henry] NCI, Off Canc Clin Prote Res, Bethesda, MD 20892 USA. [Carr, Steven A.; Kuhn, Eric] Broad Inst MIT & Harvard, Cambridge, MA USA. [Chan, Daniel W.; Chen, Jing; Thomas, Stefani; Zhang, Zhen] Johns Hopkins Univ, Sch Med, Dept Pathol, Div Clin Chem, Baltimore, MD 21205 USA. [Fenyoe, David; Ruggles, Kelly V.] NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY USA. [Ketchum, Karen A.] ESAC Inc, Data Coordinating Ctr, Rockville, MD USA. [Liu, Tao; Qian, Wei-Jun; Rodland, Karin D.; Smith, Richard D.; Wu, Chaochao] Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. [Liu, Tao; Smith, Richard D.] Pacific NW Natl Lab, Environm Mol Sci Lab, Richland, WA 99352 USA. [Scott, Mitchell G.] Washington Univ, Sch Med, Dept Pathol & Immunol, Div Lab & Genom Med, St Louis, MO USA. RP Whiteaker, JR (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. OI Fenyo, David/0000-0001-5049-3825; Ruggles, Kelly/0000-0002-0152-0863 FU NCI NIH HHS [U24 CA159988, U01 CA164186, U01CA164186, U24 CA160019, U24 CA160034, U24 CA160035, U24 CA160036, U24CA159988, U24CA160019, U24CA160034, U24CA160035, U24CA160036]; NIGMS NIH HHS [R01 GM103551] NR 12 TC 3 Z9 3 U1 0 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-3524-6; 978-1-4939-3522-2 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1410 BP 223 EP 236 DI 10.1007/978-1-4939-3524-6_13 D2 10.1007/978-1-4939-3524-6 PG 14 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BE4BX UT WOS:000371487700014 PM 26867747 ER PT J AU Taichman, DB Backus, J Baethge, C Bauchner, H de Leeuw, PW Drazen, JM Fletcher, J Frizelle, FA Groves, T Haileamlak, A James, A Laine, C Peiperl, L Pinborg, A Sahni, P Wu, SN AF Taichman, Darren B. Backus, Joyce Baethge, Christopher Bauchner, Howard de Leeuw, Peter W. Drazen, Jeffrey M. Fletcher, John Frizelle, Frank A. Groves, Trish Haileamlak, Abraham James, Astrid Laine, Christine Peiperl, Larry Pinborg, Anja Sahni, Peush Wu, Sinan TI Sharing clinical trial data: a proposal from the International Committee of Medical Journal Editors SO REVISTA MEDICA DE CHILE LA English DT Editorial Material C1 [Backus, Joyce] Natl Lib Med, Bethesda, MD 20894 USA. RP Taichman, DB (reprint author), Amer Coll Physicians, 190 N Independence Mall West, Philadelphia, PA 19106 USA. EM dtaichman@acponline.org NR 1 TC 1 Z9 1 U1 0 U2 1 PU SOC MEDICA SANTIAGO PI SANTIAGO 9 PA BERNARDA MORIN 488 PROVIDENCIA, CASILLA 168 CORREO 55, SANTIAGO 9, 00000, CHILE SN 0034-9887 EI 0717-6163 J9 REV MED CHILE JI Rev. Medica Chile PD JAN PY 2016 VL 144 IS 1 BP 11 EP 13 DI 10.7326/M15-2928 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DF3WV UT WOS:000371280000002 PM 26998977 ER PT J AU Aksu, M Korkmaz, S AF Aksu, Murat Korkmaz, Selda TI Sleep medicine education in Turkey SO SLEEP AND BIOLOGICAL RHYTHMS LA English DT Article DE Sleep; Education; Turkey AB In Turkey, the onset of sleep studies has extended over by 1960s. At that time, some Turkish scientists joined to the different sleep researches, which were conducted in Europe. In fact, the acceptance of the more scientists by Ismet Karacan who was the director of a sleep unit in USA has been important stage for Turkish sleep medicine. In this sleep center, many researchers came from different subspecialties such as neurologist, pulmonologist, and psychiatrist got training on different aspect of sleep and were in a part of scientific sleep investigations. After that education period, most of them returned to Turkey and founded the sleep unit in their institutions. In addition, they supported the scientists who were interested in sleep medicine in different places of Turkey. After the formation of awareness about sleep medicine and the elevation of the number of sleep centers, Turkish Sleep Medicine Society (TSMS) was established in 1997. This society is responsible for all sleep certification program for both medical doctors and sleep technicians. A large number of universities include 2-year electro-neurophysiology programs for technicians. After this education, if technicians want to have a specialty about sleep, they should apply to TSMS to get a certificate for sleep specialty. C1 [Aksu, Murat; Korkmaz, Selda] Acibadem Univ, Istanbul, Turkey. [Aksu, Murat] Acibadem Univ, Fac Med, Atakent Hosp Istanbul, Istanbul, Turkey. [Korkmaz, Selda] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. RP Aksu, M (reprint author), Acibadem Univ, Istanbul, Turkey.; Aksu, M (reprint author), Acibadem Univ, Fac Med, Atakent Hosp Istanbul, Istanbul, Turkey. EM murat.aksu@acibadem.edu.tr; korkmazs78@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 1446-9235 EI 1479-8425 J9 SLEEP BIOL RHYTHMS JI Sleep Biol. Rhythms PD JAN PY 2016 VL 14 SU 1 BP S45 EP S46 DI 10.1007/s41105-015-0012-z PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DF6ZI UT WOS:000371506800008 ER PT J AU Qin, J Zhang, H Landi, M Caporaso, N Yu, K AF Qin, Jing Zhang, Hong Landi, Maria Caporaso, Neil Yu, Kai TI A hybrid parametric and empirical likelihood model for evaluating interactions in case-control studies SO STATISTICS AND ITS INTERFACE LA English DT Article DE Case-control; Genetic association studies; Hybrid parametric and empirical likelihood; Interaction test ID GENE-ENVIRONMENT INDEPENDENCE; LUNG-CANCER; SUSCEPTIBILITY LOCUS; LOGISTIC-REGRESSION; DISTRIBUTIONS; ASSOCIATION; EFFICIENCY; VARIANTS; DISEASE; DESIGN AB The case-control design provides an effective way to collect covariate information conditioning on subjects' disease status. The standard logistic regression model can be used to model the interaction between two covariates under such a design, but the prospective logistic regression method might not be the most efficient one when certain appropriate constraints can be imposed on the covariate distribution. We develop a hybrid approach for the statistical inference of the interaction under the case-control design. We use a parametric model to characterize the conditional distribution of one covariate given the another covariate in the control population, while leaving the distribution of the later covariate to be fully nonparametric. A maximum hybrid parametric and empirical likelihood method is adopted for the evaluation of all parameters. The estimator and the associated test derived from the proposed semiparametric model are suitable for evaluating the interaction between two covariates of various types (discrete or continuous). Asymptotic results for both the estimators and the test statistics were established, and the advantages of the proposed method over the existing ones are demonstrated through simulation results and a real data example. C1 [Qin, Jing] NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Zhang, Hong] Fudan Univ, Sch Life Sci, Inst Biostat, Shanghai 200433, Peoples R China. [Landi, Maria; Caporaso, Neil; Yu, Kai] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Qin, J (reprint author), NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jingqin@niaid.nih.gov; zhanghfd@fudan.edu.cn; landim@mail.nih.gov; caporasn@mail.nih.gov; yuka@mail.nih.gov FU State Key Development Program for Basic Research of China [2012CB316500]; National Natural Science Foundation of China [11371101]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX This research was supported by the State Key Development Program for Basic Research of China (Grant No. 2012CB316500) (HZ), the National Natural Science Foundation of China (Grant No. 11371101) (HZ), and the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (HZ, KY). NR 29 TC 0 Z9 0 U1 4 U2 6 PU INT PRESS BOSTON, INC PI SOMERVILLE PA PO BOX 43502, SOMERVILLE, MA 02143 USA SN 1938-7989 EI 1938-7997 J9 STAT INTERFACE JI Stat. Interface PY 2016 VL 9 IS 2 BP 147 EP 158 PG 12 WC Mathematical & Computational Biology; Mathematics, Interdisciplinary Applications SC Mathematical & Computational Biology; Mathematics GA DF2RX UT WOS:000371192600003 ER PT J AU McArthur, JC Nath, A AF McArthur, Justin C. Nath, Avindra TI In Memoriam: Richard T. Johnson, 1931-2015 SO ANNALS OF NEUROLOGY LA English DT Biographical-Item C1 [McArthur, Justin C.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Nath, Avindra] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. RP McArthur, JC (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 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 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD JAN PY 2016 VL 79 IS 1 BP 9 EP 10 DI 10.1002/ana.24576 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DE5AM UT WOS:000370642600002 PM 26660084 ER PT J AU Lubbe, SJ Escott-Price, V Brice, A Gasser, T Hardy, J Heutink, P Sharma, M Wood, NW Nalls, M Singleton, AB Williams, NM Morris, HR AF Lubbe, Steven J. Escott-Price, Valentina Brice, Alexis Gasser, Thomas Hardy, John Heutink, Peter Sharma, Manu Wood, Nicholas W. Nalls, Mike Singleton, Andrew B. Williams, Nigel M. Morris, Huw R. CA Int Parkinson's Dis Genomics TI Is the MC1R Variant p. R160W Associated With Parkinson's? SO ANNALS OF NEUROLOGY LA English DT Letter ID MELANOMA C1 [Lubbe, Steven J.; Morris, Huw R.] UCL, Dept Clin Neurosci, Inst Neurol, London, England. [Escott-Price, Valentina; Williams, Nigel M.] Cardiff Univ, Sch Med,Dept Psychol Med & Neurol, Inst Psychol Med & Clin Neurosci, Med Res Council,Ctr Neuropsychiat Genet & Genom, Cardiff, Wales. [Brice, Alexis; Wood, Nicholas W.] Univ Paris 06, Sorbonne Univ,INSERM,U 1127, CNRS UMR 7225,UMR S 1127, Inst Cerveau & Moelle Epiniere,ICM, F-75013 Paris, France. [Gasser, Thomas] Univ Tubingen, Dept Neurodegenerat Dis, Hertie Inst Clin Brain Res, Tubingen, Germany. [Gasser, Thomas; Heutink, Peter] German Ctr Neurodegenerat Dis DZNE, Genome Biol Neurodegenerat Dis, Tubingen, Germany. [Hardy, John; Sharma, Manu] UCL, Dept Mol Neurosci, Inst Neurol, London, England. [Hardy, John] UCL, Inst Neurol, Reta Lila Weston Inst, London, England. [Wood, Nicholas W.] UCL, UCL Genet Inst, London, England. [Nalls, Mike; Singleton, Andrew B.] Natl Inst Aging, Neurogenet Lab, Bethesda, MD USA. RP Lubbe, SJ (reprint author), UCL, Dept Clin Neurosci, Inst Neurol, London, England. RI Hardy, John/C-2451-2009; Lubbe, Steven/L-8261-2013; Singleton, Andrew/C-3010-2009; Morris, Huw/B-8527-2008; Wood, Nicholas/C-2505-2009; OI Morris, Huw/0000-0002-5473-3774; Wood, Nicholas/0000-0002-9500-3348; Escott-Price, Valentina/0000-0003-1784-5483 FU Intramural NIH HHS [Z01 AG000957-05]; Medical Research Council [G0700943, G1100643, MR/L010305/1, MR/L501554/1]; NCI NIH HHS [R01 CA141668, R01CA141668]; NIA NIH HHS [Z01-AG000949-02, Z01 AG000949]; NIEHS NIH HHS [Z01 ES101986]; NINDS NIH HHS [P50 NS071674, P50NS071674, R01 NS037167, R01NS037167]; Parkinson's UK [G-1107, K-1501]; Wellcome Trust [076113, 083948/Z/07/z, 085475, 090355, WT089698, WT089698 /Z/09/Z] NR 6 TC 7 Z9 7 U1 3 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD JAN PY 2016 VL 79 IS 1 BP 159 EP 161 DI 10.1002/ana.24527 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DE5AM UT WOS:000370642600017 PM 26389967 ER PT J AU Abdul-Rahman, OA Rodriguez, B Wadlinger, SR Slutsman, J Boyle, EB Merrill, LS Botkin, J Moye, J AF Abdul-Rahman, Omar A. Rodriguez, Beatriz Wadlinger, Sandra R. Slutsman, Julia Boyle, Elizabeth B. Merrill, Lori S. Botkin, Jeffrey Moye, Jack, Jr. TI Success Rates for Consent and Collection of Prenatal Biological Specimens in an Epidemiologic Survey of Child Health SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Article DE biological specimens; consent rate; epidemiologic research methods; biospecimens; genetic samples ID EXPOSED IN-UTERO; NATIONAL CHILDRENS; INFORMED-CONSENT; PREGNANT-WOMEN; LIFE; DIETHYLSTILBESTROL; ENVIRONMENT; DISEASE AB Background: The National Children's Study (NCS) Vanguard Study began enrollment in January 2009 as an initial pilot study for a planned large-scale, longitudinal U.S. cohort study of the effect of environmental influences on child health and development, with biological and environmental sample collection conducted in seven locations from April 2009 to October 2010. We sought to determine rates of consent for, and success of collection of, maternal and paternal biospecimens before and during pregnancy in the NCS Vanguard Study. Methods: Samples of blood, saliva, vaginal swabs, urine, hair, and nails were collected before and during pregnancy. All specimens were sent to a central repository for processing, storage, and quality assessment. Results: Of 780 pregnant women asked to consent to sample collection, 773 (>99%) agreed, and of 295 nonpregnant women, 292 (99%) agreed. Of 440 fathers asked to consent to sample collection, 435 (99%) agreed. Frequency of successful collection of biospecimens varied depending on sample and visit type. In descending order, the ranges over all visit types of the proportion of expected samples successfully collected from women were: urine, 92.5 to 95.7%; hair, 89.6 to 92.5%; vaginal swab, 84.2 to 88.5%; blood, 74.9 to 78.5%; 2-day saliva, 65.8 to 81.6%; and nails, 76.4 to 76.7%. For fathers, rates were highest for urine (94.9%) and lowest for hair (63.0%). Conclusion: High rates of consent for and collection of a wide variety of biospecimens can be achieved in prospective epidemiologic cohort studies of pregnant women. Ease of sample collection may be a primary factor influencing successful biospecimen collection. (C) 2015 Wiley Periodicals, Inc. C1 [Abdul-Rahman, Omar A.] Univ Mississippi, Dept Pediat, Med Ctr, Jackson, MS 39216 USA. [Rodriguez, Beatriz] Univ Hawaii, Honolulu, HI 96822 USA. [Wadlinger, Sandra R.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Slutsman, Julia; Moye, Jack, Jr.] NICHD, Natl Childrens Study Program Off, NIH, Bethesda, MD USA. [Boyle, Elizabeth B.; Merrill, Lori S.] Westat Corp, Rockville, MD USA. [Botkin, Jeffrey] Univ Utah, Salt Lake City, UT USA. RP Abdul-Rahman, OA (reprint author), 2500 North State St, Jackson, MS 39216 USA. EM oabdulrahman@umc.edu OI Boyle, Elizabeth/0000-0002-9412-7998; moye, john/0000-0001-9976-8586 FU National Children's Study by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Office of the Director of the National Institutes of Health through NICHD [HHSN275200503414C, HHSN275200503411C, HHSN275200603416C, HHSN275200503415C, HHSN275200503413C, HHSN275200503410C, HHSN275200503396C, HHSN275200503395C, HHSN275201000126U] FX Supported by the National Children's Study, supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and funded, through its appropriation, by the Office of the Director of the National Institutes of Health, with support through NICHD Contracts HHSN275200503414C, HHSN275200503411C, HHSN275200603416C, HHSN275200503415C, HHSN275200503413C, HHSN275200503410C, HHSN275200503396C, HHSN275200503395C, and HHSN275201000126U. The manuscript was developed by a Writing Team identified by the National Children's Study Publications Committee for the purpose of timely sharing of centrally collected NCS data. We acknowledge the contributions of the following Vanguard Centers and Principal Investigators: Children's Hospital of Philadelphia, Jennifer Culhane; Mt. Sinai Medical School, Philip Landrigan; South Dakota State University, Bonny Specker; University of California at Irvine, James Swanson and Dean Baker; University of North Carolina at Chapel Hill, Barbara Entwisle and Nancy Dole; University of Utah School of Medicine, Ed Clark; University of Wisconsin, Maureen Durkin. NR 28 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD JAN PY 2016 VL 106 IS 1 BP 47 EP 54 DI 10.1002/bdra.23455 PG 8 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA DE5AY UT WOS:000370644100005 PM 26407522 ER PT J AU Raznahan, A Lee, NR Greenstein, D Wallace, GL Blumenthal, JD Clasen, LS Giedd, JN AF Raznahan, Armin Lee, Nancy Raitano Greenstein, Deanna Wallace, Gregory L. Blumenthal, Jonathan D. Clasen, Liv S. Giedd, Jay N. TI Globally Divergent but Locally Convergent X- and Y-Chromosome Influences on Cortical Development SO CEREBRAL CORTEX LA English DT Article DE aneuploidy; cortical thickness; pseudoautosomal; surface area ID VOXEL-BASED MORPHOMETRY; HUMAN CEREBRAL-CORTEX; KLINEFELTER-SYNDROME; SEX-CHROMOSOMES; SURFACE-AREA; HUMAN BRAIN; MRI; ADOLESCENCE; CHILDHOOD; ANATOMY AB Owing to their unique evolutionary history, modern mammalian X- and Y-chromosomes have highly divergent gene contents counterbalanced by regulatory features, which preferentially restrict expression of X- and Y-specific genes. These 2 characteristics make opposing predictions regarding the expected dissimilarity of X- vs. Y-chromosome influences on biological structure and function. Here, we quantify this dissimilarity using in vivo neuroimaging within a rare cohort of humans with diverse sex chromosome aneuploidies (SCAs). We show that X- and Y-chromosomes have opposing effects on overall brain size but exert highly convergent influences on local brain anatomy, which manifest across biologically distinct dimensions of the cerebral cortex. Large-scale online meta-analysis of functional neuroimaging data indicates that convergent sex chromosome dosage effects preferentially impact centers for social perception, communication, and decision-making. Thus, despite an almost complete lack of sequence homology, and opposing effects on overall brain size, X- and Y-chromosomes exert congruent effects on the proportional size of cortical systems involved in adaptive social functioning. These convergent X-Y effects (i) track the dosage of those few genes that are still shared by X- and Y-chromosomes, and (ii) may provide a biological substrate for the link between SCA and increased rates of psychopathology. C1 [Raznahan, Armin; Lee, Nancy Raitano; Greenstein, Deanna; Wallace, Gregory L.; Blumenthal, Jonathan D.; Clasen, Liv S.; Giedd, Jay N.] NIMH, Sect Brain Imaging, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. [Wallace, Gregory L.] George Washington Univ, Dept Speech & Hearing Sci, Washington, DC 20052 USA. RP Raznahan, A (reprint author), NIMH, Sect Brain Imaging, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. EM raznahana@mail.nih.gov RI Lee, Nancy/M-7492-2016; OI Lee, Nancy/0000-0002-6663-0713; Wallace, Gregory/0000-0003-0329-5054 FU NIH Intramural Research Program FX This study was funded by the NIH Intramural Research Program. NR 46 TC 6 Z9 6 U1 0 U2 6 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 JAN PY 2016 VL 26 IS 1 BP 70 EP 79 DI 10.1093/cercor/bhu174 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DE9QI UT WOS:000370972500008 PM 25146371 ER PT J AU Dayan, E Sella, I Mukovskiy, A Douek, Y Giese, MA Malach, R Flash, T AF Dayan, Eran Sella, Irit Mukovskiy, Albert Douek, Yehonatan Giese, Martin A. Malach, Rafael Flash, Tamar TI The Default Mode Network Differentiates Biological From Non-Biological Motion SO CEREBRAL CORTEX LA English DT Article DE action-perception coupling; biological motion; default mode network ID MEDIAL PREFRONTAL CORTEX; EVENT-RELATED FMRI; STATE FUNCTIONAL CONNECTIVITY; TASK-INDUCED DEACTIVATION; SUPPLEMENTARY MOTOR AREA; SELF-GENERATED ACTIONS; HUMAN BRAIN; PERSPECTIVE-TAKING; SOCIAL COGNITION; RV-COEFFICIENT AB The default mode network (DMN) has been implicated in an array of social-cognitive functions, including self-referential processing, theory of mind, and mentalizing. Yet, the properties of the external stimuli that elicit DMN activity in relation to these domains remain unknown. Previous studies suggested that motion kinematics is utilized by the brain for social-cognitive processing. Here, we used functional MRI to examine whether the DMN is sensitive to parametric manipulations of observed motion kinematics. Preferential responses within core DMN structures differentiating non-biological from biological kinematics were observed for the motion of a realistically looking, human-like avatar, but not for an abstract object devoid of human form. Differences in connectivity patterns during the observation of biological versus non-biological kinematics were additionally observed. Finally, the results additionally suggest that the DMN is coupled more strongly with key nodes in the action observation network, namely the STS and the SMA, when the observed motion depicts human rather than abstract form. These findings are the first to implicate the DMN in the perception of biological motion. They may reflect the type of information used by the DMN in social-cognitive processing. C1 [Dayan, Eran; Douek, Yehonatan; Flash, Tamar] Weizmann Inst Sci, Dept Comp Sci & Appl Math, IL-76100 Rehovot, Israel. [Dayan, Eran; Sella, Irit; Malach, Rafael] Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. [Mukovskiy, Albert; Giese, Martin A.] Hertie Inst Clin Brain Res, Dept Cognit Neurol, Tubingen, Germany. [Mukovskiy, Albert; Giese, Martin A.] Univ Clin Tubingen, Ctr Integrat Neurosci, Tubingen, Germany. [Dayan, Eran] NINDS, Human Cort Physiol Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Dayan, E; Flash, T (reprint author), Weizmann Inst Sci, Dept Comp Sci & Appl Math, IL-76100 Rehovot, Israel.; Dayan, E (reprint author), Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel.; Dayan, E (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM dayane@ninds.nih.gov; tamar.flash@weizmann.ac.il OI Dayan, Eran/0000-0001-9710-9210 FU EU Commission [EC-ICT-257695 Vere, EC FP7-ICT-249858 TANGO, EC FP7-ICT-248311 AMARSi]; EU [PEOPLE-2011-ITN PITN-GA-011-290011, FP7-ICT-2013-FET-F/604102, FP7-ICT-2013-10/611909]; DFG [GI 305/4-1, KA 1258/15-1]; BMBF [FKZ: 01GQ1002A] FX This work was supported by the EU Commission, 7th Framework Programme: EC-ICT-257695 Vere, EC FP7-ICT-249858 TANGO, and EC FP7-ICT-248311 AMARSi. T.F. is an incumbent of the Dr. Hymie Moross Professorial Chair. M.G. and A.M. were also supported by EU projects ABC (PEOPLE-2011-ITN PITN-GA-011-290011), HBP (FP7-ICT-2013-FET-F/604102), and KOROIBOT (FP7-ICT-2013-10/611909), and the DFG (GI 305/4-1 and KA 1258/15-1), and BMBF, FKZ: 01GQ1002A. NR 89 TC 6 Z9 6 U1 5 U2 12 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 JAN PY 2016 VL 26 IS 1 BP 234 EP 245 DI 10.1093/cercor/bhu199 PG 12 WC Neurosciences SC Neurosciences & Neurology GA DE9QI UT WOS:000370972500023 PM 25217472 ER PT J AU Teague, H Mehta, NN AF Teague, H. Mehta, Nehal N. TI The Link Between Inflammatory Disorders and Coronary Heart Disease: a Look at Recent Studies and Novel Drugs in Development SO CURRENT ATHEROSCLEROSIS REPORTS LA English DT Review DE Inflammation; Coronary heart disease; Atherosclerosis; Psoriasis; Rheumatoid arthritis; Systemic lupus erythematosus ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; C-REACTIVE PROTEIN; POSITRON-EMISSION-TOMOGRAPHY; RANDOMIZED CONTROLLED-TRIAL; RHEUMATOID-ARTHRITIS; CARDIOVASCULAR-DISEASE; INSULIN-RESISTANCE; ACCELERATED ATHEROSCLEROSIS; VASCULAR INFLAMMATION; SEVERE PSORIASIS AB Inflammation is a critical component in the development of coronary heart disease (CHD), specifically in the process of atherogenesis. Human translational and preclinical studies have demonstrated that inflammation contributes to the development, sustainment, and progression of atherosclerosis, and epidemiological studies demonstrate that human diseases associated with increased systemic inflammation increase the risk of CHD-related events. Therefore, over the last decade, multiple clinical studies were designed to target the inflammatory cascade in order to reduce the risk of CHD and to identify which populations may benefit from these preventative treatment strategies. This review briefly summarizes inflammation as a risk factor in atherosclerosis, human disease states associated with accelerated atherosclerosis, and current treatment strategies for CHD targeting the inflammatory cascade. C1 [Teague, H.; Mehta, Nehal N.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Mehta, Nehal N.] NHLBI, Cardiovasc & Pulm Branch, NIH, CDC, 10 Ctr Dr,Room 5-5140, Bethesda, MD 20892 USA. RP Mehta, NN (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA.; Mehta, NN (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, CDC, 10 Ctr Dr,Room 5-5140, Bethesda, MD 20892 USA. EM nehal.mehta@nih.gov NR 54 TC 1 Z9 1 U1 1 U2 2 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1523-3804 EI 1534-6242 J9 CURR ATHEROSCLER REP JI Curr. Atheroscleros. Rep. PD JAN PY 2016 VL 18 IS 1 AR 3 DI 10.1007/s11883-015-0557-y PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DE7JF UT WOS:000370811300005 PM 26739273 ER PT J AU Khadka, P Croteau, DL Bohr, VA AF Khadka, Prabhat Croteau, Deborah L. Bohr, Vilhelm A. TI RECQL5 has unique strand annealing properties relative to the other human RecQ helicase proteins SO DNA REPAIR LA English DT Article DE RecQ helicase; Strand annealing; DNA repair; DNA-DNA hybrid; RNA-DNA hybrid; Aging ID WERNER-SYNDROME PROTEIN; BASE EXCISION-REPAIR; RNA-POLYMERASE-II; DNA HELICASES; FLAP ENDONUCLEASE-1; HOMOLOGOUS RECOMBINATION; GENOME MAINTENANCE; END RESECTION; BREAK REPAIR; REPLICATION AB The RecQ helicases play important roles in genome maintenance and DNA metabolism (replication, recombination, repair, and transcription). Five different homologs are present in humans, three of which are implicated in accelerated aging genetic disorders: Rothmund Thomson (RECQL4), Werner (WRN), and Bloom (BLM) syndromes. While the DNA helicase activities of the 5 human RecQ helicases have been extensively characterized, much less is known about their DNA double strand annealing activities. Strand annealing is an important integral enzymatic activity in DNA metabolism, including DNA repair. Here, we have characterized the strand annealing activities of all five human RecQ helicase proteins and compared them. Interestingly, the relative strand annealing activities of the five RecQ proteins are not directly (inversely) related to their helicase activities. RECQL5 possesses relatively strong annealing activity on long or small duplexed substrates compared to the other RecQs. Additionally, the strand annealing activity of RECQL5 is not inhibited by the presence of ATP, unlike the other RecQs. We also show that RECQL5 efficiently catalyzes annealing of RNA to DNA in vitro in the presence or absence of ATP, revealing a possible new function for RECQL5. Additionally, we investigate how different known RecQ interacting proteins, RPA, Ku, FEN1 and RAD51, regulate their strand annealing activity. Collectively, we find that the human RecQ proteins possess differential DNA double strand annealing activities and we speculate on their individual roles in DNA repair. This insight is important in view of the many cellular DNA metabolic actions of the RecQ proteins and elucidates their unique functions in the cell. Published by Elsevier B.V. C1 [Khadka, Prabhat; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Intramural Res Program, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM vbohr@nih.gov FU NIH, National Institute on Aging FX This work was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. We would like to thank individuals that contributed to the various protein purifications: Dr. Takashi Tadokoro and Dr. Tomasz Kulikowicz and Christopher Dun. NR 70 TC 2 Z9 2 U1 3 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD JAN PY 2016 VL 37 BP 53 EP 66 DI 10.1016/j.dnarep.2015.11.005 PG 14 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA DE8SK UT WOS:000370906800013 PM 26717024 ER PT J AU Lobkovsky, AE Wolf, YI Koonin, EV AF Lobkovsky, Alexander E. Wolf, Yuri I. Koonin, Eugene V. TI Evolvability of an Optimal Recombination Rate SO GENOME BIOLOGY AND EVOLUTION LA English DT Article DE recombination; allele replacement; evolvability; gene flux; genome; rearrangement ID DELETERIOUS MUTATIONS; STRUCTURED POPULATIONS; EVOLUTIONARY ADVANTAGE; FINITE POPULATIONS; SELECTION; EPISTASIS; SEX; LINKAGE; BACTERIAL; GENOMES AB Evolution and maintenance of genetic recombination and its relation to the mutational process is a long-standing, fundamental problem in evolutionary biology that is linked to the general problem of evolution of evolvability. We explored a stochastic model of the evolution of recombination using additive fitness and infinite allele assumptions but no assumptions on the sign or magnitude of the epistasis and the distribution of mutation effects. In this model, fluctuating negative epistasis and predominantly deleterious mutations arise naturally as a consequence of the additive fitness and a reservoir from which new alleles arrive with a fixed distribution of fitness effects. Analysis of the model revealed a nonmonotonic effect of recombination intensity on fitness, with an optimal recombination rate value which maximized fitness in steady state. The optimal recombination rate depended on the mutation rate and was evolvable, that is, subject to selection. The predictions of the model were compatible with the observations on the dependence between genome rearrangement rate and gene flux in microbial genomes. C1 [Lobkovsky, Alexander E.; Wolf, Yuri I.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU US Department of Health and Human Services FX The authors thank David Kristensen for help with the ATGC analysis. The authors' research was supported by intramural funds of the US Department of Health and Human Services (to National Library of Medicine). The authors declare that they have no competing financial interests. NR 58 TC 2 Z9 2 U1 1 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1759-6653 J9 GENOME BIOL EVOL JI Genome Biol. Evol. PD JAN PY 2016 VL 8 IS 1 BP 70 EP 77 DI 10.1093/gbe/evv249 PG 8 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA DE9PZ UT WOS:000370971600006 ER PT J AU Alfano, CM Bluethmann, SM Tesauro, G Perna, F Agurs-Collins, T Elena, JW Ross, SA O'Connell, M Bowles, HR Greenberg, D Nebeling, L AF Alfano, Catherine M. Bluethmann, Shirley M. Tesauro, Gina Perna, Frank Agurs-Collins, Tanya Elena, Joanne W. Ross, Sharon A. O'Connell, Mary Bowles, Heather R. Greenberg, Deborah Nebeling, Linda TI NCI Funding Trends and Priorities in Physical Activity and Energy Balance Research Among Cancer Survivors SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID INTERVENTIONS; CARE AB There is considerable evidence that a healthy lifestyle consisting of physical activity, healthy diet, and weight control is associated with reduced risk of morbidity and mortality after cancer. However, these behavioral interventions are not widely adopted in practice or community settings. Integrating heath behavior change interventions into standard survivorship care for the growing number of cancer survivors requires an understanding of the current state of the science and a coordinated scientific agenda for the future with focused attention in several priority areas. To facilitate this goal, this paper presents trends over the past decade of the National Cancer Institute (NCI) research portfolio, fiscal year 2004 to 2014, by funding mechanism, research focus, research design and methodology, primary study exposures and outcomes, and study team expertise and composition. These data inform a prioritized research agenda for the next decade focused on demonstrating value and feasibility and creating desire for health behavior change interventions at multiple levels including the survivor, clinician, and healthcare payer to facilitate the development and implementation of appropriately targeted, adaptive, effective, and sustainable programs for all survivors. C1 [Alfano, Catherine M.; Bluethmann, Shirley M.; Tesauro, Gina; Perna, Frank; Agurs-Collins, Tanya; O'Connell, Mary; Greenberg, Deborah; Nebeling, Linda] NCI, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Elena, Joanne W.] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Ross, Sharon A.] NCI, Nutr Sci Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Bowles, Heather R.] NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Alfano, CM (reprint author), Amer Canc Soc Inc, 555 11th St NW Suite 300, Washington, DC 20004 USA. EM catherine.alfano@cancer.org NR 23 TC 3 Z9 3 U1 1 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 JAN PY 2016 VL 108 IS 1 AR djv285 DI 10.1093/jnci/djv285 PG 7 WC Oncology SC Oncology GA DF2EV UT WOS:000371154700002 ER PT J AU Beachler, DC Kreimer, AR Schiffman, M Herrero, R Wacholder, S Rodriguez, AC Lowy, DR Porras, C Schiller, JT Quint, W Jimenez, S Safaeian, M Struijk, L Schussler, J Hildesheim, A Gonzalez, P AF Beachler, Daniel C. Kreimer, Aimee R. Schiffman, Mark Herrero, Rolando Wacholder, Sholom Cecilia Rodriguez, Ana Lowy, Douglas R. Porras, Carolina Schiller, John T. Quint, Wim Jimenez, Silvia Safaeian, Mahboobeh Struijk, Linda Schussler, John Hildesheim, Allan Gonzalez, Paula CA Costa Rica HPV Vaccine Trial CVT G TI Multisite HPV16/18 Vaccine Efficacy Against Cervical, Anal, and Oral HPV Infection SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HUMAN-PAPILLOMAVIRUS INFECTION; COSTA-RICA; INTRAEPITHELIAL NEOPLASIA; YOUNG-WOMEN; PARTICLE VACCINE; BROAD-SPECTRUM; UNITED-STATES; RISK-FACTORS; TRIAL; CANCER AB Background: Previous Costa Rica Vaccine Trial (CVT) reports separately demonstrated vaccine efficacy against HPV16 and HPV18 (HPV16/18) infections at the cervical, anal, and oral regions; however, the combined overall multisite efficacy (protection at all three sites) and vaccine efficacy among women infected with HPV16 or HPV18 prior to vaccination are less known. Methods: Women age 18 to 25 years from the CVT were randomly assigned to the HPV16/18 vaccine (Cervarix) or a hepatitis A vaccine. Cervical, oral, and anal specimens were collected at the four-year follow-up visit from 4186 women. Multisite and single-site vaccine efficacies (VEs) and 95% confidence intervals (CIs) were computed for one-time detection of point prevalent HPV16/18 in the cervical, anal, and oral regions four years after vaccination. All statistical tests were two-sided. Results: The multisite woman-level vaccine efficacy was highest among "naive" women (HPV16/18 seronegative and cervical HPV high-risk DNA negative at vaccination) (vaccine efficacy = 83.5%, 95% CI = 72.1% to 90.8%). Multisite woman-level vaccine efficacy was also demonstrated among women with evidence of a pre-enrollment HPV16 or HPV18 infection (seropositive for HPV16 and/or HPV18 but cervical HPV16/18 DNA negative at vaccination) (vaccine efficacy = 57.8%, 95% CI = 34.4% to 73.4%), but not in those with cervical HPV16 and/or HPV18 DNA at vaccination (anal/oral HPV16/18 VE = 25.3%, 95% CI = -40.4% to 61.1%). Concordant HPV16/18 infections at two or three sites were also less common in HPV16/18-infected women in the HPV vaccine vs control arm (7.4% vs 30.4%, P < .001). Conclusions: This study found high multisite vaccine efficacy among "naive" women and also suggests the vaccine may provide protection against HPV16/18 infections at one or more anatomic sites among some women infected with these types prior to HPV16/18 vaccination. C1 [Beachler, Daniel C.; Kreimer, Aimee R.; Schiffman, Mark; Wacholder, Sholom; Safaeian, Mahboobeh; Hildesheim, Allan] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Lowy, Douglas R.; Schiller, John T.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Herrero, Rolando; Cecilia Rodriguez, Ana; Porras, Carolina; Jimenez, Silvia; Gonzalez, Paula] Fdn INCIENSA, Proyecto Epidemiol, San Jose, Costa Rica. [Herrero, Rolando] Int Agcy Res Canc, Early Detect & Prevent Sect, 150 Cours Albert Thomas, F-69372 Lyon, France. [Quint, Wim; Struijk, Linda] DDL Diagnost Lab, Voorburg, Netherlands. [Schussler, John] Informat Management Syst, Rockville, MD USA. RP Beachler, DC (reprint author), 9609 Med Ctr Dr,Room 6E-220, Bethesda, MD 20892 USA. EM daniel.beachler@nih.gov FU NCI [N01-CP-11005]; National Institutes of Health Office of Research on Women's Health; GlaxoSmithKline Biologicals (GSK) (US Food and Drug Administration) [BB-IND 7920] FX The Costa Rica HPV Vaccine Trial is a long-standing collaboration between investigators in Costa Rica and the National Cancer Institute (NCI). The trial is sponsored and funded by the NCI (contract N01-CP-11005), with funding support from the National Institutes of Health Office of Research on Women's Health. GlaxoSmithKline Biologicals (GSK) provided vaccine and support for aspects of the trial associated with regulatory submission needs of the company under a Clinical Trials Agreement (US Food and Drug Administration BB-IND 7920) during the four-year, randomized blinded phase of our study. John T. Schiller and Douglas R. Lowy report that they are named inventors on US Government-owned HPV vaccine patents that are licensed to GlaxoSmithKline and Merck and for which the National Cancer Institute receives licensing fees. They are entitled to limited royalties as specified by federal law. The other authors declare that they have no conflicts of interest. NR 39 TC 2 Z9 2 U1 2 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD JAN PY 2016 VL 108 IS 1 AR djv302 DI 10.1093/jnci/djv302 PG 8 WC Oncology SC Oncology GA DF2EV UT WOS:000371154700004 ER PT J AU Jatoi, I Bandos, H Jeong, JH Anderson, WF Romond, EH Mamounas, EP Wolmark, N AF Jatoi, Ismail Bandos, Hanna Jeong, Jong-Hyeon Anderson, William F. Romond, Edward H. Mamounas, Eleftherios P. Wolmark, Norman TI Time-Varying Effects of Breast Cancer Adjuvant Systemic Therapy SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID RECEPTOR-NEGATIVE TUMORS; LONG-TERM SURVIVAL; DOXORUBICIN-CYCLOPHOSPHAMIDE; NONPROPORTIONAL HAZARDS; SEQUENTIAL METHOTREXATE; CHEMOTHERAPY; TRIAL; TAMOXIFEN; FLUOROURACIL; RECURRENCE AB Background: The benefits of breast cancer adjuvant systemic treatments are generally assumed to be proportional (or constant) over time, but limited data suggest that some treatment effects may vary with time. We therefore systematically assessed the proportional hazards assumption across all 19 breast cancer adjuvant systemic therapy trials in the National Surgical Adjuvant Breast and Bowel Project (NSABP) database. Methods: The NSABP breast cancer trials were tested for the proportionality of hazard rates between randomized treatment groups for five endpoints: overall survival, disease-free survival and recurrence, local-regional recurrence, or distant recurrence as first events. When the proportional hazards assumption did not hold, a "change point for the relative risk" technique was used to identify the temporal breakdown of the treatment effect. Results: Time-varying treatment effects were observed in nearly half of the trials (nine of 19). In six (B-05, B-11, B-12, B-14, B-16, and B-20), novel treatment benefits diminished statistically significantly at specific time points following surgery. In B-09 and B-31, novel treatment benefits were delayed and emerged more than one year after surgery (1.57 and 1.32 years correspondingly), but the benefit in B-09 reversed after the third year of follow-up. In one trial (B-23), the initial advantage and subsequent disadvantage of one of the regimens was evident. Conclusions: Breast cancer adjuvant systemic therapy can have statistically significant time-varying effects, which should be considered in the design, analysis, reporting, and translation of clinical trials. These time-dependent effects will have greater relevance as the number of long-term breast cancer survivors increases. C1 [Jatoi, Ismail; Romond, Edward H.; Mamounas, Eleftherios P.; Wolmark, Norman] NRG Oncol Natl Surg Adjuvant Breast & Bowel Proje, Pittsburgh, PA USA. [Jatoi, Ismail] Univ Texas Hlth Sci Ctr San Antonio, Dept Surg, San Antonio, TX 78229 USA. [Bandos, Hanna; Jeong, Jong-Hyeon] Univ Pittsburgh, Grad Sch Publ Hlth, NRG Oncol Stat & Data Management Ctr, Pittsburgh, PA USA. [Bandos, Hanna; Jeong, Jong-Hyeon] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Anderson, William F.] NCI, NIH, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Romond, Edward H.] Univ Kentucky, Markey Canc Ctr, Lexington, KY USA. [Mamounas, Eleftherios P.] Orlando Hlth, UF Canc Ctr, Orlando, FL USA. [Wolmark, Norman] Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. RP Jatoi, I (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Surg, Div Surg Oncol, 7703 Floyd Curl Dr,Mail Code 7738, San Antonio, TX 78229 USA. EM jatoi@uthscsa.edu OI Jeong, Jong/0000-0003-0596-2201 FU National Institute of Health NCI HHS PHS [U10CA-180868, U10CA-180822, UG1-CA-189867, U10-CA-44066] FX National Institute of Health NCI HHS PHS U10CA-180868, -180822, UG1-CA-189867, and U10-CA-44066 (AR). NR 37 TC 1 Z9 1 U1 1 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 JAN PY 2016 VL 108 IS 1 AR djv304 DI 10.1093/jnci/djv304 PG 8 WC Oncology SC Oncology GA DF2EV UT WOS:000371154700014 ER PT J AU Lih, CJ Chen, AP AF Lih, Chih-Jian Chen, Alice P. TI N of 2 Responders With LMNA-NTRK1 SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID LUNG-CANCER; CHEMOTHERAPY; INHIBITION; CRIZOTINIB; ANTIBODY; FUSIONS C1 [Lih, Chih-Jian] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Mol Characterizat & Clin Assay Dev Lab, Frederick, MD USA. [Chen, Alice P.] NCI, Early Clin Trials Dev Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Lih, CJ (reprint author), Bldg 31 Room 3A44,31 Ctr Dr, Bethesda, MD 20814 USA. EM chenali@mail.nih.gov NR 12 TC 0 Z9 0 U1 0 U2 1 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 JAN PY 2016 VL 108 IS 1 AR djv376 DI 10.1093/jnci/djv376 PG 2 WC Oncology SC Oncology GA DF2EV UT WOS:000371154700018 ER PT J AU Saxena, N Maio, N Crooks, DR Ricketts, CJ Yang, YF Wei, MH Fan, TWM Lane, AN Sourbier, C Singh, A Killian, JK Meltzer, PS Vocke, CD Rouault, TA Linehan, WM AF Saxena, Neetu Maio, Nunziata Crooks, Daniel R. Ricketts, Christopher J. Yang, Youfeng Wei, Ming-Hui Fan, Teresa W-M. Lane, Andrew N. Sourbier, Carole Singh, Anamika Killian, J. Keith Meltzer, Paul S. Vocke, Cathy D. Rouault, Tracey A. Linehan, W. Marston TI SDHB-Deficient Cancers: The Role of Mutations That Impair Iron Sulfur Cluster Delivery SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID RENAL-CELL CARCINOMA; SUCCINATE-DEHYDROGENASE; GERMLINE MUTATIONS; GENE-MUTATIONS; HIGH-FREQUENCY; KIDNEY CANCER; COMPLEX-II; PARAGANGLIOMA; PHEOCHROMOCYTOMA; TUMOR AB Background: Mutations in the Fe-S cluster-containing SDHB subunit of succinate dehydrogenase cause familial cancer syndromes. Recently the tripeptide motif L(I)YR was identified in the Fe-S recipient protein SDHB, to which the cochaperone HSC20 binds. Methods: In order to characterize the metabolic basis of SDH-deficient cancers we performed stable isotope-resolved metabolomics in a novel SDHB-deficient renal cell carcinoma cell line and conducted bioinformatics and biochemical screening to analyze Fe-S cluster acquisition and assembly of SDH in the presence of other cancer-causing SDHB mutations. Results: We found that the SDHBR46Q mutation in UOK269 cells disrupted binding of HSC20, causing rapid degradation of SDHB. In the absence of SDHB, respiration was undetectable in UOK269 cells, succinate was elevated to 351.4 +/- 63.2 nmol/mg cellular protein, and glutamine became the main source of TCA cycle metabolites through reductive carboxylation. Furthermore, HIF1 alpha, but not HIF2 alpha, increased markedly and the cells showed a strong DNA CpG island methylator phenotype (CIMP). Biochemical and bioinformatic screening revealed that 37% of disease-causing missense mutations in SDHB were located in either the L(I)YR Fe-S transfer motifs or in the 11 Fe-S cluster-ligating cysteines. Conclusions: These findings provide a conceptual framework for understanding how particular mutations disproportionately cause the loss of SDH activity, resulting in accumulation of succinate and metabolic remodeling in SDHB cancer syndromes. C1 [Saxena, Neetu; Maio, Nunziata; Singh, Anamika; Rouault, Tracey A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, Bldg 35A,Rm 2D908, Bethesda, MD 20892 USA. [Crooks, Daniel R.; Ricketts, Christopher J.; Yang, Youfeng; Wei, Ming-Hui; Sourbier, Carole; Vocke, Cathy D.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Fan, Teresa W-M.; Lane, Andrew N.] Univ Kentucky, Dept Toxicol & Canc Biol, Lexington, KY USA. [Killian, J. Keith; Meltzer, Paul S.] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, Bldg 35A,Rm 2D908, Bethesda, MD 20892 USA.; Linehan, WM (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, 10 Ctr Dr MSC 1107,CRC Room 1W 5940, Bethesda, MD 20892 USA. EM rouault@mail.nih.gov; wml@nih.gov FU National Cancer Institute, Center for Cancer Research; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health (NIH) by the NIH Office of Rare Diseases Research (ORDR); National Center for Advancing Translational Sciences (NCATS); NIH Office of Intramural Research; NIH [5R01ES022191, 3R01ES022191-04S1, 1U24DK097215-01A1] FX This research was supported by the Intramural Research Programs of the National Cancer Institute, Center for Cancer Research, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, as well as through a National Institutes of Health (NIH) Bench-to-Bedside award made possible by the NIH Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), NIH Office of Intramural Research, and NIH grants 5R01ES022191, 3R01ES022191-04S1, and 1U24DK097215-01A1. NR 43 TC 4 Z9 4 U1 3 U2 7 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 JAN PY 2016 VL 108 IS 1 AR djv287 DI 10.1093/jnci/djv287 PG 11 WC Oncology SC Oncology GA DF2EV UT WOS:000371154700024 ER PT J AU Wang, F Yang, K Wang, Z Ma, Y Gutkind, JS Hida, N Niu, G Tian, J AF Wang, Fu Yang, Kai Wang, Zhe Ma, Ying Gutkind, J. Silvio Hida, Naoki Niu, Gang Tian, Jie TI Combined image guided monitoring the pharmacokinetics of rapamycin loaded human serum albumin nanoparticles with a split luciferase reporter SO NANOSCALE LA English DT Article ID MAMMALIAN TARGET; SIGNALING PATHWAY; CANCER-THERAPY; DRUG-DELIVERY; CELLS; INHIBITION; METABOLISM; PACLITAXEL; SYSTEMS; CARRIER AB Imaging guided techniques have been increasingly employed to investigate the pharmacokinetics (PK) and biodistribution of nanoparticle based drug delivery systems. In most cases, however, the PK profiles of drugs could vary significantly from those of drug delivery carriers upon administration in the blood circulation, which complicates the interpretation of image findings. Herein we applied a genetically encoded luciferase reporter in conjunction with near infrared (NIR) fluorophores to investigate the respective PK profiles of a drug and its carrier in a biodegradable drug delivery system. In this system, a prototype hydrophobic agent, rapamycin (Rapa), was encapsulated into human serum albumin (HSA) to form HSA Rapa nanoparticles, which were then labeled with Cy5 fluorophore to facilitate the fluorescence imaging of HSA carrier. Meanwhile, we employed transgenetic HN12 cells that were modified with a split luciferase reporter, whose bioluminescence function is regulated by Rapa, to reflect the PK profile of the encapsulated agent. It was interesting to discover that there existed an obvious inconsistency of PK behaviors between HSA carrier and rapamycin in vitro and in vivo through near infrared fluorescence imaging (NIFRI) and bioluminescence imaging (BLI) after treatment with Cy5 labeled HSA Rapa. Nevertheless, HSA Rapa nanoparticles manifested favorable in vivo PK and tumor suppression efficacy in a follow-up therapeutic study. The developed strategy of combining a molecular reporter and a fluorophore in this study could be extended to other drug delivery systems to provide profound insights for non-invasive real-time evaluation of PK profiles of drug-loaded nanoparticles in pre-clinical studies. C1 [Wang, Fu; Tian, Jie] Xidian Univ, Engn Res Ctr Mol & Neuro Imaging, Sch Life Sci & Technol, Minist Educ, Xian 710071, Shaanxi, Peoples R China. [Wang, Fu; Yang, Kai; Wang, Zhe; Ma, Ying; Hida, Naoki; Niu, Gang] Natl Inst Biomed Imaging & Bioeng, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Yang, Kai] Soochow Univ, Coll Med, Collaborat Innovat Ctr Suzhou Nano Sci & Technol, Sch Radiat Med & Protect, Suzhou 215123, Jiangsu, Peoples R China. [Yang, Kai] Soochow Univ, Coll Med, Collaborat Innovat Ctr Suzhou Nano Sci & Technol, Sch Radiol & Interdisciplinary Sci RAD X, Suzhou 215123, Jiangsu, Peoples R China. [Yang, Kai] Soochow Univ, Coll Med, Collaborat Innovat Ctr Radiat Med, Jiangsu Higher Educ Inst, Suzhou 215123, Jiangsu, Peoples R China. [Gutkind, J. Silvio] Natl Inst Craniofacial & Dent Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Tian, Jie] Chinese Acad Sci, Inst Automat, Key Lab Mol Imaging, Beijing 100190, Peoples R China. RP Wang, F; Tian, J (reprint author), Xidian Univ, Engn Res Ctr Mol & Neuro Imaging, Sch Life Sci & Technol, Minist Educ, Xian 710071, Shaanxi, Peoples R China.; Wang, F (reprint author), Natl Inst Biomed Imaging & Bioeng, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA.; Tian, J (reprint author), Chinese Acad Sci, Inst Automat, Key Lab Mol Imaging, Beijing 100190, Peoples R China. EM fwang@xidian.edu.cn; jaytian99@gmail.com RI Tian, Jie/H-1190-2011; OI Tian, Jie/0000-0003-0498-0432; Wang, Fu/0000-0001-9222-0833 FU National Basic Research and Development Program of China (973 Program) [2013CB733803]; National Natural Science Foundation of China [81571721, 81301214]; Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH) FX This work was supported partly by The National Basic Research and Development Program of China (973 Program) ( no. 2013CB733803), National Natural Science Foundation of China ( no. 81571721, no. 81301214), and the Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering (NIBIB), and National Institutes of Health (NIH). NR 32 TC 2 Z9 2 U1 9 U2 36 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-3364 EI 2040-3372 J9 NANOSCALE JI Nanoscale PY 2016 VL 8 IS 7 BP 3991 EP 4000 DI 10.1039/c5nr07308a PG 10 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA DE6RQ UT WOS:000370761700017 PM 26818100 ER PT J AU Federoff, M Price, TR Sailer, A Scholz, S Hernandez, D Nicolas, A Singleton, AB Nalls, M Houlden, H AF Federoff, M. Price, T. R. Sailer, A. Scholz, S. Hernandez, D. Nicolas, A. Singleton, A. B. Nalls, M. Houlden, H. TI Genome-wide estimate of the heritability of Multiple System Atrophy SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Multiple System Atrophy; Genetics; Atypical parkinsonisms ID PROGRESSIVE SUPRANUCLEAR PALSY; AMYOTROPHIC-LATERAL-SCLEROSIS; GENOTYPE IMPUTATION; PARKINSONS-DISEASE; COMMON VARIANTS; ASSOCIATION; CRITERIA AB Introduction: Multiple System Atrophy (MSA) is a neurodegenerative disease which presents heterogeneously with symptoms and signs of parkinsonism, ataxia and autonomic dysfunction. Although MSA typically occurs sporadically, rare pathology-proven MSA families following either autosomal recessive or autosomal dominant patterns have been described, indicating a heritable contribution to the pathogenesis. Methods: We used Genome-Wide Complex Trait Analysis (GCTA) to estimate the heritable component of MSA due to common coding variability in imputed genotype data of 907 MSA cases and 3866 population matched controls. GCTA only assesses the effect of putative causal variants in linkage disequilibrium (LD) with all common SNPs on the genotyping platform. Results: We estimate the heritability among common variants of MSA in pooled cases at 2.09-6.65%, with a wider range of values in geographic and diagnostic subgroups. Meta-analysis of our geographic cohorts reveals high between-group heterogeneity. Contributions of single chromosomes are generally negligible. We suggest that all calculated MSA heritability among common variants could be explained by the presence of misdiagnosed cases in the clinical subgroup based on a Bayesian estimate using literature-derived rates of misdiagnosis. Discussion: MSA is a challenging disease to study due to high rates of misdiagnosis and low prevalence. Given our low estimates of heritability, common genetic variation appears to play a less prominent role in risk for MSA than in other complex neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis. The success of future gene discovery efforts rests on large pathologically-confirmed case series and an interrogation of both common and rare genetic variants. Published by Elsevier Ltd. C1 [Federoff, M.; Price, T. R.; Scholz, S.; Hernandez, D.; Nicolas, A.; Singleton, A. B.; Nalls, M.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Federoff, M.; Sailer, A.; Houlden, H.] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Scholz, S.] NINDS, Neurodegenerat Dis Res Grp, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Federoff, M (reprint author), NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM monica.federoff22@gmail.com RI Singleton, Andrew/C-3010-2009; Houlden, Henry/C-1532-2008; OI Houlden, Henry/0000-0002-2866-7777; Federoff, Monica/0000-0002-7920-2136; Scholz, Sonja/0000-0002-6623-0429 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services [ZO1 AG000949] FX This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project ZO1 AG000949. NR 24 TC 6 Z9 6 U1 2 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 EI 1873-5126 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD JAN PY 2016 VL 22 BP 35 EP 41 DI 10.1016/j.parkreldis.2015.11.005 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA DE8JU UT WOS:000370883100006 PM 26589003 ER PT J AU Wu, T Zhang, JR Hallett, M Feng, T Hou, YN Chan, P AF Wu, Tao Zhang, Jiarong Hallett, Mark Feng, Tao Hou, Yanan Chan, Piu TI Neural correlates underlying micrographia in Parkinson's disease SO BRAIN LA English DT Article DE Parkinson's disease; micrographia; attention; dopaminergic intervention; sequence effect ID PROGRESSIVE SUPRANUCLEAR PALSY; POSITRON-EMISSION-TOMOGRAPHY; BASAL GANGLIA; FUNCTIONAL MRI; HANDWRITING MOVEMENTS; AUTOMATIC MOVEMENTS; SUBTHALAMIC NUCLEUS; KINEMATIC ANALYSIS; DRAWING MOVEMENTS; FRONTAL-CORTEX AB Micrographia is a common symptom in Parkinson's disease, which manifests as either a consistent or progressive reduction in the size of handwriting or both. Neural correlates underlying micrographia remain unclear. We used functional magnetic resonance imaging to investigate micrographia-related neural activity and connectivity modulations. In addition, the effect of attention and dopaminergic administration on micrographia was examined. We found that consistent micrographia was associated with decreased activity and connectivity in the basal ganglia motor circuit; while progressive micrographia was related to the dysfunction of basal ganglia motor circuit together with disconnections between the rostral supplementary motor area, rostral cingulate motor area and cerebellum. Attention significantly improved both consistent and progressive micrographia, accompanied by recruitment of anterior putamen and dorsolateral prefrontal cortex. Levodopa improved consistent micrographia accompanied by increased activity and connectivity in the basal ganglia motor circuit, but had no effect on progressive micrographia. Our findings suggest that consistent micrographia is related to dysfunction of the basal ganglia motor circuit; while dysfunction of the basal ganglia motor circuit and disconnection between the rostral supplementary motor area, rostral cingulate motor area and cerebellum likely contributes to progressive micrographia. Attention improves both types of micrographia by recruiting additional brain networks. Levodopa improves consistent micrographia by restoring the function of the basal ganglia motor circuit, but does not improve progressive micrographia, probably because of failure to repair the disconnected networks. C1 [Wu, Tao; Zhang, Jiarong; Hou, Yanan; Chan, Piu] Capital Med Univ, Key Lab Neurodegenerat Disorders, Dept Neurobiol, Minist Educ,Beijing Inst Geriatr,Xuanwu Hosp, Beijing 100053, Peoples R China. [Wu, Tao; Zhang, Jiarong; Feng, Tao; Hou, Yanan; Chan, Piu] Beijing Inst Brain Disorders, Parkinson Dis Ctr, Beijing Key Lab Parkinsons Dis, Beijing, Peoples R China. [Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Feng, Tao] China Natl Clin Res Ctr Neurol Dis, Beijing, Peoples R China. [Feng, Tao] Capital Med Univ, Beijing Tiantan Hosp, Ctr Neurodegenerat Dis, Dept Neurol, Beijing 100053, Peoples R China. RP Wu, T (reprint author), Capital Med Univ, Key Lab Neurodegenerat Disorders, Dept Neurobiol, Minist Educ,Beijing Inst Geriatr,Xuanwu Hosp, Beijing 100053, Peoples R China. EM wutao69@gmail.com FU National Science Foundation of China [81071012, 81271429]; Seed Grant of International Alliance of Translational Neuroscience [PXM2014_014226_000015]; NINDS FX This work was supported by grants from the National Science Foundation of China (81071012 and 81271429), and Seed Grant of International Alliance of Translational Neuroscience (PXM2014_014226_000015). Dr Hallett is supported by the NINDS Intramural Program. NR 109 TC 8 Z9 8 U1 5 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD JAN 1 PY 2016 VL 139 BP 144 EP 160 DI 10.1093/brain/awv319 PN 1 PG 17 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DD8VM UT WOS:000370205000025 PM 26525918 ER PT J AU Berman, RA Gotts, SJ McAdams, HM Greenstein, D Lalonde, F Clasen, L Watsky, RE Shora, L Ordonez, AE Raznahan, A Martin, A Gogtay, N Rapoport, J AF Berman, Rebecca A. Gotts, Stephen J. McAdams, Harrison M. Greenstein, Dede Lalonde, Francois Clasen, Liv Watsky, Rebecca E. Shora, Lorie Ordonez, Anna E. Raznahan, Armin Martin, Alex Gogtay, Nitin Rapoport, Judith TI Disrupted sensorimotor and social-cognitive networks underlie symptoms in childhood-onset schizophrenia SO BRAIN LA English DT Article DE psychosis; schizophrenia; positive symptoms; negative symptoms; neuropsychiatry: imaging ID AUTISM SPECTRUM DISORDERS; RESTING STATE FMRI; INTRINSIC FUNCTIONAL CONNECTIVITY; GLOBAL SIGNAL REGRESSION; COROLLARY DISCHARGE; SENSORY PREDICTION; BRAIN-DEVELOPMENT; DEFAULT MODE; 1ST-DEGREE RELATIVES; EFFERENCE COPY AB Schizophrenia is increasingly recognized as a neurodevelopmental disorder with altered connectivity among brain networks. In the current study we examined large-scale network interactions in childhood-onset schizophrenia, a severe form of the disease with salient genetic and neurobiological abnormalities. Using a data-driven analysis of resting-state functional magnetic resonance imaging fluctuations, we characterized data from 19 patients with schizophrenia and 26 typically developing controls, group matched for age, sex, handedness, and magnitude of head motion during scanning. This approach identified 26 regions with decreased functional correlations in schizophrenia compared to controls. These regions were found to organize into two function-related networks, the first with regions associated with social and higher-level cognitive processing, and the second with regions involved in somatosensory and motor processing. Analyses of across-and within-network regional interactions revealed pronounced across-network decreases in functional connectivity in the schizophrenia group, as well as a set of across-network relationships with overall negative coupling indicating competitive or opponent network dynamics. Critically, across-network decreases in functional connectivity in schizophrenia predicted the severity of positive symptoms in the disorder, such as hallucinations and delusions. By contrast, decreases in functional connectivity within the social-cognitive network of regions predicted the severity of negative symptoms, such as impoverished speech and flattened affect. These results point toward the role that abnormal integration of sensorimotor and social-cognitive processing may play in the pathophysiology and symptomatology of schizophrenia. C1 [Berman, Rebecca A.; McAdams, Harrison M.; Greenstein, Dede; Lalonde, Francois; Clasen, Liv; Watsky, Rebecca E.; Shora, Lorie; Ordonez, Anna E.; Raznahan, Armin; Gogtay, Nitin; Rapoport, Judith] NIMH, Child Psychiat Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Gotts, Stephen J.; Martin, Alex] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Berman, RA (reprint author), Neuropsychol Lab, Room 1B80,49 Convent Dr, Bethesda, MD 20892 USA. EM bermanr@mail.nih.gov FU National Institute of Mental Health (NIH), Division of Intramural Research [ZIAMH002581] FX This research was funded by the National Institute of Mental Health (NIH), Division of Intramural Research (ZIAMH002581). NR 115 TC 4 Z9 4 U1 3 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD JAN 1 PY 2016 VL 139 BP 276 EP 291 DI 10.1093/brain/awv306 PN 1 PG 16 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DD8VM UT WOS:000370205000034 PM 26493637 ER PT J AU Zhang, SL Wei, JS Li, SQ Badgett, TC Song, YK Agarwal, S Coarfa, C Tolman, C Hurd, L Liao, HL He, JB Wen, XY Liu, ZH Thiele, CJ Westermann, F Asgharzadeh, S Seeger, RC Maris, JM Auvil, JMG Smith, MA Kolaczyk, ED Shohet, J Khan, J AF Zhang, Shile Wei, Jun S. Li, Samuel Q. Badgett, Tom C. Song, Young K. Agarwal, Saurabh Coarfa, Cristian Tolman, Catherine Hurd, Laura Liao, Hongling He, Jianbin Wen, Xinyu Liu, Zhihui Thiele, Carol J. Westermann, Frank Asgharzadeh, Shahab Seeger, Robert C. Maris, John M. Auvil, Jamie M. Guidry Smith, Malcolm A. Kolaczyk, Eric D. Shohet, Jason Khan, Javed TI MYCN controls an alternative RNA splicing program in high-risk metastatic neuroblastoma SO CANCER LETTERS LA English DT Article DE Neuroblastoma; Splicing; MYCN-amplification; RNA-seq; RNA isoforms ID EXON ARRAY ANALYSIS; KINASE MESSENGER-RNA; PYRUVATE-KINASE; HNRNP PROTEINS; TUMOR-GROWTH; NEURONAL DIFFERENTIATION; CANCER METABOLISM; PROSTATE-CANCER; GENE-EXPRESSION; LUNG-CANCER AB The molecular mechanisms underlying the aggressive behavior of MYCN driven neuroblastoma (NBL) is under intense investigation; however, little is known about the impact of this family of transcription factors on the splicing program. Here we used high-throughput RNA sequencing to systematically study the expression of RNA isoforms in stage 4 MYCN-amplified NBL, an aggressive subtype of metastatic NBL. We show that MYCN-amplified NBL tumors display a distinct gene splicing pattern affecting multiple cancer hallmark functions. Six splicing factors displayed unique differential expression patterns in MYCN-amplified tumors and cell lines, and the binding motifs for some of these splicing factors are significantly enriched in differentially-spliced genes. Direct binding of MYCN to promoter regions of the splicing factors PTBP1 and HNRNPA1 detected by ChIP-seq demonstrates that MYCN controls the splicing pattern by direct regulation of the expression of these key splicing factors. Furthermore, high expression of PTBP1 and HNRNPA1 was significantly associated with poor overall survival of stage4 NBL patients (p <= 0.05). Knocking down PTBP1, HNRNPA1 and their downstream target PKM2, an isoform of pro-tumor-growth, result in repressed growth of NBL cells. Therefore, our study reveals a novel role of MYCN in controlling global splicing program through regulation of splicing factors in addition to its well-known role in the transcription program. These findings suggest a therapeutically potential to target the key splicing factors or gene isoforms in high-risk NBL with MYCN-amplification. Published by Elsevier Ireland Ltd. C1 [Zhang, Shile; Wei, Jun S.; Li, Samuel Q.; Badgett, Tom C.; Song, Young K.; Tolman, Catherine; Hurd, Laura; Liao, Hongling; He, Jianbin; Wen, Xinyu; Khan, Javed] NCI, Oncogen Sect, Genet Branch, NIH, Bethesda, MD 20892 USA. [Zhang, Shile; Kolaczyk, Eric D.] Boston Univ, Program Bioinformat, Boston, MA 02218 USA. [Badgett, Tom C.] Kentucky Childrens Hosp, Pediat Hematol & Oncol, Lexington, KY 40536 USA. [Agarwal, Saurabh; Coarfa, Cristian; Shohet, Jason] Baylor Coll Med, Dept Pediat, Ctr Cell & Gene Therapy, Texas Childrens Canc Ctr, Houston, TX 77030 USA. [Liu, Zhihui; Thiele, Carol J.] NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Westermann, Frank] German Canc Res Ctr, Neuroblastoma Genom, B030,Neuenheimer Feld 280, D-69120 Heidelberg, Germany. [Asgharzadeh, Shahab; Seeger, Robert C.] Childrens Hosp Los Angeles, Div Hematol Oncol, Los Angeles, CA 90027 USA. [Asgharzadeh, Shahab; Seeger, Robert C.] Childrens Hosp Los Angeles, Saban Res Inst, Los Angeles, CA 90027 USA. [Asgharzadeh, Shahab; Seeger, Robert C.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90089 USA. [Maris, John M.] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA. [Maris, John M.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Maris, John M.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Auvil, Jamie M. Guidry] NCI, Off Canc Genom, Bethesda, MD 20892 USA. [Smith, Malcolm A.] NCI, Clin Invest Branch, Rockville, MD 20850 USA. [Kolaczyk, Eric D.] Boston Univ, Dept Math & Stat, Boston, MA 02218 USA. RP Khan, J (reprint author), NCI, Oncogen Sect, Genet Branch, NIH, Bethesda, MD 20892 USA. EM khanjav@mail.nih.gov RI Khan, Javed/P-9157-2014; OI Khan, Javed/0000-0002-5858-0488; Agarwal, Saurabh/0000-0001-9758-6746 FU Intramural NIH HHS [Z01 BC010806-01, Z01 BC011002-01] NR 64 TC 4 Z9 4 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PY 2016 VL 371 IS 2 BP 214 EP 224 DI 10.1016/j.canlet.2015.11.045 PG 11 WC Oncology SC Oncology GA DE2KX UT WOS:000370457300009 PM 26683771 ER PT J AU Kaur, G Reinhart, RA Monks, A Evans, D Morris, J Polley, E Teicher, BA AF Kaur, Gurmeet Reinhart, Russell A. Monks, Anne Evans, David Morris, Joel Polley, Eric Teicher, Beverly A. TI Bromodomain and hedgehog pathway targets in small cell lung cancer SO CANCER LETTERS LA English DT Article DE Small cell lung cancer; SCLC; SCLC gene expression; Hedgehog inhibitors; Bromodomain inhibitors ID C-MYC; BET BROMODOMAINS; LINES; INHIBITION; AMPLIFICATION; LYMPHOMA; LEUKEMIA AB Small cell lung cancer (SCLC) is an extremely aggressive cancer that frequently recurs. Twenty-three human SCLC lines were selected representing varied Myc status. Gene expression of lung cancer, stem-like, hedgehog pathway, and notch pathway genes were determined by RT2-PCR array and Exon 1.0 ST array. Etoposide and topotecan concentration response was examined. The IC50's for etoposide and topotecan ranged over nearly 3 logs upon 96 hrs exposure to the drugs. Myc status, TOP2A, TOP2B and TOP1 mRNA expression or topoisomerase 1 and topoisomerase 2 protein did not account for the range in the sensitivity to the drugs. gamma-secretase inhibitors, RO429097 and PF-03084014, had little activity in the SCLC lines over ranges covering the clinical Cmax concentrations. MYC amplified lines tended to be more sensitive to the bromodomain inhibitor JQ1. The Smo antagonists, erismodegib and vismodegib and the Gli antagonists, HPI1 and SEN-450 had a trend toward greater sensitivity of the MYC amplified line. Recurrent SCLC is among the most recalcitrant cancers and drug development efforts in this cancer are a high priority. Published by Elsevier Ireland Ltd. C1 [Kaur, Gurmeet] NCI, Mol Pharmacol Branch, Div Canc Treatment & Diag, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Reinhart, Russell A.; Monks, Anne; Evans, David] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Morris, Joel; Teicher, Beverly A.] NCI, Dev Therapeut Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Polley, Eric] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Teicher, BA (reprint author), NCI, Dev Therapeut Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. EM Beverly.Teicher@nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract 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 Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 43 TC 4 Z9 4 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PY 2016 VL 371 IS 2 BP 225 EP 239 DI 10.1016/j.canlet.2015.12.001 PG 15 WC Oncology SC Oncology GA DE2KX UT WOS:000370457300010 PM 26683772 ER PT J AU Nadal, R Bellmunt, J AF Nadal, Rosa Bellmunt, Joaquim TI The evolving role of enzalutamide on the treatment of prostate cancer SO FUTURE ONCOLOGY LA English DT Article DE castration-resistant prostate cancer; enzalutamide; hormone-sensitive prostate cancer; prostate cancer; STRIVE ID OPEN-LABEL; ANTITUMOR-ACTIVITY; RESISTANCE; ABIRATERONE; CHEMOTHERAPY; DOCETAXEL; MDV3100; MONOTHERAPY; INHIBITOR; EFFICACY AB The field of prostate cancer has witnessed incredible progress in the last decade, owing to the approval of multiple survival-prolonging treatments for metastatic castration-resistant prostate cancer (mCRPC). Enzalutamide is a nonsteroidal androgen receptor inhibitor that targets multiple steps in the androgen receptor signaling axis. It has been approved for the treatment of mCRPC both in the postdocetaxel and in the chemotherapy-naive settings. We summarize the milestones in the development of enzalutamide in patients with prostate cancer. Special focus is placed on the results of the STRIVE Phase II clinical trial comparing head to head enzalutamide and bicalutamide in patients with nonmetastatic and mCRPC who have failed androgen deprivation and in other ongoing trials in the same setting and in earlier disease phases. C1 [Nadal, Rosa] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Bellmunt, Joaquim] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bellmunt, Joaquim] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Nadal, R (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.; Bellmunt, J (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA.; Bellmunt, J (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM rosa.nadalrios@nih.gov; Joaquim_bellmunt@dfci.harvard.edu FU Pierre Fabre; Astellas Pharma; Pfizer; Takeda/Millennium FX J Bellmunt has received consultancy and lecture fees from Pierre Fabre, Astellas Pharma and Pfizer and research funding from Takeda/Millennium. 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 28 TC 0 Z9 0 U1 0 U2 1 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1479-6694 EI 1744-8301 J9 FUTURE ONCOL JI Future Oncol. PY 2016 VL 12 IS 5 BP 607 EP 616 DI 10.2217/fon.15.351 PG 10 WC Oncology SC Oncology GA DE5TQ UT WOS:000370695600007 PM 26839021 ER PT J AU Banegas, MP Guy, GP de Moor, JS Ekwueme, DU Virgo, KS Kent, EE Nutt, S Zheng, ZY Rechis, R Yabroff, KR AF Banegas, Matthew P. Guy, Gery P., Jr. de Moor, Janet S. Ekwueme, Donatus U. Virgo, Katherine S. Kent, Erin E. Nutt, Stephanie Zheng, Zhiyuan Rechis, Ruth Yabroff, K. Robin TI For Working-Age Cancer Survivors, Medical Debt And Bankruptcy Create Financial Hardships SO HEALTH AFFAIRS LA English DT Article ID UNITED-STATES; PROSTATE-CANCER; CLINICAL ONCOLOGY; AMERICAN SOCIETY; ECONOMIC BURDEN; CARE; BREAST; COST; POPULATION; EMPLOYMENT AB The rising medical costs associated with cancer have led to considerable financial hardship for patients and their families in the United States. Using data from the LIVESTRONG 2012 survey of 4,719 cancer survivors ages 18-64, we examined the proportions of survivors who reported going into debt or filing for bankruptcy as a result of cancer, as well as the amount of debt incurred. Approximately one-third of the survivors had gone into debt, and 3 percent had filed for bankruptcy. Of those who had gone into debt, 55 percent incurred obligations of $10,000 or more. Cancer survivors who were younger, had lower incomes, and had public health insurance were more likely to go into debt or file for bankruptcy, compared to those who were older, had higher incomes, and had private insurance, respectively. Future longitudinal population-based studies are needed to improve understanding of financial hardship among US working-age cancer survivors throughout the cancer care trajectory and, ultimately, to help stakeholders develop evidence-based interventions and policies to reduce the financial hardship of cancer. C1 [Banegas, Matthew P.] Kaiser Permanente Ctr Hlth Res, Portland, OR USA. [Guy, Gery P., Jr.] Centers Dis Control & Prevent CDC, Atlanta, GA USA. [de Moor, Janet S.; Yabroff, K. Robin] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Ekwueme, Donatus U.] CDC, Atlanta, GA 30333 USA. [Virgo, Katherine S.] Emory Univ, Dept Hlth Policy & Management, Atlanta, GA 30322 USA. [Kent, Erin E.] NCI, Outcomes Res Branch, Appl Res Program, Healthcare Delivery Res Program,Div Canc Control, Bethesda, MD 20892 USA. [Nutt, Stephanie] LIVESTRONG Fdn, Austin, TX USA. [Zheng, Zhiyuan] Amer Canc Soc, Atlanta, GA 30329 USA. [Rechis, Ruth] LIVESTRONG Fdn, Programs & Strategy, Austin, TX USA. RP Banegas, MP (reprint author), Kaiser Permanente Ctr Hlth Res, Portland, OR USA. EM Matthew.P.Banegas@kpchr.org NR 50 TC 7 Z9 7 U1 2 U2 5 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD JAN PY 2016 VL 35 IS 1 BP 54 EP 61 DI 10.1377/hlthaff.2015.0830 PG 8 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA DD1PV UT WOS:000369694700008 PM 26733701 ER PT J AU Tinoco, YO Montgomery, JM Kasper, MR Nelson, MI Razuri, H Guezala, MC Azziz-Baumgartner, E Widdowson, MA Barnes, J Gilman, RH Bausch, DG Gonzalez, AE AF Tinoco, Yeny O. Montgomery, Joel M. Kasper, Mathew R. Nelson, Martha I. Razuri, Hugo Guezala, Maria C. Azziz-Baumgartner, Eduardo Widdowson, Marc-Alain Barnes, John Gilman, Robert H. Bausch, Daniel G. Gonzalez, Armando E. TI Transmission dynamics of pandemic influenza A(H1N1) pdm09 virus in humans and swine in backyard farms in Tumbes, Peru SO INFLUENZA AND OTHER RESPIRATORY VIRUSES LA English DT Article DE Antibodies; backyard pig farms; human-animal transmission; influenza ID H1N1 2009 VIRUS; A VIRUS; PIGS; REASSORTMENT; EMERGENCE; OUTBREAK; ARGENTINA; INFECTION; KOREA AB Objectives We aimed to determine the frequency of pH1N1 transmission between humans and swine on backyard farms in Tumbes, Peru. Design Two-year serial cross-sectional study comprising four sampling periods: March 2009 (pre-pandemic), October 2009 (peak of the pandemic in Peru), April 2010 (1st post-pandemic period), and October 2011 (2nd post-pandemic period). Sample Backyard swine serum, tracheal swabs, and lung sample were collected during each sampling period. Main outcome measures We assessed current and past pH1N1 infection in swine through serological testing, virus culture, and RTPCR and compared the results with human incidence data from a population-based active surveillance cohort study in Peru. Results Among 1303 swine sampled, the antibody prevalence to pH1N1 was 0% pre-pandemic, 8% at the peak of the human pandemic (October 2009), and 24% in April 2010 and 1% in October 2011 (post-pandemic sampling periods). Trends in swine seropositivity paralleled those seen in humans in Tumbes. The pH1N1 virus was isolated from three pigs during the peak of the pandemic. Phylogenetic analysis revealed that these viruses likely represent two separate human-to-swine transmission events in backyard farm settings. Conclusions Our findings suggest that human-to-swine pH1N1 transmission occurred during the pandemic among backyard farms in Peru, emphasizing the importance of interspecies transmission in backyard pig populations. Continued surveillance for influenza viruses in backyard farms is warranted. C1 [Tinoco, Yeny O.; Montgomery, Joel M.; Kasper, Mathew R.; Razuri, Hugo; Guezala, Maria C.; Bausch, Daniel G.] US Naval, Med Res Unit 6, Lima, Peru. [Tinoco, Yeny O.; Gilman, Robert H.] Johns Hopkins Sch Publ Hlth, Baltimore, MD USA. [Montgomery, Joel M.] US Ctr Dis Control & Prevent, Div Global Hlth Protect, Nairobi, Kenya. [Nelson, Martha I.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Azziz-Baumgartner, Eduardo; Widdowson, Marc-Alain; Barnes, John] US Ctr Dis Control & Prevent, Atlanta, GA USA. [Bausch, Daniel G.] Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Gonzalez, Armando E.] San Marcos Univ, Sch Vet, Lima, Peru. RP Tinoco, YO (reprint author), US Embassy Lima, NAMRU 6, Ctr Med Naval Av Venezuela Cdra 36 S-N, Callao 2, Peru. EM ytinoco1@jhu.edu FU Bill and Melinda Gates Foundation [23981]; Centers for Disease Control and Prevention; Armed Forces Health Surveillance Center Global Emerging Infections Surveillance and Response System; NIH/NSF 'Ecology and Evolution of Infectious Diseases' award from the Fogarty International Center at the U.S. National Institutes of Health [3R01-TW005869]; Fogarty International Center [D43-TW001140)002E] FX We thank Hugo Garcia and Ayvar Viterbo from CEP in Peru and Maria Silva, Karen Segovia, and Bruno Ghersi from NAMRU-6, for their valuable assistance. Work performed in this study was supported by funding from the Bill and Melinda Gates Foundation (23981), the Centers for Disease Control and Prevention, the Armed Forces Health Surveillance Center Global Emerging Infections Surveillance and Response System, the NIH/NSF 'Ecology and Evolution of Infectious Diseases' award from the Fogarty International Center at the U.S. National Institutes of Health (3R01-TW005869), and a training grant from the Fogarty International Center (D43-TW001140)002E. NR 44 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1750-2640 EI 1750-2659 J9 INFLUENZA OTHER RESP JI Influenza Other Respir. Viruses PD JAN PY 2016 VL 10 IS 1 BP 47 EP 56 DI 10.1111/irv.12329 PG 10 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA DD9BS UT WOS:000370221300007 PM 26011186 ER PT J AU MacLeod, EL Hall, KD McGuire, PJ AF MacLeod, Erin L. Hall, Kevin D. McGuire, Peter J. TI Computational modeling to predict nitrogen balance during acute metabolic decompensation in patients with urea cycle disorders SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Article ID MUSCLE PROTEIN-SYNTHESIS; HUMAN SKELETAL-MUSCLE; MANAGEMENT; FAT; INFECTION; NUTRITION; HUMANS AB Nutritional management of acute metabolic decompensation in amino acid inborn errors of metabolism (AA IEM) aims to restore nitrogen balance. While nutritional recommendations have been published, they have never been rigorously evaluated. Furthermore, despite these recommendations, there is a wide variation in the nutritional strategies employed amongst providers, particularly regarding the inclusion of parenteral lipids for protein-free caloric support. Since randomized clinical trials during acute metabolic decompensation are difficult and potentially dangerous, mathematical modeling of metabolism can serve as a surrogate for the preclinical evaluation of nutritional interventions aimed at restoring nitrogen balance during acute decompensation in AA IEM. Avalidated computational model of human macronutrient metabolism was adapted to predict nitrogen balance in response to various nutritional interventions in a simulated patient with a urea cycle disorder (UCD) during acute metabolic decompensation due to dietary non-adherence or infection. The nutritional interventions were constructed from published recommendations as well as clinical anecdotes. Overall, dextrose alone (DEX) was predicted to be better at restoring nitrogen balance and limiting nitrogen excretion during dietary non-adherence and infection scenarios, suggesting that the published recommended nutritional strategy involving dextrose and parenteral lipids (ISO) may be suboptimal. The implications for patients with AA IEM are that the medical course during acute metabolic decompensation may be influenced by the choice of protein-free caloric support. These results are also applicable to intensive care patients undergoing catabolism (postoperative phase or sepsis), where parenteral nutritional support aimed at restoring nitrogen balance may be more tailored regarding metabolic fuel selection. C1 [MacLeod, Erin L.] Childrens Natl Hlth Syst, Div Genet & Metab, Washington, DC USA. [Hall, Kevin D.] NIDDK, NIH, Bethesda, MD 20892 USA. [McGuire, Peter J.] NHGRI, NIH, 49 Convent Dr,4A62, Bethesda, MD 20892 USA. RP McGuire, PJ (reprint author), NHGRI, NIH, 49 Convent Dr,4A62, Bethesda, MD 20892 USA. EM peter.mcguire@nih.gov FU Intramural Research Program of the National Institutes of Health FX PJM and KDH are supported by the Intramural Research Program of the National Institutes of Health. NR 23 TC 0 Z9 0 U1 1 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 EI 1573-2665 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD JAN PY 2016 VL 39 IS 1 BP 17 EP 24 DI 10.1007/s10545-015-9882-0 PG 8 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA DE0YN UT WOS:000370351900003 PM 26260782 ER PT J AU Zhao, BX Huang, P Rong, PF Wang, Y Gao, MY Huang, HY Sun, K Chen, XY Li, WW AF Zhao, Bingxia Huang, Peng Rong, Pengfei Wang, Yu Gao, Mengyu Huang, Haiyan Sun, Kang Chen, Xiaoyuan Li, Wanwan TI Facile synthesis of ternary CdMnS QD-based hollow nanospheres as fluorescent/magnetic probes for bioimaging SO JOURNAL OF MATERIALS CHEMISTRY B LA English DT Article ID TEMPLATE-FREE SYNTHESIS; FREE HYDROTHERMAL SYNTHESIS; ZNO QUANTUM DOTS; MAGNETIC-RESONANCE; CONTRAST AGENTS; PHOTOCATALYTIC PROPERTIES; SILICA SPHERES; DRUG-DELIVERY; NANOPARTICLES; MICROSPHERES AB In this study, fluorescent/magnetic dual-functional hollow nanospheres conducted by ternary CdMnS nanoparticles were synthesized via a facile Ostwald-ripening process. The as-prepared hollow nanospheres exhibited bright and tunable emission under excitation with a 365 nm UV light coupled with a strong MR signal, suggesting their promising applications in bioimaging. C1 [Zhao, Bingxia; Gao, Mengyu; Sun, Kang; Li, Wanwan] Shanghai Jiao Tong Univ, Sch Mat Sci & Engn, State Key Lab Met Matrix Composites, 800 Dongchuan Rd, Shanghai 200240, Peoples R China. [Zhao, Bingxia] Southern Med Univ, Canc Res Inst, Guangzhou 510515, Guangdong, Peoples R China. [Huang, Peng; Wang, Yu; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Rong, Pengfei] Cent S Univ, Xiangya Hosp 3, Dept Radiol, Changsha 410013, Hunan, Peoples R China. [Huang, Haiyan] Shanghai Jiao Tong Univ, Inst Syst Biomed, Ctr Comparat Biomed, Key Lab Syst Biomed,Minist Educ, Shanghai 200240, Peoples R China. RP Sun, K; Li, WW (reprint author), Shanghai Jiao Tong Univ, Sch Mat Sci & Engn, State Key Lab Met Matrix Composites, 800 Dongchuan Rd, Shanghai 200240, Peoples R China. EM ksun@sjtu.edu.cn; wwli@sjtu.edu.cn RI Huang, Peng/R-2480-2016 OI Huang, Peng/0000-0003-3651-7813 FU National Natural Science Foundation of China [81371645]; Science and Technology Committee of Shanghai [15PJD020, 15441905800]; Medicine & Engineering Cross Research Foundation of Shanghai Jiao Tong University [YG2012MS61, YG2014MS33]; Scientific Research Starting Foundation of Southern Medical University [PY2015N003] FX This work was financially supported by the National Natural Science Foundation of China (Project No. 81371645), Science and Technology Committee of Shanghai (Project No. 15PJD020, 15441905800), Medicine & Engineering Cross Research Foundation of Shanghai Jiao Tong University (Project No. YG2012MS61, YG2014MS33), and the Scientific Research Starting Foundation of Southern Medical University (Project No. PY2015N003). We thank the Instrumental Analysis Center of SJTU for the assistance with TEM, XRD and ICP-MS characterizations. NR 61 TC 1 Z9 1 U1 8 U2 22 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2050-750X EI 2050-7518 J9 J MATER CHEM B JI J. Mat. Chem. B PY 2016 VL 4 IS 7 BP 1208 EP 1212 DI 10.1039/c5tb01963j PG 5 WC Materials Science, Biomaterials SC Materials Science GA DE2AC UT WOS:000370427400001 ER PT J AU Lerner, ZF Board, WJ Browning, RC AF Lerner, Zachary F. Board, Wayne J. Browning, Raymond C. TI Pediatric Obesity and Walking Duration Increase Medial Tibiofemoral Compartment Contact Forces SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE gait biomechanics; musculoskeletal modeling; subject-specific; joint loading; opensim ID PHYSICAL-ACTIVITY; LOWER-EXTREMITY; CHILDHOOD OBESITY; CHILDREN; KNEE; ADOLESCENTS; OVERWEIGHT; ALIGNMENT; MUSCLE; PREDICTIONS AB With the high prevalence of pediatric obesity there is a need for structured physical activity during childhood. However, altered tibiofemoral loading during physical activity in obese children likely contribute to their increased risk of orthopedic disorders of the knee. The goal of this study was to determine the effects of pediatric obesity and walking duration on medial and lateral tibiofemoral contact forces. We collected experimental biomechanics data during treadmill walking at 1m.s(-1) for 20 min in 10 obese and 10 healthy-weight 8-12 year-olds. We created subject-specific musculoskeletal models using radiographic measures of tibiofemoral alignment and centers-of-pressure, and predicted medial and lateral tibiofemoral contact forces at the beginning and end of each trial. Obesity and walking duration affected tibiofemoral loading. At the beginning of the trail, the average percent of the total load passing through the medial compartment during stance was 85% in the obese children and 63% in the healthy-weight children; at the end of the trial, the medial distribution was 90% in the obese children and 72% in the healthy-weight children. Medial compartment loading rates were 1.78 times greater in the obese participants. The medial compartment loading rate increased 17% in both groups at the end compared to the beginning of the trial (p = 0.001). We found a strong linear relationship between body-fat percentage and the mediallateral load distribution (r(2) = 0.79). Altered tibiofemoral loading during walking in obese children may contribute to their increased risk of knee pain and pathology. (C) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. C1 [Lerner, Zachary F.] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bldg 10, Bethesda, MD 20892 USA. [Lerner, Zachary F.; Browning, Raymond C.] Colorado State Univ, Sch Biomed Engn, Ft Collins, CO 80523 USA. [Board, Wayne J.; Browning, Raymond C.] Colorado State Univ, Dept Hlth & Exercise Sci, Ft Collins, CO 80523 USA. RP Lerner, ZF (reprint author), NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bldg 10, Bethesda, MD 20892 USA.; Lerner, ZF (reprint author), Colorado State Univ, Sch Biomed Engn, Ft Collins, CO 80523 USA. EM zachary.lerner@nih.gov FU Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health [F31HD080261]; American College of Sports Medicine FX Grant sponsor: Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number; Grant number: F31HD080261;; Grant sponsor: American College of Sports Medicine. NR 30 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-0266 EI 1554-527X J9 J ORTHOP RES JI J. Orthop. Res. PD JAN PY 2016 VL 34 IS 1 BP 97 EP 105 DI 10.1002/jor.23028 PG 9 WC Orthopedics SC Orthopedics GA DD9LN UT WOS:000370247100016 PM 26271943 ER PT S AU Yoon, JH Gorospe, M AF Yoon, Je-Hyun Gorospe, Myriam BE Feng, Y Zhang, L TI Cross-Linking Immunoprecipitation and qPCR (CLIP-qPCR) Analysis to Map Interactions Between Long Noncoding RNAs and RNA-Binding Proteins SO LONG NON-CODING RNAS: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE CLIP; lncRNA; RBP; Ribonucleoprotein complexes; qPCR ID POSTTRANSCRIPTIONAL GENE-REGULATION; MICRORNAS; REVEALS; BRAIN AB Mammalian cells express a wide range of transcripts, some protein-coding RNAs (mRNA) and many noncoding (nc) RNAs. Long (l) ncRNAscan modulates protein expression patterns by regulating gene transcription, pre-mRNA splicing, mRNA export, mRNA degradation, protein translation, and protein ubiquitination. Given the growing recognition that lncRNAs have a robust impact upon gene expression, there is rising interest in elucidating the levels and regulation of lncRNAs. A number of high-throughput methods have been developed recently to map the interaction of lncRNAs and RNA-binding proteins (RBPs). However, few of these approaches are suitable for mapping and quantifying RBP-lncRNA interactions. Here, we describe the recently developed method CLIP-qPCR (cross-linking and immunoprecipitation followed by reverse transcription and quantitative PCR) for mapping and quantifying RBP-lncRNA interactions. C1 [Yoon, Je-Hyun] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Gorospe, Myriam] NIA, Lab Genet & Genom, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Yoon, JH (reprint author), Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. FU Intramural NIH HHS [, ZIA AG000511-18] NR 16 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-3378-5; 978-1-4939-3376-1 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1402 BP 11 EP 17 DI 10.1007/978-1-4939-3378-5_2 D2 10.1007/978-1-4939-3378-5 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BE3DL UT WOS:000370535500003 PM 26721479 ER PT J AU Asher, I Guri, KM Elbirt, D Bezalel, SR Maldarelli, F Mor, O Grossman, Z Sthoeger, ZM AF Asher, Ilan Guri, Keren Mahlab Elbirt, Daniel Bezalel, Shira Rosenberg Maldarelli, Frank Mor, Orna Grossman, Zehava Sthoeger, Zev M. TI Characteristics and Outcome of Patients Diagnosed With HIV at Older Age SO MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; POPULATION; DIVERSITY; INFECTION; PEOPLE; EUROPE; AIDS AB To characterize the clinical, virological, and immunological status at presentation as well as the outcome of patients diagnosed with HIV above the age of 50.A retrospective study of 418 patients newly diagnosed with HIV in 1 Israeli center, between the years 2004 and 2013.Patients with new HIV diagnosis 50 years of age defined as older" and <50 defined as younger." Patients were evaluated every 1 to 3 months (mean follow-up 5333 months). Patients with <2 CD4/viral-load measurements or with <1 year of follow-up were excluded. Time of HIV infection was estimated by HIV sequence ambiguity assay. Ambiguity index 0.43 indicated recent (1 year) HIV infection.Eighty nine (21%) patients were diagnosed with HIV at an older age. Those older patients presented with significant lower CD4 cell counts and higher viral-load compared with the younger patients. At the end of the study, the older patients had higher mortality rate (21% vs 3.5%; P<0.001) and lower CD4 cell counts (381 +/- 228 vs 483 +/- 261cells/L; P<0.001) compared with the younger patients. This difference was also observed between older and younger patients with similar CD4 cell counts and viral load at the time of HIV diagnosis and among patients with a recent (1 year) HIV infection.One-fifth of HIV patients are diagnosed at older age (50 years). Those older patients have less favorable outcome compared with the younger patients. This point to the need of educational and screening programs within older populations and for a closer follow-up of older HIV patients. C1 [Asher, Ilan; Guri, Keren Mahlab; Elbirt, Daniel; Bezalel, Shira Rosenberg; Sthoeger, Zev M.] Hebrew Univ Jerusalem, Hadassah Med Sch, Allergy & Neve AIDS Ctr, Unit Clin Immunol, IL-91010 Jerusalem, Israel. [Asher, Ilan; Guri, Keren Mahlab; Elbirt, Daniel; Bezalel, Shira Rosenberg; Sthoeger, Zev M.] Hebrew Univ Jerusalem, Hadassah Med Sch, Kaplan Med Ctr, Dept Med B, IL-91010 Jerusalem, Israel. [Maldarelli, Frank; Grossman, Zehava] NCI, Frederick, MD 21701 USA. [Mor, Orna] Minist Hlth, Cent Virol Lab, Ramat Gan, Israel. [Grossman, Zehava] Tel Aviv Univ, Sch Publ Hlth, IL-69978 Tel Aviv, Israel. RP Sthoeger, ZM (reprint author), Kaplan Med Ctr, Dept Med B, IL-76100 Rehovot, Israel.; Sthoeger, ZM (reprint author), Kaplan Med Ctr, Clin Immunol Allergy & AIDS, IL-76100 Rehovot, Israel. EM zev_s@clalit.org.il NR 28 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7974 EI 1536-5964 J9 MEDICINE JI Medicine (Baltimore) PD JAN PY 2016 VL 95 IS 1 AR e2327 DI 10.1097/MD.0000000000002327 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA DE3ID UT WOS:000370520200013 PM 26735534 ER PT J AU Driscoll, CA Barr, CS AF Driscoll, Carlos A. Barr, Christina S. TI Studying longitudinal trajectories in animal models of psychiatric illness and their translation to the human condition SO NEUROSCIENCE RESEARCH LA English DT Review DE Primate; Genetic; Stress; Social attachment; OPRM1; CRH; Serotonin transporter ID SEROTONIN TRANSPORTER GENE; CORTICOTROPIN-RELEASING HORMONE; NONHUMAN PRIMATE MODEL; STRESSFUL LIFE EVENTS; SINGLE-NUCLEOTIDE POLYMORPHISM; INFANT RHESUS MACAQUES; PRENATAL STRESS; ALCOHOL-CONSUMPTION; BISPHENOL-A; MONOAMINE-OXIDASE AB Many forms of psychopathology and/or psychiatric illness can occur through the pathways of altered environmental sensitivity, impulsivity, social functioning, and anxious responding. While these traits are also heritable, environmental conditions are known to play a critical role. The genetic factors that contribute to these traits may be adaptive in certain contexts, but can - under the environmental conditions commonly faced among modern humans - also be key moderators of risk for psychopathological outcomes. This article will discuss how animal studies inform us of the various environmental mechanisms through which prenatal or early postnatal environmental challenge can produce long-term effects on behavior and will briefly address how pre-copulatory, pre-natal and early postnatal epigenetic effects can contribute to persistent alterations in offspring behavior. Its main focus will be how nonhuman primate studies have helped us to understand how genetic vulnerability factors can moderate responses to early environmental factors, suggesting pathways through which early stress might produce long-term effects, thus pointing to systems that might moderate risk for psychiatric illnesses in humans. (C) 2015 Published by Elsevier Ireland Ltd. C1 [Driscoll, Carlos A.; Barr, Christina S.] NIAAA, Sect Comparat Behav Genom, NIH, LNG, 5625 Fishers Lane,3S-32, Bethesda, MD 20852 USA. RP Barr, CS (reprint author), NIAAA, Sect Comparat Behav Genom, NIH, LNG, 5625 Fishers Lane,3S-32, Bethesda, MD 20852 USA. EM cbarr@mail.nih.gov OI Driscoll, Carlos/0000-0003-2392-505X NR 150 TC 1 Z9 1 U1 2 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0168-0102 EI 1872-8111 J9 NEUROSCI RES JI Neurosci. Res. PD JAN PY 2016 VL 102 BP 67 EP 77 DI 10.1016/j.neures.2015.08.001 PG 11 WC Neurosciences SC Neurosciences & Neurology GA DD8MH UT WOS:000370180400009 PM 26276350 ER PT J AU Schisterman, EF Sjaarda, LA AF Schisterman, Enrique F. Sjaarda, Lindsey A. TI No Right Answers without Knowing Your Question SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Editorial Material ID BIRTH-WEIGHT PARADOX; PERINATAL EPIDEMIOLOGY; CIGARETTE-SMOKING; MORTALITY; OUTCOMES; BIAS C1 [Schisterman, Enrique F.; Sjaarda, Lindsey A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Epidemiol Branch, 6100 Execut Blvd,7B03, Rockville, MD 20854 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Epidemiol Branch, 6100 Execut Blvd,7B03, Rockville, MD 20854 USA. EM schistee@mail.nih.gov OI Sjaarda, Lindsey/0000-0003-0539-8110; Schisterman, Enrique/0000-0003-3757-641X FU Intramural NIH HHS [Z01 HD008761-05] NR 19 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 EI 1365-3016 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD JAN PY 2016 VL 30 IS 1 BP 20 EP 22 DI 10.1111/ppe.12258 PG 3 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA DD9MB UT WOS:000370248700005 PM 26768057 ER PT J AU Skakkebaek, NE Rajpert-De Meyts, E Louis, GMB Toppari, J Andersson, AM Eisenberg, ML Jensen, TK Jorgensen, N Swan, SH Sapra, KJ Ziebe, S Priskorn, L Juul, A AF Skakkebaek, Niels E. Rajpert-De Meyts, Ewa Louis, Germaine M. Buck Toppari, Jorma Andersson, Anna-Maria Eisenberg, Michael L. Jensen, Tina Kold Jorgensen, Niels Swan, Shanna H. Sapra, Katherine J. Ziebe, Soren Priskorn, Laerke Juul, Anders TI MALE REPRODUCTIVE DISORDERS AND FERTILITY TRENDS: INFLUENCES OF ENVIRONMENT AND GENETIC SUSCEPTIBILITY SO PHYSIOLOGICAL REVIEWS LA English DT Review ID GERM-CELL TUMORS; CARCINOMA-IN-SITU; GENOME-WIDE ASSOCIATION; TESTICULAR DYSGENESIS SYNDROME; ANDROGEN RECEPTOR GENE; ENDOCRINE-DISRUPTING CHEMICALS; BODY-MASS INDEX; HORMONE-BINDING GLOBULIN; EPIGENETIC TRANSGENERATIONAL ACTIONS; ACTIVATING TRANSCRIPTION FACTOR-3 AB It is predicted that Japan and European Union will soon experience appreciable decreases in their populations due to persistently low total fertility rates (TFR) below replacement level (2.1 child per woman). In the United States, where TFR has also declined, there are ethnic differences. Caucasians have rates below replacement, while TFRs among African-Americans and Hispanics are higher. We review possible links between TFR and trends in a range of male reproductive problems, including testicular cancer, disorders of sex development, cryptorchidism, hypospadias, low testosterone levels, poor semen quality, childlessness, changed sex ratio, and increasing demand for assisted reproductive techniques. We present evidence that several adult male reproductive problems arise in utero and are signs of testicular dysgenesis syndrome (TDS). Although TDS might result from genetic mutations, recent evidence suggests that it most often is related to environmental exposures of the fetal testis. However, environmental factors can also affect the adult endocrine system. Based on our review of genetic and environmental factors, we conclude that environmental exposures arising from modern lifestyle, rather than genetics, are the most important factors in the observed trends. These environmental factors might act either directly or via epigenetic mechanisms. In the latter case, the effects of exposures might have an impact for several generations post-exposure. In conclusion, there is an urgent need to prioritize research in reproductive physiology and pathophysiology, particularly in highly industrialized countries facing decreasing populations. We highlight a number of topics that need attention by researchers in human physiology, pathophysiology, environmental health sciences, and demography. C1 Univ Copenhagen, Rigshosp, Dept Growth & Reprod, DK-2100 Copenhagen, Denmark. Univ Copenhagen, Rigshosp, EDMaRC, DK-2100 Copenhagen, Denmark. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. Univ Turku, Dept Physiol & Pediat, Turku, Finland. Turku Univ Hosp, FIN-20520 Turku, Finland. Stanford Univ, Male Reprod Med & Surg Program, Stanford, CA 94305 USA. Icahn Sch Med Mt Sinai, New York, NY 10029 USA. Rigshosp, Fertil Clin, DK-2100 Copenhagen, Denmark. RP Skakkebaek, NE (reprint author), Rigshosp, Univ Dept Growth & Reprod, DK-2100 Copenhagen, Denmark.; Skakkebaek, NE (reprint author), Rigshosp, EDMaRC, DK-2100 Copenhagen, Denmark. EM nes@rh.dk RI Jorgensen, Niels/A-8148-2012; OI Jorgensen, Niels/0000-0003-4827-0838; Juul, Anders/0000-0002-0534-4350; Buck Louis, Germaine/0000-0002-1774-4490 FU Danish Medical Research Council; Danish Cancer Society; Danish Innovation Fund; Kirsten and Freddy Johansen's Fund; Academy of Finland; Sigrid Juselius Foundation; Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Work in the laboratories of N. E. Skakkebaek, E. Rajpert-De Meyts, A. Juul, A.-M. Andersson, N. Jorgensen, L. Priskorn, and T. K. Jensen was generously supported by the Danish Medical Research Council, the Danish Cancer Society, the Danish Innovation Fund, and Kirsten and Freddy Johansen's Fund. J. Toppari has received grant support from Academy of Finland and Sigrid Juselius Foundation. G. M. Buck Louis and K. J. Sapra are supported by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 477 TC 25 Z9 25 U1 11 U2 38 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0031-9333 EI 1522-1210 J9 PHYSIOL REV JI Physiol. Rev. PD JAN 1 PY 2016 VL 96 IS 1 BP 55 EP 97 DI 10.1152/physrev.00017.2015 PG 43 WC Physiology SC Physiology GA DE1JM UT WOS:000370383200003 PM 26582516 ER PT J AU Homwong, N Jarvis, MC Lam, HC Diaz, A Rovira, A Nelson, M Marthaler, D AF Homwong, Nitipong Jarvis, Matthew C. Lam, Ham Ching Diaz, Andres Rovira, Albert Nelson, Martha Marthaler, Douglas TI Characterization and evolution of porcine deltacoronavirus in the United States SO PREVENTIVE VETERINARY MEDICINE LA English DT Article DE Porcine deltacoronavirus; Bayesian analysis; Swine oral fluid ID TRANSMISSIBLE GASTROENTERITIS VIRUS; RESPIRATORY CORONAVIRUS; PHYLOGENETIC ANALYSIS; RAPID DETECTION; ROTAVIRUS; SEQUENCES; SWINE; CLASSIFICATION; IMMUNITY; SAMPLES AB Porcine deltacoronavirus (PDCoV) was identified in multiple states across the United States (US) in 2014. In this study, we investigate the presence of PDCoV in diagnostic samples, which were further categorized by case identification (ID), and the association between occurrence, age, specimen and location between March and September 2014. Approximately, 7% of the case IDs submitted from the US were positive for PDCoV. Specimens were categorized into eight groups, and the univariate analysis indicated that oral fluids had 1.89 times higher odds of detecting PDCoV compared to feces. While the 43-56 day age group had the highest percentage of PDCoV positives (8.4%), the univariate analysis indicated no significant differences between age groups. However, multivariable analysis for age adjusted by specimen indicated the >147 day age group had 59% lower odds than suckling pigs of being positive for PDCoV. The percentage of PDCoV in diagnostic samples decreased to <1% in September 2014. In addition, 19 complete PDCoV genomes were sequenced, and Bayesian analysis was conducted to estimate the emergence of the US Glade. The evolutionary rate of the PDCoV genome is estimated to be 3.8 x 10(-4) substitutions/site/year (2.3 x 10(-4)-5.4 x 10(-4), 95% HPD). Our results indicate that oral fluids continue to be a valuable specimen to monitor swineherd health, and PDCoV has been circulating in the US prior to 2014. (C) 2015 The Authors. Published by Elsevier B.V. C1 [Homwong, Nitipong; Jarvis, Matthew C.; Lam, Ham Ching; Diaz, Andres; Rovira, Albert; Marthaler, Douglas] Univ Minnesota, Dept Vet Populat Med, Coll Vet Med, 1333 Gortner Ave, St Paul, MN 55108 USA. [Nelson, Martha] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Marthaler, D (reprint author), Univ Minnesota, Dept Vet Populat Med, Coll Vet Med, 1333 Gortner Ave, St Paul, MN 55108 USA. EM marth027@umn.edu FU Rapid Agricultural Response Fund FX This study was supported by the Rapid Agricultural Response Fund, established by the Minnesota legislature and administered by the UM Agricultural Experiment Station. We would like to thank the faculty and personnel, especially Mary Thurn and Katerina Herzberg, at the UMVDL for their technical services and diagnostic testing. NR 38 TC 6 Z9 8 U1 5 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-5877 EI 1873-1716 J9 PREV VET MED JI Prev. Vet. Med. PD JAN 1 PY 2016 VL 123 BP 168 EP 174 DI 10.1016/j.prevetmed.2015.11.001 PG 7 WC Veterinary Sciences SC Veterinary Sciences GA DE0HU UT WOS:000370306500020 PM 26611652 ER PT J AU Jarvis, MC Lam, HC Zhang, Y Wang, LY Hesse, RA Hause, BM Vlasova, A Wang, QH Zhang, JQ Nelson, MI Murtaugh, MP Marthaler, D AF Jarvis, Matthew C. Lam, Ham Ching Zhang, Yan Wang, Leyi Hesse, Richard A. Hause, Ben M. Vlasova, Anastasia Wang, Qiuhong Zhang, Jianqiang Nelson, Martha I. Murtaugh, Michael P. Marthaler, Douglas TI Genomic and evolutionary inferences between American and global strains of porcine epidemic diarrhea virus SO PREVENTIVE VETERINARY MEDICINE LA English DT Article DE Porcine epidemic diarrhea virus; Molecular analysis; Bayesian analysis; Complete genome ID SARS-CORONAVIRUS; UNITED-STATES; POPULATION-DYNAMICS; AMINOPEPTIDASE-N; OUTBREAK; SEQUENCE; CHINA; INSIGHTS; RECEPTOR; GENE AB Porcine epidemic diarrhea virus (PEDV) has caused severe economic losses both recently in the United States (US) and historically throughout Europe and Asia. Traditionally, analysis of the spike gene has been used to determine phylogenetic relationships between PEDV strains. We determined the complete genomes of 93 PEDV field samples from US swine and analyzed the data in conjunction with complete genome sequences available from GenBank (n=126) to determine the most variable genomic areas. Our results indicate high levels of variation within the ORF1 and spike regions while the C-terminal domains of structural genes were highly conserved. Analysis of the Receptor Binding Domains in the spike gene revealed a limited number of amino acid substitutions in US strains compared to Asian strains. Phylogenetic analysis of the complete genome sequence data revealed high rates of recombination, resulting in differing evolutionary patterns in phylogenies inferred for the spike region versus whole genomes. These finding suggest that significant genetic events outside of the spike region have contributed to the evolution of PEDV. (C) 2015 The Authors. Published by Elsevier B.V. C1 [Jarvis, Matthew C.; Lam, Ham Ching; Marthaler, Douglas] Univ Minnesota, Coll Vet Med, Dept Vet Populat Med, St Paul, MN 55108 USA. [Zhang, Yan; Wang, Leyi] Ohio Dept Agr, Anim Dis Diagnost Lab, Reynoldsburg, OH USA. [Hesse, Richard A.; Hause, Ben M.] Kansas State Univ, Kansas State Vet Diagnost Lab, Manhattan, KS 66506 USA. [Hesse, Richard A.; Hause, Ben M.] Kansas State Univ, Dept Diagnost Med & Pathobiol, Manhattan, KS 66506 USA. [Vlasova, Anastasia; Wang, Qiuhong] Ohio State Univ, Ohio Agr Res & Dev Ctr, Food Anim Hlth Res Program, Dept Vet Prevent Med,Coll Food Agr & Environm Sci, Wooster, OH 44691 USA. [Zhang, Jianqiang] Iowa State Univ, Dept Vet Diagnost & Prod Anim Med, Coll Vet Med, Ames, IA USA. [Nelson, Martha I.] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Murtaugh, Michael P.] Univ Minnesota, Coll Vet Med, Dept Vet & Biomed Sci, St Paul, MN 55108 USA. RP Marthaler, D (reprint author), Univ Minnesota, Coll Vet Med, Vet Populat Med, 1333 Gortner Ave, St Paul, MN 55108 USA. EM marth027@umn.edu RI Wang, Leyi/G-9448-2014 OI Wang, Leyi/0000-0001-5813-9505 FU Rapid Agricultural Response Fund FX This study was supported partially by the Rapid Agricultural Response Fund, established by the Minnesota legislature and administered by the University of Minnesota Agricultural Experiment Station, and by Boehringer Ingelheim Vetmedica, Inc. NR 45 TC 6 Z9 6 U1 4 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-5877 EI 1873-1716 J9 PREV VET MED JI Prev. Vet. Med. PD JAN 1 PY 2016 VL 123 BP 175 EP 184 DI 10.1016/j.prevetmed.2015.10.020 PG 10 WC Veterinary Sciences SC Veterinary Sciences GA DE0HU UT WOS:000370306500021 PM 26611651 ER PT B AU Alter, KE AF Alter, Katharine E. BE Brashear, A TI Guidance Techniques for Botulinum Toxin Injections: A Comparison SO SPASTICITY: DIAGNOSIS AND MANAGEMENT, SECOND EDITION LA English DT Article; Book Chapter ID MANUAL NEEDLE PLACEMENT; RANDOMIZED CONTROLLED-TRIAL; END-PLATE ZONE; CEREBRAL-PALSY; GASTROCNEMIUS-MUSCLE; CERVICAL DYSTONIA; ELECTRICAL-STIMULATION; GUIDED INJECTION; A INJECTION; ELECTROMYOGRAPHIC GUIDANCE C1 [Alter, Katharine E.] NICHHD, Baltimore, MD USA. [Alter, Katharine E.] NIH, Funct & Appl Biomech Sect, Rehabil Med, Baltimore, MD USA. [Alter, Katharine E.] Mt Washington Pediat Hosp, Rehabil Programs, Baltimore, MD USA. RP Alter, KE (reprint author), NICHHD, Baltimore, MD USA.; Alter, KE (reprint author), NIH, Funct & Appl Biomech Sect, Rehabil Med, Baltimore, MD USA.; Alter, KE (reprint author), Mt Washington Pediat Hosp, Rehabil Programs, Baltimore, MD USA. NR 86 TC 0 Z9 0 U1 0 U2 0 PU DEMOS MEDICAL PUBLICATIONS PI NEW YORK PA 11 WEST 42ND STREET, 15TH FLOOR, NEW YORK, NY 10036 USA BN 978-1-62070-072-3 PY 2016 BP 153 EP 179 PG 27 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA BE1AP UT WOS:000367632500013 ER PT J AU Haase, AD AF Haase, Astrid D. TI A Small RNA-Based Immune System Defends Germ Cells against Mobile Genetic Elements SO STEM CELLS INTERNATIONAL LA English DT Review ID PIWI-INTERACTING RNAS; DROSOPHILA-MELANOGASTER; PIRNA BIOGENESIS; TRANSPOSABLE ELEMENTS; HYBRID DYSGENESIS; MOUSE OOCYTES; PROCESSING FACTORS; FEMALE STERILITY; INHERITED PIRNAS; DNA METHYLATION AB Transposons are mobile genetic elements that threaten the survival of species by destabilizing the germline genomes. Limiting the spread of these selfish elements is imperative. Germ cells employ specialized small regulatory RNA pathways to restrain transposon activity. PIWI proteins and Piwi-interacting RNAs (piRNAs) silence transposons at the transcriptional and posttranscriptional level with loss-of-function mutant animals universally exhibiting sterility often associated with germ cell defects. This short review aims to illustrate basic strategies of piRNA-guided defense against transposons. Mechanisms of piRNA silencing are most readily studied in Drosophila melanogaster, which serves as a model to delineate molecular concepts and as a reference for mammalian piRNA systems. PiRNA pathways utilize two major strategies to handle the challenges of transposon control: (1) the hard-wired molecular memory of prior transpositions enables recognition of mobile genetic elements and discriminates transposons from host genes; (2) a feed-forward adaptation mechanism shapes piRNA populations to selectively combat the immediate threat of transposon transcripts. In flies, maternally contributed PIWI-piRNA complexes bolster both of these lines of defense and ensure transgenerational immunity. While recent studies have provided a conceptual framework of what could be viewed as an ancient immune system, we are just beginning to appreciate its many molecular innovations. C1 [Haase, Astrid D.] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Haase, AD (reprint author), NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. EM astrid.haase@nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX The author would like to thank Katalin Fejes Toth, Chrysi Kanellopoulou, Antoine Molaro, Tara Dutka, and Markus Hafner for interesting discussions and critical comments on the manuscript. The author is supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 130 TC 0 Z9 0 U1 1 U2 6 PU HINDAWI LTD PI LONDON PA ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, WIT 5HE, ENGLAND SN 1687-966X EI 1687-9678 J9 STEM CELLS INT JI Stem Cells Int. PY 2016 AR 7595791 DI 10.1155/2016/7595791 PG 9 WC Cell & Tissue Engineering SC Cell Biology GA DD9YO UT WOS:000370281800001 ER PT J AU Hayes, SA Pandiri, AR Ton, TVT Hong, HHL Clayton, NP Shockley, KR Peddada, SD Gerrish, K Wyde, M Sills, RC Hoenerhoff, MJ AF Hayes, Schantel A. Pandiri, Arun R. Ton, Thai-vu T. Hong, Hue-Hua L. Clayton, Natasha P. Shockley, Keith R. Peddada, Shyamal D. Gerrish, Kevin Wyde, Michael Sills, Robert C. Hoenerhoff, Mark J. TI Renal Cell Carcinomas in Vinylidene Chloride-exposed Male B6C3F1 Mice Are Characterized by Oxidative Stress and TP53 Pathway Dysregulation SO TOXICOLOGIC PATHOLOGY LA English DT Article DE renal cell carcinoma; renal tubular hyperplasia; global gene expression; microarray; vinylidene chloride; National Toxicology Program; carcinogenicity bioassay; quantitative PCR; immunohistochemistry; mutation analysis ID MESSENGER-RNA; C-MYC; IMMUNOHISTOCHEMICAL DETECTION; GLUTATHIONE CONJUGATION; PROTEIN EXPRESSION; TUMOR PATHOLOGY; HISTONE H2AX; CYCLE ARREST; PROBE LEVEL; P53 GENE AB Vinylidene chloride (VDC) has been widely used in the production of plastics and flame retardants. Exposure of B6C3F1 mice to VDC in the 2-year National Toxicology Program carcinogenicity bioassay resulted in a dose-dependent increases in renal cell hyperplasia, renal cell adenoma, and renal cell carcinomas (RCCs). Among those differentially expressed genes from controls and RCC of VDC-exposed mice, there was an overrepresentation of genes from pathways associated with chronic xenobiotic and oxidative stress as well as c-Myc overexpression and dysregulation of TP53 cell cycle checkpoint and DNA damage repair pathways in RCC. Trend analysis comparing RCC, VDC-exposed kidney, and chamber control kidney showed a conservation of pathway dysregulation in terms of overrepresentation of xenobiotic and oxidative stress, and DNA damage and cell cycle checkpoint pathways in both VDC-exposed kidney and RCC, suggesting that these mechanisms play a role in the pathogenesis of RCC in VDC-exposed mice. C1 [Hayes, Schantel A.] Pathol Associates Inc, Charles River Labs, Res Triangle Pk, NC USA. [Pandiri, Arun R.] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. [Pandiri, Arun R.; Ton, Thai-vu T.; Hong, Hue-Hua L.; Clayton, Natasha P.; Sills, Robert C.; Hoenerhoff, Mark J.] NIEHS, Cellular & Mol Pathol Branch, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. [Shockley, Keith R.; Peddada, Shyamal D.] NIEHS, Biostat & Computat Biol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. [Gerrish, Kevin] NIEHS, Microarray Core Toxicol & Pharmacol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. [Wyde, Michael] NIEHS, Toxicol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. RP Hoenerhoff, MJ (reprint author), Univ Michigan, Unit Lab Anim Med, Vivo Anim Core, North Campus Res Complex,2800 Plymouth Rd,Bldg 36, Ann Arbor, MI 48109 USA. EM hoenerho@med.umich.edu FU Intramural NIH HHS [Z99 ES999999] NR 74 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JAN PY 2016 VL 44 IS 1 BP 71 EP 87 DI 10.1177/0192623315610820 PG 17 WC Pathology; Toxicology SC Pathology; Toxicology GA DE1YE UT WOS:000370422100008 PM 26682919 ER PT J AU Weinberg, CR AF Weinberg, Clarice R. TI Invited Commentary: Troubling Trends in Birth Weight SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE birth weight; racial disparities; surrogate markers; trends AB Birth weight is a strong predictor of the health of newborns. Consequently, the report by Catov et al. in this issue of the Journal (Am J Epidemiol. 2016;183(1):15-23), in which they showed downward trends in birth weights in a Pittsburgh, Pennsylvania, hospital from 1997 to 2011, raises concerns. The widening gap reported between birth weights of babies born to white and African-American women could correspond to a widening gap in actual health outcomes. However, if the relation between birth weight and health outcomes is not causal, these trends may be epiphenomena of limited concern. C1 [Weinberg, Clarice R.] Natl Inst Environm Hlth Sci, Biostat & Computat Biol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. RP Weinberg, CR (reprint author), Natl Inst Environm Hlth Sci, Biostat & Computat Biol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM Weinber2@niehs.nih.gov NR 5 TC 1 Z9 1 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JAN 1 PY 2016 VL 183 IS 1 BP 24 EP 25 DI 10.1093/aje/kwv196 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DD5WG UT WOS:000369994800003 PM 26667252 ER PT J AU Reinders, I Murphy, RA Brouwer, IA Visser, M Launer, L Siggeirsdottir, K Eiriksdottir, G Gudnason, V Jonsson, PV Lang, TF Harris, TB AF Reinders, Ilse Murphy, Rachel A. Brouwer, Ingeborg A. Visser, Marjolein Launer, Lenore Siggeirsdottir, Kristin Eiriksdottir, Gudny Gudnason, Vilmundur Jonsson, Palmi V. Lang, Thomas F. Harris, Tamara B. CA AGES-Reykjavik Study TI Muscle Quality and Myosteatosis: Novel Associations With Mortality Risk The Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE adipose tissue; aging; computed tomography; mortality risk; muscle; muscle composition; strength ID ALL-CAUSE MORTALITY; BODY-MASS INDEX; OLDER MEXICAN-AMERICANS; SKELETAL-MUSCLE; PHYSICAL PERFORMANCE; COMPUTED-TOMOGRAPHY; HANDGRIP STRENGTH; DISABILITY; MEN; PREDICTOR AB Muscle composition may affect mortality risk, but prior studies have been limited to specific samples or less precise determination of muscle composition. We evaluated associations of thigh muscle composition, determined using computed tomography imaging, and knee extension strength with mortality risk among 4,824 participants aged 76.4 (standard deviation (SD), 5.5) years from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study (2002-2006). Cox proportional hazards models were used to estimate hazard ratios. After 8.8 years of follow-up, there were 1,942 deaths. For men, each SD-increment increase in muscle lean area, muscle quality, and strength was associated with lower mortality risk, with decreases ranging between 11% and 22%. Each SD-increment increase in intermuscular adipose tissue and intramuscular adipose tissue was associated with higher mortality risk (hazard ratio (HR) = 1.13 (95% confidence interval (CI): 1.06, 1.22) and HR = 1.23 (95% CI: 1.15, 1.30), respectively). For women, each SD-increment increase in muscle lean area, muscle quality, and strength was associated with lower mortality risk, with decreases ranging between 12% and 19%. Greater intramuscular adipose tissue was associated with an 8% higher mortality risk (HR = 1.08, 95% CI: 1.01, 1.16). This study shows that muscle composition is associated with mortality risk. These results also show the importance of improving muscle strength and area and lowering muscle adipose tissue infiltration. C1 [Reinders, Ilse; Murphy, Rachel A.; Launer, Lenore; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, 7201 Wisconsin Ave,3C-309 Gateway Bldg, Bethesda, MD 20814 USA. [Reinders, Ilse; Brouwer, Ingeborg A.; Visser, Marjolein] Vrije Univ Amsterdam, Fac Earth & Life Sci, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Reinders, Ilse; Brouwer, Ingeborg A.; Visser, Marjolein] Vrije Univ Amsterdam, Fac Earth & Life Sci, Dept Hlth Sci, Amsterdam, Netherlands. [Visser, Marjolein] Vrije Univ Amsterdam, Med Ctr, Dept Nutr & Dietet, Internal Med Unit, Amsterdam, Netherlands. [Siggeirsdottir, Kristin; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Res Inst, Kopavogur, Iceland. [Gudnason, Vilmundur; Jonsson, Palmi V.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Jonsson, Palmi V.] Landspitali Natl Univ Hosp, Dept Geriatr, Reykjavik, Iceland. [Harris, Tamara B.] Univ Calif San Francisco, Sch Med, Dept Radiol & Biomed Imaging, San Francisco, CA USA. RP Reinders, I (reprint author), NIA, Lab Epidemiol & Populat Sci, 7201 Wisconsin Ave,3C-309 Gateway Bldg, Bethesda, MD 20814 USA. EM ilse.reinders@nih.gov FU National Institute on Aging, US National Institutes of Health [N01-AG-12100]; National Institute on Aging Intramural Research Program; Althingi (Icelandic Parliament); Hjartavernd (Icelandic Heart Association) FX This work was supported by the National Institute on Aging, US National Institutes of Health (grant N01-AG-12100), the National Institute on Aging Intramural Research Program, Hjartavernd (Icelandic Heart Association), and the Althingi (the Icelandic Parliament). NR 42 TC 3 Z9 3 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JAN 1 PY 2016 VL 183 IS 1 BP 53 EP 60 DI 10.1093/aje/kwv153 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DD5WG UT WOS:000369994800008 PM 26643983 ER PT J AU Huynh, T Quick, H Ramachandran, G Banerjee, S Stenzel, M Sandler, DP Engel, LS Kwok, RK Blair, A Stewart, PA AF Tran Huynh Quick, Harrison Ramachandran, Gurumurthy Banerjee, Sudipto Stenzel, Mark Sandler, Dale P. Engel, Lawrence S. Kwok, Richard K. Blair, Aaron Stewart, Patricia A. TI A Comparison of the beta-Substitution Method and a Bayesian Method for Analyzing Left-Censored Data SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Article DE beta-substitution; Bayesian; exposure assessment; left-censored data ID WATER-QUALITY DATA; RISK-ASSESSMENT; EXPOSURE DATA; STATISTICS AB Classical statistical methods for analyzing exposure data with values below the detection limits are well described in the occupational hygiene literature, but an evaluation of a Bayesian approach for handling such data is currently lacking. Here, we first describe a Bayesian framework for analyzing censored data. We then present the results of a simulation study conducted to compare the beta-substitution method with a Bayesian method for exposure datasets drawn from lognormal distributions and mixed lognormal distributions with varying sample sizes, geometric standard deviations (GSDs), and censoring for single and multiple limits of detection. For each set of factors, estimates for the arithmetic mean (AM), geometric mean, GSD, and the 95th percentile (X-0.95) of the exposure distribution were obtained. We evaluated the performance of each method using relative bias, the root mean squared error (rMSE), and coverage (the proportion of the computed 95% uncertainty intervals containing the true value). The Bayesian method using non-informative priors and the beta-substitution method were generally comparable in bias and rMSE when estimating the AM and GM. For the GSD and the 95th percentile, the Bayesian method with non-informative priors was more biased and had a higher rMSE than the beta-substitution method, but use of more informative priors generally improved the Bayesian method's performance, making both the bias and the rMSE more comparable to the beta-substitution method. An advantage of the Bayesian method is that it provided estimates of uncertainty for these parameters of interest and good coverage, whereas the beta-substitution method only provided estimates of uncertainty for the AM, and coverage was not as consistent. Selection of one or the other method depends on the needs of the practitioner, the availability of prior information, and the distribution characteristics of the measurement data. We suggest the use of Bayesian methods if the practitioner has the computational resources and prior information, as the method would generally provide accurate estimates and also provides the distributions of all of the parameters, which could be useful for making decisions in some applications. C1 [Tran Huynh; Ramachandran, Gurumurthy] Univ Minnesota, Div Environm Hlth Sci, Minneapolis, MN 55455 USA. [Quick, Harrison; Banerjee, Sudipto] Univ Minnesota, Div Biostat, Minneapolis, MN 55455 USA. [Stenzel, Mark] Exposure Assessment Applicat LLC, Arlington, VA 22207 USA. [Sandler, Dale P.; Engel, Lawrence S.; Kwok, Richard K.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Engel, Lawrence S.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Blair, Aaron] NCI, Gaithersburg, MD 20892 USA. [Stewart, Patricia A.] Stewart Exposure Assessments LLC, Arlington, VA 22207 USA. RP Ramachandran, G (reprint author), Univ Minnesota, Div Environm Hlth Sci, Minneapolis, MN 55455 USA. EM ramac002@umn.edu RI Kwok, Richard/B-6907-2017; OI Kwok, Richard/0000-0002-6794-8360; Sandler, Dale/0000-0002-6776-0018 FU Intramural Research Program of NIH, National Institute of Environmental Health Sciences [ZO1 ES 102945] FX This work is funded in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, ZO1 ES 102945. NR 33 TC 1 Z9 1 U1 3 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0003-4878 EI 1475-3162 J9 ANN OCCUP HYG JI Ann. Occup. Hyg. PD JAN PY 2016 VL 60 IS 1 BP 56 EP 73 DI 10.1093/annhyg/mev049 PG 18 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA DD5XE UT WOS:000369997400006 PM 26209598 ER PT B AU Tabor, KM Burgess, HA AF Tabor, Kathryn M. Burgess, Harold A. BE Keene, AC Yoshizawa, M McGaugh, SE TI Transgenesis and Future Applications for Cavefish Research SO BIOLOGY AND EVOLUTION OF THE MEXICAN CAVEFISH LA English DT Article; Book Chapter ID GREEN-FLUORESCENT PROTEIN; GERM-LINE TRANSMISSION; TARGETED CELL ABLATION; FUNCTIONAL GROUND PLAN; ZEBRAFISH EMBRYOS; DIPHTHERIA-TOXIN; GENE-TRANSFER; MEDAKA FISH; TRANSPOSABLE ELEMENT; NEURONAL-ACTIVITY C1 [Tabor, Kathryn M.; Burgess, Harold A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, Bethesda, MD USA. RP Tabor, KM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, Bethesda, MD USA. NR 90 TC 0 Z9 0 U1 1 U2 2 PU ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL ROAD, LONDON NW1 7DX, ENGLAND BN 978-0-12-802365-5; 978-0-12-802148-4 PY 2016 BP 379 EP 392 DI 10.1016/B978-0-12-802148-4.00019-0 PG 14 WC Evolutionary Biology; Fisheries; Marine & Freshwater Biology SC Evolutionary Biology; Fisheries; Marine & Freshwater Biology GA BE2PX UT WOS:000369832800021 ER PT J AU Desante, J Degrazia, D Danis, M AF Desante, Jennifer Degrazia, David Danis, Marion TI Parents of Adults with Diminished Self-Governance Unique Responsibilities SO CAMBRIDGE QUARTERLY OF HEALTHCARE ETHICS LA English DT Article DE parents; children; autonomy; decisionmaking capacity; independence; cognitive limitations; mental illness AB Most theories of parenthood assume, at least implicitly, that a child will grow up to be an independent, autonomous adult. However, some children with cognitive limitations or psychiatric illness are unable to do so. For this reason, these accounts do not accommodate the circumstances and responsibilities of parents of such adult children. Our article attempts to correct this deficiency. In particular, we describe some of the common characteristics and experiences of this population of parents and children, examine the unique aspects of their relationships, review several philosophical accounts of parental obligations, consider how these accounts might be extrapolated to semiautonomous adult children, and provide suggestions about parental obligations to promote autonomy and independence in adult children with cognitive limitations or psychiatric illness. In extending accounts of parental responsibilities to the case of semiautonomous adults, we find that the parental role includes the duty to continue to provide care-indefinitely if necessary-while cultivating autonomy and independence. C1 [Desante, Jennifer; Degrazia, David] NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. [Desante, Jennifer] Cincinnati Childrens Hosp Med Ctr, Eth Ctr, Cincinnati, OH 45229 USA. [Desante, Jennifer] Cincinnati Childrens Hosp Med Ctr, Div Hosp Med, Cincinnati, OH 45229 USA. [Degrazia, David] George Washington Univ, Dept Philosophy, Washington, DC USA. [Danis, Marion] NIH, Sect Eth & Hlth Policy, Dept Clin Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Danis, Marion] NIH, Ctr Clin, Bioeth Consultat Serv, Bethesda, MD 20892 USA. RP Desante, J (reprint author), Cincinnati Childrens Hosp Med Ctr, Eth Ctr, Cincinnati, OH 45229 USA.; Desante, J (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Hosp Med, Cincinnati, OH 45229 USA. FU National Institutes of Health Clinical Center FX The authors wish to thank colleagues in the Department of Bioethics at the National Institutes of Health for their feedback and suggestions. We especially thank Joseph Millum and David Wasserman for their input. We would also like to thank Tomi Kushner, Grant Gillett, and an anonymous reviewer for helpful feedback. This work was supported, in part, by intramural funds from the National Institutes of Health Clinical Center. The views expressed are the authors' own. They do not represent the position or policy of the National Institutes of Health, the U.S. Public Health Service, or the Department of Health and Human Services. NR 23 TC 0 Z9 0 U1 0 U2 0 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 JAN PY 2016 VL 25 IS 1 BP 92 EP 106 DI 10.1017/S0963180115000328 PG 15 WC Health Care Sciences & Services; Health Policy & Services; Social Sciences, Biomedical SC Health Care Sciences & Services; Biomedical Social Sciences GA DD0EV UT WOS:000369594100010 PM 26788950 ER PT J AU Xu, L Nussinov, R Ma, BY AF Xu, Liang Nussinov, Ruth Ma, Buyong TI Allosteric stabilization of the amyloid-beta peptide hairpin by the fluctuating N-terminal SO CHEMICAL COMMUNICATIONS LA English DT Article ID ALZHEIMERS-DISEASE; AGGREGATION BEHAVIOR; A2V MUTATION; ZINC-BINDING; PROTEIN; OLIGOMERS; FIBRILS; DYNAMICS; MONOMERS; WATER AB Immobilized ions modulate nearby hydrophobic interactions and influence molecular recognition and self-assembly. We simulated disulfide bond-locked double mutants (L17C/L34C) and observed allosteric modulation of the peptide's intra-molecular interactions by the N-terminal tail. We revealed that the non-contacting charged N-terminal residues help the transfer of entropy to the surrounding solvation shell and stabilizing beta-hairpin. C1 [Xu, Liang] Dalian Univ Technol, Sch Chem, Dalian, Peoples R China. [Nussinov, Ruth; Ma, Buyong] NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Ma, BY (reprint author), NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. EM mabuyong@mail.nih.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU NIH [HHSN261200800001E]; Intramural Research Program of the CCR, NCI, NIH; China Scholarship Council [CSC201306065001] FX This work was supported by NIH contract number HHSN261200800001E. This research was supported (in part) by the Intramural Research Program of the CCR, NCI, NIH. Xu thanks China Scholarship Council (CSC201306065001). MD simulations were performed at the Biowulf PC/Linux cluster at the NIH (http://biowulf.nih.gov/). NR 36 TC 3 Z9 3 U1 1 U2 10 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1359-7345 EI 1364-548X J9 CHEM COMMUN JI Chem. Commun. PY 2016 VL 52 IS 8 BP 1733 EP 1736 DI 10.1039/c5cc08107f PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA DC9WJ UT WOS:000369572000046 PM 26666686 ER PT J AU Geller, NL Kim, DY Tian, X AF Geller, Nancy L. Kim, Dong-Yun Tian, Xin TI Smart Technology in Lung Disease Clinical Trials SO CHEST LA English DT Article DE clinical trials; lung disease; mobile health; personal electronic devices; smart technology ID RANDOMIZED CONTROLLED-TRIAL; COST-EFFECTIVENESS; MANAGEMENT-SYSTEM; HEALTH; CONSENT; DESIGN; IMPLEMENTATION; INTERVENTIONS; SELECTION; EFFICACY AB This article describes the use of smart technology by investigators and patients to facilitate lung disease clinical trials and make them less costly and more efficient. By "smart technology" we include various electronic media, such as computer databases, the Internet, and mobile devices. We first describe the use of electronic health records for identifying potential subjects and then discuss electronic informed consent. We give several examples of using the Internet and mobile technology in clinical trials. Interventions have been delivered via the World Wide Web or via mobile devices, and both have been used to collect outcome data. We discuss examples of new electronic devices that recently have been introduced to collect health data. While use of smart technology in clinical trials is an exciting development, comparison with similar interventions applied in a conventional manner is still in its infancy. We discuss advantages and disadvantages of using this omnipresent, powerful tool in clinical trials, as well as directions for future research. C1 [Geller, Nancy L.; Kim, Dong-Yun; Tian, Xin] NHLBI, Off Biostat Res, NIH, 6701 Rockledge Dr,MSC 7913, Bethesda, MD 20892 USA. RP Geller, NL (reprint author), NHLBI, Off Biostat Res, NIH, 6701 Rockledge Dr,MSC 7913, Bethesda, MD 20892 USA. EM gellern@nhlbi.nih.gov NR 38 TC 2 Z9 2 U1 2 U2 3 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD JAN PY 2016 VL 149 IS 1 BP 22 EP 26 DI 10.1378/chest.15-1314 PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DD1BI UT WOS:000369655600015 PM 26135330 ER PT J AU Stroud, LR Papandonatos, GD Salisbury, AL Phipps, MG Huestis, MA Niaura, R Padbury, JF Marsit, CJ Lester, BM AF Stroud, Laura R. Papandonatos, George D. Salisbury, Amy L. Phipps, Maureen G. Huestis, Marilyn A. Niaura, Raymond Padbury, James F. Marsit, Carmen J. Lester, Barry M. TI Epigenetic Regulation of Placental NR3C1: Mechanism Underlying Prenatal Programming of Infant Neurobehavior by Maternal Smoking? SO CHILD DEVELOPMENT LA English DT Article ID GLUCOCORTICOID-RECEPTOR; NEWBORN NEUROBEHAVIOR; IN-UTERO; CHILD-DEVELOPMENT; TOBACCO EXPOSURE; DNA METHYLATION; BIRTH-WEIGHT; PREGNANCY; STRESS; BRAIN AB Epigenetic regulation of the placental glucocorticoid receptor gene (NR3C1) was investigated as a mechanism underlying links between maternal smoking during pregnancy (MSDP) and infant neurobehavior in 45 mother-infant pairs (49% MSDP-exposed; 52% minorities; ages 18-35). The Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scale was administered 7 times over the 1st postnatal month; methylation of placental NR3C1 was assessed via bisulfite pyrosequencing. Increased placental NR3C1 methylation was associated with increased infant attention and self-regulation, and decreased lethargy and need for examiner soothing over the 1st postnatal month. A causal steps approach revealed that NR3C1 methylation and MSDP were independently associated with lethargic behavior. Although preliminary, results highlight the importance of epigenetic mechanisms in elucidating pathways to neurobehavioral alterations from MSDP. C1 [Stroud, Laura R.; Papandonatos, George D.; Salisbury, Amy L.; Phipps, Maureen G.; Padbury, James F.; Lester, Barry M.] Brown Univ, Providence, RI 02912 USA. [Huestis, Marilyn A.] NIH, Bethesda, MD USA. [Niaura, Raymond] Truth Initiat, Washington, DC USA. [Marsit, Carmen J.] Dartmouth Coll, Dartmouth, NS, Canada. RP Stroud, LR (reprint author), Ctr Behav Med, Coro West,Suite 309,164 Summit Ave, Providence, RI 02906 USA.; Stroud, LR (reprint author), Ctr Prevent Med, Coro West,Suite 309,164 Summit Ave, Providence, RI 02906 USA. EM laura_stroud@brown.edu FU National Institutes of Health [R01 DA019558, R01 DA031188]; Flight Attendant Medical Research Institute Clinical Innovator Award FX Preparation of this manuscript was supported by the National Institutes of Health (R01 DA019558 and R01 DA031188 to Laura R. Stroud) and the Flight Attendant Medical Research Institute Clinical Innovator Award to Laura R. Stroud. We gratefully acknowledge the families who contributed to this study and the Maternal-Infant Studies Laboratory staff for their assistance with data collection. We also thank Polly Gobin for her assistance with data management. We are also grateful to Cheryl Boyce and Nicolette Borek, Program Officers, for their support of this work and this field. NR 50 TC 5 Z9 5 U1 3 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-3920 EI 1467-8624 J9 CHILD DEV JI Child Dev. PD JAN-FEB PY 2016 VL 87 IS 1 BP 49 EP 60 DI 10.1111/cdev.12482 PG 12 WC Psychology, Educational; Psychology, Developmental SC Psychology GA DD3UK UT WOS:000369848300004 PM 26822442 ER PT J AU Jakobsen, KV Umstead, L Simpson, EA AF Jakobsen, Krisztina V. Umstead, Lindsey Simpson, Elizabeth A. TI Efficient Human Face Detection in Infancy SO DEVELOPMENTAL PSYCHOBIOLOGY LA English DT Article DE own-species bias; attention capture; eye tracking; saliency; face learning; visual attention; infant; perceptual attunement; social orienting; face processing; face specialization ID VISUAL-SEARCH; 1ST YEAR; ATTENTION; PERCEPTION; RACE; OWN; RECOGNITION; PREFERENCE; DISCRIMINATION; DISPLAYS AB Adults detect conspecific faces more efficiently than heterospecific faces; however, the development of this own-species bias (OSB) remains unexplored. We tested whether 6- and 11-month-olds exhibit OSB in their attention to human and animal faces in complex visual displays with high perceptual load (25 images competing for attention). Infants (n = 48) and adults (n = 43) passively viewed arrays containing a face among 24 non-face distractors while we measured their gaze with remote eye tracking. While OSB is typically not observed until about 9 months, we found that, already by 6 months, human faces were more likely to be detected, were detected more quickly (attention capture), and received longer looks (attention holding) than animal faces. These data suggest that 6-month-olds already exhibit OSB in face detection efficiency, consistent with perceptual attunement. This specialization may reflect the biological importance of detecting conspecific faces, a foundational ability for early social interactions. (C) 2015 Wiley Periodicals, Inc. Dev Psychobiol 58: 129-136, 2016. C1 [Jakobsen, Krisztina V.; Umstead, Lindsey] James Madison Univ, Dept Psychol, Harrisonburg, VA 22807 USA. [Simpson, Elizabeth A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Dickerson, MD USA. [Simpson, Elizabeth A.] Univ Parma, Dept Neurosci, I-43100 Parma, Italy. [Simpson, Elizabeth A.] Univ Miami, Dept Psychol, POB 248185, Coral Gables, FL 33146 USA. RP Simpson, EA (reprint author), Univ Miami, Dept Psychol, 5665 Ponce de Leon, Coral Gables, FL 33146 USA. EM elizabethannsimpson@gmail.com FU NICHD [P01HD064653]; Alvin V., Jr. and Nancy C. Baird Professorship FX This research was supported by the Alvin V., Jr. and Nancy C. Baird Professorship (KVJ) and NICHD P01HD064653 (EAS). Special thanks to Fabrice Damon for the saliency map analysis and to Matthew R. Lee, Veronica Eisenmann, Erik Simmons, and Alison Fullerton for comments on an earlier version of the manuscript. We would also like to thank all of the infants and parents who participated in the study and the undergraduate research assistants who contributed to the project. A portion of this study was presented at the Eighth Biennial Meeting of the Cognitive Development Society. NR 48 TC 3 Z9 3 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0012-1630 EI 1098-2302 J9 DEV PSYCHOBIOL JI Dev. Psychobiol. PD JAN PY 2016 VL 58 IS 1 BP 129 EP 136 DI 10.1002/dev.21338 PG 8 WC Developmental Biology; Psychology SC Developmental Biology; Psychology GA DD7YQ UT WOS:000370141300012 PM 26248583 ER PT J AU Milanesi, A Lee, JW Kim, NH Liu, YY Yang, A Sedrakyan, S Kahng, A Cervantes, V Tripuraneni, N Cheng, SY Perin, L Brent, GA AF Milanesi, Anna Lee, Jang-Won Kim, Nam-Ho Liu, Yan-Yun Yang, An Sedrakyan, Sargis Kahng, Andrew Cervantes, Vanessa Tripuraneni, Nikita Cheng, Sheue-yann Perin, Laura Brent, Gregory A. TI Thyroid Hormone Receptor alpha Plays an Essential Role in Male Skeletal Muscle Myoblast Proliferation, Differentiation, and Response to Injury SO ENDOCRINOLOGY LA English DT Article ID GROWTH-PLATE CHONDROCYTES; INSULIN-RESISTANCE; SATELLITE CELLS; SOLEUS MUSCLE; GENE; MYOD; MICE; EXPRESSION; MUTATION; MOUSE AB Thyroid hormone plays an essential role in myogenesis, the process required for skeletal muscle development and repair, although the mechanisms have not been established. Skeletal muscle develops from the fusion of precursor myoblasts into myofibers. We have used the C2C12 skeletal muscle myoblast cell line, primary myoblasts, and mouse models of resistance to thyroid hormone (RTH) alpha and beta, to determine the role of thyroid hormone in the regulation of myoblast differentiation. T-3, which activates thyroid hormone receptor (TR) alpha and beta, increased myoblast differentiation whereas GC1, a selective TR beta agonist, was minimally effective. Genetic approaches confirmed that TR alpha plays an important role in normal myoblast proliferation and differentiation and acts through the Wnt/beta-catenin signaling pathway. Myoblasts with TR alpha knockdown, or derived from RTH-TR alpha PV (a frame-shift mutation) mice, displayed reduced proliferation and myogenic differentiation. Moreover, skeletal muscle from the TR alpha 1PV mutant mouse had impaired in vivo regeneration after injury. RTH-TR beta PV mutant mouse model skeletal muscle and derived primary myoblasts did not have altered proliferation, myogenic differentiation, or response to injury when compared with control. In conclusion, TR alpha plays an essential role in myoblast homeostasis and provides a potential therapeutic target to enhance skeletal muscle regeneration. C1 [Milanesi, Anna; Liu, Yan-Yun; Yang, An; Brent, Gregory A.] Univ Calif Los Angeles, Vet Affairs Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Los Angeles, CA 90073 USA. [Lee, Jang-Won; Kim, Nam-Ho; Kahng, Andrew; Cervantes, Vanessa] Cedars Sinai Med Ctr, Dept Neurosurg, Los Angeles, CA 90048 USA. [Sedrakyan, Sargis; Tripuraneni, Nikita; Perin, Laura] Univ So Calif, Childrens Hosp Los Angeles, Dept Urol, Los Angeles, CA 90027 USA. [Cheng, Sheue-yann] NCI, Bethesda, MD 20892 USA. RP Milanesi, A; Brent, GA (reprint author), VA Greater Angeles Healthcare Syst, Dept Med, 111,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM amilanesi@mednet.ucla.edu; gbrent@mednet.ucla.edu FU National Institutes of Health (NIH) Grant [1K08DK097295]; NIH [RO1DK98576]; NIH/National Center for Advancing Translational Science University of California, Los Angeles, Clinical and Translational Science Institute [UL1TR000124] FX This work was supported by National Institutes of Health (NIH) Grant No. 1K08DK097295 (to A.M.), and NIH RO1DK98576 (to G.A.B.). The research described was supported by NIH/National Center for Advancing Translational Science University of California, Los Angeles, Clinical and Translational Science Institute Grant No. UL1TR000124. NR 61 TC 3 Z9 3 U1 2 U2 4 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD JAN PY 2016 VL 157 IS 1 BP 4 EP 15 DI 10.1210/en.2015-1443 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DD5KM UT WOS:000369962600002 PM 26451739 ER PT J AU Smith, K Firth, K Smeeding, S Wolever, R Kaufman, J Delgado, R Bellanti, D Xenalcis, L AF Smith, Katherine Firth, Kimberly Smeeding, Sandra Wolever, Ruth Kaufman, Joanna Delgado, Roxana Bellanti, Dawn Xenalcis, Lea TI GUIDELINES FOR CREATING, IMPLEMENTING, AND EVALUATING MIND-BODY PROGRAMS IN A MILITARY HEALTHCARE SETTING SO EXPLORE-THE JOURNAL OF SCIENCE AND HEALING LA English DT Article DE Mind-body skills; Empowerment; Guidelines; Program evaluation; Healthcare; Military healthcare ID POSTTRAUMATIC-STRESS-DISORDER; RANDOMIZED CONTROLLED-TRIAL; TRAUMATIC BRAIN-INJURY; CENTERED MEDICAL HOME; ALTERNATIVE MEDICINE; MINDFULNESS MEDITATION; VETERANS-IMPLICATIONS; INTEGRATIVE MEDICINE; PEER SUPPORT; CHRONIC PAIN AB Research suggests that the development of mind-body skills can improve individual and family resilience, particularly related to the stresses of illness, trauma, and caregiving. To operationalize the research evidence that mind body skills help with health and recovery, Samueli Institute, in partnership with experts in mind body programming, created a set of guidelines for developing and evaluating mind-body programs for service members, veterans, and their families. The Guidelines for Creating, Implementing, and Evaluating Mind-Body Programs in a Military Healthcare Setting outline key strategies and issues to consider when developing, implementing, and evaluating a mind body focused family empowerment approach in a military healthcare setting. Although these guidelines were developed specifically for a military setting, most of the same principles can be applied to the development of programs in the civilian setting as well. The guidelines particularly address issues unique to mind-body programs, such as choosing evidence-based modalities, licensure and credentialing, safety and contraindications, and choosing evaluation measures that capture the holistic nature of these types of programs. The guidelines are practical, practice-based guidelines, developed by experts in the fields of program development and evaluation, mind-body therapies, patient- and family-centered care, as well as, experts in military and veteran's health systems. They provide a flexible framework to create mind body family empowerment programs and describe important issues that program developers and evaluators are encouraged to address to ensure the development of the most impactful, successful, evidence-supported programs possible. C1 [Smith, Katherine; Firth, Kimberly; Delgado, Roxana; Bellanti, Dawn; Xenalcis, Lea] Samueli Inst, Optimal Healing Environm, 1737 King St,Suite 600, Alexandria, VA 22314 USA. [Firth, Kimberly] NIA, NIH, Bethesda, MD 20892 USA. [Smeeding, Sandra] San Francisco VA Med Ctr, San Francisco, CA USA. [Wolever, Ruth] Duke Sch Med, Dept Psychiat & Behav Sci, Durham, NC USA. [Wolever, Ruth] Duke Integrat Med, Durham, NC USA. [Wolever, Ruth] Vanderbilt Hlth Coaching, Osher Ctr Integrat Med Vanderbilt, Nashville, TN USA. [Wolever, Ruth] Vanderbilt Univ Sch Med, Phys Med & Rehabil, Nashville, TN USA. [Wolever, Ruth] Vanderbilt Univ Sch Med, Dept Psychiat, Nashville, TN USA. [Wolever, Ruth] Vanderbilt Sch Nursing, Nashville, TN USA. [Kaufman, Joanna] Inst Patient & Family Centered Care, Bethesda, MD USA. [Smeeding, Sandra] Salt Lake City VA Healthcare Syst, Integrat Hlth Clin & Program, Salt Lake City, UT USA. [Wolever, Ruth] Duke Sch Med, Durham, NC USA. [Wolever, Ruth] Duke Integrat Med, Durham, NC USA. RP Smith, K (reprint author), Samueli Inst, Optimal Healing Environm, 1737 King St,Suite 600, Alexandria, VA 22314 USA. EM ksmith@siib.org FU US Army Medical Research and Materiel Command, United States [W81XWH-11-1-0759] FX This work is supported by the US Army Medical Research and Materiel Command, United States, under Award no. W81XWH-11-1-0759. The views, opinions and/or findings contained in this report are those of the author(s) and should not be construed as an official Department of the Army position, policy or decision unless so designated by other documentation. NR 102 TC 0 Z9 0 U1 6 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1550-8307 EI 1878-7541 J9 EXPLORE-NY JI Explore-J Sci. Heal. PD JAN-FEB PY 2016 VL 12 IS 1 BP 18 EP 33 DI 10.1016/j.explore.2015.10.002 PG 16 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA DD1LG UT WOS:000369682600007 PM 26686476 ER PT J AU Maholmes, V Tamburro, RF Jenkins, TL AF Maholmes, Valerie Tamburro, Robert F. Jenkins, Tammara L. TI Toward a Research Agenda on Pediatric Trauma and Critical Illness SO JAMA PEDIATRICS LA English DT Editorial Material C1 [Maholmes, Valerie; Tamburro, Robert F.; Jenkins, Tammara L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Trauma & Crit Illness Branch, NIH, US Dept HHS, Bethesda, MD 20852 USA. RP Maholmes, V (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Trauma & Crit Illness Branch, NIH, US Dept HHS, 6100 Execut Blvd,8B07A, Bethesda, MD 20852 USA. EM maholmev@mail.nih.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD JAN PY 2016 VL 170 IS 1 BP 7 EP 8 DI 10.1001/jamapediatrics.2015.2740 PG 2 WC Pediatrics SC Pediatrics GA DD1AL UT WOS:000369653100006 PM 26550766 ER PT J AU Uusitalo, U Liu, X Yang, JM Aronsson, CA Hummel, S Butterworth, M Lernmark, A Rewers, M Hagopian, W She, JX Simell, O Toppari, J Ziegler, AG Akolkar, B Krischer, J Norris, JM Virtanen, SM AF Uusitalo, Ulla Liu, Xiang Yang, Jimin Aronsson, Carin Andren Hummel, Sandra Butterworth, Martha Lernmark, Ake Rewers, Marian Hagopian, William She, Jin-Xiong Simell, Olli Toppari, Jorma Ziegler, Anette G. Akolkar, Beena Krischer, Jeffrey Norris, Jill M. Virtanen, Suvi M. CA TEDDY Study Grp TI Association of Early Exposure of Probiotics and Islet Autoimmunity in the TEDDY Study SO JAMA PEDIATRICS LA English DT Article ID GLUTAMIC-ACID DECARBOXYLASE; GUT MICROBIOTA; INTESTINAL MICROBIOTA; IMMUNE-SYSTEM; HUMAN INFANT; HUMAN-MILK; CHILDREN; RISK; PERMEABILITY; DISEASES AB IMPORTANCE Probiotics have been hypothesized to affect immunologic responses to environmental exposures by supporting healthy gut microbiota and could therefore theoretically be used to prevent the development of type 1 diabetes mellitus (T1DM)-associated islet autoimmunity. OBJECTIVE To examine the association between supplemental probiotic use during the first year of life and islet autoimmunity among children at increased genetic risk of T1DM. DESIGN, SETTING, AND PARTICIPANTS In this ongoing prospective cohort study that started September 1, 2004, children from 6 clinical centers, 3 in the United States (Colorado, Georgia/Florida, and Washington) and 3 in Europe (Finland, Germany, and Sweden), were followed up for T1DM-related autoantibodies. Blood samples were collected every 3 months between 3 and 48 months of age and every 6 months thereafter to determine persistent islet autoimmunity. Details of infant feeding, including probiotic supplementation and infant formula use, were monitored from birth using questionnaires and diaries. We applied time-to-event analysis to study the association between probiotic use and islet autoimmunity, stratifying by country and adjusting for family history of type 1 diabetes, HLA-DR-DQ genotypes, sex, birth order, mode of delivery, exclusive breastfeeding, birth year, child's antibiotic use, and diarrheal history, as well as maternal age, probiotic use, and smoking. Altogether 8676 infants with an eligible genotype were enrolled in the follow-up study before the age of 4 months. The final sample consisted of 7473 children with the age range of 4 to 10 years (as of October 31, 2014). EXPOSURES Early intake of probiotics. MAIN OUTCOMES AND MEASURES Islet autoimmunity revealed by specific islet autoantibodies. RESULTS Early probiotic supplementation (at the age of 0-27 days) was associated with a decreased risk of islet autoimmunity when compared with probiotic supplementation after 27 days or no probiotic supplementation (hazard ratio [HR], 0.66; 95% CI, 0.46-0.94). The association was accounted for by children with the DR3/4 genotype (HR, 0.40; 95% CI, 0.21-0.74) and was absent among other genotypes (HR, 0.97; 95% CI, 0.62-1.54). CONCLUSIONS AND RELEVANCE Early probiotic supplementation may reduce the risk of islet autoimmunity in children at the highest genetic risk of T1DM. The result needs to be confirmed in further studies before any recommendation of probiotics use is made. C1 [Uusitalo, Ulla; Liu, Xiang; Yang, Jimin; Butterworth, Martha; Krischer, Jeffrey] Univ S Florida, Hlth Informat Inst, Morsani Coll Med, Tampa, FL 33612 USA. [Aronsson, Carin Andren; Lernmark, Ake] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Hummel, Sandra; Ziegler, Anette G.] Helmholtz Zentrum Munchen, Diabet Res Inst, Munich, Germany. [Hummel, Sandra; Ziegler, Anette G.] Tech Univ Munich, Klinikum Rechts Isar, Forschergrp Diabet, D-80290 Munich, Germany. [Hummel, Sandra; Ziegler, Anette G.] Forschergrp Diabet eV, Munich, Germany. [Rewers, Marian] Univ Colorado, Barbara Davis Ctr Childhood Diabet, Sch Med, Aurora, CO USA. [Hagopian, William] Pacific Northwest Diabet Res Inst, Seattle, WA USA. [She, Jin-Xiong] Georgia Regents Univ, Med Coll Georgia, Augusta, GA USA. [Simell, Olli; Toppari, Jorma] Univ Turku, Dept Pediat, Turku, Finland. [Simell, Olli; Toppari, Jorma] Turku Univ Hosp, FIN-20520 Turku, Finland. [Toppari, Jorma] Univ Turku, Dept Physiol, Inst Biomed, Turku, Finland. [Akolkar, Beena] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD USA. [Norris, Jill M.] Univ Colorado Denver, Dept Epidemiol, Colorado Sch Publ Hlth, Aurora, CO USA. [Virtanen, Suvi M.] Natl Inst Hlth & Welf, Nutr Unit, Helsinki, Finland. [Virtanen, Suvi M.] Univ Tampere, Sch Hlth Sci, FIN-33101 Tampere, Finland. [Virtanen, Suvi M.] Univ Tampere, Ctr Child Hlth Res, FIN-33101 Tampere, Finland. [Virtanen, Suvi M.] Tampere Univ Hosp, Tampere, Finland. [Virtanen, Suvi M.] Sci Ctr Pirkanmaa Hosp Dist, Tampere, Finland. RP Uusitalo, U (reprint author), Univ S Florida, Hlth Informat Inst, Morsani Coll Med, 3650 Spectrum Blvd, Tampa, FL 33612 USA. EM ulla.uusitalo@epi.usf.edu OI Warncke, Katharina/0000-0003-1758-7656; Chen, Wei-Min/0000-0002-2643-2333 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences [U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, HHSN267200700014C]; Juvenile Diabetes Research Foundation; Centers for Disease Control and Prevention; National Institutes of Health/National Center for Advancing Translational Sciences Clinical and Translational Science [UL1 TR000064, UL1 TR001082] FX This study was supported by grants U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, and UC4 DK100238 and contract HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, Juvenile Diabetes Research Foundation, and Centers for Disease Control and Prevention. This work is supported in part by the National Institutes of Health/National Center for Advancing Translational Sciences Clinical and Translational Science Awards UL1 TR000064 (University of Florida) and UL1 TR001082 (University of Colorado). NR 54 TC 14 Z9 14 U1 8 U2 17 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD JAN PY 2016 VL 170 IS 1 BP 20 EP 28 DI 10.1001/jamapediatrics.2015.2757 PG 9 WC Pediatrics SC Pediatrics GA DD1AL UT WOS:000369653100012 PM 26552054 ER PT J AU Schernthaner-Reiter, MH Trivellin, G Stratakis, CA AF Schernthaner-Reiter, Marie Helene Trivellin, Giampaolo Stratakis, Constantine A. TI MEN1, MEN4, and Carney Complex: Pathology and Molecular Genetics SO NEUROENDOCRINOLOGY LA English DT Article DE Multiple endocrine neoplasias; Pituitary adenomas; Pituitary hyperplasia; Protein kinase A; Menin; Genetics ID MULTIPLE ENDOCRINE NEOPLASIA; NODULAR ADRENOCORTICAL DISEASE; TUMOR-SUPPRESSOR MENIN; ZOLLINGER-ELLISON-SYNDROME; SPOTTY SKIN PIGMENTATION; HUMAN PITUITARY-TUMORS; HISTONE METHYLTRANSFERASE COMPLEX; ISOLATED FAMILIAL SOMATOTROPINOMA; GENOTYPE-PHENOTYPE CORRELATION; INTERACTING PROTEIN GENE AB Pituitary adenomas are a common feature of a subset of endocrine neoplasia syndromes, which have otherwise highly variable disease manifestations. We provide here a review of the clinical features and human molecular genetics of multiple endocrine neoplasia (MEN) type 1 and 4 (MEN1 and MEN4, respectively) and Carney complex (CNC). MEN1, MEN4, and CNC are hereditary autosomal dominant syndromes that can present with pituitary adenomas. MEN1 is caused by inactivating mutations in the MEN1 gene, whose product menin is involved in multiple intracellular pathways contributing to transcriptional control and cell proliferation. MEN1 clinical features include primary hyperparathyroidism, pancreatic neuroendocrine tumours and prolactinomas as well as other pituitary adenomas. A subset of patients with pituitary adenomas and other MEN1 features have mutations in the CDKN1B gene; their disease has been called MEN4. Inactivating mutations in the type 1a regulatory subunit of protein kinase A (PKA; the PRKAR1A gene), that lead to dysregulation and activation of the PKA pathway, are the main genetic cause of CNC, which is clinically characterised by primary pigmented nodular adrenocortical disease, spotty skin pigmentation (lentigines), cardiac and other myxomas and acromegaly due to somatotropinomas or somatotrope hyperplasia. (C) 2015 S. Karger AG, Basel C1 [Schernthaner-Reiter, Marie Helene; Trivellin, Giampaolo; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Sect Endocrinol & Genet, NIH, Bethesda, MD USA. RP Schernthaner-Reiter, MH (reprint author), NICHD, SEGEN, PDEGEN, NIH,Clin Res Ctr, 10 Ctr Dr,Bldg 10,Room 1-3330,MSC1103, Bethesda, MD 20892 USA. EM helene@schernthaner.eu RI Trivellin, Giampaolo/J-6583-2016; OI Trivellin, Giampaolo/0000-0003-2384-4153; Schernthaner-Reiter, Marie Helene/0000-0002-7972-7610 FU Austrian Science Fund (FWF) [J-3482]; Intramural Research Program (IRP) of NICHD, NIH FX M.H.S.-R. is supported by the Austrian Science Fund (FWF) J-3482. This work was supported mainly by the Intramural Research Program (IRP) of NICHD, NIH. NR 194 TC 16 Z9 16 U1 1 U2 6 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0028-3835 EI 1423-0194 J9 NEUROENDOCRINOLOGY JI Neuroendocrinology PY 2016 VL 103 IS 1 BP 18 EP 31 DI 10.1159/000371819 PG 14 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA DD8FI UT WOS:000370160500003 PM 25592387 ER PT J AU Kesarwala, AH Krishna, MC Mitchell, JB AF Kesarwala, A. H. Krishna, M. C. Mitchell, J. B. TI Oxidative stress in oral diseases SO ORAL DISEASES LA English DT Review DE oxidative species; reactive oxygen species; reactive nitrogen species; cancer; radiation ID SQUAMOUS-CELL CARCINOMA; REACTIVE OXYGEN; DNA-DAMAGE; HYDROGEN-PEROXIDE; CANCER-CELLS; SUPEROXIDE-DISMUTASE; LIPID-PEROXIDATION; FREE-RADICALS; NECK-CANCER; NASOPHARYNGEAL CARCINOMA AB Oxidative species, including reactive oxygen species (ROS), are components of normal cellular metabolism and are required for intracellular processes as varied as proliferation, signal transduction, and apoptosis. In the situation of chronic oxidative stress, however, ROS contribute to various pathophysiologies and are involved in multiple stages of carcinogenesis. In head and neck cancers specifically, many common risk factors contribute to carcinogenesis via ROS-based mechanisms, including tobacco, areca quid, alcohol, and viruses. Given their widespread influence on the process of carcinogenesis, ROS and their related pathways are attractive targets for intervention. The effects of radiation therapy, a central component of treatment for nearly all head and neck cancers, can also be altered via interfering with oxidative pathways. These pathways are also relevant to the development of many benign oral diseases. In this review, we outline how ROS contribute to pathophysiology with a focus toward head and neck cancers and benign oral diseases, describing potential targets and pathways for intervention that exploit the role of oxidative species in these pathologic processes. C1 [Kesarwala, A. H.] NCI, Canc Res Ctr, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Krishna, M. C.; Mitchell, J. B.] NCI, Ctr Canc Res, Radiat Biol Branch, NIH, Bldg 10 CRC,Room B3-B69,10 Ctr Dr, Bethesda, MD 20892 USA. RP Mitchell, JB (reprint author), NCI, Ctr Canc Res, Radiat Biol Branch, NIH, Bldg 10 CRC,Room B3-B69,10 Ctr Dr, Bethesda, MD 20892 USA. EM jbm@helix.nih.gov FU Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 109 TC 2 Z9 2 U1 4 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X EI 1601-0825 J9 ORAL DIS JI Oral Dis. PD JAN PY 2016 VL 22 IS 1 BP 9 EP 18 DI 10.1111/odi.12300 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DD6SF UT WOS:000370053800002 PM 25417961 ER PT J AU Tan, ML Perrin, BS Niu, SQ Huang, Q Ichiye, T AF Tan, Ming-Liang Perrin, B. Scott, Jr. Niu, Shuqiang Huang, Qi Ichiye, Toshiko TI Protein dynamics and the all-ferrous [Fe4S4] cluster in the nitrogenase iron protein SO PROTEIN SCIENCE LA English DT Article DE reduction potentials; elastic network mode analysis; metalloprotein; iron-sulfur proteins ID DENSITY-FUNCTIONAL THEORY; VINELANDII FE PROTEIN; AZOTOBACTER-VINELANDII; REDUCTION POTENTIALS; NUCLEOTIDE-BINDING; 4FE-4S CLUSTER; REDOX STATE; MOSSBAUER; RESONANCE AB In nitrogen fixation by Azotobacter vinelandii nitrogenase, the iron protein (FeP) binds to and subsequently transfers electrons to the molybdenum-FeP, which contains the nitrogen fixation site, along with hydrolysis of two ATPs. However, the nature of the reduced state cluster is not completely clear. While reduced FeP is generally thought to contain an [Fe4S4](1+) cluster, evidence also exists for an all-ferrous [Fe4S4](0) cluster. Since the former indicates a single electron is transferred per two ATPs hydrolyzed while the latter indicates two electrons could be transferred per two ATPs hydrolyzed, an all-ferrous [Fe4S4](0) cluster in FeP is potenially two times more efficient. However, the 1+/0 reduction potential has been measured in the protein at both 460 and 790 mV, causing the biological significance to be questioned. Here, "density functional theory plus Poisson Boltzmann" calculations show that cluster movement relative to the protein surface observed in the crystal structures could account for both measured values. In addition, elastic network mode analysis indicates that such movement occurs in low frequency vibrations of the protein, implying protein dynamics might lead to variations in reduction potential. Furthermore, the different reductants used in the conflicting measurements of the reduction potential could be differentially affecting the protein dynamics. Moreover, even if the all-ferrous cluster is not the biologically relevant cluster, mutagenesis to stabilize the conformation with the more exposed cluster may be useful for bioengineering more efficient enzymes. C1 [Tan, Ming-Liang; Niu, Shuqiang; Huang, Qi; Ichiye, Toshiko] Georgetown Univ, Dept Chem, Washington, DC 20057 USA. [Perrin, B. Scott, Jr.; Ichiye, Toshiko] NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Ichiye, T (reprint author), Georgetown Univ, Dept Chem, Washington, DC 20057 USA.; Ichiye, T (reprint author), NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM ti9@georgetown.edu FU National Institutes of Health [GM045303] FX Grant sponsor: National Institutes of Health; Grant number: GM045303. NR 37 TC 1 Z9 1 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD JAN PY 2016 VL 25 IS 1 SI SI BP 12 EP 18 DI 10.1002/pro.2772 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DD3KJ UT WOS:000369820800003 PM 26271353 ER PT J AU Lee, J Miller, BT Brooks, BR AF Lee, Juyong Miller, Benjamin T. Brooks, Bernard R. TI Computational scheme for pH-dependent binding free energy calculation with explicit solvent SO PROTEIN SCIENCE LA English DT Article DE constant-pH simulation; absolute binding free energy calculation; binding affinity; pH-dependence; Bennett acceptance ratio; EDS-HREM; host-guest system ID REPLICA-EXCHANGE METHOD; BENNETTS ACCEPTANCE RATIO; ISOTROPIC PERIODIC SUM; MOLECULAR-DYNAMICS; CONSTANT-PH; FORCE-FIELD; CUCURBITURIL HOMOLOGS; ATOMIC CHARGES; PK(A) VALUES; SIMULATION AB We present a computational scheme to compute the pH-dependence of binding free energy with explicit solvent. Despite the importance of pH, the effect of pH has been generally neglected in binding free energy calculations because of a lack of accurate methods to model it. To address this limitation, we use a constant-pH methodology to obtain a true ensemble of multiple protonation states of a titratable system at a given pH and analyze the ensemble using the Bennett acceptance ratio (BAR) method. The constant pH method is based on the combination of enveloping distribution sampling (EDS) with the Hamiltonian replica exchange method (HREM), which yields an accurate semi-grand canonical ensemble of a titratable system. By considering the free energy change of constraining multiple protonation states to a single state or releasing a single protonation state to multiple states, the pH dependent binding free energy profile can be obtained. We perform benchmark simulations of a host-guest system: cucurbit[7]uril (CB[7]) and benzimidazole (BZ). BZ experiences a large pK(a) shift upon complex formation. The pH-dependent binding free energy profiles of the benchmark system are obtained with three different long-range interaction calculation schemes: a cutoff, the particle mesh Ewald (PME), and the isotropic periodic sum (IPS) method. Our scheme captures the pH-dependent behavior of binding free energy successfully. Absolute binding free energy values obtained with the PME and IPS methods are consistent, while cutoff method results are off by 2 kcal mol(-1). We also discuss the characteristics of three long-range interaction calculation methods for constant-pH simulations. C1 [Lee, Juyong; Miller, Benjamin T.; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Lee, J (reprint author), NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM juyong.lee@nih.gov RI Lee, Juyong/A-7869-2013 OI Lee, Juyong/0000-0003-1174-4358 FU Intramural Research Program of the NIH, NHLBI FX Grant sponsor: Intramural Research Program of the NIH, NHLBI. NR 70 TC 5 Z9 5 U1 4 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD JAN PY 2016 VL 25 IS 1 SI SI BP 231 EP 243 DI 10.1002/pro.2755 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DD3KJ UT WOS:000369820800022 PM 26189656 ER PT J AU Gopich, IV Szabo, A AF Gopich, Irina V. Szabo, Attila TI Influence of diffusion on the kinetics of multisite phosphorylation SO PROTEIN SCIENCE LA English DT Article DE enzyme; kinase; binding; catalysis; translational and rotational diffusion; encounter complex; steady-state approximation; escape and capture probabilities; splitting probability ID CONTROLLED REACTION-RATES; ERK MAP KINASE; PROCESSIVITY; PROBABILITY; RELAXATION; COORDINATE; BINDING; SYSTEMS; PATHWAY; ENZYME AB When an enzyme modifies multiple sites on a substrate, the influence of the relative diffusive motion of the reactants cannot be described by simply altering the rate constants in the rate equations of chemical kinetics. We have recently shown that, even as a first approximation, new transitions between the appropriate species must also be introduced. The physical reason for this is that a kinase, after phosphorylating one site, can rebind and modify another site instead of diffusing away. The corresponding new rate constants depend on the capture or rebinding probabilities that an enzyme-substrate pair, which is formed after dissociation from one site, reacts at the other site rather than diffusing apart. Here we generalize our previous work to describe both random and sequential phosphorylation by considering inequivalent modification sites. In addition, anisotropic reactive sites (instead of uniformly reactive spheres) are explicitly treated by using localized sink and source terms in the reaction-diffusion equations for the enzyme-substrate pair distribution function. Finally, we show that our results can be rederived using a phenomenological approach based on introducing transient encounter complexes into the standard kinetic scheme and then eliminating them using the steady-state approximation. C1 [Gopich, Irina V.; Szabo, Attila] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Gopich, IV (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM irinag@niddk.nih.gov RI Szabo, Attila/H-3867-2012 FU Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX This research was supported by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). NR 32 TC 3 Z9 3 U1 4 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD JAN PY 2016 VL 25 IS 1 SI SI BP 244 EP 254 DI 10.1002/pro.2722 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DD3KJ UT WOS:000369820800023 PM 26096178 ER PT S AU Ma, WX Wong, WT AF Ma, Wenxin Wong, Wai T. BE Rickman, CB LaVail, MM Anderson, RE Grimm, C Hollyfield, J Ash, J TI Aging Changes in Retinal Microglia and their Relevance to Age-related Retinal Disease SO RETINAL DEGENERATIVE DISEASES: MECHANISMS AND EXPERIMENTAL THERAPY SE Advances in Experimental Medicine and Biology LA English DT Article; Proceedings Paper CT 16th International Symposium on Retinal Degeneration (RD) CY JUL 13-18, 2014 CL Pacific Grove, CA DE Microglia; Aging; Complement; Retinal pigment epithelium; Senescence ID MACULAR DEGENERATION; UNITED-STATES; MOUSE RETINA; VISUAL IMPAIRMENT; GENE-EXPRESSION; ACTIVATION; ACCUMULATION; PREVALENCE; INFLAMMATION; GLAUCOMA AB Age-related retinal diseases, such as age-related macular degeneration (AMD) and glaucoma, contain features of chronic retinal inflammation that may promote disease progression. However, the relationship between aging and neuroinflammation is unclear. Microglia are long-lived, resident immune cells of the retina, and mediate local neuroinflammatory reactions. We hypothesize that aging changes in microglia may be causally linked to neuroinflammatory changes underlying age-dependent retinal diseases. Here, we review the evidence for (1) how the retinal microglial phenotype changes with aging, (2) the factors that drive microglial aging in the retina, and (3) aging-related changes in microglial gene expression. We examine how these aspects of microglial aging changes may relate to pathogenic mechanisms of immune dysregulation driving the progression of age-related retinal disease. These relationships can highlight microglial aging as a novel target for the prevention and treatment of retinal disease. C1 [Ma, Wenxin; Wong, Wai T.] NEI, Unit Neuron Glia Interact Retinal Dis, NIH, 6 Ctr Dr,6-125, Bethesda, MD 20892 USA. RP Wong, WT (reprint author), NEI, Unit Neuron Glia Interact Retinal Dis, NIH, 6 Ctr Dr,6-125, Bethesda, MD 20892 USA. EM wongw@nei.nih.gov RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU Intramural NIH HHS [Z01 EY000463-01] NR 26 TC 3 Z9 3 U1 0 U2 3 PU SPRINGER INT PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 0065-2598 BN 978-3-319-17121-0; 978-3-319-17120-3 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2016 VL 854 BP 73 EP 78 DI 10.1007/978-3-319-17121-0_11 PG 6 WC Medicine, Research & Experimental; Ophthalmology SC Research & Experimental Medicine; Ophthalmology GA BE2OL UT WOS:000369715400011 PM 26427396 ER PT S AU Fuller, JA Berlinicke, CA Inglese, J Zack, DJ AF Fuller, John A. Berlinicke, Cynthia A. Inglese, James Zack, Donald J. BE Rickman, CB LaVail, MM Anderson, RE Grimm, C Hollyfield, J Ash, J TI Use of a Machine Learning-Based High Content Analysis Approach to Identify Photoreceptor Neurite Promoting Molecules SO RETINAL DEGENERATIVE DISEASES: MECHANISMS AND EXPERIMENTAL THERAPY SE Advances in Experimental Medicine and Biology LA English DT Article; Proceedings Paper CT 16th International Symposium on Retinal Degeneration (RD) CY JUL 13-18, 2014 CL Pacific Grove, CA DE Photoreceptor; Neuritogenesis; Imaging; qHTS; High content analysis; Machine learning; Phenotypic screening; Protein kinase; Inhibitor ID ACTIVATED PROTEIN-KINASE; PC12 CELLS; HETEROGENEITY AB High content analysis (HCA) has become a leading methodology in phenotypic drug discovery efforts. Typical HCA workflows include imaging cells using an automated microscope and analyzing the data using algorithms designed to quantify one or more specific phenotypes of interest. Due to the richness of high content data, unappreciated phenotypic changes may be discovered in existing image sets using interactive machine-learning based software systems. Primary postnatal day four retinal cells from the photoreceptor (PR) labeled QRX-EGFP reporter mice were isolated, seeded, treated with a set of 234 profiled kinase inhibitors and then cultured for 1 week. The cells were imaged with an Acumen platebased laser cytometer to determine the number and intensity of GFP-expressing, i.e. PR, cells. Wells displaying intensities and counts above threshold values of interest were re-imaged at a higher resolution with an INCell2000 automated microscope. The images were analyzed with an open source HCA analysis tool, PhenoRipper (Rajaram et al., Nat Methods 9: 635-637, 2012), to identify the high GFP-inducing treatments that additionally resulted in diverse phenotypes compared to the vehicle control samples. The pyrimidinopyrimidone kinase inhibitor CHEMBL-1766490, a pan kinase inhibitor whose major known targets are p38 alpha and the Src family member lck, was identified as an inducer of photoreceptor neuritogenesis by using the open-source HCA program PhenoRipper. This finding was corroborated using a cell-based method of image analysis that measures quantitative differences in the mean neurite length in GFP expressing cells. Interacting with data using machine learning algorithms may complement traditional HCA approaches by leading to the discovery of small molecule-induced cellular phenotypes in addition to those upon which the investigator is initially focusing. C1 [Fuller, John A.; Berlinicke, Cynthia A.; Zack, Donald J.] Johns Hopkins Univ, Sch Med, Ophthalmol Mol Biol & Genet, Neurosci, 400 N Broadway,Smith 3001, Baltimore, MD 21231 USA. [Fuller, John A.; Berlinicke, Cynthia A.; Zack, Donald J.] Johns Hopkins Univ, Sch Med, Inst Med Genet, Wilmer Eye Inst, 400 N Broadway,Smith 3001, Baltimore, MD 21231 USA. [Inglese, James] NHGRI, NCATS, NIH, 9800 Med Ctr Dr,MSC 3370, Rockville, MD 20850 USA. RP Fuller, JA (reprint author), Johns Hopkins Univ, Sch Med, Ophthalmol Mol Biol & Genet, Neurosci, 400 N Broadway,Smith 3001, Baltimore, MD 21231 USA.; Fuller, JA (reprint author), Johns Hopkins Univ, Sch Med, Inst Med Genet, Wilmer Eye Inst, 400 N Broadway,Smith 3001, Baltimore, MD 21231 USA. EM jfulle19@jhmi.edu; cdoughe1@jhmi.edu; jinglese@mail.nih.gov; donzack@gmail.com OI Fuller, John/0000-0002-6587-146X NR 16 TC 1 Z9 2 U1 3 U2 21 PU SPRINGER INT PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 0065-2598 BN 978-3-319-17121-0; 978-3-319-17120-3 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2016 VL 854 BP 597 EP 603 DI 10.1007/978-3-319-17121-0_79 PG 7 WC Medicine, Research & Experimental; Ophthalmology SC Research & Experimental Medicine; Ophthalmology GA BE2OL UT WOS:000369715400079 PM 26427464 ER PT S AU Polato, F Becerra, SP AF Polato, Federica Becerra, S. Patricia BE Rickman, CB LaVail, MM Anderson, RE Grimm, C Hollyfield, J Ash, J TI Pigment Epithelium-Derived Factor, a Protective Factor for Photoreceptors in Vivo SO RETINAL DEGENERATIVE DISEASES: MECHANISMS AND EXPERIMENTAL THERAPY SE Advances in Experimental Medicine and Biology LA English DT Article; Proceedings Paper CT 16th International Symposium on Retinal Degeneration (RD) CY JUL 13-18, 2014 CL Pacific Grove, CA DE PEDF; Retinal degeneration; Neuroprotection; Photoreceptor; Animal models ID INDUCED CELL-DEATH; RETINAL DEGENERATION; ROYAL-COLLEGE; SURGEONS RATS; GENE-TRANSFER; FACTOR PEDF; RCS RAT; RECEPTOR; IDENTIFICATION; MECHANISMS AB Pigment epithelium-derived factor (PEDF) is a natural protein of the retina with demonstrable neurotrophic properties, found in the interphotoreceptor matrix in intimate contact with photoreceptors. This review summarizes the effects of PEDF on photoreceptors in several animal models of retinal degeneration. C1 [Polato, Federica; Becerra, S. Patricia] NEI, Sect Prot Struct & Funct, Lab Retinal Cell & Mol Biol, NIH, NIH NEI BG 6,Room 134,6 Ctr Dr MSC 0608, Bethesda, MD 20892 USA. RP Polato, F (reprint author), NEI, Sect Prot Struct & Funct, Lab Retinal Cell & Mol Biol, NIH, NIH NEI BG 6,Room 134,6 Ctr Dr MSC 0608, Bethesda, MD 20892 USA. EM polatof@mail.nih.gov; becerras@nei.nih.gov NR 19 TC 2 Z9 2 U1 1 U2 3 PU SPRINGER INT PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 0065-2598 BN 978-3-319-17121-0; 978-3-319-17120-3 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2016 VL 854 BP 699 EP 706 DI 10.1007/978-3-319-17121-0_93 PG 8 WC Medicine, Research & Experimental; Ophthalmology SC Research & Experimental Medicine; Ophthalmology GA BE2OL UT WOS:000369715400093 PM 26427478 ER PT S AU Valapala, M Sergeev, Y Wawrousek, E Hose, S Zigler, JS Sinha, D AF Valapala, Mallika Sergeev, Yuri Wawrousek, Eric Hose, Stacey Zigler, J. Samuel Sinha, Debasish BE Rickman, CB LaVail, MM Anderson, RE Grimm, C Hollyfield, J Ash, J TI Modulation of V-ATPase by beta A3/A1-Crystallin in Retinal Pigment Epithelial Cells SO RETINAL DEGENERATIVE DISEASES: MECHANISMS AND EXPERIMENTAL THERAPY SE Advances in Experimental Medicine and Biology LA English DT Article; Proceedings Paper CT 16th International Symposium on Retinal Degeneration (RD) CY JUL 13-18, 2014 CL Pacific Grove, CA DE Retinal pigment epithelial cells; Phagocytosis; Autophagy; Lysosomes; beta A3/A1-crystallin ID AUTOPHAGY; DEGRADATION; DYSFUNCTION; MECHANISMS; RPE; ROD AB We have previously demonstrated that beta A3/A1-crystallin, a member of the beta/gamma-crystallin superfamily, is expressed in the astrocytes and retinal pigment epithelial (RPE) cells of the eye. In order to understand the physiological functions of beta A3/A1-crystallin in RPE cells, we generated conditional knockout (cKO) mice where Cryba1, the gene encoding beta A3/A1-crystallin, is deleted specifically from the RPE using the Cre-loxP system. By utilizing the cKO model, we have shown that this protein is required by RPE cells for proper lysosomal degradation of photoreceptor outer segments (OS) that have been internalized in phagosomes and also for the proper functioning of the autophagy process. We also reported that beta A3/A1-crystallin is trafficked to lysosomes, where it regulates endolysosomal acidification by modulating the activity of the lysosomal V-ATPase complex. Our results show that the V-ATPase activity in cKO RPE is significantly lower than WT RPE. Since, V-ATPase is important for regulating lysosomal pH, we noticed that endolysosomal pH was higher in the cKO cells compared to the WT cells. Increased lysosomal pH in cKO RPE is also associated with reduced Cathepsin D activity. Cathepsin D is a major lysosomal aspartic protease involved in the degradation of the OS and hence we believe that reduced proteolytic activity contributes to impaired degradation of OS in the cKO RPE. Reduced lysosomal activity in the cKO RPE also contributes to the incomplete degradation of the autophagosomes. Our results also suggest that beta A3/A1-crystallin regulates V-ATPase activity by binding to the V-0 subunit of the V-ATPase complex. Taken together, these results suggest a novel mechanism by which beta A3/A1-crystallin regulates lysosomal function by modulating the activity of V-ATPase. C1 [Valapala, Mallika; Hose, Stacey; Zigler, J. Samuel; Sinha, Debasish] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21287 USA. [Sergeev, Yuri] NIH, Bethesda, MD 20814 USA. [Wawrousek, Eric] NEI, Bethesda, MD 20892 USA. RP Valapala, M (reprint author), Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21287 USA. EM mvalapa1@jhmi.edu; Yuri.sergeev@nih.gov; wawrouseke@nei.nih.gov; srohrer1@jhmi.edu; szigler1@jhmi.edu; debasish@jhmi.edu FU National Institutes of Health [RO1EY019037-S]; Research to Prevent Blindness FX DS is supported by National Institutes of Health: RO1EY019037-S, Bright focus and Research to Prevent Blindness (an unrestricted grant to The Wilmer Eye Institute). NR 17 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER INT PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 0065-2598 BN 978-3-319-17121-0; 978-3-319-17120-3 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2016 VL 854 BP 779 EP 784 DI 10.1007/978-3-319-17121-0_104 PG 6 WC Medicine, Research & Experimental; Ophthalmology SC Research & Experimental Medicine; Ophthalmology GA BE2OL UT WOS:000369715400104 PM 26427489 ER PT S AU Sepulcre, J Masdeu, JC AF Sepulcre, Jorge Masdeu, Joseph C. BE Castrillo, JI Oliver, SG TI Advanced Neuroimaging Methods Towards Characterization of Early Stages of Alzheimer's Disease SO SYSTEMS BIOLOGY OF ALZHEIMER'S DISEASE SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Alzheimer's disease; Neuroimaging; Network analysis; Amyloid; Graph theory; Early stages; Functional connectivity magnetic resonance imaging (fcMRI); Positron emission tomography (PET) ID MILD COGNITIVE IMPAIRMENT; INTRINSIC FUNCTIONAL CONNECTIVITY; AMYLOID-BETA DEPOSITION; COMPLEX BRAIN NETWORKS; PITTSBURGH COMPOUND-B; A-BETA; NEURITIC PLAQUES; NEURODEGENERATIVE DISEASES; NEUROFIBRILLARY TANGLES; CASCADE HYPOTHESIS AB In the past 5 years, imaging network properties in the brain of patients with Alzheimer's disease (AD) has revolutionized our understanding of this disorder. Postmortem data had already suggested that the damage spreads along functional neural networks, but postmortem studies do not provide information on the temporal evolution of the damage in the same patient, essential to determine spreading. These data can be provided by functional and structural neuroimaging, which allow for the visualization over time of the progressive damage inflicted by AD. Functional networks can be mapped by determining the synchrony across brain regions of the blood oxygenation level dependence (BOLD) signal on functional magnetic resonance imaging (MRI) during quiet wakefulness. Other less extensively used techniques are also useful. For instance, amyloid deposition can be imaged and its progression mapped to determine whether it follows brain networks, and, if so, which are affected earliest. Network patterns of neurobiological changes, including tau deposition, may prove critical to our understanding of the neurobiology of AD and therefore open the way for therapeutic interventions. C1 [Sepulcre, Jorge] Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, Boston, MA USA. [Sepulcre, Jorge] Harvard Univ, Sch Med, Boston, MA USA. [Sepulcre, Jorge] Athinioula A Martinos Ctr Biomed Imaging Charlest, Charlestown, MA USA. [Masdeu, Joseph C.] Cornell Univ, Weill Med Coll, Nantz Natl Alzheimer Ctr & Neuroimaging, Houston Methodist Neurol Inst, Houston, TX USA. [Masdeu, Joseph C.] NIMH, Sect Integrat Neuroimaging, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Sepulcre, J (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, Boston, MA USA.; Sepulcre, J (reprint author), Harvard Univ, Sch Med, Boston, MA USA.; Sepulcre, J (reprint author), Athinioula A Martinos Ctr Biomed Imaging Charlest, Charlestown, MA USA.; Sepulcre, J (reprint author), Cornell Univ, Weill Med Coll, Nantz Natl Alzheimer Ctr & Neuroimaging, Houston Methodist Neurol Inst, Houston, TX USA. NR 69 TC 0 Z9 0 U1 1 U2 34 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-2627-5; 978-1-4939-2626-8 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1303 BP 509 EP 519 DI 10.1007/978-1-4939-2627-5_31 D2 10.1007/978-1-4939-2627-5 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Clinical Neurology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA BE2UR UT WOS:000370127800032 PM 26235088 ER PT J AU Hoffmann, AR Proctor, LM Surette, MG Suchodolski, JS AF Hoffmann, A. Rodrigues Proctor, L. M. Surette, M. G. Suchodolski, J. S. TI The Microbiome: The Trillions of Microorganisms That Maintain Health and Cause Disease in Humans and Companion Animals SO VETERINARY PATHOLOGY LA English DT Review DE microbiome; microbial ecology; human microbiome project; respiratory; gastrointestinal; skin ID INFLAMMATORY-BOWEL-DISEASE; COMMUNITY-ACQUIRED PNEUMONIA; RIBOSOMAL-RNA GENE; CANINE ATOPIC-DERMATITIS; UPPER RESPIRATORY-TRACT; HUMAN SKIN MICROBIOME; INVASIVE ESCHERICHIA-COLI; GUT MICROBIOME; SMALL-INTESTINE; GRANULOMATOUS COLITIS AB The microbiome is the complex collection of microorganisms, their genes, and their metabolites, colonizing the human and animal mucosal surfaces, digestive tract, and skin. It is now well known that the microbiome interacts with its host, assisting in digestion and detoxification, supporting immunity, protecting against pathogens, and maintaining health. Studies published to date have demonstrated that healthy individuals are often colonized with different microbiomes than those with disease involving various organ systems. This review covers a brief history of the development of the microbiome field, the main objectives of the Human Microbiome Project, and the most common microbiomes inhabiting the human respiratory tract, companion animal digestive tract, and skin in humans and companion animals. The main changes in the microbiomes in patients with pulmonary, gastrointestinal, and cutaneous lesions are described. C1 [Hoffmann, A. Rodrigues] Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Pathobiol, College Stn, TX 77843 USA. [Proctor, L. M.] NHGRI, NIH, Bethesda, MD 20892 USA. [Surette, M. G.] McMaster Univ, Farncombe Family Digest Hlth Res Inst, Fac Hlth Sci, Dept Med,Dept Biochem & Biomed Sci, Hamilton, ON, Canada. [Suchodolski, J. S.] Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Small Anim Clin Sci, College Stn, TX USA. RP Hoffmann, AR (reprint author), Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Pathobiol, College Stn, TX 77843 USA. EM arodrigues@cvm.tamu.edu NR 129 TC 5 Z9 6 U1 20 U2 50 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0300-9858 EI 1544-2217 J9 VET PATHOL JI Vet. Pathol. PD JAN PY 2016 VL 53 IS 1 BP 10 EP 21 DI 10.1177/0300985815595517 PG 12 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA DD0SM UT WOS:000369629800003 ER PT J AU Harvey, JB Hong, HHL Bhusari, S Ton, TV Wang, Y Foley, JF Peddada, SD Hooth, M DeVito, M Nyska, A Pandiri, AR Hoenerhoff, MJ AF Harvey, J. B. Hong, H. -H. L. Bhusari, S. Ton, T. -V. Wang, Y. Foley, J. F. Peddada, S. D. Hooth, M. DeVito, M. Nyska, A. Pandiri, A. R. Hoenerhoff, M. J. TI F344/NTac Rats Chronically Exposed to Bromodichloroacetic Acid Develop Mammary Adenocarcinomas With Mixed Luminal/Basal Phenotype and Tgf beta Dysregulation SO VETERINARY PATHOLOGY LA English DT Article DE breast cancer; basal; F344/NTac rat; gene expression; luminal; transforming growth factor beta; environmental pollutants ID GROWTH-FACTOR-BETA; ORDER-RESTRICTED INFERENCE; CHLORINATION BY-PRODUCTS; GENE-EXPRESSION DATA; BREAST-CANCER; DICHLOROACETIC ACID; EPITHELIAL-CELLS; DRINKING-WATER; PROGRESSION; CARCINOGENICITY AB Breast cancer is the most common cancer and the second-leading cause of cancer mortality in women in the United States. A recent 2-year National Toxicology Program carcinogenicity study showed an increased incidence of proliferative mammary lesions (hyperplasia, fibroadenoma, adenocarcinoma) in F344/NTac rats exposed to bromodichloroacetic acid (BDCA), a disinfection by-product in finished drinking water with widespread human exposure. We hypothesized that the increase in mammary tumors observed in BDCA-exposed F344/NTac rats may be due to underlying molecular changes relevant for human breast cancer. The objective of the study was to compare (1) gene and protein expression and (2) mutation spectra of relevant human breast cancer genes between normal untreated mammary gland and mammary tumors from control and BDCA-exposed animals to identify molecular changes relevant for human cancer. Histologically, adenocarcinomas from control and BDCA-exposed animals were morphologically very similar, were estrogen/progesterone receptor positive, and displayed a mixed luminal/basal phenotype. Gene expression analysis showed a positive trend in the number of genes associated with human breast cancer, with proportionally more genes represented in the BDCA-treated tumor group. Additionally, a 5-gene signature representing possible Tgf beta pathway activation in BDCA-treated adenocarcinomas was observed, suggesting that this pathway may be involved in the increased incidence of mammary tumors in BDCA-exposed animals. C1 [Harvey, J. B.; Hong, H. -H. L.; Bhusari, S.; Ton, T. -V.; Wang, Y.; Foley, J. F.; Pandiri, A. R.; Hoenerhoff, M. J.] NIEHS, Invest Pathol Grp, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. [Harvey, J. B.] N Carolina State Univ, Coll Vet Med, Raleigh, NC 27695 USA. [Wang, Y.; Foley, J. F.] NIEHS, Special Tech Grp, Cellular & Mol Pathol Branch, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. [Peddada, S. D.] NIEHS, Biostat Branch, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. [Hooth, M.] NIEHS, Program Operat Branch, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. [DeVito, M.] NIEHS, Gen Toxicol Grp, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. [Nyska, A.] Integrated Lab Syst Inc, Res Triangle Pk, NC USA. [Pandiri, A. R.] Expt Pathol Labs, Res Triangle Pk, NC USA. RP Hoenerhoff, MJ (reprint author), NIEHS, Invest Pathol Grp, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA.; Hoenerhoff, MJ (reprint author), Univ Michigan, Unit Lab Anim Med, North Campus Res Complex,Bldg 36,Rm 178, Ann Arbor, MI 48103 USA. EM hoenerho@med.umich.edu FU Division of the National Toxicology Program, National Institutes of Environmental Health Sciences, National Institutes of Health FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Division of the National Toxicology Program, National Institutes of Environmental Health Sciences, National Institutes of Health. NR 66 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0300-9858 EI 1544-2217 J9 VET PATHOL JI Vet. Pathol. PD JAN PY 2016 VL 53 IS 1 BP 170 EP 181 DI 10.1177/0300985815571680 PG 12 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA DD0SM UT WOS:000369629800017 PM 25732176 ER PT J AU Hardcastle, K Scott, D Safronetz, D Brining, DL Ebihara, H Feldmann, H LaCasse, RA AF Hardcastle, K. Scott, D. Safronetz, D. Brining, D. L. Ebihara, H. Feldmann, H. LaCasse, R. A. TI Laguna Negra Virus Infection Causes Hantavirus Pulmonary Syndrome in Turkish Hamsters (Mesocricetus brandti) SO VETERINARY PATHOLOGY LA English DT Article DE Laguna Negra virus; hantavirus; hantavirus pulmonary syndrome; Mesocricetus brandti; Turkish hamsters; lungs; interstitial pneumonia; pulmonary edema ID NEW-WORLD HANTAVIRUSES; ANDES VIRUS; DISEASE; MODEL; EPIDEMIOLOGY AB Laguna Negra virus (LNV) is a New World hantavirus associated with severe and often fatal cardiopulmonary disease in humans, known as hantavirus pulmonary syndrome (HPS). Five hamster species were evaluated for clinical and serologic responses following inoculation with 4 hantaviruses. Of the 5 hamster species, only Turkish hamsters infected with LNV demonstrated signs consistent with HPS and a fatality rate of 43%. Clinical manifestations in infected animals that succumbed to disease included severe and rapid onset of dyspnea, weight loss, leukopenia, and reduced thrombocyte numbers as compared to uninfected controls. Histopathologic examination revealed lung lesions that resemble the hallmarks of HPS in humans, including interstitial pneumonia and pulmonary edema, as well as generalized infection of endothelial cells and macrophages in major organ tissues. Histologic lesions corresponded to the presence of viral antigen in affected tissues. To date, there have been no small animal models available to study LNV infection and pathogenesis. The Turkish hamster model of LNV infection may be important in the study of LNV-induced HPS pathogenesis and development of disease treatment and prevention strategies. C1 [Hardcastle, K.] Boston Univ, Natl Emerging Infect Dis Labs, Boston, MA 02215 USA. [Hardcastle, K.; Scott, D.; Brining, D. L.; LaCasse, R. A.] NIAID, Rocky Mt Labs, Rocky Mt Vet Branch, Div Intramural Res,NIH, Hamilton, MT 59840 USA. [Safronetz, D.; Ebihara, H.; Feldmann, H.] NIAID, Rocky Mt Labs, Virol Lab, Div Intramural Res,NIH, Hamilton, MT 59840 USA. [Brining, D. L.] Univ Colorado, Off Anim Resources, Boulder, CO 80309 USA. RP LaCasse, RA (reprint author), NIAID, Rocky Mt Labs, Rocky Mt Vet Branch, Div Intramural Res,NIH, Hamilton, MT 59840 USA.; LaCasse, RA (reprint author), Rocky Mt Vet Branch, RML 903 South 4th St, Hamilton, MT USA. EM rlacasse@niaid.nih.gov FU Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was financially supported by the Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health. NR 28 TC 3 Z9 3 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0300-9858 EI 1544-2217 J9 VET PATHOL JI Vet. Pathol. PD JAN PY 2016 VL 53 IS 1 BP 182 EP 189 DI 10.1177/0300985815570071 PG 8 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA DD0SM UT WOS:000369629800018 PM 25722219 ER PT J AU Raghavan, R Ashour, FS Bailey, R AF Raghavan, Ramkripa Ashour, Fayrouz Sakr Bailey, Regan TI A Review of Cutoffs for Nutritional Biomarkers SO ADVANCES IN NUTRITION LA English DT Review DE cutoffs; nutritional biomarkers; Youden index; ROC curve; nutritional assessment; nutritional surveillance; nutritional deficiency; reference values ID SOLUBLE TRANSFERRIN RECEPTOR; OPTIMAL CUT-POINT; RETINOL-BINDING-PROTEIN; REFERENCE VALUES; IRON-DEFICIENCY; REFERENCE INTERVALS; SERUM FERRITIN; YOUDEN INDEX; CARDIOVASCULAR-DISEASE; OPTIMAL CUTPOINTS AB The nutritional status of an individual or population needs to be assessed through valid and reliable biomarkers. Cutoffs generally have an underlying relation to health status and are one of the important quantitative criteria against which biomarker outputs are compared. For this reason, cutoffs are integral for surveys, surveillance, screening, interventions, monitoring, and evaluation. Despite their importance, nutritional biomarker cutoffs have not been adequately addressed in the literature. Furthermore, the field has not reached a consensus on which cutoff to use for each biomarker, and different cutoffs are often used for the same biomarkers in published studies. This review provides a comprehensive overview of cutoffs related to nutritional biomarkers and highlights some of the high- priority research gaps and challenges of using micronutrient case studies. C1 [Raghavan, Ramkripa] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, Ctr Early Life Origins Dis, Baltimore, MD USA. [Ashour, Fayrouz Sakr] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Bailey, Regan] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. RP Raghavan, R (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, Ctr Early Life Origins Dis, Baltimore, MD USA. EM ramkripa@gmail.com NR 72 TC 4 Z9 4 U1 1 U2 4 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 EI 2156-5376 J9 ADV NUTR JI Adv. Nutr. PD JAN PY 2016 VL 7 IS 1 BP 112 EP 120 DI 10.3945/an.115.009951 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DC3HX UT WOS:000369111500011 PM 26773019 ER PT J AU Ahluwalia, N Dwyer, J Terry, A Moshfegh, A Johnson, C AF Ahluwalia, Namanjeet Dwyer, Johanna Terry, Ana Moshfegh, Alanna Johnson, Clifford TI Update on NHANES Dietary Data: Focus on Collection, Release, Analytical Considerations, and Uses to Inform Public Policy SO ADVANCES IN NUTRITION LA English DT Review DE dietary assessment; epidemiology; nutritional surveillance; public policy; nutrition databases; usual intake; nutrition policy ID NUTRITION EXAMINATION SURVEY; HEALTHY EATING INDEX-2005; INTAKE DISTRIBUTIONS; NATIONAL-HEALTH; 24-HOUR RECALL; ENERGY; CHILDREN; EPIDEMIOLOGY; INSTRUMENTS; POPULATIONS AB NHANES is the cornerstone for national nutrition monitoring to inform nutrition and health policy. Nutritional assessment in NHANES is described with a focus on dietary data collection, analysis, and uses in nutrition monitoring. NHANES has been collecting thorough data on diet, nutritional status, and chronic disease in cross-sectional surveys with nationally representative samples since the early 1970s. Continuous data collection began in 1999 with public data release in 2-y cycles on; similar to 10,000 participants. In 2002, the Continuing Survey of Food Intakes by Individuals and the NHANES dietary component weremerged, forming a consolidated dietary data collection known asWhatWe Eat in America; since then, 24-h recalls have been collected on 2 d using the USDA's Automated Multiple-Pass Method. Detailed and targeted food-frequency questionnaires have been collected in some NHANES cycles. Dietary supplement use data have been collected (in detail since 2007) so that total nutrient intakes can be described for the population. The continuous NHANES can adapt its content to address emerging public health needs and reflect federal priorities. Changes in data collection methods are made after expert input and validation/ crossover studies. NHANES dietary data are used to describe intake of foods, nutrients, food groups, and dietary patterns by the US population and large sociodemographic groups to plan and evaluate nutrition programs and policies. Usual dietary intake distributions can be estimated after adjusting for day-to-day variation. NHANES remains open and flexible to incorporate improvements while maintaining data quality and providing timely data to track the nation's nutrition and health status. In summary, NHANES collects dietary data in the context of its broad, multipurpose goals; the strengths and limitations of these data are also discussed in this review. C1 [Ahluwalia, Namanjeet; Terry, Ana; Johnson, Clifford] CDC, Natl Ctr Hlth Stat, Natl Hlth & Nutr Examinat Survey, Hyattsville, MD USA. [Dwyer, Johanna] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. [Moshfegh, Alanna] USDA, Food Surveys Res Grp, Beltsville, MD 20705 USA. RP Ahluwalia, N (reprint author), CDC, Natl Ctr Hlth Stat, Natl Hlth & Nutr Examinat Survey, Hyattsville, MD USA. EM n.ahluwalia@cdc.gov NR 70 TC 8 Z9 8 U1 3 U2 7 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 EI 2156-5376 J9 ADV NUTR JI Adv. Nutr. PD JAN PY 2016 VL 7 IS 1 BP 121 EP 134 DI 10.3945/an.115.009258 PG 14 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DC3HX UT WOS:000369111500012 PM 26773020 ER PT J AU Raiten, DJ Neufeld, LM De-Regil, LM Pasricha, SR Darnton-Hill, I Hurrell, R Murray-Kolb, LE Nair, KM Wefwafwa, T Kupka, R Phall, MC Ashour, FAS AF Raiten, Daniel J. Neufeld, Lynnette M. De-Regil, Luz-Maria Pasricha, Sant-Rayn Darnton-Hill, Ian Hurrell, Richard Murray-Kolb, Laura E. Nair, K. Madhavan Wefwafwa, Terry Kupka, Roland Phall, Modou Cheyassin Ashour, Fayrouz A. Sakr TI Integration to Implementation and the Micronutrient Forum: A Coordinated Approach for Global Nutrition. Case Study Application: Safety and Effectiveness of Iron Interventions SO ADVANCES IN NUTRITION LA English DT Review DE anemias; international nutrition; interventions; iron; public health ID RANDOMIZED CONTROLLED-TRIAL; DEVELOPING-COUNTRIES; YOUNG-CHILDREN; GAMBIAN CHILDREN; AFRICAN CHILDREN; STABLE-ISOTOPE; COTE-DIVOIRE; ANEMIA; FORTIFICATION; MALARIA AB Paramount among the challenges to our ability to address the role of food and nutrition in health promotion and disease prevention is how to design and implement context-specific interventions and guidance. The Integration to Effective Implementation (I-to-I) concept is intended to address the complexities of the global health context through engagement of the continuum of stakeholders involved in the food and nutrition enterprise. The 2014 Micronutrient Forum (MNF) Global Conference held in Addis Ababa, Ethiopia, in June 2014 offered the opportunity to apply the I-to-I approach with the use of current concerns about the safety and effectiveness of interventions to prevent and treat iron deficiency (ID) as a case study. ID is associated with a range of adverse outcomes, especially in pregnant and nonpregnant women, infants, and primary school-age children. Strategies to combat ID include iron supplementation, multiple micronutrient powders, and food-based interventions to enhance dietary iron intake. Recent reports indicate potential increased adverse risks when iron is provided in areas with high infection burdens (e.g., malaria). This paradox has weakened iron intervention programs. Furthermore, the selection and interpretation of available biomarkers for assessing iron nutrition have been found to be compromised by the inflammatory process. These issues highlight the need for a comprehensive approach that considers basic biology, assessment, interventions, and howthese can be translated into appropriate programs and policies. The application of the I-to-I with the use of the MNF offered an opportunity to explore how that might be achieved. C1 [Raiten, Daniel J.; Ashour, Fayrouz A. Sakr] NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bldg 10, Bethesda, MD 20892 USA. [Neufeld, Lynnette M.] Global Alliance Improved Nutr, Geneva, Switzerland. [De-Regil, Luz-Maria] Micronutrient Initiat, Ottawa, ON, Canada. [Pasricha, Sant-Rayn] Univ Oxford, MRC Weatherall Inst Mol Med, Oxford, England. [Darnton-Hill, Ian] Univ Sydney, Fac Med, Boden Inst Obes Nutr Exercise & Eating Disorders, Sydney, NSW 2006, Australia. [Hurrell, Richard] Swiss Fed Inst Technol, Inst Food Nutr & Hlth, Zurich, Switzerland. [Murray-Kolb, Laura E.] Penn State Univ, Nut Sci, State Coll, PA USA. [Nair, K. Madhavan] Indian Council Med Res, Natl Inst Nutr, Dept Biophys, Jamai Osmania Po, Hyderabad 500007, Andhra Pradesh, India. [Wefwafwa, Terry] Minist Hlth, Div Nutr, Nairobi, Kenya. [Kupka, Roland] UNICEF, New York, NY USA. [Phall, Modou Cheyassin] Natl Nutr Agcy, Banjul, Gambia. RP Raiten, DJ (reprint author), NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bldg 10, Bethesda, MD 20892 USA. EM raitend@mail.nih.gov FU The Iron and Malaria Project - Bill and Melinda Gates Foundation; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Supported by the parent grant The Iron and Malaria Project, funded by the Bill and Melinda Gates Foundation and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. This is a free access article, distributed under terms (http://www.nutrition.org/publications/guidelines-and-policies/license/) that permit unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. NR 69 TC 0 Z9 0 U1 4 U2 9 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 EI 2156-5376 J9 ADV NUTR JI Adv. Nutr. PD JAN PY 2016 VL 7 IS 1 BP 135 EP 148 DI 10.3945/an.115.008581 PG 14 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DC3HX UT WOS:000369111500013 PM 26773021 ER PT J AU Murphy, SP Yates, AA Atkinson, SA Barr, SI Dwyer, J AF Murphy, Suzanne P. Yates, Allison A. Atkinson, Stephanie A. Barr, Susan I. Dwyer, Johanna TI History of Nutrition: The Long Road Leading to the Dietary Reference Intakes for the United States and Canada SO ADVANCES IN NUTRITION LA English DT Article DE dietary assessment; dietary intake; dietary reference intakes; nutrient requirements; nutrition policy ID FOOD GUIDANCE-SYSTEM; VITAMIN-D; FOLATE; HEALTH; POPULATION; SERUM AB The Dietary Reference Intakes (DRIs) are reference values to guide the planning and assessing of nutrient intakes in the United States and Canada. The DRI framework was conceptualized in 1994, and the first reports were issued from 1997-2004, based on work by expert panels and subcommittees under the guidance of the Food and Nutrition Board of the Institute of Medicine. Numerous conventions, challenges, and controversies were encountered during the process of defining and setting the DRIs, including the definition of the framework, the use of chronic disease endpoints, lack of data on requirements for children and youth, and methods for addressing nonessential bioactive substances with potential health benefits. DRIs may be used to plan and assess the nutrient intakes of both individuals and population groups, but the new paradigm particularly improved methods used for groups. It is now possible to estimate both the prevalence of inadequate intake and the prevalence of potentially excessive intake within a group. The DRIs have served as a potent influence on national nutrition policies, including those related to dietary guidance, food labeling, nutrition monitoring, food assistance programs, and military nutrition standards. Because of this important impact on nutrition policy, the DRIs must be based on the best possible and most up-to-date science. Unfortunately, no updates to specific DRIs are currently planned. Despite the long and challenging road that led to the current DRIs, it must not finish in a dead end. Monetary resources and political will are crucial to maintaining and continuously updating the DRIs. C1 [Murphy, Suzanne P.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Yates, Allison A.] Natl Acad Sci, Inst Med, Consultant Food & Nutr Board, Washington, DC 20418 USA. [Atkinson, Stephanie A.] McMaster Univ, Dept Pediat, Hamilton, ON, Canada. [Barr, Susan I.] Univ British Columbia, Food Nutr & Hlth, Vancouver, BC V5Z 1M9, Canada. [Dwyer, Johanna] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. [Dwyer, Johanna] Tufts Univ, Sch Med, Medford, MA 02155 USA. [Dwyer, Johanna] Tufts Univ, Friedman Sch Nutr Sci & Policy, Medford, MA 02155 USA. RP Murphy, SP (reprint author), Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. EM suzanne@cc.hawaii.edu FU ASN; ASN History of Nutrition Committee FX This article is a review from the symposium History of Nutrition: The Long Road Leading to the Dietary Reference Intakes held 31 March 2015, at the American Society for Nutrition (ASN) Scientific Sessions and Annual Meeting at Experimental Biology 2015 in Boston, MA. The symposium was sponsored by the ASN and the ASN History of Nutrition Committee. NR 54 TC 2 Z9 2 U1 2 U2 8 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 EI 2156-5376 J9 ADV NUTR JI Adv. Nutr. PD JAN PY 2016 VL 7 IS 1 BP 157 EP 168 DI 10.3945/an.115.010322 PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DC3HX UT WOS:000369111500015 PM 27180379 ER PT J AU Costello, R Wallace, TC Rosanoff, A AF Costello, Rebecca Wallace, Taylor C. Rosanoff, Andrea TI Magnesium SO ADVANCES IN NUTRITION LA English DT Editorial Material C1 [Costello, Rebecca] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. [Wallace, Taylor C.] Natl Osteoporosis Fdn, Washington, DC USA. [Rosanoff, Andrea] Ctr Magnesium Educ & Res, Pahoa, HI USA. RP Rosanoff, A (reprint author), Ctr Magnesium Educ & Res, Pahoa, HI USA. EM costellb@od.nih.gov NR 11 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 EI 2156-5376 J9 ADV NUTR JI Adv. Nutr. PD JAN PY 2016 VL 7 IS 1 BP 199 EP 201 DI 10.3945/an.115.008524 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DC3HX UT WOS:000369111500019 PM 26773023 ER PT J AU Hernandez, D Feaster, DJ Gooden, L Douaihy, A Mandler, R Erickson, SJ Kyle, T Haynes, L Schwartz, R Das, M Metsch, L AF Hernandez, Diana Feaster, Daniel J. Gooden, Lauren Douaihy, Antoine Mandler, Raul Erickson, Sarah J. Kyle, Tiffany Haynes, Louise Schwartz, Robert Das, Moupali Metsch, Lisa TI Self-Reported HIV and HCV Screening Rates and Serostatus Among Substance Abuse Treatment Patients SO AIDS AND BEHAVIOR LA English DT Article DE HIV/HCV testing and linkage to care; HIV/HCV sceening and serostatus; Community based substance abuse treatment programs; Substance abuse treatment patients ID HEPATITIS-C VIRUS; INJECTION-DRUG-USERS; HUMAN-IMMUNODEFICIENCY-VIRUS; OPIOID TREATMENT PROGRAMS; NEW-YORK-CITY; UNITED-STATES; NATIONWIDE SURVEY; RISK BEHAVIORS; PUBLIC-HEALTH; INFECTION AB Substance users are at increased risk for HIV and HCV infection. Still, many substance use treatment programs (SUTP) fail to offer HIV/HCV testing. The present secondary analysis of screening data from a multi-site randomized trial of rapid HIV testing examines self-reported HIV/HCV testing patterns and serostatus of 2473 SUTP patients in 12 community-based sites that had not previously offered on-site testing. Results indicate that most respondents screened for the randomized trial tested more than a year prior to intake for HIV (52 %) and HCV (38 %). Prevalence rates were 3.6 and 30 % for HIV and HCV, respectively. The majority of participants that were HIV (52.2 %) and HCV-positive (40.5 %) reported having been diagnosed within the last 1-5 years. Multivariable logistic regression showed that members of high-risk groups were more likely to have tested. Bundled HIV/HCV testing and linkage to care issues are recommended for expanding testing in community-based SUTP settings. C1 [Hernandez, Diana; Gooden, Lauren; Metsch, Lisa] Columbia Univ, Mailman Sch Publ Hlth, Dept Sociomed Sci, 722 W 168th St,Rm 934, New York, NY 10032 USA. [Feaster, Daniel J.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Douaihy, Antoine] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Mandler, Raul] NIDA, Bethesda, MD 20892 USA. [Erickson, Sarah J.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. [Kyle, Tiffany] Ctr Drug Free Living, Orlando, FL USA. [Haynes, Louise] Med Univ S Carolina, Charleston, SC 29425 USA. [Schwartz, Robert] Friends Res Inst, Baltimore, MD USA. [Das, Moupali] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. RP Hernandez, D (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Sociomed Sci, 722 W 168th St,Rm 934, New York, NY 10032 USA. EM dh2494@columbia.edu FU National Drug Abuse Treatment Clinical Trials Network [U10DA013720, U10DA13720-095, U10DA020036, U10DA15815, U10DA13034, U10DA013038, U10DA013732, U10DA13036, U10DA13727, U10DA015833, HHSN271200522081C, HHSN271200522071C] FX Funding for this study and analysis was provided by the National Drug Abuse Treatment Clinical Trials Network under the following cooperative agreements, awards, and contracts: U10DA013720, U10DA13720-095, U10DA020036, U10DA15815, U10DA13034, U10DA013038, U10DA013732, U10DA13036, U10DA13727, U10DA015833, HHSN271200522081C, and HHSN271200522071C. We acknowledge the site principal investigators: David Avila, Michael DeBernardi, Lillian Donnard, Antoine Douaihy, Louise Haynes, Ray Muszynski, Patricia E. Penn, Ned Snead, Kevin Stewart, Robert C. Werstlein, and Katharina Wiest. Site principal investigators' contributions to the work reported in this article included directing all aspects of the proposed study at their site(s), having overall responsibility for achieving the specific aims of the study, maintaining the proposed study schedule and budget, supervising the project staff, and ensuring quality control over all aspects of this study. We also acknowledge the following site staff: Walitta Abdullah, Elizabeth Alonso, Anika Alvanzo, Anna Amberg, Holly Angel, Rebekka M. Arias, Natasha Arocho, Carolyn Baron-Myak, Sarah Battle, Melissa Beddingfield, Dan Blazer, Stacy Botex, Sarah Bowles, Audrey Brooks, Elizabeth Buttrey, Betty Caldwell, Lynn Calvin, Maria Campanella, Sarah Carney, Angela Casey-Willingham, Jack Chally, Roberta Chavez, Nicholas Cohen, Zoe Cummings, Elisa Cupelli, Dennis Daley, Meredith Davis, Kay Debski, Andrea Dedier, Ashley Dibble, Bruce Dillard, Debbie Drosdick, Monica Eiden, Matthew Elmore, Sarah Essex, Laura Feldberg, Elizabeth Ferris, John Gary, Daniel Gerwien, Marisa Gholson, Melissa Gordon, Lauren Griebel, Laurel Hall, Stephanie Hart, Joshua Hefferen, Beverly Holmes, Christine Horne, Alice Huang, Aleks Jankowska, Beth Jeffries, Kristen Jehl, Eve Jelstrom, Andrew Johnson, Jacob Johnson, Sharma Johnson, Emily Kinsling-Law, Amy Knapp, Eric Kohler, Beatrice Koon, Emily Kraus, Lynn Kunkel, Robert Kushner, Diane Lape, Theresa Latham, Larry Lee, Carol Luna-Anderson, Sue McDavit, Michael McKinney, Cindy Merly, Melody Mickens, Jenni Mulholland, Roger Owen, Barbara Paschke, Wayne Pennachi, Sharon Pickrel, Kimberly Pressley, John Reynolds, Gillian Rossman, Lauretta Safford, Christine Sanchez, Lynn Sanchez, Dorothy Sandstrom, Carmel Scharenbroich, Robert Schwartz, Nicolangelo Scibelli, Michael Shopshire, Jessica Sides, Eugene Somoza, Maxine Stitzer, Joseph Sullivan, Krishna Suwal, Danielle Terrell, Lauren Thomas, Rena Treacher, Dominic Usher, Angel Valencia, Tammy Van Linter, Rosa Verdeja, Joanne Weidemann, Brandi Welles, Lindsay Worth, and Pamela Yus. Site staff contributions to the work reported in this article included conducting recruitment and enrollment activities, performing assessment interviews, conducting study interventions, performing quality assurance monitoring activities, performing data entry, and completing other day-to-day study activities that led to the collection of the study data. We also would like to acknowledge Jacques Normand and Lynda Erinoff of the National Institute on Drug Abuse, Office of the Director, AIDS Research Program, for their review of the article and contributions to protocol development. NR 62 TC 0 Z9 0 U1 1 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD JAN PY 2016 VL 20 IS 1 BP 204 EP 214 DI 10.1007/s10461-015-1074-2 PG 11 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DC9DH UT WOS:000369520800021 PM 25952768 ER PT J AU Urano, E Ablan, SD Mandt, R Pauly, GT Sigano, DM Schneider, JP Martin, DE Nitz, TJ Wild, CT Freed, EO AF Urano, Emiko Ablan, Sherimay D. Mandt, Rebecca Pauly, Gary T. Sigano, Dina M. Schneider, Joel P. Martin, David E. Nitz, Theodore J. Wild, Carl T. Freed, Eric O. TI Alkyl Amine Bevirimat Derivatives Are Potent and Broadly Active HIV-1 Maturation Inhibitors SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; BETULINIC ACID-DERIVATIVES; RESOURCE-LIMITED SETTINGS; CA-SP1 CLEAVAGE SITE; DRUG-RESISTANCE; VIRION MATURATION; GAG POLYPROTEIN; PARTICLE MATURATION; VIRAL PROTEASE; TYPE-1 AB Concomitant with the release of human immunodeficiency virus type 1 (HIV-1) particles from the infected cell, the viral protease cleaves the Gag polyprotein precursor at a number of sites to trigger virus maturation. We previously reported that a betulinic acid-derived compound, bevirimat (BVM), blocks HIV-1 maturation by disrupting a late step in protease-mediated Gag processing: the cleavage of the capsid-spacer peptide 1 (CA-SP1) intermediate to mature CA. BVM was shown in multiple clinical trials to be safe and effective in reducing viral loads in HIV-1-infected patients. However, naturally occurring polymorphisms in the SP1 region of Gag (e.g., SP1-V7A) led to a variable response in some BVM-treated patients. The reduced susceptibility of SP1-polymorphic HIV-1 to BVM resulted in the discontinuation of its clinical development. To overcome the loss of BVM activity induced by polymorphisms in SP1, we carried out an extensive medicinal chemistry campaign to develop novel maturation inhibitors. In this study, we focused on alkyl amine derivatives modified at the C-28 position of the BVM scaffold. We identified a set of derivatives that are markedly more potent than BVM against an HIV-1 clade B clone (NL4-3) and show robust antiviral activity against a variant of NL4-3 containing the V7A polymorphism in SP1. One of the most potent of these compounds also strongly inhibited a multiclade panel of primary HIV-1 isolates. These data demonstrate that C-28 alkyl amine derivatives of BVM can, to a large extent, overcome the loss of susceptibility imposed by polymorphisms in SP1. C1 [Urano, Emiko; Ablan, Sherimay D.; Mandt, Rebecca; Freed, Eric O.] NCI, Ctr Canc Res, HIV Dynam & Replicat Program, Virus Cell Interact Sect, Frederick, MD 21701 USA. [Pauly, Gary T.; Sigano, Dina M.; Schneider, Joel P.] NCI, Ctr Canc Res, Biol Chem Lab, Chem Synth Grp, Frederick, MD 21701 USA. [Martin, David E.; Nitz, Theodore J.; Wild, Carl T.] DFH Pharma, Gaithersburg, MD USA. RP Freed, EO (reprint author), NCI, Ctr Canc Res, HIV Dynam & Replicat Program, Virus Cell Interact Sect, Frederick, MD 21701 USA. EM efreed@nih.gov FU HHS; National Institutes of Health (NIH) [1R41AI108457-1, N01-AI-70041]; Intramural Research Program [BC 010778, BC 01151]; Division of AIDS, NIH [HHSN272200700041C] FX HHS | National Institutes of Health (NIH) provided funding to Eric O. Freed and Joel P. Schneider and under grant numbers BC 010778 and BC 011515 from the Intramural Research Program. HHS vertical bar NIH provided funding to Carl Wild under grant number 1R41AI108457-1 and by contract N01-AI-70041. This work was also supported by the Intramural AIDS Targeted Antiviral Program and was conducted in part by Southern Research Institute, using federal funds from the Division of AIDS, NIH, under contract HHSN272200700041C, entitled "Confirmatory In Vitro Evaluations of HIV Therapeutics." NR 47 TC 7 Z9 7 U1 3 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JAN PY 2016 VL 60 IS 1 BP 190 EP 197 DI 10.1128/AAC.02121-15 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA DC3XZ UT WOS:000369154600023 ER PT J AU McMullan, LK Flint, M Dyall, J Albarino, C Olinger, GG Foster, S Sethna, P Hensley, LE Nichol, ST Lanier, ER Spiropoulou, CF AF McMullan, Laura K. Flint, Mike Dyall, Julie Albarino, Cesar Olinger, Gene G. Foster, Scott Sethna, Phiroze Hensley, Lisa E. Nichol, Stuart T. Lanier, E. Randall Spiropoulou, Christina F. TI The lipid moiety of brincidofovir is required for in vitro antiviral activity against Ebola virus SO ANTIVIRAL RESEARCH LA English DT Article DE Ebola; Antiviral therapy; In vitro screen; Brincidofovir ID CYTOMEGALOVIRUS DNA-POLYMERASE; HIGH-THROUGHPUT; CIDOFOVIR DIPHOSPHATE; T-705 FAVIPIRAVIR; INFECTION; INHIBITORS; OUTBREAK; DISEASE; PLASMA; MODEL AB Brincidofovir (BCV) is the 3-hexadecyloxy-l-propanol (HDP) lipid conjugate of the acyclic nucleoside phosphonate cidofovir (CDV). BCV has established broad-spectrum activity against double-stranded DNA (dsDNA) viruses; however, its activity against RNA viruses has been less thoroughly evaluated. Here, we report that BCV inhibited infection of Ebola virus in multiple human cell lines. Unlike the mechanism of action for BCV against cytomegalovirus and other dsDNA viruses, phosphorylation of CDV to the diphosphate form appeared unnecessary. Instead, antiviral activity required the lipid moiety and in vitro activity against EBOV was observed for several HDP-nucleotide conjugates. (C) 2015 Published by Elsevier B.V. C1 [McMullan, Laura K.; Flint, Mike; Albarino, Cesar; Nichol, Stuart T.; Spiropoulou, Christina F.] Ctr Dis Control & Prevent, Viral Special Pathogens Branch, Div High Consequence Pathogens & Pathol, Atlanta, GA 30333 USA. [Dyall, Julie; Olinger, Gene G.; Hensley, Lisa E.] NIAID, Integrated Res Facil, NIH, Frederick, MD USA. [Foster, Scott; Sethna, Phiroze; Lanier, E. Randall] Chimerix, Durham, NC USA. RP Spiropoulou, CF (reprint author), Ctr Dis Control & Prevent, Viral Special Pathogens Branch, Div High Consequence Pathogens & Pathol, Natl Ctr Emerging & Zoonot Infect Dis, 1600 Clifton Rd,MS G-14, Atlanta, GA 30333 USA. EM ccs8@cdc.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID); Integrated Research Facility, Division of Clinical Research, NIAID; Battelle Memorial Institute (BMI); NIAID [HHSN272200700016I] FX We thank Tanya Klimova for assistance with editing this manuscript and Robert Hart for analytical chemistry support. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. SF, PS and ERL are employees of Chimerix. This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID); Integrated Research Facility, Division of Clinical Research, NIAID; and Battelle Memorial Institute's (BMI) prime contract with NIAID (Contract # HHSN272200700016I). J.D. performed this work as employee of Tunnell Consulting, Inc. a subcontractor to BMI. G.G.O. Jr performed this work as employee of Midwest Research Institute a subcontractor to BMI. NR 22 TC 11 Z9 11 U1 3 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD JAN PY 2016 VL 125 BP 71 EP 78 DI 10.1016/j.antiviral.2015.10.010 PG 8 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA DC4PX UT WOS:000369203900011 PM 26526586 ER PT J AU Jinsmaa, Y Sullivan, P Sharabi, Y Goldstein, DS AF Jinsmaa, Yunden Sullivan, Patricia Sharabi, Yehonatan Goldstein, David S. TI DOPAL is transmissible to and oligomerizes alpha-synuclein in human glial cells SO AUTONOMIC NEUROSCIENCE-BASIC & CLINICAL LA English DT Article DE Glial cytoplasmic inclusions; Multiple system atrophy; Synuclein; DOPAL; Parkinson's disease ID MULTIPLE SYSTEM ATROPHY; TOXIC DOPAMINE METABOLITE; CYTOPLASMIC INCLUSIONS; 3,4-DIHYDROXYPHENYLACETALDEHYDE; OLIGODENDROCYTES; AGGREGATION; EXPRESSION; DISEASE AB Introduction: Glial cytoplasmic inclusions (GCIs) containing alpha-synuclein (AS) are a neuropathologic hallmark of multiple system atrophy (MSA). Oligomerized AS is thought to be the pathogenic form of the protein. Glial cells normally express little AS, but they can take up AS from the extracellular fluid. 3,4-Dihydroxyphenylacetaldehyde (DOPAL), an obligate intermediate in the intra-neuronal metabolism of dopamine (DA), potently oligomerizes AS. In this study we tested whether DOPAL is taken up by human glial cells and augments intracellular oligomerization of AS. Methods: DOPAL (exogenous or endogenous from co-incubation with PC12 cells) and AS (native or A53T mutant form) were added to the incubation medium of glial cells (glioblastoma or MO3.13 oligodendrocytes). Glial cellular contents of DOPAL and its intracellular metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were measured at up to 180 min of incubation. Glial cellular AS oligomers were quantified by Western blotting. Results: Neither glioblastoma nor MO3.13 cells contained endogenous catecholamines or AS. Co-incubation of the cells with DA-producing PC12 cells produced time-related increases in DOPAL and DOPAC contents. Similarly, glial cellular DOPAL and DOPAC contents increased rapidly after addition of DOPAL to the medium. After addition of native or A53T-AS, intracellular AS also increased. Incubation of glial cells with both DOPAL and AS enhanced the intracellular oligomerization of native and A53T-AS. Conclusions: DOPAL is transmissible to glial cells and enhances intracellular oligomerization of AS. An interaction of DOPAL with AS might help explain the formation of CGIs in MSA. Published by Elsevier B.V. C1 [Jinsmaa, Yunden; Sullivan, Patricia; Goldstein, David S.] NINDS, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,NIH, 9000 Rockville Pike,10-5N220, Bethesda, MD 20892 USA. [Sharabi, Yehonatan] Chaim Sheba Med Ctr, Hypertens Unit, IL-52621 Tel Hashomer, Israel. [Sharabi, Yehonatan] Tel Aviv Univ, Tel Hashomer, Israel. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,NIH, 9000 Rockville Pike,10-5N220, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov OI Goldstein, David/0000-0002-5709-9940 FU Division of Intramural Research, NINDS, NIH FX The research reported here was supported by the Division of Intramural Research, NINDS, NIH. NR 20 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1566-0702 EI 1872-7484 J9 AUTON NEUROSCI-BASIC JI Auton. Neurosci-Basic Clin. PD JAN PY 2016 VL 194 BP 46 EP 51 DI 10.1016/j.autneu.2015.12.008 PG 6 WC Neurosciences SC Neurosciences & Neurology GA DC8JB UT WOS:000369464600007 PM 26777075 ER PT J AU Li, J Zheng, S Chen, B Butte, AJ Swamidass, SJ Lu, ZY AF Li, Jiao Zheng, Si Chen, Bin Butte, Atul J. Swamidass, S. Joshua Lu, Zhiyong TI A survey of current trends in computational drug repositioning SO BRIEFINGS IN BIOINFORMATICS LA English DT Article DE computational drug repositioning; integrative strategies; genome; phenome; chemical structure; drug combination; prediction validation ID PHENOME-WIDE ASSOCIATION; TRANSCRIPTIONAL RESPONSES; EXPRESSION PROFILES; SMALL MOLECULES; SYSTEMATIC IDENTIFICATION; PERSONALIZED MEDICINE; ANTICANCER DRUGS; CAUSAL INFERENCE; LUNG-CANCER; CELL-GROWTH AB Computational drug repositioning or repurposing is a promising and efficient tool for discovering new uses from existing drugs and holds the great potential for precision medicine in the age of big data. The explosive growth of large-scale genomic and phenotypic data, as well as data of small molecular compounds with granted regulatory approval, is enabling new developments for computational repositioning. To achieve the shortest path toward new drug indications, advanced data processing and analysis strategies are critical for making sense of these heterogeneous molecular measurements. In this review, we show recent advancements in the critical areas of computational drug repositioning from multiple aspects. First, we summarize available data sources and the corresponding computational repositioning strategies. Second, we characterize the commonly used computational techniques. Third, we discuss validation strategies for repositioning studies, including both computational and experimental methods. Finally, we highlight potential opportunities and use-cases, including a few target areas such as cancers. We conclude with a brief discussion of the remaining challenges in computational drug repositioning. C1 Chinese Acad Med Sci, Inst Med Informat, Beijing 100020, Peoples R China. [Li, Jiao; Zheng, Si] Chinese Acad Med Sci, Inst Med Informat, 3rd Yabao Rd, Beijing 100020, Peoples R China. [Chen, Bin] Stanford Sch Med, Stanford, CA USA. [Butte, Atul J.] Stanford Univ, Pediat & Genet, Stanford, CA 94305 USA. [Butte, Atul J.] Stanford Univ, Med Pathol & Comp Sci, Stanford, CA 94305 USA. [Butte, Atul J.] Stanford Univ, Div Syst Med, Stanford, CA 94305 USA. [Butte, Atul J.] Lucile Packard Childrens Hosp, Palo Alto, CA USA. [Swamidass, S. Joshua] Washington Univ, Lab & Genom Med Pathol & Immunol Dept, St Louis, MO 63130 USA. [Lu, Zhiyong] NIH, Natl Ctr Biotechnol Informat, Biomed Text Min Res Grp, Bethesda, MD USA. RP Li, J (reprint author), Chinese Acad Med Sci, Inst Med Informat, 3rd Yabao Rd, Beijing 100020, Peoples R China. EM li.jiao@imicams.ac.cn FU NIH Intramural Research Program, National Library of Medicine; National Key Technology Research and Development Program of China [2013BAI06B01]; National Population and Health Scientific Data Sharing Program of China; Fundamental Research Funds for the Central Universities [13R0101] FX NIH Intramural Research Program, National Library of Medicine (to Z.L.), the National Key Technology Research and Development Program of China (Grant No. 2013BAI06B01), the National Population and Health Scientific Data Sharing Program of China, the Fundamental Research Funds for the Central Universities (Grant No. 13R0101). NR 101 TC 22 Z9 22 U1 13 U2 20 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 JAN PY 2016 VL 17 IS 1 SI SI BP 2 EP 12 DI 10.1093/bib/bbv020 PG 11 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA DC4WA UT WOS:000369219800002 PM 25832646 ER PT J AU Khare, R Good, BM Leaman, R Su, AI Lu, ZY AF Khare, Ritu Good, Benjamin M. Leaman, Robert Su, Andrew I. Lu, Zhiyong TI Crowdsourcing in biomedicine: challenges and opportunities SO BRIEFINGS IN BIOINFORMATICS LA English DT Article DE Amazon Mechanical Turk; big data mining; biomedicine; community challenges; crowdsourcing; games ID PROTEIN-STRUCTURE PREDICTION; AMAZON MECHANICAL TURK; MEDICAL-EDUCATION; NORMALIZATION; TEXT; KNOWLEDGE; TRENDS; CANCER; TERMS; GAME AB The use of crowdsourcing to solve important but complex problems in biomedical and clinical sciences is growing and encompasses a wide variety of approaches. The crowd is diverse and includes online marketplace workers, health information seekers, science enthusiasts and domain experts. In this article, we review and highlight recent studies that use crowdsourcing to advance biomedicine. We classify these studies into two broad categories: (i) mining big data generated from a crowd (e.g. search logs) and (ii) active crowdsourcing via specific technical platforms, e.g. labor markets, wikis, scientific games and community challenges. Through describing each study in detail, we demonstrate the applicability of different methods in a variety of domains in biomedical research, including genomics, biocuration and clinical research. Furthermore, we discuss and highlight the strengths and limitations of different crowdsourcing platforms. Finally, we identify important emerging trends, opportunities and remaining challenges for future crowdsourcing research in biomedicine. C1 [Khare, Ritu] Childrens Hosp Philadelphia, Dept Biomed & Hlth Informat, Philadelphia, PA USA. [Good, Benjamin M.; Su, Andrew I.] Scripps Res Inst, Dept Mol & Expt Med, San Diego, CA USA. [Leaman, Robert] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Lu, Zhiyong] NIH, Natl Ctr Biotechnol Informat, Biomed Text Min Grp, Bethesda, MD 20894 USA. RP Lu, ZY (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM zhiyong.lu@nih.gov OI Su, Andrew I./0000-0002-9859-4104 FU NIH Intramural Research Program, National Library of Medicine; National Institute of General Medical Sciences of the National Institutes of Health [R01GM089820, R01GM083924, 1U54GM114833]; National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR001114] FX NIH Intramural Research Program, National Library of Medicine (RL, ZL). National Institute of General Medical Sciences of the National Institutes of Health (R01GM089820, R01GM083924 and 1U54GM114833); National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR001114). NR 95 TC 4 Z9 4 U1 8 U2 17 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 JAN PY 2016 VL 17 IS 1 SI SI BP 23 EP 32 DI 10.1093/bib/bbv021 PG 10 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA DC4WA UT WOS:000369219800004 PM 25888696 ER PT J AU Huang, CC Lu, ZY AF Huang, Chung-Chi Lu, Zhiyong TI Community challenges in biomedical text mining over 10 years: success, failure and the future SO BRIEFINGS IN BIOINFORMATICS LA English DT Article DE biomedical natural language processing (BioNLP); BioNLP challenges; BioNLP shared tasks; critical assessment; text mining ID BIONLP SHARED TASK; BIOCREATIVE III; CLINICAL TEXT; DOCUMENT CLASSIFICATION; GENE NORMALIZATION; INFORMATION; ANNOTATION; ARTICLES; QUALITY; CORPUS AB One effective way to improve the state of the art is through competitions. Following the success of the Critical Assessment of protein Structure Prediction (CASP) in bioinformatics research, a number of challenge evaluations have been organized by the text-mining research community to assess and advance natural language processing (NLP) research for biomedicine. In this article, we review the different community challenge evaluations held from 2002 to 2014 and their respective tasks. Furthermore, we examine these challenge tasks through their targeted problems in NLP research and biomedical applications, respectively. Next, we describe the general workflow of organizing a Biomedical NLP (BioNLP) challenge and involved stakeholders (task organizers, task data producers, task participants and end users). Finally, we summarize the impact and contributions by taking into account different BioNLP challenges as a whole, followed by a discussion of their limitations and difficulties. We conclude with future trends in BioNLP challenge evaluations. C1 [Lu, Zhiyong] NIH, NCBI, NLM, Text Min Res Grp, Bethesda, MD 20894 USA. RP Lu, ZY (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM Zhiyong.lu@nih.gov FU National Institutes of Health intramural research program, National Library of Medicine FX This work was supported by the National Institutes of Health intramural research program, National Library of Medicine. NR 120 TC 9 Z9 9 U1 7 U2 15 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 JAN PY 2016 VL 17 IS 1 SI SI BP 132 EP 144 DI 10.1093/bib/bbv024 PG 13 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA DC4WA UT WOS:000369219800013 PM 25935162 ER PT J AU Kim, M Hernandez, L Annunziata, CM AF Kim, M. Hernandez, L. Annunziata, C. M. TI Caspase 8 expression may determine the survival of women with ovarian cancer SO CELL DEATH & DISEASE LA English DT Editorial Material ID CISPLATIN-RESISTANCE; CLEAVED CASPASE-3; CARCINOMA; PROGNOSIS C1 [Kim, M.; Hernandez, L.; Annunziata, C. M.] NCI, Womens Malignancies Branch, Ctr Canc Res, 10 Ctr Dr,Room 4B54, Bethesda, MD 20892 USA. RP Annunziata, CM (reprint author), NCI, Womens Malignancies Branch, Ctr Canc Res, 10 Ctr Dr,Room 4B54, Bethesda, MD 20892 USA. EM annunzic@mail.nih.gov RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 NR 11 TC 2 Z9 2 U1 0 U2 0 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 JAN PY 2016 VL 7 AR e2045 DI 10.1038/cddis.2015.398 PG 2 WC Cell Biology SC Cell Biology GA DC4HG UT WOS:000369181000008 PM 26775699 ER PT J AU Ihne, JL Gallagher, NM Sullivan, M Callicott, JH Green, AE AF Ihne, Jessica L. Gallagher, Natalie M. Sullivan, Marie Callicott, Joseph H. Green, Adam E. TI Is less really more: Does a prefrontal efficiency genotype actually confer better performance when working memory becomes difficult? SO CORTEX LA English DT Article DE COMT; Working memory; Neural efficiency; Dopamine; DLPFC ID CATECHOL-O-METHYLTRANSFERASE; COMT VAL(108/158) MET; INDIVIDUAL-DIFFERENCES; GENETIC ASSOCIATION; BRAIN ACTIVATION; VAL(158)MET POLYMORPHISM; CAPACITY CONSTRAINTS; INHIBITOR TOLCAPONE; EXECUTIVE FUNCTION; STERNBERG TASK AB Perhaps the most widely studied effect to emerge from the combination of neuroimaging and human genetics is the association of the COMT-Val(108/158)bMet polymorphism with prefrontal activity during working memory. COMT-Val is a putative risk factor in schizophrenia, which is characterized by disordered prefrontal function. Work in healthy populations has sought to characterize mechanisms by which the valine (Val) allele may lead to disadvantaged prefrontal cognition. Lower activity in methionine (Met) carriers has been interpreted as advantageous neural efficiency. Notably, however, studies reporting COMT effects on neural efficiency have generally not reported working memory performance effects. Those studies have employed relatively low/easy working memory loads. Higher loads are known to elicit individual differences in working memory performance that are not visible at lower loads. If COMT-Met confers greater neural efficiency when working memory is easy, a reasonable prediction is that Met carriers will be better able to cope with increasing demand for neural resources when working memory becomes difficult. To our knowledge, this prediction has thus far gone untested. Here, we tested performance on three working memory tasks. Performance on each task was measured at multiple levels of load/difficulty, including loads more demanding than those used in prior studies. We found no genotype-by-load interactions or main effects of COMT genotype on accuracy or reaction time. Indeed, even testing for performance differences at each load of each task failed to find a single significant effect of COMT genotype. Thus, even if COMT genotype has the effects on prefrontal efficiency that prior work has suggested, such effects may not directly impact high-load working memory ability. The present findings accord with previous evidence that behavioral effects of COMT are small or nonexistent and, more broadly, with a growing consensus that substantial effects on phenotype will not emerge from candidate gene studies. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Ihne, Jessica L.; Gallagher, Natalie M.; Sullivan, Marie; Green, Adam E.] Georgetown Univ, Dept Psychol, 302C White Gravenor Hall,3700 O St,NW,Box 571001, Washington, DC 20057 USA. [Callicott, Joseph H.] NIMH, Clin Brain Disorders Branch, Washington, DC USA. RP Green, AE (reprint author), Georgetown Univ, Dept Psychol, 302C White Gravenor Hall,3700 O St,NW,Box 571001, Washington, DC 20057 USA. EM aeg58@Georgetown.edu OI Reed, Jessica/0000-0003-0550-7284 FU National Science Foundation [DRL-1420481]; American Legacy Foundation; John Templeton Foundation [ID51971]; Georgetown University; National Institute of Mental Health Intramural Research program; Georgetown University Office of Biomedical Graduate Education FX This research was sponsored in part by the National Science Foundation (DRL-1420481 to A. Green), and grants from The American Legacy Foundation, The John Templeton Foundation (ID51971), and Partners in Research at Georgetown University to A. Green, funds from the National Institute of Mental Health Intramural Research program to K. Berman, and graduate student support to J. Ihne from the Georgetown University Office of Biomedical Graduate Education. We thank D. Dickinson for thoughtful comments on data analysis. NR 75 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 EI 1973-8102 J9 CORTEX JI Cortex PD JAN PY 2016 VL 74 BP 79 EP 95 DI 10.1016/j.cortex.2015.10.025 PG 17 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DC8GS UT WOS:000369458500007 PM 26649915 ER PT J AU Morris, LS Kundu, P Dowell, N Mechelmans, DJ Favre, P Irvine, MA Robbins, TW Daw, N Bullmore, ET Harrison, NA Voon, V AF Morris, Laurel S. Kundu, Prantile Dowell, Nicholas Mechelmans, Daisy J. Favre, Pauline Irvine, Michael A. Robbins, Trevor W. Daw, Nathaniel Bullmore, Edward T. Harrison, Neil A. Voon, Valerie TI Fronto-striatal organization: Defining functional and microstructural substrates of behavioural flexibility SO CORTEX LA English DT Article DE Fronto-striatal loops; Goal-directed; Habit; Microstructure; Neurite density ID INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; OBSESSIVE-COMPULSIVE DISORDER; LATERAL ORBITOFRONTAL CORTEX; MEDIAL PREFRONTAL CORTEX; HUMAN CEREBRAL-CORTEX; BASAL GANGLIA; HUMAN BRAIN; INDIVIDUAL-DIFFERENCES; DORSOLATERAL STRIATUM; PREDICTION ERRORS AB Discrete yet overlapping frontal-striatal circuits mediate broadly dissociable cognitive and behavioural processes. Using a recently developed multi-echo resting-state functional MRI (magnetic resonance imaging) sequence with greatly enhanced signal compared to noise ratios, we map frontal cortical functional projections to the striatum and striatal projections through the direct and indirect basal ganglia circuit. We demonstrate distinct limbic (ventromedial prefrontal regions, ventral striatum VS, ventral tegmental area VTA), motor (supplementary motor areas SMAs, putamen, substantia nigra) and cognitive (lateral prefrontal and caudate) functional connectivity. We confirm the functional nature of the cortico-striatal connections, demonstrating correlates of well-established goal-directed behaviour (involving medial orbitofrontal cortex mOFC and VS), probabilistic reversal learning (lateral orbitofrontal cortex 10FC and VS) and attentional shifting (dorsolateral prefrontal cortex dlPFC and VS) while assessing habitual model-free (SMA and putamen) behaviours on an exploratory basis. We further use neurite orientation dispersion and density imaging (NODDI) to show that more goal-directed model-based learning (MBc) is also associated with higher mOFC neurite density and habitual model-free learning (MFc) implicates neurite complexity in the putamen. This data highlights similarities between a computational account of MFc and conventional measures of habit learning. We highlight the intrinsic functional and structural architecture of parallel systems of behavioural control. (C) 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). C1 [Morris, Laurel S.; Robbins, Trevor W.] Univ Cambridge, Dept Psychol, Cambridge CB2 0QQ, England. [Morris, Laurel S.; Robbins, Trevor W.; Bullmore, Edward T.; Voon, Valerie] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 0QQ, England. [Kundu, Prantile; Mechelmans, Daisy J.; Irvine, Michael A.; Bullmore, Edward T.; Voon, Valerie] Univ Cambridge, Addenbrookes Hosp, Dept Psychiat, Level E4,Box 189,Hills Rd, Cambridge CB2 0QQ, England. [Kundu, Prantile] NIMH, Sect Funct Imaging Methods, Bethesda, MD 20892 USA. [Dowell, Nicholas; Harrison, Neil A.] Brighton & Sussex Med Sch, Dept Psychiat, Brighton, E Sussex, England. [Favre, Pauline] Univ Grenoble Alpes, Lab Psychol & Neurocognit, Grenoble, France. [Daw, Nathaniel] NYU, Ctr Neural Sci, New York, NY 10003 USA. [Daw, Nathaniel] NYU, Dept Psychol, 6 Washington Pl, New York, NY 10003 USA. [Bullmore, Edward T.; Voon, Valerie] Cambridgeshire & Peterborough NHS Fdn Trust, Cambridge, England. [Bullmore, Edward T.; Voon, Valerie] NIHR Cambridge Biomed Res Ctr, Cambridge, England. RP Voon, V (reprint author), Univ Cambridge, Addenbrookes Hosp, Dept Psychiat, Level E4,Box 189,Hills Rd, Cambridge CB2 0QQ, England. EM vv247@cam.ac.uk OI Bullmore, Edward/0000-0002-8955-8283; Kundu, Prantik/0000-0001-9367-3068 FU MRC; WT; Lundbeck; Eli Lilly; GSK; Wellcome Trust [093705/Z/10/Z]; Cambridge NIHR Biomedical Research Centre FX VV and NAH are Wellcome Trust (WT) intermediate Clinical Fellows. LM is in receipt of an MRC studentship. The BCNI is supported by a WT and MRC grant. ETB is employed part-time by the University of Cambridge and part-time by GSK PLC and is a shareholder of GSK. TWR is a consultant for Cambridge Cognition, Eli Lilly, GSK, Merck, Sharpe and Dohme, Lundbeck, Teva and Shire Pharmaceuticals. He is or has been in receipt of research grants from Lundbeck, Eli Lilly and GSK and is an editor for Springer-Verlag (Psychopharmacology). The remaining authors declare no competing financial interests. The study was funded by the Wellcome Trust Fellowship grant for VV (093705/Z/10/Z) and Cambridge NIHR Biomedical Research Centre. NR 75 TC 12 Z9 12 U1 6 U2 15 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 EI 1973-8102 J9 CORTEX JI Cortex PD JAN PY 2016 VL 74 BP 118 EP 133 DI 10.1016/j.cortex.2015.11.004 PG 16 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DC8GS UT WOS:000369458500010 PM 26673945 ER PT J AU Steel, A Song, S Bageac, D Knutson, KM Keisler, A Saad, ZS Gotts, SJ Wassermann, EM Wilkinson, L AF Steel, Adam Song, Sunbin Bageac, Devin Knutson, Kristine M. Keisler, Aysha Saad, Ziad S. Gotts, Stephen J. Wassermann, Eric M. Wilkinson, Leonora TI Shifts in connectivity during procedural learning after motor cortex stimulation: A combined transcranial magnetic stimulation/functional magnetic resonance imaging study SO CORTEX LA English DT Article DE Continuous theta burst stimulation; Functional connectivity; Primary motor cortex; Probabilistic sequence learning; Procedural learning ID THETA-BURST STIMULATION; AUTISM SPECTRUM DISORDERS; DORSAL PREMOTOR CORTEX; FUNCTIONAL MRI; MEMORY CONSOLIDATION; CORTICAL CONNECTIONS; PREFRONTAL CORTEX; CAUSAL INFLUENCES; BASAL GANGLIA; IMPLICIT AB Inhibitory transcranial magnetic stimulation (TMS), of which continuous theta burst stimulation (cTBS) is a common form, has been used to inhibit cortical areas during investigations of their function. cTBS applied to the primary motor area (M1) depresses motor output excitability via a local effect and impairs procedural motor learning. This could be due to an effect on M1 itself and/or to changes in its connectivity with other nodes in the learning network. To investigate this issue, we used functional magnetic resonance imaging to measure changes in brain activation and connectivity during implicit procedural learning after real and sham cTBS of M1. Compared to sham, real cTBS impaired motor sequence learning, but caused no local or distant changes in brain activation. Rather, it reduced functional connectivity between motor (M1, dorsal premotor & supplementary motor areas) and visual (superior & inferior occipital gyri) areas. It also increased connectivity between frontal associative (superior & inferior frontal gyri), cingulate (dorsal & middle cingulate), and temporal areas. This potentially compensatory shift in coupling, from a motor-based learning network to an associative learning network accounts for the behavioral effects of cTBS of M1. The findings suggest that the inhibitory TMS affects behavior via relatively subtle and distributed effects on connectivity within networks, rather than by taking the stimulated area "offline". Published by Elsevier Ltd. C1 [Steel, Adam; Bageac, Devin; Knutson, Kristine M.; Keisler, Aysha; Wassermann, Eric M.; Wilkinson, Leonora] NINDS, Behav Neurol Unit, NIH, 10 Ctr Dr,MSC 1440, Bethesda, MD 20892 USA. [Song, Sunbin] NINDS, Human Cort Physiol Sect, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. [Saad, Ziad S.] NIMH, Sci & Stat Comp Core, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. [Gotts, Stephen J.] NIMH, Lab Brain & Cognit, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. RP Wassermann, EM (reprint author), NINDS, Behav Neurol Unit, NIH, 10 Ctr Dr,MSC 1440, Bethesda, MD 20892 USA. EM adam.steel@nih.gov; songss@mail.nih.gov; devin.bageac@nih.gov; knutsonk@ninds.nih.gov; ayshakeisler@gmail.com; saadz@mail.nih.gov; gottss@mail.nih.gov; wasser-manne@ninds.nih.gov; Leonora.Willdnson@nih.gov OI Steel, Adam/0000-0001-8876-933X FU Clinical Neuroscience Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health [1ZIANS002977-14]; National Institute of Mental Health, Division of Intramural Research [1ZICMH002888] FX The authors declare no conflict of interest. Funding came from the Clinical Neuroscience Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health (1ZIANS002977-14).; Drs. S.G. Gotts and Z.S. Saad were supported by the National Institute of Mental Health, Division of Intramural Research (1ZICMH002888). NR 72 TC 1 Z9 1 U1 3 U2 10 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 EI 1973-8102 J9 CORTEX JI Cortex PD JAN PY 2016 VL 74 BP 134 EP 148 DI 10.1016/j.cortex.2015.10.004 PG 15 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DC8GS UT WOS:000369458500011 PM 26673946 ER PT J AU Zhu, YY Zhang, CL AF Zhu, Yeyi Zhang, Cuilin TI Prevalence of Gestational Diabetes and Risk of Progression to Type 2 Diabetes: a Global Perspective SO CURRENT DIABETES REPORTS LA English DT Review DE Gestational diabetes; Prevalence; Screening; Diagnosis; Type 2 diabetes; Pregnancy ID ABNORMAL GLUCOSE-TOLERANCE; STUDY-GROUPS CRITERIA; INTERNATIONAL ASSOCIATION; PREGNANCY OUTCOMES; INCREASING PREVALENCE; INSULIN-RESISTANCE; METABOLIC SYNDROME; IADPSG CRITERIA; INDIAN WOMEN; YOUNG-WOMEN AB Despite the increasing epidemic of diabetes mellitus affecting populations at different life stages, the global burden of gestational diabetes mellitus (GDM) is not well assessed. Systematically synthesized data on global prevalence estimates of GDM are lacking, particularly among developing countries. The hyperglycemic intrauterine environment as exemplified in pregnancies complicated by GDM might not only reflect but also fuel the epidemic of type 2 diabetes mellitus (T2DM). We comprehensively reviewed available data in the past decade in an attempt to estimate the contemporary global prevalence of GDM by country and region. We reviewed the risk of progression from GDM to T2DM as well. Synthesized data demonstrate wide variations in both prevalence estimates of GDM and the risk of progression from GDM to T2DM. Direct comparisons of GDM burden across countries or regions are challenging given the great heterogeneity in screening approaches, diagnostic criteria, and underlying population characteristics. In this regard, collaborative efforts to estimate global GDM prevalence would be a large but important leap forward. Such efforts may have substantial public health implications in terms of informing health policy makers and healthcare providers for disease burden and for developing more targeted and effective diabetes prevention and management strategies globally. C1 [Zhu, Yeyi; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B03G, Rockville, MD 20852 USA. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B03G, Rockville, MD 20852 USA. EM zhangcu@mail.nih.gov NR 78 TC 9 Z9 10 U1 6 U2 12 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1534-4827 EI 1539-0829 J9 CURR DIABETES REP JI Curr. Diabetes Rep. PD JAN PY 2016 VL 16 IS 1 AR 7 DI 10.1007/s11892-015-0699-x PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DC5JB UT WOS:000369256200007 PM 26742932 ER PT J AU Wen, L Shi, YB AF Wen, Luan Shi, Yun-Bo TI Regulation of growth rate and developmental timing by Xenopus thyroid hormone receptor SO DEVELOPMENT GROWTH & DIFFERENTIATION LA English DT Review DE amphibian metamorphosis; de-repression; thyroid hormone receptor; transcriptional regulation; Xenopus laevis; Xenopus tropicalis ID EFFECTOR NUCLEASES TALENS; TARGETED GENE DISRUPTION; RETINOIC ACID RECEPTORS; INTESTINAL STEM-CELLS; ACTION IN-VIVO; POSTEMBRYONIC DEVELOPMENT; AMPHIBIAN METAMORPHOSIS; COREPRESSOR COMPLEX; TRANSCRIPTIONAL ACTIVATION; PROTEIN METHYLTRANSFERASE AB Thyroid hormone (TH) is critical for vertebrate postembryonic development, a period around birth in mammals when plasma TH levels are high. Interestingly, TH receptors (TRs), especially TR, are expressed prior to the synthesis and secretion of zygotic TH, suggesting the existence of unliganded TR during development. However, the role of unliganded TR during mammalian development has been difficult to study, in part due to the relatively weak phenotype of TR knockout mice. Amphibian metamorphosis resembles postembryonic development in mammals and is controlled by TH via TRs. Like in mammals, TR gene is highly activated and is the major TR expressed prior to the synthesis of endogenous TH. By using TALEN (transcriptional activator like effector nucleases)-mediated gene editing approach, we and others have now shown that unliganded TR has two independent functions during Xenopus premetamorphosis, i.e. inhibiting growth rate and slowing development. Furthermore, molecular and transgenic studies have shown that unliganded TR accomplishes these via the recruitment of histone deacetylase (HDAC)-containing corepressor complexes to repress the expression of TH-inducible genes. C1 [Wen, Luan; Shi, Yun-Bo] NICHHD, Sect Mol Morphogenesis, Program Cell Regulat & Metab, NIH, Bldg 18T,Rm 106, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), NICHHD, Sect Mol Morphogenesis, Program Cell Regulat & Metab, NIH, Bldg 18T,Rm 106, Bethesda, MD 20892 USA. EM Shi@helix.nih.gov FU Intramural Research Program of NICHD, NIH FX The work in the authors' laboratory has been supported by the Intramural Research Program of NICHD, NIH. NR 95 TC 3 Z9 3 U1 5 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0012-1592 EI 1440-169X J9 DEV GROWTH DIFFER JI Dev. Growth Diff. PD JAN PY 2016 VL 58 IS 1 SI SI BP 106 EP 115 DI 10.1111/dgd.12231 PG 10 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA DC6QI UT WOS:000369344300010 PM 26219216 ER PT J AU Liu, SS Saloustros, E Berthon, A Starost, MF Sahut-Barnola, I Salpea, P Szarek, E Faucz, FR Martinez, A Stratakis, CA AF Liu, Sisi Saloustros, Emmanouil Berthon, Annabel Starost, Matthew F. Sahut-Barnola, Isabelle Salpea, Paraskevi Szarek, Eva Faucz, Fabio R. Martinez, Antoine Stratakis, Constantine A. TI Celecoxib reduces glucocorticoids in vitro and in a mouse model with adrenocortical hyperplasia SO ENDOCRINE-RELATED CANCER LA English DT Article DE cAMP; prostaglandin E2; celecoxib; primary pigmented nodular adrenocortical disease (PPNAD); adrenal tumors ID SUBUNIT TYPE 1A; PITUITARY-ADRENAL AXIS; REGULATORY SUBUNIT; CUSHING-SYNDROME; CARNEY COMPLEX; CELL-LINE; INCREASED EXPRESSION; CORTISOL SECRETION; CYCLIC-AMP; PROTEIN AB Primary pigmented nodular adrenocortical disease (PPNAD), whether in the context of Carney complex (CNC) or isolated, leads to ACTH-independent Cushing's syndrome (CS). CNC and PPNAD are caused typically by inactivating mutations of PRKAR1A, a gene coding for the type 1a regulatory subunit (R1a) of cAMP-dependent protein kinase (PKA). Mice lacking Prkar1a, specifically in the adrenal cortex (AdKO) developed CS caused by bilateral adrenal hyperplasia (BAH), which is formed from the abnormal proliferation of fetal-like adrenocortical cells. Celecoxib is a cyclooxygenase 2 (COX2) inhibitor. In bone, Prkar1a inhibition is associated with COX2 activation and prostaglandin E2 (PGE2) production that, in turn, activates proliferation of bone stromal cells. We hypothesized that COX2 inhibition may have an effect in PPNAD. In vitro treatment of human cell lines, including one from a patient with PPNAD, with celecoxib resulted in decreased cell viability. We then treated AdKO and control mice with 1500 mg/kg celecoxib or vehicle. Celecoxib treatment led to decreased PGE2 and corticosterone levels, reduced proliferation and increased apoptosis of adrenocortical cells, and decreased steroidogenic gene expression. We conclude that, in vitro and in vivo, celecoxib led to decreased steroidogenesis. In a mouse model of PPNAD, celecoxib caused histological changes that, at least in part, reversed BAH and this was associated with a reduction of corticosterone levels. C1 [Liu, Sisi; Saloustros, Emmanouil; Berthon, Annabel; Salpea, Paraskevi; Szarek, Eva; Faucz, Fabio R.; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet SEGEN, Program Dev Endocrinol & Genet PDEGEN, NIH, 10 Ctr Dr,Bldg 10 Clin Res Ctr,Room 1-3330, Bethesda, MD 20892 USA. [Starost, Matthew F.] NIH, ORS, DVR, OD, Bldg 10, Bethesda, MD 20892 USA. [Sahut-Barnola, Isabelle; Martinez, Antoine] Clermont Univ, Genet Reprod & Dev, CNRS, UMR6247, Aubiere, France. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet SEGEN, Program Dev Endocrinol & Genet PDEGEN, NIH, 10 Ctr Dr,Bldg 10 Clin Res Ctr,Room 1-3330, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov OI Saloustros, Emmanouil /0000-0002-0485-0120 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA FX This work was supported by the Intramural Research Program (IRP) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. NR 45 TC 0 Z9 0 U1 0 U2 0 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 JAN PY 2016 VL 23 IS 1 BP 15 EP 25 DI 10.1530/ERC-15-0472 PG 11 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA DC4ZJ UT WOS:000369229200006 PM 26438728 ER PT J AU Park, JW Han, CR Zhao, L Willingham, MC Cheng, SY AF Park, Jeong Won Han, Cho Rong Zhao, Li Willingham, Mark C. Cheng, Sheue-yann TI Inhibition of STAT3 activity delays obesity-induced thyroid carcinogenesis in a mouse model SO ENDOCRINE-RELATED CANCER LA English DT Article DE thyroid cancer; JAK2-STAT3 signaling; obesity; STAT3 inhibitor; preclinical mouse model; Pten-deficiency; thyroid hormone receptor beta mutant ID EPITHELIAL-MESENCHYMAL TRANSITION; ENDOTHELIAL GROWTH-FACTOR; TRANSCRIPTION 3 STAT3; BODY-MASS INDEX; SIGNAL TRANSDUCERS; CANCER RISK; TUMOR INVASION; UP-REGULATION; LUNG-CANCER; EXPRESSION AB Compelling epidemiologic studies indicate that obesity is a risk factor for many human cancers, including thyroid cancer. In recent decades, the incidence of thyroid cancer has dramatically increased along with a marked rise in obesity prevalence. We previously demonstrated that a high fat diet (HFD) effectively induced the obese phenotype in a mouse model of thyroid cancer (Thrb(PV/PV) Pten(+/-) mice). Moreover, HFD activates the STAT3 signal pathway to promote more aggressive tumor phenotypes. The aim of the present study was to evaluate the effect of S3I-201, a specific inhibitor of STAT3 activity, on HFD-induced aggressive cancer progression in the mouse model of thyroid cancer. WT and Thrb(PV/PV)Pten(+/-) mice were treated with HFD together with S3I-201 or vehicle-only as controls. We assessed the effects of S3I-201 on HFD-induced thyroid cancer progression, the leptin-JAK2-STAT3 signaling pathway, and key regulators of epithelial-mesenchymal transition (EMT). S3I-201 effectively inhibited HFD-induced aberrant activation of STAT3 and its downstream targets to markedly inhibit thyroid tumor growth and to prolong survival. Decreased protein levels of cyclins D1 and B1, cyclin dependent kinase 4 (CDK4), CDK6, and phosphorylated retinoblastoma protein led to the inhibition of tumor cell proliferation in S3I-201-treated Thrb(PV/PV)Pten(+/-) mice. Reduced occurrence of vascular invasion and blocking of anaplasia and lung metastasis in thyroid tumors of S3I-201-treated Thrb(PV/PV)Pten(+/-) mice were mediated via decreased expression of vimentin and matrix metalloproteinases, two key effectors of EMT. The present findings suggest that inhibition of the STAT3 activity would be a novel treatment strategy for obesity-induced thyroid cancer. C1 [Park, Jeong Won; Han, Cho Rong; Zhao, Li; Willingham, Mark C.; Cheng, Sheue-yann] NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5128, Bethesda, MD 20892 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5128, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov FU 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 48 TC 3 Z9 4 U1 3 U2 6 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 JAN PY 2016 VL 23 IS 1 BP 53 EP 63 DI 10.1530/ERC-15-0417 PG 11 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA DC4ZJ UT WOS:000369229200010 PM 26552408 ER PT J AU Marx, SJ AF Marx, Stephen J. TI Hyperplasia in glands with hormone excess SO ENDOCRINE-RELATED CANCER LA English DT Review DE neonate; proliferation; GPCR; cyclic AMP; signal transduction; parathyroid; thyroid; gonad; adrenal cortex ID FAMILIAL HYPOCALCIURIC HYPERCALCEMIA; CALCIUM-SENSING RECEPTOR; NEONATAL SEVERE HYPERPARATHYROIDISM; OVARIAN HYPERSTIMULATION SYNDROME; NON-AUTOIMMUNE HYPERTHYROIDISM; EXTRACELLULAR CA2+-SENSING RECEPTOR; ALDOSTERONE-PRODUCING ADENOMAS; PROTEIN-COUPLED RECEPTORS; LEYDIG-CELL HYPERPLASIA; KCNJ5 POTASSIUM CHANNEL AB Five syndromes share predominantly hyperplastic glands with a primary excess of hormones: neonatal severe primary hyperparathyroidism, from homozygous mutated CASR, begins severely in utero; congenital non-autoimmune thyrotoxicosis, from mutated TSHR, varies from severe with fetal onset to mild with adult onset; familial male-limited precocious puberty, from mutated LHR, expresses testosterone oversecretion in young boys; hereditary ovarian hyperstimulation syndrome, from mutated FSHR, expresses symptomatic systemic vascular permeabilities during pregnancy; and familial hyperaldosteronism type IIIA, from mutated KCNJ5, presents in young children with hypertension and hypokalemia. The grouping of these five syndromes highlights predominant hyperplasia as a stable tissue endpoint and as their tissue stage for all of the hormone excess. Comparisons were made among this and two other groups of syndromes, forming a continuum of gland staging: predominant oversecretions express little or no hyperplasia; predominant hyperplasias express little or no neoplasia; and predominant neoplasias express nodules, adenomas, or cancers. Hyperplasias may progress (5 of 5) to neoplastic stages while predominant oversecretions rarely do (1 of 6; frequencies differ P < 0.02). Hyperplasias do not show tumor multiplicity (0 of 5) unlike neoplasias that do (13 of 19; P < 0.02). Hyperplasias express mutation of a plasma membrane-bound sensor (5 of 5), while neoplasias rarely do (3 of 14; P < 0.002). In conclusion, the multiple distinguishing themes within the hyperplasias establish a robust pathophysiology. It has the shared and novel feature of mutant sensors in the plasma membrane, suggesting that these are major contributors to hyperplasia. C1 [Marx, Stephen J.] NIDDK, Genet & Endocrinol Sect, NIH, Bldg 10,Room 9C-103, Bethesda, MD 20892 USA. RP Marx, SJ (reprint author), NIDDK, Genet & Endocrinol Sect, NIH, Bldg 10,Room 9C-103, Bethesda, MD 20892 USA. EM marxs@mail.nih.gov FU Intramural Research Programs of the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Child Health and Human Development FX Support was from the Intramural Research Programs of the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute of Child Health and Human Development. No support was from grants. NR 132 TC 2 Z9 2 U1 1 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 JAN PY 2016 VL 23 IS 1 BP R1 EP R14 DI 10.1530/ERC-15-0171 PG 14 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA DC4ZJ UT WOS:000369229200001 PM 26407873 ER PT J AU Popp, NA Yu, DK Green, B Chew, EY Ning, BT Chan, CC Tuo, JS AF Popp, Nicholas A. Yu, Dianke Green, Bridgett Chew, Emily Y. Ning, Baitang Chan, Chi-Chao Tuo, Jingsheng TI Functional single nucleotide polymorphism in IL-17A 3 untranslated region is targeted by miR-4480 in vitro and may be associated with age-related macular degeneration SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE microRNA; age-related macular degeneration; inflammation; IL-17A; SNPs; epigenetics; genetics ID EYE DISEASE; GENETIC ASSOCIATION; NLRP3 INFLAMMASOME; RISK-FACTORS; CELLS; MICRORNAS; AUTOIMMUNITY; INDUCTION; REPLICATE; UVEITIS AB Age-related macular degeneration (AMD) is a leading cause of irreversible central vision loss in the elderly. Genetic factors contributing to AMD include single nucleotide polymorphisms (SNPs) in immune-related genes including CFH, C2, CFI, C9, and C3, thus implicating these pathways in AMD pathogenesis. MicroRNAs (miRNAs) are powerful regulators of gene expression and execute this function by binding to the 3 untranslated region (3UTR) of target mRNAs, leading to mRNA degradation. In this study, we searched for the possible association of SNPs in the 3UTR region of IL-17A, a gene implicated in AMD pathogenesis without any previous SNP association with AMD. Using two independent sample cohorts of Caucasian subjects, six SNPs in the IL-17A 3-UTR were selected for genotyping based on bioinformatic predictions of the SNP effect on microRNA binding. The SNP rs7747909 was found to be associated with AMD (P<0.05) in the NEI cohort, using a dominant model logistic regression. Luciferase reporter gene assays and RNA electrophoretic mobility shift assays were performed using ARPE-19 cells to confirm the preferential binding of microRNAs to the major allele of the SNP. Our findings support the hypothesis that microRNA-mediated gene dysregulation may play a role in the pathogenesis of AMD. Environ. Mol. Mutagen. 57:58-64, 2016. (c) 2015 Wiley Periodicals, Inc. C1 [Popp, Nicholas A.; Chan, Chi-Chao; Tuo, Jingsheng] NEI, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Yu, Dianke; Green, Bridgett; Ning, Baitang] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Chew, Emily Y.] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Tuo, JS (reprint author), NEI, Immunopathol Sect, Immunol Lab, 10 Ctr Dr,Bldg 10,Room 10N103, Bethesda, MD 20892 USA. EM jingsheng.tuo@nih.gov FU NEI Intramural Research Program FX Grant sponsor: NEI Intramural Research Program. NR 38 TC 0 Z9 0 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD JAN PY 2016 VL 57 IS 1 BP 58 EP 64 DI 10.1002/em.21982 PG 7 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DB7MT UT WOS:000368700300007 PM 26765636 ER PT S AU Shindo, S Moore, R Negishi, M AF Shindo, Sawako Moore, Rick Negishi, Masahiko BE Eyster, KM TI Detection and Functional Analysis of Estrogen Receptor alpha Phosphorylated at Serine 216 in Mouse Neutrophils SO ESTROGEN RECEPTORS: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Estrogen receptor alpha (ER alpha); Phosphorylation; Neutrophils; Migration; Infiltration; Mouse uterus; Immunohistochemistry; Immunofluorescence staining ID UTERUS AB Serine 216 constitutes a protein kinase C phosphorylation motif located within the DNA binding domain of estrogen receptor alpha (ER alpha). In this chapter we present experimental procedures confirming that mouse ER alpha is phosphorylated at serine 216 in peripheral blood neutrophils and in neutrophils that infiltrate the uterus, as well as the role of phosphoserine 216 in neutrophil migration. A phospho-peptide antibody (alpha P-S216) was utilized in Western blot, immunohistochemistry, and double immunofluorescence staining to detect this phosphorylation of an endogenous ER alpha. Both immunohistochemistry (with alpha P-S216 or neutrophil marker Ly6G antibody) and double immunofluorescence staining of mouse uterine sections prepared from C3H/HeNCrIBR females revealed that phosphorylated ER alpha was expressed in all infiltrating neutrophils during hormonal cycles but not in any other of the other uterine cells. Neutrophils infiltrate the uterus from the blood stream. White blood cells (WBC) were prepared from peripheral blood of C3H/HeNCrIBR females or males and double immunostained. Blood neutrophils also expressed phosphorylated ER alpha but in only about 20 % of cells in both sexes. Only the neutrophils expressing phosphorylated ER alpha spontaneously migrated in in vitro Transwell migration assays and infiltrated the uterus in mice. C1 [Shindo, Sawako; Moore, Rick; Negishi, Masahiko] NIEHS, Reprod & Dev Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Shindo, S (reprint author), NIEHS, Reprod & Dev Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. FU Intramural NIH HHS; NIEHS NIH HHS [Z01ES1005-01] NR 12 TC 0 Z9 0 U1 1 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-3127-9; 978-1-4939-3126-2 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1366 BP 413 EP 424 DI 10.1007/978-1-4939-3127-9_32 D2 10.1007/978-1-4939-3127-9 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA BE2GX UT WOS:000369231500033 PM 26585153 ER PT J AU Anic, GM Park, Y Subar, AF Schap, TE Reedy, J AF Anic, G. M. Park, Y. Subar, A. F. Schap, T. E. Reedy, J. TI Index-based dietary patterns and risk of lung cancer in the NIH-AARP diet and health study SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID RETIRED-PERSONS DIET; POOLED ANALYSIS; AMERICAN-ASSOCIATION; NATIONAL-INSTITUTES; PROSPECTIVE COHORT; NUTRIENT PATTERNS; SELENIUM STATUS; HEAVY SMOKERS; CONSUMPTION; METAANALYSIS AB BACKGROUND/OBJECTIVES: Dietary pattern analysis considers combinations of food intake and may offer a better measure to assess diet-cancer associations than examining individual foods or nutrients. Although tobacco exposure is the major risk factor for lung cancer, few studies have examined whether dietary patterns, based on preexisting dietary guidelines, influence lung cancer risk. After controlling for smoking, we examined associations between four diet quality indices-Healthy Eating Index-2010 (HEI-2010), Alternate Healthy Eating Index-2010 (AHEI-2010), alternate Mediterranean Diet score (aMED) and Dietary Approaches to Stop Hypertension (DASH)-and lung cancer risk in the NIH-AARP (National Institutes of Health-American Association of Retired Persons) Diet and Health study. SUBJECTS/METHODS: Baseline dietary intake was assessed in 460 770 participants. Over a median of 10.5 years of follow-up, 9272 incident lung cancer cases occurred. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and confidence intervals (CIs). RESULTS: Comparing highest to lowest quintiles, HRs (95% CIs) for lung cancer were as follows: HEI-2010 = 0.83 (0.77-0.89), AHEI-2010 = 0.86 (0.80-0.92), aMED = 0.85 (0.79-0.91) and DASH = 0.84 (0.78-0.90). Among the individual components of the dietary indices, higher consumption of whole grains and fruits was significantly inversely associated with lung cancer risk for several of the diet indices. Total index score analyses stratified by smoking status showed inverse associations with lung cancer for former smokers; however, only HEI-2010 was inversely associated in current smokers and no index score was inversely associated among never smokers. CONCLUSIONS: Although smoking is the factor most strongly associated with lung cancer, this study adds to a growing body of evidence that diet may have a modest role in reducing lung cancer risk, especially among former smokers. C1 [Anic, G. M.; Schap, T. E.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [Anic, G. M.; Park, Y.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E316, Bethesda, MD 20892 USA. [Park, Y.] Washington Univ, Sch Med, Dept Surg, Div Publ Hlth Sci, St Louis, MO 63110 USA. [Subar, A. F.; Schap, T. E.; Reedy, J.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Anic, GM (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E316, Bethesda, MD 20892 USA. EM gabriella.anic@gmail.com OI Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 36 TC 3 Z9 3 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 EI 1476-5640 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD JAN PY 2016 VL 70 IS 1 BP 123 EP 129 DI 10.1038/ejcn.2015.122 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DC7XS UT WOS:000369434800020 PM 26264348 ER PT J AU Li, H Wright, PW McCullen, M Anderson, SK AF Li, H. Wright, P. W. McCullen, M. Anderson, S. K. TI Characterization of KIR intermediate promoters reveals four promoter types associated with distinct expression patterns of KIR subtypes SO GENES AND IMMUNITY LA English DT Article ID NATURAL-KILLER-CELLS; IG-LIKE RECEPTORS; NK CELLS; GENE-EXPRESSION; DNA METHYLATION; REPERTOIRES; FAMILY; IDENTIFICATION; TRANSCRIPTION; ACQUISITION AB The human killer cell immunoglobulin-like receptor (KIR) genes contain multiple promoters that control the process of gene activation and variegated expression of KIR on natural killer (NK) and T cells. Specific subfamilies of KIR genes have differences in the timing and tissue specificity of expression: however, previous studies of the proximal KIR promoters have not shown significant differences in activity between differentially expressed KIR gene subsets. The recent identification of an intermediate KIR promoter (Prol) associated with KIR2DL1 expression suggested a central role for this element in KIR expression. The current study identifies Prol elements in all of the KIR genes, revealing four classes of Prol that correspond with four distinct expression phenotypes of KIR subgroups: KIR2DL2/S2/L3 that are expressed early in reconstituting NK after transplant; KIR2DL4 that is expressed by CD56-bright NK in a non-variegated manner; KIR3DL3 that is not expressed by circulating NK cells; and the remaining KIR that are expressed by subsets of CD56-dim NK. The four classes of Prol are structurally diverse and display distinct functional properties. Altogether, these results indicate that KIR Prol elements contribute to the tissue/cell-type specificity of KIR transcription and cooperate with the probabilistic proximal promoter to control KIR expression. C1 [Li, H.; Wright, P. W.; Anderson, S. K.] Leidos Biomed Res Inc, Frederick Natl Lab, Basic Sci Program, Bldg 560,Room 31-93, Ft Detrick, MD 21702 USA. [Li, H.; Wright, P. W.; McCullen, M.; Anderson, S. K.] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Anderson, SK (reprint author), Leidos Biomed Res Inc, Frederick Natl Lab, Basic Sci Program, Bldg 560,Room 31-93, Ft Detrick, MD 21702 USA. EM andersonst@mail.nih.gov OI McCullen, Matthew/0000-0001-9138-1483 FU National Cancer Institute (NCI), NIH [HHSN261200800001E]; NIH, NCI, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute (NCI), NIH, under contract HHSN261200800001E. This research was supported in part by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 26 TC 1 Z9 1 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 EI 1476-5470 J9 GENES IMMUN JI Genes Immun. PD JAN-FEB PY 2016 VL 17 IS 1 BP 66 EP 74 DI 10.1038/gene.2015.56 PG 9 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA DC8KQ UT WOS:000369468800009 PM 26656451 ER PT J AU Masuda, T Xu, XL Dimitriadis, EK Lahusen, T Deng, CX AF Masuda, Takaaki Xu, Xiaoling Dimitriadis, Emilios K. Lahusen, Tyler Deng, Chu-Xia TI "DNA Binding Region" of BRCA1 Affects Genetic Stability through modulating the Intra-S-Phase Checkpoint SO INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES LA English DT Article DE BRCA1; DNA binding; Intra-S-phase checkpoint; Genomic instability ID CELL-CYCLE CHECKPOINT; BREAST-CANCER; DAMAGE RESPONSE; PHOSPHOPEPTIDE RECOGNITION; OVARIAN-CANCER; REPLICATION; PROTEIN; INSTABILITY; ASSOCIATION; TOPBP1 AB The breast cancer associated gene 1 (BRCA1) contains 3 domains: an N-terminal RING domain with ubiquitin E3 ligase activity, C-terminal BRCT protein interaction domain and a central region. RING and BRCT domains are well characterized, yet the function of the central region remains unclear. In this study, we identified an essential DNA binding region (DBR: 421-701 amino acids) within the central region of human BRCA1, and found that BRCA1 brings DNA together and preferably binds to splayed-arm DNA in a sequence-independent manner. To investigate the biological role of the DBR, we generated mouse ES cells, which lack the DBR (Delta DBR) by using the TALEN method. The Delta DBR cells exhibited decreased survival as compared to the wild type (WT) cells treated with a PARP inhibitor, however they have an intact ability to conduct DNA repair mediated by homologous recombination (HR). The Delta DBR cells continued to incorporate more EdU in the presence of hydroxyurea (HU), which causes replication stress and exhibited reduced viability than the WT cells. Moreover, phosphorylation of CHK1, which regulates the intra-S phase checkpoint, was moderately decreased in Delta DBR cells. These data suggest that DNA binding by BRCA1 affects the stability of DNA replication folks, resulting in weakened intra-S-phase checkpoint control in the Delta DBR cells. The Delta DBR cells also exhibited an increased number of abnormal chromosome structures as compared with WT cells, indicating that the Delta DBR cells have increased genetic instability. Thus, we demonstrated that the DBR of BRCA1 modulates genetic stability through the intra-S-phase checkpoint activated by replication stress. C1 [Masuda, Takaaki; Lahusen, Tyler; Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. [Xu, Xiaoling; Deng, Chu-Xia] Univ Macau, Fac Hlth Sci, Macau, Peoples R China. [Dimitriadis, Emilios K.] Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, Bethesda, MD USA. RP Deng, CX (reprint author), Univ Macau, Fac Hlth Sci, Macau, Peoples R China. EM cxdeng@umac.mo RI deng, chuxia/N-6713-2016 FU National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases; Faculty of Health Sciences, University of Macau SAR, China FX This work was supported, in part, by the Intramural Research Program of the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases, and by start-up funds to CXD of the Faculty of Health Sciences, University of Macau SAR, China. NR 43 TC 1 Z9 1 U1 3 U2 9 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1449-2288 J9 INT J BIOL SCI JI Int. J. Biol. Sci. PY 2016 VL 12 IS 2 BP 133 EP 143 DI 10.7150/ijbs.14242 PG 11 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA DC7YX UT WOS:000369438200001 PM 26884712 ER PT J AU Hussain, SP AF Hussain, S. Perwez TI Pancreatic Cancer: Current Progress and Future Challenges SO INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES LA English DT Editorial Material DE Pancreatic Cancer ID DUCTAL ADENOCARCINOMA; PHYSICAL BARRIERS AB Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, remains one of the highly lethal malignancies. The highly refractory nature of clinically advanced disease and lack of a reliable biomarker for early detection are major obstructions in improving patient outcome. The recent efforts, however, in understanding the pancreatic tumor biology have resulted in the recognition of novel addictions as well as vulnerabilities of tumor cells and are being assessed for their clinical potential. This special issue highlights some of the recent progress, complexity and challenges towards improving disease outcome in patients with this lethal malignancy. C1 [Hussain, S. Perwez] NCI, Head Pancreat Canc Unit, Human Carcinogenesis Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Hussain, SP (reprint author), NCI, Head Pancreat Canc Unit, Human Carcinogenesis Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM hussainp@mail.nih.gov FU Intramural NIH HHS NR 13 TC 3 Z9 3 U1 3 U2 6 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1449-2288 J9 INT J BIOL SCI JI Int. J. Biol. Sci. PY 2016 VL 12 IS 3 BP 270 EP 272 DI 10.7150/ijbs.14950 PG 3 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA DC7ZH UT WOS:000369439200001 PM 26929733 ER PT J AU Smith, JP Fonkoua, LK Moody, TW AF Smith, Jill P. Fonkoua, Lionel K. Moody, Terry W. TI The Role of Gastrin and CCK Receptors in Pancreatic Cancer and other Malignancies SO INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES LA English DT Review DE peptide gastrin ID HIGH-FAT DIET; CHOLECYSTOKININ RECEPTOR; GENE-EXPRESSION; STELLATE CELLS; GROWTH-FACTOR; FUNCTIONAL EXPRESSION; DUCTAL ADENOCARCINOMA; MOLECULAR-MECHANISMS; COLORECTAL-CANCER; STIMULATES GROWTH AB The gastrointestinal (GI) peptide gastrin is an important regulator of the release of gastric acid from the stomach parietal cells and it also plays an important role in growth of the gastrointestinal tract. It has become apparent that gastrin and its related peptide cholecystokinin (CCK) are also significantly involved with growth of GI cancers as well as other malignancies through activation of the cholecystokinin-B (CCK-B) receptor. Of interest, gastrin is expressed in the embryologic pancreas but not in the adult pancreas; however, gastrin becomes re-expressed in pancreatic cancer where it stimulates growth of this malignancy by an autocrine mechanism. Strategies to down-regulate gastrin or interfere with its interface with the CCK receptor with selective antibodies or receptor antagonists hold promise for the treatment of pancreatic cancer and other gastrin - responsive tumors. C1 [Smith, Jill P.] Georgetown Univ, Dept Med, Washington, DC USA. [Fonkoua, Lionel K.] Penn State Univ, Coll Med, Hershey, PA USA. [Moody, Terry W.] NCI, NIH, Bethesda, MD 20892 USA. RP Smith, JP (reprint author), Georgetown Univ, Dept Med, Washington, DC USA. EM jps261@georgetown.edu FU William Donner Foundation FX Support for this work was provided in part by the William Donner Foundation. NR 109 TC 1 Z9 1 U1 3 U2 10 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1449-2288 J9 INT J BIOL SCI JI Int. J. Biol. Sci. PY 2016 VL 12 IS 3 BP 283 EP 291 DI 10.7150/ijbs.14952 PG 9 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA DC7ZH UT WOS:000369439200003 PM 26929735 ER PT J AU Amundadottir, LT AF Amundadottir, Laufey T. TI Pancreatic Cancer Genetics SO INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES LA English DT Review DE pancreatic tumors ID GENOME-WIDE ASSOCIATION; ABO BLOOD-GROUP; PEUTZ-JEGHERS-SYNDROME; TYPE-2 DIABETES SUSCEPTIBILITY; FAMILIAL ADENOMATOUS POLYPOSIS; MULTIPLE INDEPENDENT VARIANTS; OVARIAN-CANCER; HEREDITARY PANCREATITIS; TRANSCRIPTION FACTORS; COHORT CONSORTIUM AB Although relatively rare, pancreatic tumors are highly lethal [1]. In the United States, an estimated 48,960 individuals will be diagnosed with pancreatic cancer and 40,560 will die from this disease in 2015 [1]. Globally, 337,872 new pancreatic cancer cases and 330,391 deaths were estimated in 2012 [2]. In contrast to most other cancers, mortality rates for pancreatic cancer are not improving; in the US, it is predicted to become the second leading cause of cancer related deaths by 2030 [3, 4]. The vast majority of tumors arise in the exocrine pancreas, with pancreatic ductal adenocarcinoma (PDAC) accounting for approximately 95% of tumors. Tumors arising in the endocrine pancreas (pancreatic neuroendocrine tumors) represent less than 5% of all pancreatic tumors [5]. Smoking, type 2 diabetes mellitus (T2D), obesity and pancreatitis are the most consistent epidemiological risk factors for pancreatic cancer [5]. Family history is also a risk factor for developing pancreatic cancer with odds ratios (OR) ranging from 1.7-2.3 for first-degree relatives in most studies, indicating that shared genetic factors may play a role in the etiology of this disease [6-9]. This review summarizes the current knowledge of germline pancreatic cancer risk variants with a special emphasis on common susceptibility alleles identified through Genome Wide Association Studies (GWAS). C1 [Amundadottir, Laufey T.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Amundadottir, LT (reprint author), Adv Technol Ctr, 8717 Grovemont Circle, Bethesda, MD 20892 USA. EM amundadottirl@mail.nih.gov NR 164 TC 5 Z9 5 U1 10 U2 18 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1449-2288 J9 INT J BIOL SCI JI Int. J. Biol. Sci. PY 2016 VL 12 IS 3 BP 314 EP 325 DI 10.7150/ijbs.15001 PG 12 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA DC7ZH UT WOS:000369439200006 PM 26929738 ER PT J AU Marin, SJ Doyle, K Chang, A Concheiro-Guisan, M Huestis, MA Johnson-Davis, KL AF Marin, Stephanie J. Doyle, Kelly Chang, Annie Concheiro-Guisan, Marta Huestis, Marilyn A. Johnson-Davis, Kamisha L. TI One Hundred False-Positive Amphetamine Specimens Characterized by Liquid Chromatography Time-of-Flight Mass Spectrometry SO JOURNAL OF ANALYTICAL TOXICOLOGY LA English DT Article ID CROSS-REACTIVITY; META-CHLOROPHENYLPIPERAZINE; TRAZODONE METABOLITE; IMMUNOASSAY; URINE; DRUG; ASSAYS; CEDIA AB Some amphetamine (AMP) and ecstacy (MDMA) urine immunoassay (IA) kits are prone to false-positive results due to poor specificity of the antibody. We employed two techniques, high-resolution mass spectrometry (HRMS) and an in silico structure search, to identify compounds likely to cause false-positive results. Hundred false-positive IA specimens for AMP and/or MDMA were analyzed by an Agilent 6230 time-of-flight (TOF) mass spectrometer. Separately, SciFinder (Chemical Abstracts) was used as an in silico structure search to generate a library of compounds that are known to cross-react with AMP/MDMA IAs. Chemical formulas and exact masses of 145 structures were then compared against masses identified by TOF. Compounds known to have cross-reactivity with the IAs were identified in the structure-based search. The chemical formulas and exact masses of 145 structures (of 20 chemical formulas) were compared against masses identified by TOF. Urine analysis by HRMS correlates accurate mass with chemical formulae, but provides little information regarding compound structure. Structural data of targeted antigens can be utilized to correlate HRMS-derived chemical formulas with structural analogs. C1 [Marin, Stephanie J.] ARUP Inst Clin & Expt Pathol, 500 Chipeta Way, Salt Lake City, UT 84108 USA. [Doyle, Kelly; Johnson-Davis, Kamisha L.] ARUP Labs Inc, 500 Chipeta Way, Salt Lake City, UT 84108 USA. [Doyle, Kelly; Johnson-Davis, Kamisha L.] Univ Utah, Hlth Sci Ctr, Dept Pathol, Salt Lake City, UT 84132 USA. [Chang, Annie] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Concheiro-Guisan, Marta; Huestis, Marilyn A.] NIDA, Baltimore, MD USA. [Concheiro-Guisan, Marta] CUNY, John Jay Coll, Dept Sci, New York, NY 10021 USA. RP Marin, SJ (reprint author), ARUP Inst Clin & Expt Pathol, 500 Chipeta Way, Salt Lake City, UT 84108 USA. EM stephanie.marin@aruplab.com FU ARUP Institute for Clinical and Experimental Pathology(TM); ARUP Laboratories, Inc. FX Funding, instrumentation and physical facilities to conduct this research was provided by the ARUP Institute for Clinical and Experimental Pathology(TM) and ARUP Laboratories, Inc. We are grateful to the staff of the Clinical Toxicology laboratories for their cooperation and assistance during data collection. NR 16 TC 2 Z9 2 U1 2 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0146-4760 EI 1945-2403 J9 J ANAL TOXICOL JI J. Anal. Toxicol. PD JAN-FEB PY 2016 VL 40 IS 1 BP 37 EP 42 DI 10.1093/jat/bkv101 PG 6 WC Chemistry, Analytical; Toxicology SC Chemistry; Toxicology GA DC5AC UT WOS:000369231100005 PM 26342055 ER PT J AU Hassan, R Alley, E Kindler, H Antonia, S Jahan, T Grous, J Honarmand, S Mcdougall, K Whiting, C Nair, N Enstrom, A Lemmens, E Tsujikawa, T Kumar, S Coussens, LM Murphy, A Thomas, A Brockstedt, DG AF Hassan, R. Alley, E. Kindler, H. Antonia, S. Jahan, T. Grous, J. Honarmand, S. Mcdougall, K. Whiting, C. Nair, N. Enstrom, A. Lemmens, E. Tsujikawa, T. Kumar, S. Coussens, L. M. Murphy, A. Thomas, A. Brockstedt, D. G. TI Mesothelin-targeted immunotherapy CRS-207 plus chemotherapy as treatment for malignant pleural mesothelioma (MPM) SO LUNG CANCER LA English DT Meeting Abstract C1 [Hassan, R.; Thomas, A.] NCI, Thorac & Gi Oncol Branch, Bethesda, MD 20892 USA. [Alley, E.] Univ Penn, Div Hematol & Oncol, Philadelphia, PA 19104 USA. [Kindler, H.] Univ Chicago, Sect Hematol & Oncol, Gastrointestinal Oncol & Mesothelioma Programs, Chicago, IL 60637 USA. [Antonia, S.] Univ S Florida, H Lee Moffitt Canc Ctr, Thorac Oncol Dept, Tampa, FL 33682 USA. [Jahan, T.] Univ Calif San Francisco, Dept Med, Div Hematol Oncol, San Francisco, CA USA. [Grous, J.] Aduro Biotech Inc, Med, Berkeley, CA USA. [Honarmand, S.; Mcdougall, K.; Murphy, A.] Aduro Biotech Inc, Clin Operat, Berkeley, CA USA. [Whiting, C.; Nair, N.; Enstrom, A.; Lemmens, E.] Aduro Biotech Inc, Immune Monitoring & Biomarker Dev, Berkeley, CA USA. [Tsujikawa, T.; Kumar, S.; Coussens, L. M.] Oregon Hlth & Sci Univ, Cell & Dev Biol, Portland, OR 97201 USA. [Brockstedt, D. G.] Aduro Biotech Inc, Res & Dev, Berkeley, CA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 EI 1872-8332 J9 LUNG CANCER JI Lung Cancer PD JAN PY 2016 VL 91 SU 1 MA 87 BP S31 EP S32 PG 2 WC Oncology; Respiratory System SC Oncology; Respiratory System GA DC8GP UT WOS:000369458200086 ER PT J AU Chien, WW Isgrig, K Roy, S Belyantseva, IA Drummond, MC May, LA Fitzgerald, TS Friedman, TB Cunningham, LL AF Chien, Wade W. Isgrig, Kevin Roy, Soumen Belyantseva, Inna A. Drummond, Meghan C. May, Lindsey A. Fitzgerald, Tracy S. Friedman, Thomas B. Cunningham, Lisa L. TI Gene Therapy Restores Hair Cell Stereocilia Morphology in Inner Ears of Deaf Whirler Mice SO MOLECULAR THERAPY LA English DT Article ID SENSORINEURAL HEARING-LOSS; MOUSE MUTANT WHIRLER; UNCONVENTIONAL MYOSIN; COCHLEAR FUNCTION; KNOCKOUT MICE; ELONGATION; PROTEIN; ACTIN; LOCALIZATION; MUTATIONS AB Hereditary deafness is one of the most common disabilities affecting newborns. Many forms of hereditary deafness are caused by morphological defects of the stereocilia bundles on the apical surfaces of inner ear hair cells, which are responsible for sound detection. We explored the effectiveness of gene therapy in restoring the hair cell stereocilia architecture in the whirlin mouse model of human deafness, which is deaf due to dysmorphic, short stereocilia. Wild-type whirlin cDNA was delivered via adeno-associated virus (AAV8) by injection through the round window of the cochleas in neonatal whirler mice. Subsequently, whirlin expression was detected in infected hair cells (IHCs), and normal stereocilia length and bundle architecture were restored. Whirlin gene therapy also increased inner hair cell survival in the treated ears compared to the contralateral nontreated ears. These results indicate that a form of inherited deafness due to structural defects in cochlear hair cells is amenable to restoration through gene therapy. C1 [Chien, Wade W.] NIDCD, Neurotol Program, NIH, 31A Convent Dr,Room 1F220, Bethesda, MD 20892 USA. [Chien, Wade W.] Johns Hopkins Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD USA. [Isgrig, Kevin; Roy, Soumen; May, Lindsey A.; Cunningham, Lisa L.] NIDCD, Sect Sensory Cell Biol, NIH, Bethesda, MD USA. [Belyantseva, Inna A.; Drummond, Meghan C.; Friedman, Thomas B.] NIDCD, Lab Mol Genet, NIH, Bethesda, MD USA. [Fitzgerald, Tracy S.] NIDCD, Mouse Auditory Testing Core Facil, Bethesda, MD USA. RP Chien, WW (reprint author), NIDCD, Neurotol Program, NIH, 31A Convent Dr,Room 1F220, Bethesda, MD 20892 USA. EM wade.chien@nih.gov FU intramural NIDCD surgeon-scientist training program; Triological Society Research Career Development Award FX This work was supported by the intramural NIDCD surgeon-scientist training program and the Triological Society Research Career Development Award (to W.W.C.). There are no conflicts of interest. We thank Andrew J. Griffith (NIDCD) and Carmen C. Brewer (NIDCD) for critiquing the manuscript. NR 32 TC 7 Z9 7 U1 2 U2 7 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 JAN PY 2016 VL 24 IS 1 BP 17 EP 25 DI 10.1038/mt.2015.150 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DD0XJ UT WOS:000369644300003 PM 26307667 ER PT J AU Salewsky, B Hildebrand, G Rothe, S Parplys, AC Radszewski, J Kieslich, M Wessendorf, P Krenzlin, H Borgmann, K Nussenzweig, A Sperling, K Digweed, M AF Salewsky, Bastian Hildebrand, Gabriele Rothe, Susanne Parplys, Ann Christin Radszewski, Janina Kieslich, Moritz Wessendorf, Petra Krenzlin, Harald Borgmann, Kerstin Nussenzweig, Andre Sperling, Karl Digweed, Martin TI Directed Alternative Splicing in Nijmegen Breakage Syndrome: Proof of Principle Concerning Its Therapeutical Application SO MOLECULAR THERAPY LA English DT Article ID DUCHENNE MUSCULAR-DYSTROPHY; DNA-REPLICATION; CHROMOSOME INSTABILITY; DAMAGE RESPONSE; REPAIR PROTEIN; NIBRIN PROTEIN; NBS1; COMPLEX; CELLS; ACTIVATION AB Over 90% of patients with Nijmegen breakage syndrome (NBS), a hereditary cancer disorder, are homoallelic for a 5 bp deletion in the NBN gene involved in the cellular response to DNA damage. This hypomorphic mutation leads to a carboxy-terminal protein fragment, p70-nibrin, with some residual function. Average age at malignancy, typically lymphoma, is 9.7 years. NBS patients are hypersensitive to chemotherapeutic and radiotherapeutic treatments, thus prevention of cancer development is of particular importance. Expression of an internally deleted NBN protein, p80-nibrin, has been previously shown to be associated with a milder cellular phenotype and absence of cancer in a 62-year-old NBS patient. Here we show that cells from this patient, unlike other NBS patients, have DNA replication and origin firing rates comparable to control cells. We used here antisense oligonucleotides to enforce alternative splicing in NBS patient cells and efficiently generate the same internally deleted p80-nibrin protein. Injecting the same antisense sequences as morpholino oligomers (VivoMorpholinos) into the tail vein of a humanized NBS murine mouse model also led to efficient alternative splicing in vivo. Thus, proof of principle for the use of antisense oligonucleotides as a potential cancer prophylaxis has been demonstrated. C1 [Salewsky, Bastian; Hildebrand, Gabriele; Rothe, Susanne; Radszewski, Janina; Kieslich, Moritz; Wessendorf, Petra; Krenzlin, Harald; Sperling, Karl; Digweed, Martin] Charite Univ Med Berlin, Inst Med & Human Genet, Augustenburger Pl 1, D-13353 Berlin, Germany. [Parplys, Ann Christin; Borgmann, Kerstin] Univ Med Ctr Hamburg Eppendorf, Lab Radiobiol & Expt Radiat Oncol, Hamburg, Germany. [Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. RP Digweed, M (reprint author), Charite Univ Med Berlin, Inst Med & Human Genet, Augustenburger Pl 1, D-13353 Berlin, Germany. EM martin.digweed@charite.de FU Deutsche Krebshilfe [108864] FX The authors are grateful to the animal facility of the Charite for mouse breeding and care. This work was supported by the Deutsche Krebshilfe (grant number 108864 to M.D.). The authors declare that no conflict of interest exists. NR 42 TC 4 Z9 4 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD JAN PY 2016 VL 24 IS 1 BP 117 EP 124 DI 10.1038/mt.2015.144 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DD0XJ UT WOS:000369644300013 PM 26265251 ER PT J AU Nalls, MA Keller, MF Hernandez, DG Chen, L Stone, DJ Singleton, AB AF Nalls, Mike A. Keller, Margaux F. Hernandez, Dena G. Chen, Lan Stone, David J. Singleton, Andrew B. CA Parkinson's Progression Marker Ini TI Baseline genetic associations in the Parkinson's Progression Markers Initiative (PPMI) SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; genetics; genetic risk score; GWAS ID COMMON LRRK2 MUTATION; DISEASE; GENOME AB BackgroundThe Parkinson's Progression Marker Initiative is an international multicenter study whose main goal is investigating markers for Parkinson's disease (PD) progression as part of a path to a treatment for the disease. This manuscript describes the baseline genetic architecture of this study, providing not only a catalog of disease-linked variants and mutations, but also quantitative measures with which to adjust for population structure. MethodsThree hundred eighty-three newly diagnosed typical PD cases, 65 atypical PD and 178 healthy controls, from the Parkinson's Progression Marker Initiative study have been genotyped on the NeuroX or Immunochip arrays. These data are freely available to all researchers interested in pursuing PD research within the Parkinson's Progression Marker Initiative. ResultsThe Parkinson's Progression Marker Initiative represents a study population with low genetic heterogeneity. We recapitulate known PD associations from large-scale genome-wide association studies and refine genetic risk score models for PD predictability (area under the curve, approximate to 0.74). We show the presence of six LRRK2 p.G2019S and nine GBA p.N370S mutation carriers. ConclusionsThe Parkinson's Progression Marker Initiative study and its genetic data are useful in studies of PD biomarkers. The genetic architecture described here will be useful in the analysis of myriad biological and clinical traits within this study. (c) 2015 International Parkinson and Movement Disorder Society C1 [Nalls, Mike A.; Hernandez, Dena G.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Keller, Margaux F.; Chen, Lan; Stone, David J.] Merck Res Labs, Genet & Pharmacogen, West Point, PA USA. RP Singleton, AB (reprint author), NIA, Neurogenet Lab, Bldg 35,1A, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Singleton, Andrew/C-3010-2009; corvol, jean-christophe/I-6387-2012 OI corvol, jean-christophe/0000-0001-7325-0199 FU Intramural Research Program of the National Institute on Aging [Z01-AG000949-02, 2003-077] FX This work was supported by the Intramural Research Program of the National Institute on Aging, (project numbers Z01-AG000949-02), human subjects protocol 2003-077. NR 17 TC 1 Z9 1 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD JAN PY 2016 VL 31 IS 1 BP 79 EP 85 DI 10.1002/mds.26374 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA DC7WL UT WOS:000369431300016 PM 26268663 ER PT J AU Alexander, GM Farris, S Pirone, JR Zheng, CG Colgin, LL Dudek, SM AF Alexander, Georgia M. Farris, Shannon Pirone, Jason R. Zheng, Chenguang Colgin, Laura L. Dudek, Serena M. TI Social and novel contexts modify hippocampal CA2 representations of space SO NATURE COMMUNICATIONS LA English DT Article ID MESSENGER RIBONUCLEIC-ACIDS; IMMEDIATE-EARLY GENES; COMPLEX-SPIKE CELLS; SYNAPTIC PLASTICITY; PYRAMIDAL CELLS; RAT HIPPOCAMPUS; PATTERN SEPARATION; ENTORHINAL CORTEX; VASOPRESSIN V1B; DENTATE GYRUS AB The hippocampus supports a cognitive map of space and is critical for encoding declarative memory (who, what, when and where). Recent studies have implicated hippocampal subfield CA2 in social and contextual memory but how it does so remains unknown. Here we find that in adult male rats, presentation of a social stimulus (novel or familiar rat) or a novel object induces global remapping of place fields in CA2 with no effect on neuronal firing rate or immediate early gene expression. This remapping did not occur in CA1, suggesting this effect is specific for CA2. Thus, modification of existing spatial representations might be a potential mechanism by which CA2 encodes social and novel contextual information. C1 [Alexander, Georgia M.; Farris, Shannon; Dudek, Serena M.] NIEHS, Neurobiol Lab, NIH, 111 TW Alexander Dr,Mail Drop F2-04, Res Triangle Pk, NC 27709 USA. [Pirone, Jason R.] Social & Sci Syst Inc, 1009 Slater Rd,Suite 120, Durham, NC 27703 USA. [Zheng, Chenguang; Colgin, Laura L.] Univ Texas Austin, Ctr Learning & Memory, 1 Univ Stn Stop C7000,NMS 4-104, Austin, TX 78712 USA. [Zheng, Chenguang; Colgin, Laura L.] Univ Texas Austin, Dept Neurosci, Austin, TX 78712 USA. [Pirone, Jason R.] SciOme LLC, 2 Davis Dr, Res Triangle Pk, NC 27709 USA. RP Dudek, SM (reprint author), NIEHS, Neurobiol Lab, NIH, 111 TW Alexander Dr,Mail Drop F2-04, Res Triangle Pk, NC 27709 USA. EM Dudek@niehs.nih.gov RI Zheng, Chenguang/O-7980-2016; OI Zheng, Chenguang/0000-0002-4782-8732; Dudek, Serena M./0000-0003-4094-8368; Farris, Shannon/0000-0003-4473-1684 FU Intramural Research Program of the U.S. National Institutes of Health, NIEHS [Z01 ES100221]; NIMH [1R01MH102450-01A1]; Office of Naval Research Young Investigator award [N00014-14-1-0322] FX This research is supported by the Intramural Research Program of the U.S. National Institutes of Health, NIEHS (Z01 ES100221 to S.M.D.), as well as grant number 1R01MH102450-01A1 from NIMH (to L.L.C.) and Office of Naval Research Young Investigator award N00014-14-1-0322 (to L.L.C.). We thank Patricia Jensen, David Armstrong and the members of the Dudek lab for critically reading this manuscript; Ritika Patil and Katelyn Bobbitt for their technical assistance; as well as the NIEHS fluorescent microscopy core and animal care staff for their support. NR 62 TC 7 Z9 7 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JAN PY 2016 VL 7 AR 10300 DI 10.1038/ncomms10300 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC2AH UT WOS:000369019100001 PM 26806606 ER PT J AU Furlan, L Conforto, AB Cohen, LG Sterr, A AF Furlan, Leonardo Conforto, Adriana Bastos Cohen, Leonardo G. Sterr, Annette TI Upper Limb Immobilisation: A Neural Plasticity Model with Relevance to Poststroke Motor Rehabilitation SO NEURAL PLASTICITY LA English DT Review ID TRANSCRANIAL MAGNETIC STIMULATION; INDUCED MOVEMENT THERAPY; NONINVASIVE BRAIN-STIMULATION; INVASIVE CORTICAL STIMULATION; CHRONIC STROKE; SOMATOSENSORY STIMULATION; INTERHEMISPHERIC INTERACTIONS; CORTICOSPINAL EXCITABILITY; NEUROLOGICAL PRINCIPLES; CHRONIC HEMIPARESIS AB Advances in our understanding of the neural plasticity that occurs after hemiparetic stroke have contributed to the formulation of theories of poststroke motor recovery. These theories, in turn, have underpinned contemporary motor rehabilitation strategies for treating motor deficits after stroke, such as upper limb hemiparesis. However, a relative drawback has been that, in general, these strategies are most compatible with the recovery profiles of relatively high-functioning stroke survivors and therefore do not easily translate into benefit to those individuals sustaining low-functioning upper limb hemiparesis, who otherwise have poorer residual function. For these individuals, alternative motor rehabilitation strategies are currently needed. In this paper, we will review upper limb immobilisation studies that have been conducted with healthy adult humans and animals. Then, we will discuss how the findings from these studies could inspire the creation of a neural plasticity model that is likely to be of particular relevance to the context of motor rehabilitation after stroke. For instance, as will be elaborated, such model could contribute to the development of alternative motor rehabilitation strategies for treating poststroke upper limb hemiparesis. The implications of the findings from those immobilisation studies for contemporary motor rehabilitation strategies will also be discussed and perspectives for future research in this arena will be provided as well. C1 [Furlan, Leonardo; Sterr, Annette] Univ Surrey, Fac Hlth & Med Sci, Sch Psychol, Guildford GU2 7XH, Surrey, England. [Conforto, Adriana Bastos; Sterr, Annette] Univ Sao Paulo, Clin Hosp, Neurol Clin Div, Ave Dr Eneas C Aguiar 255-5084, BR-05403010 Sao Paulo, SP, Brazil. [Conforto, Adriana Bastos] Hosp Israelita Albert Einstein, Inst Ensino & Pesquisa, Ave Albert Einstein 627-701, BR-05601901 Sao Paulo, SP, Brazil. [Cohen, Leonardo G.] Natl Inst Neurol Disorders & Stroke, Human Cort Physiol & Stroke Rehabil Sect, NIH, Bldg 10,Room 7D54, Bethesda, MD 20892 USA. RP Sterr, A (reprint author), Univ Surrey, Fac Hlth & Med Sci, Sch Psychol, Guildford GU2 7XH, Surrey, England.; Sterr, A (reprint author), Univ Sao Paulo, Clin Hosp, Neurol Clin Div, Ave Dr Eneas C Aguiar 255-5084, BR-05403010 Sao Paulo, SP, Brazil. EM a.sterr@surrey.ac.uk FU CAPES Foundation, Ministry of Education, Brazil [BEX 0996/14-9] FX Leonardo Furlan is funded by CAPES Foundation, Ministry of Education, Brazil (BEX 0996/14-9). The authors are grateful to Lewis Dunne for editorial assistance. NR 134 TC 1 Z9 1 U1 0 U2 2 PU HINDAWI LTD PI LONDON PA ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, WIT 5HE, ENGLAND SN 2090-5904 EI 1687-5443 J9 NEURAL PLAST JI Neural. Plast. PY 2016 AR 8176217 DI 10.1155/2016/8176217 PG 17 WC Neurosciences SC Neurosciences & Neurology GA DC5SQ UT WOS:000369281100001 ER PT J AU Day, T Read, AF AF Day, Troy Read, Andrew F. TI Does High-Dose Antimicrobial Chemotherapy Prevent the Evolution of Resistance? SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID MUTANT SELECTION WINDOW; VITRO DYNAMIC-MODEL; STAPHYLOCOCCUS-AUREUS; ANTIBIOTIC-RESISTANCE; DRUG-RESISTANCE; MYCOBACTERIUM-TUBERCULOSIS; STREPTOCOCCUS-PNEUMONIAE; PSEUDOMONAS-AERUGINOSA; PHARMACODYNAMIC EVALUATION; INTRAABDOMINAL INFECTION AB High-dose chemotherapy has long been advocated as a means of controlling drug resistance in infectious diseases but recent empirical studies have begun to challenge this view. We develop a very general framework for modeling and understanding resistance emergence based on principles from evolutionary biology. We use this framework to show how high-dose chemotherapy engenders opposing evolutionary processes involving the mutational input of resistant strains and their release from ecological competition. Whether such therapy provides the best approach for controlling resistance therefore depends on the relative strengths of these processes. These opposing processes typically lead to a unimodal relationship between drug pressure and resistance emergence. As a result, the optimal drug dose lies at either end of the therapeutic window of clinically acceptable concentrations. We illustrate our findings with a simple model that shows how a seemingly minor change in parameter values can alter the outcome from one where high-dose chemotherapy is optimal to one where using the smallest clinically effective dose is best. A review of the available empirical evidence provides broad support for these general conclusions. Our analysis opens up treatment options not currently considered as resistance management strategies, and it also simplifies the experiments required to determine the drug doses which best retard resistance emergence in patients. C1 [Day, Troy] Queens Univ, Dept Math & Stat, Jeffery Hall, Kingston, ON K7L 3N6, Canada. [Day, Troy] Queens Univ, Dept Biol, Jeffery Hall, Kingston, ON K7L 3N6, Canada. [Day, Troy; Read, Andrew F.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Read, Andrew F.] Penn State Univ, Ctr Infect Dis Dynam, Dept Biol, University Pk, PA 16802 USA. [Read, Andrew F.] Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. RP Day, T (reprint author), Queens Univ, Dept Math & Stat, Jeffery Hall, Kingston, ON K7L 3N6, Canada.; Day, T (reprint author), Queens Univ, Dept Biol, Jeffery Hall, Kingston, ON K7L 3N6, Canada.; Day, T (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM tday@mast.queensu.ca FU Research and Policy in Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate; Department of Homeland Security; Fogarty International Center; National Institutes of Health; Natural Sciences and Engineering Research Council of Canada; National Institute of General Medical Sciences FX The authors receive funding from the Research and Policy in Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, the Department of Homeland Security, the Fogarty International Center, the National Institutes of Health, the Natural Sciences and Engineering Research Council of Canada, and the National Institute of General Medical Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 8 Z9 8 U1 7 U2 15 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 JAN PY 2016 VL 12 IS 1 AR e1004689 DI 10.1371/journal.pcbi.1004689 PG 20 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA DC6YS UT WOS:000369366100023 PM 26820986 ER PT J AU Kravats, AN Tonddast-Navaei, S Stan, G AF Kravats, Andrea N. Tonddast-Navaei, Sam Stan, George TI Coarse-Grained Simulations of Topology-Dependent Mechanisms of Protein Unfolding and Translocation Mediated by ClpY ATPase Nanomachines SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID PLUS PROTEOLYTIC MACHINE; ESCHERICHIA-COLI; SUBSTRATE PROTEIN; CONFORMATIONAL-CHANGES; DEGRADATION MACHINE; CRYSTAL-STRUCTURE; FUELED MACHINES; HSLUV PROTEASE; AAA; CHAPERONE AB Clp ATPases are powerful ring shaped nanomachines which participate in the degradation pathway of the protein quality control system, coupling the energy from ATP hydrolysis to threading substrate proteins (SP) through their narrow central pore. Repetitive cycles of sequential intra-ring ATP hydrolysis events induce axial excursions of diaphragm-forming central pore loops that effect the application of mechanical forces onto SPs to promote unfolding and translocation. We perform Langevin dynamics simulations of a coarse-grained model of the ClpY ATPase-SP system to elucidate the molecular details of unfolding and translocation of an alpha/beta model protein. We contrast this mechanism with our previous studies which used an all-alpha SP. We find conserved aspects of unfolding and translocation mechanisms by allosteric ClpY, including unfolding initiated at the tagged C-terminus and translocation via a power stroke mechanism. Topology-specific aspects include the time scales, the rate limiting steps in the degradation pathway, the effect of force directionality, and the translocase efficacy. Mechanisms of ClpY-assisted unfolding and translocation are distinct from those resulting from non-allosteric mechanical pulling. Bulk unfolding simulations, which mimic Atomic Force Microscopy-type pulling, reveal multiple unfolding pathways initiated at the C-terminus, N-terminus, or simultaneously from both termini. In a non-allosteric ClpY ATPase pore, mechanical pulling with constant velocity yields larger effective forces for SP unfolding, while pulling with constant force results in simultaneous unfolding and translocation. C1 [Kravats, Andrea N.; Tonddast-Navaei, Sam; Stan, George] Univ Cincinnati, Dept Chem, Cincinnati, OH USA. [Kravats, Andrea N.] NCI, Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. [Tonddast-Navaei, Sam] Georgia Inst Technol, Dept Biol, Atlanta, GA 30332 USA. RP Stan, G (reprint author), Univ Cincinnati, Dept Chem, Cincinnati, OH USA. EM george.stan@uc.edu FU American Heart Association; National Science Foundation CAREER [MCB-0952082]; Procter and Gamble fellowship; University Research Council fellowship at the University of Cincinnati FX This work has been supported by grants from the American Heart Association (www.heart.org) and National Science Foundation CAREER grant no. MCB-0952082 (www.nsf.gov) to GS and a Procter and Gamble fellowship (www.pg.com) and an University Research Council fellowship at the University of Cincinnati (www.uc.edu) to ANK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 83 TC 1 Z9 1 U1 1 U2 7 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 JAN PY 2016 VL 12 IS 1 AR e1004675 DI 10.1371/journal.pcbi.1004675 PG 24 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA DC6YS UT WOS:000369366100018 PM 26734937 ER PT J AU Dyke, SOM Philippakis, AA De Argila, JR Paltoo, DN Luetkemeier, ES Knoppers, BM Brookes, AJ Spalding, JD Thompson, M Roos, M Boycott, KM Brudno, M Hurles, M Rehm, HL Matern, A Fiume, M Sherry, ST AF Dyke, Stephanie O. M. Philippakis, Anthony A. Rambla De Argila, Jordi Paltoo, Dina N. Luetkemeier, Erin S. Knoppers, Bartha M. Brookes, Anthony J. Spalding, J. Dylan Thompson, Mark Roos, Marco Boycott, Kym M. Brudno, Michael Hurles, Matthew Rehm, Heidi L. Matern, Andreas Fiume, Marc Sherry, Stephen T. TI Consent Codes: Upholding Standard Data Use Conditions SO PLOS GENETICS LA English DT Article ID ONTOLOGY; DISEASE C1 [Dyke, Stephanie O. M.; Knoppers, Bartha M.] McGill Univ, Fac Med, Ctr Genom & Policy, Montreal, PQ, Canada. [Philippakis, Anthony A.; Rehm, Heidi L.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Rambla De Argila, Jordi] CRG, Barcelona, Spain. [Rambla De Argila, Jordi] UPF, Barcelona, Spain. [Paltoo, Dina N.; Luetkemeier, Erin S.] Off Sci Policy, Bethesda, MD USA. [Paltoo, Dina N.; Luetkemeier, Erin S.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Brookes, Anthony J.] Univ Leicester, Dept Genet, Univ Rd, Leicester LE1 7RH, Leics, England. [Spalding, J. Dylan] EMBL EBI, Wellcome Trust Genome Campus, Cambridge, England. [Thompson, Mark; Roos, Marco] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Boycott, Kym M.] Univ Ottawa, Childrens Hosp, Eastern Ontario Res Inst, Ottawa, ON, Canada. [Brudno, Michael] Hosp Sick Children, Ctr Computat Med, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Brudno, Michael] Univ Toronto, Dept Comp Sci, Toronto, ON, Canada. [Hurles, Matthew] Wellcome Trust Sanger Inst, Wellcome Genome Campus, Cambridge, England. [Rehm, Heidi L.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Rehm, Heidi L.] Harvard Univ, Sch Med, Boston, MA USA. [Matern, Andreas] Bioreference Labs Inc, Elmwood Pk, NJ USA. [Fiume, Marc] DNAstack, Toronto, ON, Canada. [Sherry, Stephen T.] US Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD USA. RP Dyke, SOM (reprint author), McGill Univ, Fac Med, Ctr Genom & Policy, Montreal, PQ, Canada. EM Stephanie.Dyke@mcgill.ca OI Spalding, John Dylan/0000-0002-4285-2493 FU Canadian Institutes of Health Research [EP1-120608, EP2-120609]; Canada Research Chair in Law and Medicine; Public Population Project in Genomics and Society (P3G); Intramural Research Program of the NIH, Office of the Director, Office of Science Policy; Canada Research Chairs Program; ODEX4all (NWO) [650.002.002]; European Commission [305444] FX SOMD is supported by the Canadian Institutes of Health Research (grants EP1-120608; EP2-120609), the Canada Research Chair in Law and Medicine, and the Public Population Project in Genomics and Society (P3G). DNP and ESL are supported, in part, by the Intramural Research Program of the NIH, Office of the Director, Office of Science Policy. BMK is supported by the Canada Research Chairs Program. MT and MR are sponsored by ODEX4all (NWO 650.002.002) and funding from the European Commission (FP-7 project RD-Connect, grant agreement No. 305444). The funders had no role in the preparation of the article. NR 20 TC 4 Z9 4 U1 0 U2 0 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 JAN PY 2016 VL 12 IS 1 AR e1005772 DI 10.1371/journal.pgen.1005772 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA DC6ZN UT WOS:000369368200018 PM 26796797 ER PT J AU Faraji, F Hu, Y Yang, HH Lee, MP Winkler, GS Hafner, M Hunter, KW AF Faraji, Farhoud Hu, Ying Yang, Howard H. Lee, Maxwell P. Winkler, G. Sebastian Hafner, Markus Hunter, Kent W. TI Post-transcriptional Control of Tumor Cell Autonomous Metastatic Potential by CCR4-NOT Deadenylase CNOT7 SO PLOS GENETICS LA English DT Article ID ANTIPROLIFERATIVE PROTEIN TOB; MESSENGER-RNA DEADENYLATION; MOUSE MAMMARY-TUMOR; BREAST-CANCER; STRUCTURAL BASIS; COMPLEX; EXPRESSION; CAF1; SUBUNITS; TRANSCRIPTION AB Accumulating evidence supports the role of an aberrant transcriptome as a driver of metastatic potential. Deadenylation is a general regulatory node for post-transcriptional control by microRNAs and other determinants of RNA stability. Previously, we demonstrated that the CCR4-NOT scaffold component Cnot2 is an inherited metastasis susceptibility gene. In this study, using orthotopic metastasis assays and genetically engineered mouse models, we show that one of the enzymatic subunits of the CCR4-NOT complex, Cnot7, is also a metastasis modifying gene. We demonstrate that higher expression of Cnot7 drives tumor cell autonomous metastatic potential, which requires its deadenylase activity. Furthermore, metastasis promotion by CNOT7 is dependent on interaction with CNOT1 and TOB1. CNOT7 ribonucleoprotein-immunoprecipitation (RIP) and integrated transcriptome wide analyses reveal that CNOT7-regulated transcripts are enriched for a tripartite 3'UTR motif bound by RNA-binding proteins known to complex with CNOT7, TOB1, and CNOT1. Collectively, our data support a model of CNOT7, TOB1, CNOT1, and RNA-binding proteins collectively exerting post-transcriptional control on a metastasis suppressive transcriptional program to drive tumor cell metastasis. C1 [Faraji, Farhoud; Yang, Howard H.; Lee, Maxwell P.; Hunter, Kent W.] NCI, Metastasis Susceptibil Sect, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Faraji, Farhoud] St Louis Univ, Sch Med, St Louis, MO USA. [Hu, Ying] NCI, Ctr Biomed Informat & Informat Technol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Winkler, G. Sebastian] Univ Nottingham, Sch Pharm, Nottingham NG7 2RD, England. [Hafner, Markus] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Hunter, KW (reprint author), NCI, Metastasis Susceptibil Sect, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. EM hunterk@mail.nih.gov OI Winkler, Sebastiaan/0000-0002-0476-162X; Faraji, Farhoud/0000-0001-5078-813X FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript NR 58 TC 2 Z9 2 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JAN PY 2016 VL 12 IS 1 AR e1005820 DI 10.1371/journal.pgen.1005820 PG 23 WC Genetics & Heredity SC Genetics & Heredity GA DC6ZN UT WOS:000369368200048 PM 26807845 ER PT J AU Sulkowski, MJ Han, TH Ott, C Wang, Q Verheyen, EM Lippincott-Schwartz, J Serpe, M AF Sulkowski, Mikolaj J. Han, Tae Hee Ott, Carolyn Wang, Qi Verheyen, Esther M. Lippincott-Schwartz, Jennifer Serpe, Mihaela TI A Novel, Noncanonical BMP Pathway Modulates Synapse Maturation at the Drosophila Neuromuscular Junction SO PLOS GENETICS LA English DT Article ID BONE MORPHOGENETIC PROTEINS; TGF-BETA SUPERFAMILY; PRESYNAPTIC TRANSMITTER RELEASE; GLUTAMATE-RECEPTOR EXPRESSION; NEURAL-TUBE CLOSURE; RETROGRADE SIGNAL; II RECEPTOR; APICOBASAL POLARITY; GENETIC-ANALYSIS; ADAPTER PROTEIN AB At the Drosophila NMJ, BMP signaling is critical for synapse growth and homeostasis. Signaling by the BMP7 homolog, Gbb, in motor neurons triggers a canonical pathway-which modulates transcription of BMP target genes, and a noncanonical pathway-which connects local BMP/BMP receptor complexes with the cytoskeleton. Here we describe a novel noncanonical BMP pathway characterized by the accumulation of the pathway effector, the phosphorylated Smad (pMad), at synaptic sites. Using genetic epistasis, histology, super resolution microscopy, and electrophysiology approaches we demonstrate that this novel pathway is genetically distinguishable from all other known BMP signaling cascades. This novel pathway does not require Gbb, but depends on presynaptic BMP receptors and specific postsynaptic glutamate receptor subtypes, the type-A receptors. Synaptic pMad is coordinated to BMP's role in the transcriptional control of target genes by shared pathway components, but it has no role in the regulation of NMJ growth. Instead, selective disruption of presynaptic pMad accumulation reduces the postsynaptic levels of type-A receptors, revealing a positive feedback loop which appears to function to stabilize active type-A receptors at synaptic sites. Thus, BMP pathway may monitor synapse activity then function to adjust synapse growth and maturation during development. C1 [Sulkowski, Mikolaj J.; Han, Tae Hee; Wang, Qi; Serpe, Mihaela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Cellular Regulat & Metab, NIH, Bethesda, MD USA. [Ott, Carolyn; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Biol & Metab Program, NIH, Bethesda, MD USA. [Verheyen, Esther M.] Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC V5A 1S6, Canada. RP Serpe, M (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Cellular Regulat & Metab, NIH, Bethesda, MD USA. EM mihaela.serpe@nih.gov OI Verheyen, Esther/0000-0002-9795-5094 FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development [ZIA HD008914 03, ZIA HD008869 05, ZIA HD001609 22]; Canadian Institutes of Health Research FX This work was supported by Intramural Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (https://www.nichd.nih.gov/about/org/dir/Pages/index. aspx), grants ZIA HD008914 03 and ZIA HD008869 05 awarded to MS, and ZIA HD001609 22 awarded to JLS, and by Canadian Institutes of Health Research (http://www.cihr-irsc.gc.ca/e/193.html) funds awarded to EMV. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 102 TC 3 Z9 3 U1 1 U2 6 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 JAN PY 2016 VL 12 IS 1 AR e1005810 DI 10.1371/journal.pgen.1005810 PG 31 WC Genetics & Heredity SC Genetics & Heredity GA DC6ZN UT WOS:000369368200041 PM 26815659 ER PT J AU Zarin, DA Tse, T AF Zarin, Deborah A. Tse, Tony TI Sharing Individual Participant Data (IPD) within the Context of the Trial Reporting System (TRS) SO PLOS MEDICINE LA English DT Article ID CLINICAL-TRIALS; MAJOR DEPRESSION; TRANSPARENCY; PAROXETINE; EFFICACY C1 [Zarin, Deborah A.; Tse, Tony] NIH, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. RP Zarin, DA; Tse, T (reprint author), NIH, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM dzarin@mail.nih.gov; atse@mail.nih.gov OI Tse, Tony/0000-0002-9906-6864 FU Intramural NIH HHS NR 20 TC 5 Z9 5 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD JAN PY 2016 VL 13 IS 1 AR e1001946 DI 10.1371/journal.pmed.1001946 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA DC7AL UT WOS:000369370600013 PM 26784335 ER PT J AU Serrano-Villar, S Sainz, T Ma, ZM Utay, NS Wook-Chun, T Mann, S Kashuba, AD Siewe, B Albanese, A Troia-Cancio, P Sinclair, E Somasunderam, A Yotter, T Deeks, SG Landay, A Pollard, RB Miller, CJ Moreno, S Asmuth, DM AF Serrano-Villar, Sergio Sainz, Talia Ma, Zhong-Min Utay, Netanya S. Wook-Chun, Tae Mann, Surinder Kashuba, Angela D. Siewe, Basile Albanese, Anthony Troia-Cancio, Paolo Sinclair, Elizabeth Somasunderam, Anoma Yotter, Tammy Deeks, Steven G. Landay, Alan Pollard, Richard B. Miller, Christopher J. Moreno, Santiago Asmuth, David M. TI Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naive to Antiretroviral Therapy: A Pilot Randomized Trial SO PLOS PATHOGENS LA English DT Article ID T-CELL-ACTIVATION; RALTEGRAVIR INTENSIFICATION; LYMPHOID-TISSUE; HIV-1-INFECTED PATIENTS; PREDICT MORTALITY; CLINICAL-TRIALS; GUT; MARAVIROC; INFLAMMATION; REPLICATION AB Whether initiation of antiretroviral therapy (ART) regimens aimed at achieving greater concentrations within gut associated lymphoid tissue (GALT) impacts the level of mucosal immune reconstitution, inflammatory markers and the viral reservoir remains unknown. We included 12 HIV- controls and 32 ART-naive HIV patients who were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with fixed-dose tenofovir disoproxil fumarate/emtricitabine. Rectal and duodenal biopsies were obtained at baseline and at 9 months of ART. We performed a comprehensive assay of T-cell subsets by flow cytometry, T-cell density in intestinal biopsies, plasma and tissue concentrations of antiretroviral drugs by high-performance liquid chromatography/mass spectroscopy, and plasma interleukin-6 (IL-6), lipoteichoic acid (LTA), soluble CD14 (sCD14) and zonulin-1 each measured by ELISA. Total cell-associated HIV DNA was measured in PBMC and rectal and duodenal mononuclear cells. Twenty-six HIV-infected patients completed the follow-up. In the duodenum, the quadruple regimen resulted in greater CD8(+) T-cell density decline, greater normalization of mucosal CCR5(+)CD4(+) T-cells and increase of the naive/memory CD8(+) T-cell ratio, and a greater decline of sCD14 levels and duodenal HIV DNA levels (P = 0.004 and P = 0.067, respectively), with no changes in HIV RNA in plasma or tissue. Maraviroc showed the highest drug distribution to the gut tissue, and duodenal concentrations correlated well with other T-cell markers in duodenum, i.e., the CD4/CD8 ratio, %CD4(+) and %CD8(+) HLA-DR(+)CD38(+) T-cells. Maraviroc use elicited greater activation of the mucosal naive CD8(+) T-cell subset, ameliorated the distribution of the CD8(+) T-cell maturational subsets and induced higher improvement of zonulin-1 levels. These data suggest that combined CCR5 and integrase inhibitor based combination therapy in ART treatment naive patients might more effectively reconstitute duodenal immunity, decrease inflammatory markers and impact on HIV persistence by cell-dependent mechanisms, and show unique effects of MVC in duodenal immunity driven by higher drug tissue penetration and possibly by class-dependent effects. C1 [Serrano-Villar, Sergio; Moreno, Santiago] Univ Hosp Ramon y Cajal, Madrid, Spain. [Sainz, Talia] Univ Hosp La Paz, Madrid, Spain. [Ma, Zhong-Min; Miller, Christopher J.] Calif Natl Primate Res Ctr, Davis, CA USA. [Utay, Netanya S.; Somasunderam, Anoma] Univ Texas Med Branch, Galveston, TX 77555 USA. [Wook-Chun, Tae] NIAID, Immunoregulat Lab, Bldg 10, Bethesda, MD 20892 USA. [Mann, Surinder; Troia-Cancio, Paolo; Yotter, Tammy; Pollard, Richard B.; Miller, Christopher J.; Asmuth, David M.] Univ Calif Davis, Med Ctr, Sacramento, CA 95817 USA. [Kashuba, Angela D.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Siewe, Basile; Landay, Alan] Rush Univ, Chicago, IL 60612 USA. [Albanese, Anthony] Vet Adm Northern Calif Hlth Care Syst, Mather, CA USA. [Sinclair, Elizabeth; Deeks, Steven G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Asmuth, DM (reprint author), Univ Calif Davis, Med Ctr, Sacramento, CA 95817 USA. EM dasmuth@ucdavis.edu OI Utay, Netanya/0000-0002-6407-8670; Serrano-Villar, Sergio/0000-0002-5447-3554 FU National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), NIH Roadmap for Medical Research [UL1 RR024146]; Pfizer Investigator Initiated Research Program; UCSF/Gladstone Institute of Virology & Immunology CFAR [P30 AI027763]; UNC CFAR [P30 AI50410]; Spanish Ministry of Health and Innovation; Spanish Network on AIDS Research (RIS Cohort, CoRIS) - Instituto de Salud Carlos III through the Red Tematica de Investigacion Cooperativa en Sida [RD06/006] FX This research was made possible by Grant Number UL1 RR024146 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), NIH Roadmap for Medical Research, and by a grant from Pfizer Investigator Initiated Research Program, the UCSF/Gladstone Institute of Virology & Immunology CFAR (grant number P30 AI027763), and the UNC CFAR (P30 AI50410). SSV is funded by a grant from the Spanish Ministry of Health and Innovation. SSV and TS received grants to perform this work from the Spanish Network on AIDS Research (RIS Cohort, CoRIS), which is funded by the Instituto de Salud Carlos III through the Red Tematica de Investigacion Cooperativa en Sida (RD06/006). The results and views expressed in this work do not represent those of Pfizer or the US Federal Government/Veterans Administration Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 9 Z9 9 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JAN PY 2016 VL 12 IS 1 AR e1005381 DI 10.1371/journal.ppat.1005381 PG 26 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DC7BX UT WOS:000369374500035 PM 26795282 ER PT J AU Lamart, S Simon, SL Bouville, A Moroz, BE Lee, C AF Lamart, Stephanie Simon, Steven L. Bouville, Andre Moroz, Brian E. Lee, Choonsik TI S values for I-131 based on the ICRP adult voxel phantoms SO RADIATION PROTECTION DOSIMETRY LA English DT Article ID REFERENCE COMPUTATIONAL PHANTOMS; ABSORBED FRACTIONS; INTERNAL DOSIMETRY; HUMAN ANATOMY; RADIOPHARMACEUTICALS; THERAPY; PHOTONS; MODELS AB To improve the estimates of organ doses from nuclear medicine procedures using I-131, the authors calculated a comprehensive set of I-131 S values, defined as absorbed doses in target tissues per unit of nuclear transition in source regions, for different source and target combinations. The authors used the latest reference adult male and female voxel phantoms published by the International Commission on Radiological Protection (ICRP Publication 110) and the I-131 photon and electron spectra from the ICRP Publication 107 to perform Monte Carlo radiation transport calculations using MCNPX2.7 to compute the S values. For each phantom, the authors simulated 55 source regions with an assumed uniform distribution of I-131. They computed the S values for 42 target tissues directly, without calculating specific absorbed fractions. From these calculations, the authors derived a comprehensive set of S values for I-131 for 55 source regions and 42 target tissues in the ICRP male and female voxel phantoms. Compared with the stylised phantoms from Oak Ridge National Laboratory (ORNL) that consist of 22 source regions and 24 target regions, the new data set includes 1662 additional S values corresponding to additional combinations of source-target tissues that are not available in the stylised phantoms. In a comparison of S values derived from the ICRP and ORNL phantoms, the authors found that the S values to the radiosensitive tissues in the ICRP phantoms were 1.1 (median, female) and 1.3 (median, male) times greater than the values based on the ORNL phantoms. However, for several source-target pairs, the difference was up to 10-fold. The new set of S values can be applied prospectively or retrospectively to the calculation of radiation doses in adults internally exposed to I-131, including nuclear medicine patients treated for thyroid cancer or hyperthyroidism. C1 [Lamart, Stephanie; Simon, Steven L.; Bouville, Andre; Moroz, Brian E.; Lee, Choonsik] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Lee, C (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM leechoonsik@mail.nih.gov FU National Institutes of Health; National Cancer Institute; Division of Cancer Epidemiology and Genetics FX This work was supported by the intramural research programme of the National Institutes of Health, National Cancer Institute and Division of Cancer Epidemiology and Genetics. This study utilised the high-performance computational capabilities of the Biowulf computing system at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 29 TC 1 Z9 1 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0144-8420 EI 1742-3406 J9 RADIAT PROT DOSIM JI Radiat. Prot. Dosim. PD JAN PY 2016 VL 168 IS 1 BP 92 EP 110 DI 10.1093/rpd/ncv016 PG 19 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA DC6JR UT WOS:000369326600013 PM 25829162 ER PT J AU Nguyen, V Panyutin, IV Panyutin, IG Neumann, RD AF Van Nguyen Panyutin, Irina V. Panyutin, Igor G. Neumann, Ronald D. TI A Genomic Study of DNA Alteration Events Caused by Ionizing Radiation in Human Embryonic Stem Cells via Next-Generation Sequencing SO STEM CELLS INTERNATIONAL LA English DT Article ID CLINICAL VALIDATION; HUMAN BLASTOCYSTS; CANCER; PLURIPOTENCY; MUTATIONS; LINES; GENE; EXPRESSION; CYCLE; BRAF AB Ionizing radiation (IR) is a known mutagen that is widely employed for medical diagnostic and therapeutic purposes. To study the extent of genetic variations in DNA caused by IR, we used IR-sensitive human embryonic stem cells (hESCs). Four hESC cell lines, H1, H7, H9, and H14, were subjected to IR at 0.2 or 1Gy dose and then maintained in culture for four days before being harvested for DNA isolation. Irradiation with 1Gy dose resulted in significant cell death, ranging from 60% to 90% reduction in cell population. Since IR is often implicated as a risk for inducing cancer, a primer pool targeting genomic "hotspot" regions that are frequently mutated in human cancer genes was used to generate libraries from irradiated and control samples. Using a semiconductor-based next-generation sequencing approach, we were able to consistently sequence these samples with deep coverage for reliable data analysis. A possible rare nucleotide variant was identified in the KIT gene (chr4:55593481) exclusively in H1 hESCs irradiated with 1 Gy dose. More extensive further studies are warranted to assess the extent and distribution of genetic changes in hESCs after IR exposure. C1 [Van Nguyen; Panyutin, Irina V.; Panyutin, Igor G.; Neumann, Ronald D.] NIH, Div Nucl Med, Dept Radiol & Imaging Sci, Ctr Clin, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Panyutin, IV (reprint author), NIH, Div Nucl Med, Dept Radiol & Imaging Sci, Ctr Clin, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ipanyuting@mail.nih.gov FU Intramural Research Program of the National Institutes of Health Clinical Center FX The authors thank William DeGraff for his invaluable help with cell irradiation. This research was supported by the Intramural Research Program of the National Institutes of Health Clinical Center. NR 26 TC 0 Z9 0 U1 2 U2 3 PU HINDAWI PUBLISHING CORP PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 1687-966X EI 1687-9678 J9 STEM CELLS INT JI Stem Cells Int. PY 2016 AR 1346521 DI 10.1155/2016/1346521 PG 7 WC Cell & Tissue Engineering SC Cell Biology GA DD1HI UT WOS:000369671500001 ER PT J AU Ippolito, DL AbdulHameed, MDM Tawa, GJ Baer, CE Permenter, MG McDyre, BC Dennis, WE Boyle, MH Hobbs, CA Streicker, MA Snowden, BS Lewis, JA Wallqvist, A Stallings, JD AF Ippolito, Danielle L. AbdulHameed, Mohamed Diwan M. Tawa, Gregory J. Baer, Christine E. Permenter, Matthew G. McDyre, Bonna C. Dennis, William E. Boyle, Molly H. Hobbs, Cheryl A. Streicker, Michael A. Snowden, Bobbi S. Lewis, John A. Wallqvist, Anders Stallings, Jonathan D. TI Gene Expression Patterns Associated With Histopathology in Toxic Liver Fibrosis SO TOXICOLOGICAL SCIENCES LA English DT Article DE toxic liver injury; transcriptomics; bioinformatics; fibrosis; biomarkers; histopathology ID HEPATIC STELLATE CELLS; DIBENZO-P-DIOXINS; CARBON-TETRACHLORIDE; SUBCHRONIC/CHRONIC TOXICITY; GROWTH-FACTOR; 1,2,3,4,6,7,8-HEPTACHLORODIBENZO-P-DIOXIN HPCDD; CIRRHOTIC LIVER; LUNG FIBROSIS; MOUSE MODEL; SHORT-TERM AB Toxic industrial chemicals induce liver injury, which is difficult to diagnose without invasive procedures. Identifying indicators of end organ injury can complement exposure-based assays and improve predictive power. A multiplexed approach was used to experimentally evaluate a panel of 67 genes predicted to be associated with the fibrosis pathology by computationally mining DrugMatrix, a publicly available repository of gene microarray data. Five-day oral gavage studies in male Sprague Dawley rats dosed with varying concentrations of 3 fibrogenic compounds (allyl alcohol, carbon tetrachloride, and 4,4'-methylenedianiline) and 2 nonfibrogenic compounds (bromobenzene and dexamethasone) were conducted. Fibrosis was definitively diagnosed by histopathology. The 67-plex gene panel accurately diagnosed fibrosis in both microarray and multiplexed-gene expression assays. Necrosis and inflammatory infiltration were comorbid with fibrosis. ANOVA with contrasts identified that 51 of the 67 predicted genes were significantly associated with the fibrosis phenotype, with 24 of these specific to fibrosis alone. The protein product of the gene most strongly correlated with the fibrosis phenotype PCOLCE (Procollagen C-Endopeptidase Enhancer) was dose-dependently elevated in plasma from animals administered fibrogenic chemicals (P < .05). Semiquantitative global mass spectrometry analysis of the plasma identified an additional 5 protein products of the gene panel which increased after fibrogenic toxicant administration: fibronectin, ceruloplasmin, vitronectin, insulin-like growth factor binding protein, and alpha 2-macroglobulin. These results support the data mining approach for identifying gene and/or protein panels for assessing liver injury and may suggest bridging biomarkers for molecular mediators linked to histopathology. C1 [Ippolito, Danielle L.; Dennis, William E.; Lewis, John A.; Stallings, Jonathan D.] USACEHR, Environm Hlth Program, Ft Detrick, MD 21702 USA. [AbdulHameed, Mohamed Diwan M.; Tawa, Gregory J.; Wallqvist, Anders] US Army, Dept Def, Biotechnol High Performance Comp Software Applica, Telemed & Adv Technol Res Ctr,Med Res & Mat Comma, Ft Detrick, MD 21702 USA. [Baer, Christine E.; Permenter, Matthew G.] Excet Inc, Frederick, MD 21702 USA. [McDyre, Bonna C.] Oak Ridge Inst Sci & Educ, Frederick, MD 21702 USA. [Boyle, Molly H.; Hobbs, Cheryl A.; Streicker, Michael A.] Integrated Syst Lab, Res Triangle Pk, NC 27709 USA. [Snowden, Bobbi S.] Univ Maryland, Sch Publ Hlth, Maryland Inst Appl Environm Hlth, College Pk, MD 20742 USA. [Tawa, Gregory J.] NIH, Translat Med Div, Bldg 10, Bethesda, MD 20892 USA. RP Ippolito, DL (reprint author), US Army, Biomarkers Program, Ctr Environm Hlth Res, 568 Doughten Dr, Ft Detrick, MD 21702 USA. EM Danielle.L.Ippolito2.civ@mail.mil FU Military Operational Medicine Research Program; U.S. Army's Network Science Initiative, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland; U.S. Department of Energy; U.S. Army Medical Research and Materiel Command FX The work was supported by the Military Operational Medicine Research Program and the U.S. Army's Network Science Initiative, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland. This work was also supported in part by an appointment at U.S. Army Center for Environmental Health Research administered by Oak Ridge Institute for Science and Education through an interagency agreement between U.S. Department of Energy and U.S. Army Medical Research and Materiel Command [B.C.M.]. NR 128 TC 3 Z9 3 U1 4 U2 5 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 JAN PY 2016 VL 149 IS 1 BP 67 EP 88 DI 10.1093/toxsci/kfv214 PG 22 WC Toxicology SC Toxicology GA DC5BA UT WOS:000369233900007 PM 26396155 ER PT J AU Gray, LE Furr, J Tatum-Gibbs, KR Lambright, C Sampson, H Hannas, BR Wilson, VS Hotchkiss, A Foster, PMD AF Gray, Leon Earl, Jr. Furr, Johnathan Tatum-Gibbs, Katoria R. Lambright, Christy Sampson, Hunter Hannas, Bethany R. Wilson, Vickie S. Hotchkiss, Andrew Foster, Paul M. D. TI Establishing the "Biological Relevance" of Dipentyl Phthalate Reductions in Fetal Rat Testosterone Production and Plasma and Testis Testosterone Levels SO TOXICOLOGICAL SCIENCES LA English DT Article DE anti-androgen; risk assessment; fetal male rat endocrine; dipentyl phthalate ID MALE REPRODUCTIVE DEVELOPMENT; N-BUTYL PHTHALATE; SEXUAL-DIFFERENTIATION; DI(N-BUTYL) PHTHALATE; IN-UTERO; LUTEINIZING-HORMONE; RELATIVE POTENCY; LATE-GESTATION; EXPOSURE; VINCLOZOLIN AB Phthalate esters (PEs) constitute a large class of compounds that are used for many consumer product applications. Many of the C2-C7 di-ortho PEs reduce fetal testicular hormone and gene expression levels in rats resulting in adverse effects seen later in life but it appears that relatively large reductions in fetal testosterone (T) levels and testis gene expression may be required to adversely affect reproductive development (Hannas, B. R., Lambright, C. S., Furr, J., Evans, N., Foster, P. M., Gray, E. L., and Wilson, V. S. (2012). Genomic biomarkers of phthalate-induced male reproductive developmental toxicity: a targeted RT-PCR array approach for defining relative potency. Toxicol. Sci. 125, 544-557). The objectives of this study were (1) to model the relationships between changes in fetal male rat plasma testosterone (PT), T levels in the testis (TT), T production (PROD), and testis gene expression with the reproductive malformation rates, and (2) to quantify the "biologically relevant reductions" (BRRs) in fetal T necessary to induce adverse effects in the offspring. In the fetal experiment, Harlan Sprague-Dawley rats were dosed with dipentyl phthalate (DPeP) at 0, 11, 33, 100, and 300 mg/kg/day from gestational days (GD) 14-18 and fetal testicular T, PT levels, and T Prod and gene expression were assessed on GD 18. In the postnatal experiment, rats were dosed with DPeP from GD 8-18 and reproductive development was monitored through adulthood. The dose-response curves for TT levels (ED50 = 53 mg/kg) and T PROD (ED50 = 45 mg/kg) were similar, whereas PT was reduced at ED50 = 19 mg/kg. When the reductions in TPROD and Insl3 mRNA were compared with the postnatal effects of in utero DPeP, dose-related reproductive alterations were noted when T PROD and Insl3 mRNA were reduced by > 45% and 42%, respectively. The determination of BRR levels may enable risk assessors to utilize fetal endocrine data to help establish points of departure for quantitative risk assessments. C1 [Gray, Leon Earl, Jr.; Furr, Johnathan; Tatum-Gibbs, Katoria R.; Lambright, Christy; Hannas, Bethany R.; Wilson, Vickie S.] US EPA, Reprod Toxicol Branch,Toxicol Assessment Div, Natl Hlth & Environm Effects Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Hotchkiss, Andrew] US EPA, NCEA, ORD, Washington, DC USA. [Foster, Paul M. D.] NIEHS, Natl Toxicol Program, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Sampson, Hunter] Oak Ridge Inst Sci & Educ, Oak Ridge, TN 37831 USA. [Hannas, Bethany R.] Dow Chem Co USA, Toxicol & Environm Res & Consulting, Midland, MI 48674 USA. RP Gray, LE (reprint author), US EPA, Reprod Toxicol Branch,Toxicol Assessment Div, Natl Hlth & Environm Effects Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. EM gray.earl@epa.gov OI Wilson, Vickie/0000-0003-1661-8481 FU NIH [NTP/NIEHS IA RW7592285501-1] FX Supported in part by NIH NTP/NIEHS IA RW7592285501-1. NR 31 TC 2 Z9 2 U1 5 U2 12 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 JAN PY 2016 VL 149 IS 1 BP 178 EP 191 DI 10.1093/toxsci/kfv224 PG 14 WC Toxicology SC Toxicology GA DC5BA UT WOS:000369233900016 PM 26454885 ER PT J AU Chang, CY Esber, GR Marrero-Garcia, Y Yau, HJ Bonci, A Schoenbaum, G AF Chang, Chun Yun Esber, Guillem R. Marrero-Garcia, Yasmin Yau, Hau-Jie Bonci, Antonello Schoenbaum, Geoffrey TI Brief optogenetic inhibition of dopamine neurons mimics endogenous negative reward prediction errors SO NATURE NEUROSCIENCE LA English DT Article ID VENTRAL TEGMENTAL AREA; LATERAL HABENULA; NUCLEUS-ACCUMBENS; ORBITOFRONTAL CORTEX; MESOLIMBIC DOPAMINE; SIGNALS; REINFORCEMENT; RESPONSES; OVEREXPECTATION; AVOIDANCE AB Correlative studies have strongly linked phasic changes in dopamine activity with reward prediction error signaling. But causal evidence that these brief changes in firing actually serve as error signals to drive associative learning is more tenuous. Although there is direct evidence that brief increases can substitute for positive prediction errors, there is no comparable evidence that similarly brief pauses can substitute for negative prediction errors. In the absence of such evidence, the effect of increases in firing could reflect novelty or salience, variables also correlated with dopamine activity. Here we provide evidence in support of the proposed linkage, showing in a modified Pavlovian over-expectation task that brief pauses in the firing of dopamine neurons in rat ventral tegmental area at the time of reward are sufficient to mimic the effects of endogenous negative prediction errors. These results support the proposal that brief changes in the firing of dopamine neurons serve as full-fledged bidirectional prediction error signals. C1 [Chang, Chun Yun; Marrero-Garcia, Yasmin; Yau, Hau-Jie; Bonci, Antonello; Schoenbaum, Geoffrey] NIDA, Intramural Res Program, Cellular Neurobiol Res Branch, Behav Neurophysiol Res Sect, Baltimore, MD 21224 USA. [Esber, Guillem R.] CUNY, Dept Psychol, Brooklyn Coll, New York, NY 10021 USA. [Bonci, Antonello; Schoenbaum, Geoffrey] Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD USA. [Bonci, Antonello] Johns Hopkins Univ, Dept Psychiat, Baltimore, MD USA. [Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. RP Chang, CY (reprint author), NIDA, Intramural Res Program, Cellular Neurobiol Res Branch, Behav Neurophysiol Res Sect, Baltimore, MD 21224 USA. EM tina.chang@nih.gov; geoffrey.schoenbaum@nih.gov OI YAU, HAU-JIE/0000-0001-7454-7971; Schoenbaum, Geoffrey/0000-0001-8180-0701 FU US National Institute on Drug Abuse (NIDA) FX This work was supported by the Intramural Research Program at the US National Institute on Drug Abuse (NIDA). The authors would like to thank K. Deisseroth and the Gene Therapy Center at the University of North Carolina at Chapel Hill for providing viral reagents, and G. Stuber for technical advice on their use. We would also like to thank B. Harvey and the NIDA Optogenetic and Transgenic Core and M. Morales and the NIDA Histology Core for their assistance. The opinions expressed in this article are the authors' own and do not reflect the views of the US National Institutes of Health/Department of Health and Human Services. NR 50 TC 16 Z9 16 U1 2 U2 18 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD JAN PY 2016 VL 19 IS 1 BP 111 EP + DI 10.1038/nn.4191 PG 8 WC Neurosciences SC Neurosciences & Neurology GA CZ7BH UT WOS:000367254400019 PM 26642092 ER PT J AU Garmann, RF Comas-Garcia, M Knobler, CM Gelbart, WM AF Garmann, Rees F. Comas-Garcia, Mauricio Knobler, Charles M. Gelbart, William M. TI Physical Principles in the Self-Assembly of a Simple Spherical Virus SO ACCOUNTS OF CHEMICAL RESEARCH LA English DT Review ID SINGLE-STRANDED RNA; VIRAL CAPSID PROTEIN; CHLOROTIC MOTTLE VIRUS; CRYOELECTRON MICROSCOPY; COAT PROTEINS; MOLECULES; MECHANISM; PATHWAY; GENOME; SIZES AB Viruses are unique among living organisms insofar as they can be reconstituted "from scratch", that is, synthesized from purified components. In the simplest cases, their "parts list" numbers only two: a single molecule of nucleic acid and many (but a very special number, i.e., multiples of 60) copies of a single protein. Indeed, the smallest viral genomes include essentially only two genes, on the order of a thousand times fewer than the next-simplest organisms like bacteria and yeast. For these reasons, it is possible and even fruitful to take a reductionist approach to viruses and to understand how they work in terms of fundamental physical principles. In this Account, we discuss our recent physical chemistry approach to studying the self-assembly of a particular spherical virus (cowpea chlorotic mottle virus) whose reconstitution from RNA and capsid protein has long served as a model for virus assembly. While previous studies have clarified the roles of certain physical (electrostatic, hydrophobic, steric) interactions in the stability and structure of the final virus, it has been difficult to probe these interactions during assembly because of the inherently short lifetimes of the intermediate states. We feature the role of pH in tuning the magnitude of the interactions among capsid proteins during assembly: in particular, by making the interactions between proteins sufficiently weak, we are able to stall the assembly process and interrogate the structure and composition of particular on-pathway intermediates. Further, we find that the strength of the lateral attractions between RNA-bound proteins plays a key role in addressing several outstanding questions about assembly: What determines the pathway or pathways of assembly? What is the importance of kinetic traps and hysteresis? How do viruses copackage multiple short (compared with wild-type) RNAs or single long RNAs? What determines the relative packaging efficiencies of different RNAs when they are forced to compete for an insufficient supply of protein? And what is the limit on the length of RNA that can be packaged by CCMV capsid protein? C1 [Garmann, Rees F.] Harvard Univ, Harvard John A Paulson Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Comas-Garcia, Mauricio] NCI, HIV Dynam & Replicat Program, Frederick, MD 21702 USA. [Knobler, Charles M.; Gelbart, William M.] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA. [Gelbart, William M.] Univ Calif Los Angeles, Calif NanoSyst Inst, Los Angeles, CA 90095 USA. [Gelbart, William M.] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. RP Gelbart, WM (reprint author), Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA.; Gelbart, WM (reprint author), Univ Calif Los Angeles, Calif NanoSyst Inst, Los Angeles, CA 90095 USA.; Gelbart, WM (reprint author), Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. EM gelbart@chem.ucla.edu OI Comas-Garcia, Mauricio/0000-0002-7733-5138 NR 40 TC 7 Z9 7 U1 12 U2 36 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0001-4842 EI 1520-4898 J9 ACCOUNTS CHEM RES JI Accounts Chem. Res. PD JAN PY 2016 VL 49 IS 1 BP 48 EP 55 DI 10.1021/acs.accounts.5b00350 PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA DB5OS UT WOS:000368564100007 PM 26653769 ER PT J AU Song, ML Liu, T Shi, CR Zhang, XZ Chen, XY AF Song, Manli Liu, Ting Shi, Changrong Zhang, Xiangzhong Chen, Xiaoyuan TI Bioconjugated Manganese Dioxide Nanoparticles Enhance Chemotherapy Response by Priming Tumor-Associated Macrophages toward M1-like Phenotype and Attenuating Tumor Hypoxia SO ACS NANO LA English DT Article DE hypoxia; tumor associated macrophages (TAMs); chemotherapy response; manganese dioxide (MnO2); hyaluronic acid (HA); mannose receptor ID CONTRAST AGENT; SOLID TUMOR; CANCER; MRI; OXYGENATION; METABOLISM; RADIOTHERAPY; T-1; MICROENVIRONMENT; ANGIOGENESIS AB Hypoxia promotes not only the invasiveness of tumor cells, but also chemoresistance in cancer. Tumor associated macrophages (TAMs) residing at the site of hypoxic region of tumors have been known to cooperate with tumor cells, and promote proliferation and chemoresistance. Therefore, there is an urgent need for new strategies to alleviate tumor hypoxia and enhance chemotherapy response in solid tumors. Herein, we have taken advantage of high accumulation of TAMs in hypoxic regions of tumor and high reactivity of manganese dioxide nanoparticles (MnO2 NPs) toward hydrogen peroxide (H2O2) for the simultaneous production of O-2 and regulation of pH to effectively alleviate tumor hypoxia by targeted delivery of MnO2 NPs to the hypoxic area. Furthermore, we also utilized the ability of hyaluronic acid (HA) modification in reprogramming anti-inflammatory, pro-tumoral M2 TAMs to pro-inflammatory, antitumor M1 macrophages to further enhance the ability of MnO2 NPs to lessen tumor hypoxia and modulate chemoresistance. The HA-coated, mannanconjugated MnO2 particle (Man-HA-MnO2) treatment significantly increased tumor oxygenation and down-regulated hypoxia-inducible factor-1 alpha (HIP-1 alpha) and vascular endothelial growth factor (VEGF) in the tumor. Combination treatment of the tumors with Man-HA-MnO, NPs and doxorubicin significantly increased apparent diffusion coefficient (ADC) values of breast tumor, inhibited tumor growth and tumor cell proliferation as compared with chemotherapy alone. In addition, the reaction of Man-HA-MnO2 NPs toward endogenous H2O2 highly enhanced T-1- and T-2-MRI performance for tumor imaging and detection. C1 [Song, Manli; Liu, Ting; Shi, Changrong; Zhang, Xiangzhong] Xiamen Univ, Sch Publ Hlth, State Key Lab Mol Vaccinol & Mol Diagnost, Xiamen 361102, Peoples R China. [Song, Manli; Liu, Ting; Shi, Changrong; Zhang, Xiangzhong] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361102, Peoples R China. [Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Liu, T; Zhang, XZ (reprint author), Xiamen Univ, Sch Publ Hlth, State Key Lab Mol Vaccinol & Mol Diagnost, Xiamen 361102, Peoples R China.; Liu, T; Zhang, XZ (reprint author), Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361102, Peoples R China.; Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. EM tingliu20072008@yahoo.com; zhangxzh@xmu.edu.cn; shawn.chen@nih.gov RI Zhang, Xianzhong/A-7754-2012 OI Zhang, Xianzhong/0000-0002-1001-1884 FU National Science Foundation of China [81501533]; National Key Basic Research Program of China [2014CB744503]; Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX This research was supported by the National Science Foundation of China (81501533), National Key Basic Research Program of China (2014CB744503), and the Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 47 TC 16 Z9 17 U1 42 U2 127 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 EI 1936-086X J9 ACS NANO JI ACS Nano PD JAN PY 2016 VL 10 IS 1 BP 633 EP 647 DI 10.1021/acsnano.5b06779 PG 15 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA DC3JO UT WOS:000369115800068 PM 26650065 ER PT J AU Chen, HL Song, ML Tang, J Hu, GF Xu, SY Guo, ZD Li, NN Cui, JB Zhang, XZ Chen, XY Wang, LY AF Chen, Hongli Song, Manli Tang, Juan Hu, Gaofei Xu, Suying Guo, Zhide Li, Nannan Cui, Jiabin Zhang, Xianzhong Chen, Xiaoyuan Wang, Leyu TI Ultrahigh F-19 Loaded Cu1.75S Nanoprobes for Simultaneous F-19 Magnetic Resonance Imaging and Photothermal Therapy SO ACS NANO LA English DT Article DE F-19 MRI; photothermal imaging and therapy; multifunctional nanoprobes; copper sulfide nanoparticle ID FLUORINATED GRAPHENE OXIDE; DETECT PROTEASE ACTIVITY; IN-VIVO; DRUG-DELIVERY; SILICA NANOPARTICLES; GOLD NANOPARTICLES; CONTRAST AGENT; MRI PROBE; NANOCRYSTALS; CANCER AB F-19 magnetic resonance imaging (MRI) is a powerful noninvasive, sensitive, and accurate molecular imaging technique for early diagnosis of diseases. The major challenge of F-19. MRI is signal attenuation caused by the reduced solubility of probes with increased number of fluorine atoms and the restriction of molecular mobility. Herein, we present a versatile one-pot strategy for the fabrication of a multifunctional nanoprobe with high F-19 loading (similar to 2.0 x 10(8) F-19 atoms per Cu1.75S nanoparticle). Due to the high F-19 loading and good molecular mobility that results from the small particle size (20.8 +/- 2.0 nm) and ultrathin polymer coating, this nanoprobe demonstrates ultrahigh F-19 MRI signal. In vivo tests show that this multifunctional nanoprobe is suitable for F-19 MRI and photothermal therapy. This versatile fabrication strategy has also been readily extended to other single-particle nanoprobes for ablation and sensitive multimodal imaging. C1 [Chen, Hongli; Tang, Juan; Hu, Gaofei; Xu, Suying; Li, Nannan; Cui, Jiabin; Wang, Leyu] Beijing Univ Chem Technol, State Key Lab Chem Resource Engn, Beijing 100029, Peoples R China. [Song, Manli; Guo, Zhide; Zhang, Xianzhong] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, State Key Lab Mol Vaccinol & Mol Diagnost, Xiamen 361005, Fujian, Peoples R China. [Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. RP Wang, LY (reprint author), Beijing Univ Chem Technol, State Key Lab Chem Resource Engn, Beijing 100029, Peoples R China.; Zhang, XZ (reprint author), Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, State Key Lab Mol Vaccinol & Mol Diagnost, Xiamen 361005, Fujian, Peoples R China.; Chen, XY (reprint author), NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. EM zhangxzh@xmu.edu.cn; shawn.chen@nih.gov; lywang@mail.buct.edu.cn RI Zhang, Xianzhong/A-7754-2012 OI Zhang, Xianzhong/0000-0002-1001-1884 FU National Natural Science Foundation of China [21475007, 21275015, 21271030]; State Key Project of Fundamental Research of China [2011CB932403]; National Institute of Biomedical Imaging and Bioengineering; Innovation and Promotion Project of Beijing University of Chemical Technology; Public Hatching Platform for Recruited Talents of Beijing University of Chemical Technology; High-Level Faculty Program of Beijing University of Chemical Technology [buctrc201507, buctrc201325]; BUCT Fund for Disciplines Construction and Development [XK1526] FX This research was supported in part by the National Natural Science Foundation of China (Grant Nos. 21475007, 21275015, and 21271030), the State Key Project of Fundamental Research of China (Grant No. 2011CB932403), and the intramural research program of the National Institute of Biomedical Imaging and Bioengineering. We also thank the support from the "Innovation and Promotion Project of Beijing University of Chemical Technology", the "Public Hatching Platform for Recruited Talents of Beijing University of Chemical Technology", the "High-Level Faculty Program of Beijing University of Chemical Technology (buctrc201507, buctrc201325)", and BUCT Fund for Disciplines Construction and Development (Project No. XK1526). NR 44 TC 10 Z9 10 U1 32 U2 86 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 EI 1936-086X J9 ACS NANO JI ACS Nano PD JAN PY 2016 VL 10 IS 1 BP 1355 EP 1362 DI 10.1021/acsnano.5b06759 PG 8 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA DC3JO UT WOS:000369115800151 PM 26741791 ER PT J AU Hendershot, CS Claus, ED Ramchandani, VA AF Hendershot, Christian S. Claus, Eric D. Ramchandani, Vijay A. TI Associations of OPRM1 A118G and alcohol sensitivity with intravenous alcohol self-administration in young adults SO ADDICTION BIOLOGY LA English DT Article DE Asn40Asp; pharmacogenetics; phenotype; rs1799971; SNP; subjective responses to alcohol ID OPIOID RECEPTOR GENE; HUMAN LABORATORY MODELS; FUNCTIONAL POLYMORPHISM; INDIVIDUAL-DIFFERENCES; SUBJECTIVE RESPONSES; USE DISORDERS; NALTREXONE; ETHANOL; CONSUMPTION; DRINKING AB Human laboratory and animal models implicate variation in the -opioid receptor gene (OPRM1) as relevant for alcohol-related reward. OPRM1 is associated with alcohol self-administration in non-human primate studies, but the relevance of this finding to human models is unclear. This study used computer-assisted self-infusion of ethanol (CASE) to examine associations among OPRM1 A118G genotype, subjective responses to alcohol and intravenous alcohol self-administration in young heavy drinkers (n=40, mean age=19.95 years, SD=0.82). Participants completed a 2-hour CASE session comprising a priming phase followed by ad libitum self-administration in a free-access paradigm. Participants achieved a mean peak breath alcohol concentration (BrAC) of 81.18mg% (SD=24.96). Those with the OPRM1 118G variant (GA or GG genotypes) achieved significantly higher peak BrAC (M=94.90mg%, SD=16.56) than those with the AA genotype (M=74.46mg%, SD=25.36), reflecting a significantly greater number of alcohol requests among GA/GG participants. Eighty percent of GA/GG participants surpassed a threshold defining a laboratory analog of heavy alcohol exposure (80mg%) compared with 46 percent of AA participants. Results indicated significant associations between subjective measures of alcohol sensitivity and CASE outcomes, although the pattern of findings differed across self-report measures. Subjective responses did not differ by OPRM1 status. These results offer further support for the feasibility of the CASE paradigm and provide initial evidence for an association of OPRM1 with alcohol self-administration in a human laboratory context. C1 [Hendershot, Christian S.] Ctr Addict & Mental Hlth, Campbell Family Mental Hlth Res Inst, 100 Stokes St,Room 3169, Toronto, ON M6J 1H4, Canada. [Hendershot, Christian S.] Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A1, Canada. [Claus, Eric D.] Mind Res Network & Lovelace Biomed & Environm Res, Albuquerque, NM USA. [Ramchandani, Vijay A.] NIAAA, Sect Human Psychopharmacol, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. RP Hendershot, CS (reprint author), Ctr Addict & Mental Hlth, Campbell Family Mental Hlth Res Inst, 100 Stokes St,Room 3169, Toronto, ON M6J 1H4, Canada.; Hendershot, CS (reprint author), Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A1, Canada.; Hendershot, CS (reprint author), Ctr Addict & Mental Hlth, 100 Stokes St,Room 3169, Toronto, ON M6J 1H4, Canada. EM christian.hendershot@utoronto.ca OI Hendershot, Christian/0000-0002-5328-2035 FU ABMRF/The Foundation for Alcohol Research; Canadian Institutes of Health Research (CIHR) [260418, 288905, 307742]; NIH [R21 AA020304, P60 AA007611]; NIAAA Division of Intramural Clinical and Biological Research FX This study was supported by a grant from ABMRF/The Foundation for Alcohol Research to CH. The authors also acknowledge support from Canadian Institutes of Health Research (CIHR) grants 260418, 288905, 307742 (CH), NIH R21 AA020304 (EC, CH), NIAAA Division of Intramural Clinical and Biological Research (VAR) and NIH P60 AA007611. The authors declare no conflicts of interest. NR 54 TC 5 Z9 5 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 EI 1369-1600 J9 ADDICT BIOL JI Addict. Biol. PD JAN PY 2016 VL 21 IS 1 BP 125 EP 135 DI 10.1111/adb.12165 PG 11 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA DC2ST UT WOS:000369067300010 PM 25039301 ER PT J AU Pilotto, A Sancarlo, D Pellegrini, F Rengo, F Marchionni, N Volpato, S Ferrucci, L AF Pilotto, Alberto Sancarlo, Daniele Pellegrini, Fabio Rengo, Franco Marchionni, Niccolo Volpato, Stefano Ferrucci, Luigi CA FIRI-SIGG Study Grp TI The Multidimensional Prognostic Index predicts in-hospital length of stay in older patients: a multicentre prospective study SO AGE AND AGEING LA English DT Article DE older people; length of stay; Multidimensional Prognostic Index; mortality ID COMPREHENSIVE GERIATRIC ASSESSMENT; ELDERLY PATIENTS; TERM MORTALITY; VALIDATION; PNEUMONIA; DISCHARGE; REASONS; PEOPLE; ADULTS; DEATH AB Background: prediction of length of stay (LOS) may be useful to optimise care plans to reduce the negative outcomes related to hospitalisation. Objective: to evaluate whether the Multidimensional Prognostic Index (MPI), based on a Comprehensive Geriatric Assessment (CGA), may predict LOS in hospitalised older patients. Design: prospective multicentre cohort study. Setting: twenty Geriatrics Units. Participants: patients aged 65 and older consecutively admitted to Geriatrics Units. Measurement: at admission, the CGA-based MPI was calculated by using a validated algorithm that included information on basal and instrumental activities of daily living, cognitive status, nutritional status, the risk of pressures sores, co-morbidity, number of drugs and co-habitation status. According to validated cut-offs, subjects were divided into three groups of risk, i.e. MPI-1 low risk (value a parts per thousand currency sign0.33), MPI-2 moderate risk (value 0.34-0.66) and MPI-3 severe risk of mortality (value a parts per thousand yen0.67). Results: two thousand and thirty-three patients were included; 1,159 were women (57.0%). Age- and sex-adjusted mean LOS in patients divided according to the MPI grade was MPI-1 = 10.1 (95% CI 8.6-11.8), MPI-2 = 12.47 (95% CI 10.7-14.68) and MPI-3 = 13.41 (95% CI 11.5-15.7) days (P for trend < 0.001). The overall accuracy of the MPI to predict LOS was good (C-statistic 0.74, 95% CI 0.72-0.76). Moreover, a statistically significant trend of LOS means was found even in patients stratified according to their International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) main diagnosis. Conclusions: the MPI is an accurate predictor of LOS in older patients hospitalised with the most frequent diseases. C1 [Pilotto, Alberto] EO Galliera Hosp, Dept OrthoGeriatr Rehabil & Stabilizat, I-16128 Genoa, Italy. [Pilotto, Alberto; Sancarlo, Daniele] IRCCS Casa Sollievo Sofferenza, Gerontol Geriatr Res Lab, San Giovanni Rotondo, Italy. [Pellegrini, Fabio] IRCCS Casa Sollievo Sofferenza, Biostat Unit, San Giovanni Rotondo, Italy. [Rengo, Franco] Univ Naples Federico II, Dept Geriatr, Naples, Italy. [Marchionni, Niccolo] Univ Florence, Dept Geriatr, Florence, Italy. [Volpato, Stefano] Univ Ferrara, Geriatr Unit, I-44100 Ferrara, Italy. [Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. RP Pilotto, A (reprint author), EO Galliera Hosp, Dept OrthoGeriatr Rehabil & Stabilizat, I-16128 Genoa, Italy. EM alberto.pilotto@galliera.it RI VOLPATO, STEFANO/H-2977-2014 OI VOLPATO, STEFANO/0000-0003-4335-6034 FU Italian Ministry of Health; IRCCS Program; Intramural Research Program, National Institute on Aging, USA FX This work was supported from the funding of Italian Ministry of Health, IRCCS Program 2009-2011 and Intramural Research Program, National Institute on Aging, USA. The funding agencies had no role in design or conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review or approval of the manuscript. NR 40 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0002-0729 EI 1468-2834 J9 AGE AGEING JI Age Ageing PD JAN PY 2016 VL 45 IS 1 BP 90 EP 96 DI 10.1093/ageing/afv167 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA DC2ZX UT WOS:000369089700018 PM 26764398 ER PT J AU Tweedie, D Rachrnany, L Rubovitch, V Li, YZ Holloway, HW Lehrmann, E Zhang, YQ Becker, KG Perez, E Hoffer, BJ Pick, CG Greig, NH AF Tweedie, David Rachrnany, Lital Rubovitch, Vardit Li, Yazhou Holloway, Harold W. Lehrmann, Elin Zhang, Yongqing Becker, Kevin G. Perez, Evelyn Hoffer, Barry J. Pick, Chaim G. Greig, Nigel H. TI Blast traumatic brain injury-induced cognitive deficits are attenuated by preinjury or postinjury treatment with the glucagon-like peptide-1 receptor agonist, exendin-4 SO ALZHEIMERS & DEMENTIA LA English DT Article DE Exendin-4; Blast injury; Traumatic brain injury; Neurodegeneration; Alzheimer's disease; Parkinson's disease; Behavioral deficits; Gene expression; Glucagon-like peptide-1 ID DEPENDENT INSULINOTROPIC POLYPEPTIDE; REVERSES BEHAVIORAL IMPAIRMENTS; ALZHEIMERS-DISEASE; GENE-EXPRESSION; CELL-DEATH; TNF-ALPHA; NEURODEGENERATIVE DISEASES; PARKINSONS-DISEASE; DRUG CANDIDATES; INCREASED RISK AB Introduction: Blast traumatic brain injury (B-TBI) affects military and civilian personnel. Presently, there are no approved drugs for blast brain injury. Methods: Exendin-4 (Ex-4), administered subcutaneously, was evaluated as a pretreatment (48 hours) and postinjury treatment (2 hours) on neurodegeneration, behaviors, and gene expressions in a marine open field model of blast injury. Results: B-TBI induced neurodegeneration, changes in cognition, and genes expressions linked to dementia disorders. Ex-4, administered preinjury or postinjury, ameliorated B-TBI induced neurodegeneration at 72 hours, memory deficits from days 7-14, and attenuated genes regulated by blast at day 14 postinjury. Discussion: The present data suggest shared pathologic processes between concussive and B-TBI, with end points amenable to beneficial therapeutic manipulation by Ex-4. B-TBI induced dementia-related gene pathways and cognitive deficits in mice somewhat parallel epidemiologic studies of Barnes et al. who identified a greater risk in US military veterans who experienced diverse TBIs, for dementia in later life. Published by Elsevier Inc. on behalf of the Alzheimer's Association. C1 [Tweedie, David; Li, Yazhou; Holloway, Harold W.; Greig, Nigel H.] NIA, Translat Gerontol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Rachrnany, Lital; Rubovitch, Vardit; Pick, Chaim G.] Tel Aviv Univ, Sackler Sch Med, Dept Anat & Anthropol, IL-69978 Tel Aviv, Israel. [Lehrmann, Elin; Zhang, Yongqing; Becker, Kevin G.] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Perez, Evelyn] NIA, Lab Behav Neurosci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Hoffer, Barry J.] Case Western Reserve Univ, Sch Med, Dept Neurosurg, Cleveland, OH USA. [Hoffer, Barry J.] Taipei Med Univ, Grad Program Neuroregenerat, Taipei, Taiwan. [Pick, Chaim G.] Tel Aviv Univ, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel. RP Tweedie, D (reprint author), NIA, Translat Gerontol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM tweedieda@grc.nia.nih.gov OI Lehrmann, Elin/0000-0002-9869-9475 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health [AG000333-07]; Sackler School of Medicine, Tel Aviv University; Israel Science Foundation [108/09]; Joseph Sagol Fellowship; National Science Council Taiwan [NSC101-2632-B-038-001-MY3] FX This research was supported in part by (1) the Intramural Research Program of the National Institute on Aging, National Institutes of Health, grant AG000333-07; (2) the Sackler School of Medicine, Tel Aviv University; (3) a grant from the Israel Science Foundation, grant number 108/09; (4) the Joseph Sagol Fellowship, and (5) the National Science Council Taiwan, grant NSC101-2632-B-038-001-MY3. NR 80 TC 8 Z9 8 U1 4 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 EI 1552-5279 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD JAN PY 2016 VL 12 IS 1 BP 34 EP 48 DI 10.1016/j.jalz.2015.07.489 PG 15 WC Clinical Neurology SC Neurosciences & Neurology GA DC1HU UT WOS:000368968200005 PM 26327236 ER PT J AU Wilson, ML Fleming, KA AF Wilson, Michael L. Fleming, Kenneth A. TI Global Cancer Care The Role of Pathology SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Editorial Material C1 [Wilson, Michael L.] Univ Colorado, Sch Med, Dept Pathol, Aurora, CO USA. [Fleming, Kenneth A.] NCI, Ctr Global Hlth, Washington, DC USA. RP Wilson, ML (reprint author), Univ Colorado, Sch Med, Dept Pathol, Aurora, CO USA. NR 2 TC 1 Z9 1 U1 0 U2 2 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD JAN PY 2016 VL 145 IS 1 BP 6 EP 7 DI 10.1093/AJCP/AQV030 PG 2 WC Pathology SC Pathology GA DC1GO UT WOS:000368965000001 PM 26712865 ER PT J AU Kim, J Kim, KM Noh, JH Yoon, JH Abdelmohsen, K Gorospe, M AF Kim, Jiyoung Kim, Kyoung Mi Noh, Ji Heon Yoon, Je-Hyun Abdelmohsen, Kotb Gorospe, Myriam TI Long noncoding RNAs in diseases of aging SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Review DE Senescence; Age-associated disease; Ribonucleoprotein complexes; Transcriptional control; Post-transcriptional gene regulation; Differentiation; Myocytes; mRNA translation; mRNA stability; Transcriptome ID CENTRAL-NERVOUS-SYSTEM; HUMAN MITOCHONDRIAL TRANSCRIPTOME; BETA-CELL TRANSCRIPTOME; NF-KAPPA-B; BREAST-CANCER; POOR-PROGNOSIS; HEPATOCELLULAR-CARCINOMA; DIABETES-MELLITUS; BLADDER-CANCER; MUSCLE DIFFERENTIATION AB Aging is a process during which progressive deteriorating of cells, tissues, and organs over time lead to loss of function, disease, and death. Towards the goal of extending human health span, there is escalating interest in understanding the mechanisms that govern aging-associated pathologies. Adequate regulation of expression of coding and noncoding genes is critical for maintaining organism homeostasis and preventing disease processes. Long noncoding RNAs (lncRNAs) are increasingly recognized as key regulators of gene expression at all levels transcriptional, post-transcriptional and post-translational. In this review, we discuss our emerging understanding of lncRNAs implicated in aging illnesses. We focus on diseases arising from age-driven impairment in energy metabolism (obesity, diabetes), the declining capacity to respond homeostatically to proliferative and damaging stimuli (cancer, immune dysfunction), and neurodegeneration. We identify the lncRNAs involved in these ailments and discuss the rising interest in lncRNAs as diagnostic and therapeutic targets to ameliorate age associated pathologies and prolong health. This article is part of a Special Issue entitled: Clues to long noncoding RNA taxonomy1, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa. Published by Elsevier B.V. C1 [Kim, Jiyoung; Kim, Kyoung Mi; Noh, Ji Heon; Yoon, Je-Hyun; Abdelmohsen, Kotb; Gorospe, Myriam] NIA, Genet Lab, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Abdelmohsen, K; Gorospe, M (reprint author), NIA, Genet Lab, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM abdelmohsenk@mail.nih.gov; myriam-gorospe@nih.gov OI Kim, Jiyoung/0000-0002-2938-3995 FU National Institute on Aging-Intramural Research Program of the National Institutes of Health FX This work was supported in its entirety by the National Institute on Aging-Intramural Research Program of the National Institutes of Health. NR 228 TC 9 Z9 12 U1 2 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 EI 0006-3002 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD JAN PY 2016 VL 1859 IS 1 BP 209 EP 221 DI 10.1016/j.bbagrm.2015.06.013 PG 13 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DB8DQ UT WOS:000368747600025 PM 26141605 ER PT J AU Liu, Y Wang, GH Zhang, HM Ma, Y Lang, LX Jacobson, O Kiesewetter, DO Zhu, L Gao, S Ma, QJ Chen, XY AF Liu, Yi Wang, Guohao Zhang, Huimin Ma, Ying Lang, Lixin Jacobson, Orit Kiesewetter, Dale O. Zhu, Lei Gao, Shi Ma, Qingjie Chen, Xiaoyuan TI Stable Evans Blue Derived Exendin-4 Peptide for Type 2 Diabetes Treatment SO BIOCONJUGATE CHEMISTRY LA English DT Article ID GLUCAGON-LIKE PEPTIDE-1; IN-VIVO; ALBUMIN-BINDING; RECEPTOR; INSULIN; ANALOG; PHARMACOKINETICS; MALEIMIDES; MECHANISM; CELLS AB In the treatment of type 2 diabetes mellitus, it is very important to develop therapeutics with prolonged circulation half-life. Exendin-4 is a glucagon like peptide-1 receptor (GLP-1R) agonist that has been modified in different ways for imaging insulinoma and for treating type-2 diabetes. In this work, we synthesized a maleimide derivative of truncated Evans blue dye (MEB-C3-Mal) to conjugate with (Cys(40))exendin-4 to obtain a highly stable MEB-C3-(Cys(40))exendin-4 (denoted as Abextide II). Through in situ binding with endogenous albumin, Abextide II lowers blood glucose level and prolongs the hypoglycemic effect in a type 2 diabetes mouse model more than the FDA approved Albiglutide. C1 [Liu, Yi; Gao, Shi; Ma, Qingjie] Jilin Univ, China Japan Union Hosp, Changchun 130033, Jilin, Peoples R China. [Liu, Yi; Zhang, Huimin; Ma, Ying; Lang, Lixin; Jacobson, Orit; Kiesewetter, Dale O.; Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. [Wang, Guohao; Zhu, Lei] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, State Key Lab Mol Vaccinol & Mol Diagnost, Xiamen 361102, Peoples R China. RP Ma, QJ (reprint author), Jilin Univ, China Japan Union Hosp, Changchun 130033, Jilin, Peoples R China.; Chen, XY (reprint author), NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. EM maqj@jlu.edu.cn; shawn.chen@nih.gov RI Zhu, Lei/P-9786-2016 OI Zhu, Lei/0000-0002-1820-4795 FU National Science Foundation of China [81571708, 81501506]; Research Fund of Science and Technology Department of Jilin Province [20150520154JH]; Hygiene Specific Subjects of Jilin Province [SCZSY201508]; National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX This work was supported by the National Science Foundation of China (81571708, 81501506), Research Fund of Science and Technology Department of Jilin Province (20150520154JH), Hygiene Specific Subjects of Jilin Province (SCZSY201508) and the Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 28 TC 1 Z9 1 U1 6 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD JAN PY 2016 VL 27 IS 1 BP 54 EP 58 DI 10.1021/acs.bioconjchem.5b00625 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA DB6UQ UT WOS:000368651600007 PM 26641886 ER PT J AU Ehlinger, DG Bergstrom, HC Burke, JC Fernandez, GM McDonald, CG Smith, RF AF Ehlinger, D. G. Bergstrom, H. C. Burke, J. C. Fernandez, G. M. McDonald, C. G. Smith, R. F. TI Adolescent nicotine-induced dendrite remodeling in the nucleus accumbens is rapid, persistent, and D1-dopamine receptor dependent SO BRAIN STRUCTURE & FUNCTION LA English DT Article DE Nicotine; Adolescence; Dendrite morphology; Dopamine; D1 receptor; Dendritic spine ID MEDIUM SPINY NEURONS; CONDITIONED PLACE-PREFERENCE; MESOLIMBIC DOPAMINE SYSTEM; CEREBRAL CORTICAL-NEURONS; MESSENGER-RNA EXPRESSION; STRUCTURAL PLASTICITY; MOLECULAR-MECHANISMS; DRUG-ADDICTION; DELTA-FOSB; RAT-BRAIN AB Chronic nicotine exposure during adolescence induces dendritic remodeling of medium spiny neurons (MSNs) in the nucleus accumbens (NAcc) shell. While nicotine-induced dendritic remodeling has frequently been described as persistent, the trajectory of dendrite remodeling is unknown. Specifically, no study to date has characterized the structural plasticity of dendrites in the NAcc immediately following chronic nicotine, leaving open the possibility that dendrite remodeling emerges gradually over time. Further, the neuropharmacological mechanisms through which nicotine induces dendrite remodeling are not well understood. To address these questions, rats were co-administered chronic nicotine (0.5 mg/kg) and the D1-dopamine receptor (D1DR) antagonist SCH-23390 (0.05 mg/kg) subcutaneously every other day during adolescence. Brains were then processed for Golgi-Cox staining either 1 day or 21 days following drug exposure and dendrites from MSNs in the NAcc shell digitally reconstructed in 3D. Spine density was also measured at both time points. Our morphometric results show (1) the formation of new dendritic branches and spines 1 day following nicotine exposure, (2) new dendritic branches, but not spine density, remains relatively stable for at least 21 days, (3) the co-administration of SCH-23390 completely blocked nicotine-induced dendritic remodeling of MSNs at both early and late time points, suggesting the formation of new dendritic branches in response to nicotine is D1DR-dependent, and (4) SCH-23390 failed to block nicotine-induced increases in spine density. Overall this study provides new insight into how nicotine influences the normal trajectory of adolescent brain development and demonstrates a persistent form of nicotine-induced neuroplasticity in the NAcc shell that develops rapidly and is D1DR dependent. C1 [Ehlinger, D. G.; Burke, J. C.; Fernandez, G. M.; McDonald, C. G.; Smith, R. F.] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. [Bergstrom, H. C.] NIAAA, Lab Behav & Genom Neurosci, NIH, Rockville, MD 20852 USA. RP Ehlinger, DG (reprint author), George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. EM dehlinge@gmu.edu FU Virginia Foundation for Healthy Youth FX We would like to thank David Meyers and Ebube Utomi for animal care. The work was supported by a grant from the Virginia Foundation for Healthy Youth. NR 91 TC 2 Z9 2 U1 3 U2 6 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2653 EI 1863-2661 J9 BRAIN STRUCT FUNCT JI Brain Struct. Funct. PD JAN PY 2016 VL 221 IS 1 BP 133 EP 145 DI 10.1007/s00429-014-0897-3 PG 13 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA DC0ZP UT WOS:000368946900009 PM 25257604 ER PT J AU Dine, JL O'Sullivan, CC Voeller, D Greer, YE Chavez, KJ Conway, CM Sinclair, S Stone, B Amiri-Kordestani, L Merchant, AS Hewitt, SM Steinberg, SM Swain, SM Lipkowitz, S AF Dine, Jennifer L. O'Sullivan, Ciara C. Voeller, Donna Greer, Yoshimi E. Chavez, Kathryn J. Conway, Catherine M. Sinclair, Sarah Stone, Brandon Amiri-Kordestani, Laleh Merchant, Anand S. Hewitt, Stephen M. Steinberg, Seth M. Swain, Sandra M. Lipkowitz, Stanley TI The TRAIL receptor agonist drozitumab targets basal B triple-negative breast cancer cells that express vimentin and Axl SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE TRAIL receptor agonists; Drozitumab; Triple-negative breast cancer; Vimentin; Axl ID EPITHELIAL-MESENCHYMAL TRANSITION; MOLECULAR PORTRAITS; MONOCLONAL-ANTIBODY; INDUCED APOPTOSIS; P-CADHERIN; DEATH; SUBTYPES; LIGAND; IDENTIFICATION; CARCINOMAS AB Previously, we found that GST-tagged tumor necrosis factor-related apoptosis inducing ligand preferentially killed triple-negative breast cancer (TNBC) cells with a mesenchymal phenotype by activating death receptor 5 (DR5). The purpose of this study was to explore the sensitivity of breast cancer cell lines to drozitumab, a clinically tested DR5-specific agonist; identify potential biomarkers of drozitumab-sensitive breast cancer cells; and determine if those biomarkers were present in tumors from patients with TNBC. We evaluated viability, caspase activity, and sub-G1 DNA content in drozitumab-treated breast cancer cell lines and we characterized expression of potential biomarkers by immunoblot. Expression levels of vimentin and Axl were then explored in 177 TNBC samples from a publically available cDNA microarray dataset and by immunohistochemistry (IHC) in tumor tissue samples obtained from 53 African-American women with TNBC. Drozitumab-induced apoptosis in mesenchymal TNBC cell lines but not in cell lines from other breast cancer subtypes. The drozitumab-sensitive TNBC cell lines expressed the mesenchymal markers vimentin and Axl. Vimentin and Axl mRNA and protein were expressed in a subset of human TNBC tumors. By IHC, similar to 15 % of TNBC tumors had vimentin and Axl expression in the top quartile for both. These findings indicate that drozitumab-sensitive mesenchymal TNBC cells express vimentin and Axl, which can be identified in a subset of human TNBC tumors. Thus, vimentin and Axl may be useful to identify TNBC patients who would be most likely to benefit from a DR5 agonist. C1 [Dine, Jennifer L.; O'Sullivan, Ciara C.; Voeller, Donna; Greer, Yoshimi E.; Chavez, Kathryn J.; Stone, Brandon; Amiri-Kordestani, Laleh; Lipkowitz, Stanley] NCI, Womens Malignancies Branch, Ctr Canc Res, NIH, Bldg 10,Room 4B54, Bethesda, MD 20892 USA. [Dine, Jennifer L.] NINR, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Dine, Jennifer L.; Hewitt, Stephen M.] Univ Missouri, Sinclair Sch Nursing, Columbia, MO USA. [Conway, Catherine M.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sinclair, Sarah; Swain, Sandra M.] MedStar Washington Hosp Ctr, Washington Canc Inst, Washington, DC USA. [Merchant, Anand S.] SAIC Frederick, Ctr Canc Res Bioinformat Core, Adv Biomed Comp Ctr, Frederick, MD USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lipkowitz, S (reprint author), NCI, Womens Malignancies Branch, Ctr Canc Res, NIH, Bldg 10,Room 4B54, Bethesda, MD 20892 USA. EM lipkowis@mail.nih.gov OI Swain, Sandra/0000-0002-1320-3830 FU National Cancer Institute, Center for Cancer Research; Safeway Foundation FX This research was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, and MedStar Health Research Institute supported by a grant from the Safeway Foundation. NR 49 TC 1 Z9 1 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JAN PY 2016 VL 155 IS 2 BP 235 EP 251 DI 10.1007/s10549-015-3673-z PG 17 WC Oncology SC Oncology GA DC1US UT WOS:000369003100004 PM 26759246 ER PT S AU Navarathna, DH Roberts, DD Munasinghe, J Lizak, MJ AF Navarathna, Dhammika H. Roberts, David D. Munasinghe, Jeeva Lizak, Martin J. BE Calderone, R Cihlar, R TI Imaging Candida Infections in the Host SO CANDIDA SPECIES: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Candida albicans; Noninvasive imaging; Magnetic resonance imaging; Blood-brain barrier; Kidney; Brain; Phagocytes; Inflammation ID CENTRAL-NERVOUS-SYSTEM; MOUSE MODEL AB Disseminated fungal infections caused by Candida species are associated with homing of the pathogen to specific organs in human and murine hosts. Kidneys are a primary target organ of Candida albicans, and invasion into the kidney medulla can lead to loss of renal function and death. Therefore, development of noninvasive methods to assess kidney infections could aid in the management of disseminated candidemia. We describe a magnetic resonance imaging method utilizing iron oxide-based contrast agents to noninvasively assess recruitment of phagocytes and kidney inflammation. C. albicans also colonizes the brain and can cause meningoencephalitis. We describe additional imaging methods to assess loss of the blood-brain barrier function that initiates brain infections. C1 [Navarathna, Dhammika H.; Roberts, David D.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Munasinghe, Jeeva; Lizak, Martin J.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Navarathna, DH (reprint author), NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU Intramural NIH HHS; NCI NIH HHS [Z01 SC 009173] NR 9 TC 0 Z9 0 U1 0 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-3052-4; 978-1-4939-3051-7 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1356 BP 69 EP 78 DI 10.1007/978-1-4939-3052-4_6 D2 10.1007/978-1-4939-3052-4 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Microbiology; Mycology SC Biochemistry & Molecular Biology; Microbiology; Mycology GA BE2EJ UT WOS:000369087600007 PM 26519066 ER PT J AU Shankavaram, U Camphausen, K AF Shankavaram, Uma Camphausen, Kevin TI Target inhibitory networks and drug response modeling SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT Meeting of the American-Association-for-Cancer-Research (AACR) Precision Medicine Series - Integrating Clinical Genomics and Cancer Therapy CY JUN 13-16, 2015 CL Salt Lake, UT SP Amer Assoc Canc Res C1 [Shankavaram, Uma; Camphausen, Kevin] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 1 PY 2016 VL 22 SU 1 MA 42 PG 1 WC Oncology SC Oncology GA DC2XS UT WOS:000369082700056 ER PT J AU Cleaton, JM Viboud, C Simonsen, L Hurtado, AM Chowell, G AF Cleaton, Julie M. Viboud, Cecile Simonsen, Lone Hurtado, Ana M. Chowell, Gerardo TI Characterizing Ebola Transmission Patterns Based on Internet News Reports SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE Ebola; transmission patterns; West Africa; hospital transmission; funeral transmission ID VIRUS DISEASE OUTBREAK; RISK-FACTORS; HEMORRHAGIC-FEVER; SEPTEMBER 2014; DYNAMICS; NIGERIA; UGANDA; CONGO AB Background. Detailed information on patient exposure, contact patterns, and discharge status is rarely available in real time from traditional surveillance systems in the context of an emerging infectious disease outbreak. Here, we validate the systematic collection of Internet news reports to characterize epidemiological patterns of Ebola virus disease (EVD) infections during the West African 2014-2015 outbreak. Methods. Based on 58 news reports, we analyzed 79 EVD clusters (286 cases) ranging in size from 1 to 33 cases between January 2014 and February 2015 in Guinea, Sierra Leone, and Liberia. Results. The majority of reported exposures stemmed from contact with family members (57.3%) followed by hospitals (18.2%) and funerals (12.7%). Our data indicate that funeral exposure was significantly more frequent in Sierra Leone (27.3%) followed by Guinea (18.2%) and Liberia (1.8%; chi(2) test; P < .0001). Funeral exposure was the dominant route of transmission until April 2014 (60%) and was replaced with hospital exposure in June 2014-July 2014 (70%), both of which declined after interventions were put in place. The mean reproduction number of the outbreak was 2.3 (95% confidence interval [CI], 1.8, 2.7). The case fatality rate was estimated at 74.4% (95% CI, 68.3, 79.8). Conclusions. Overall, our findings based on news reports are in close agreement with those derived from traditional epidemiological surveillance data and with those reported for prior outbreaks. Our findings support the use of real-time information from trustworthy news reports to provide timely estimates of key epidemiological parameters that may be hard to ascertain otherwise. C1 [Cleaton, Julie M.; Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. [Cleaton, Julie M.; Hurtado, Ana M.] Arizona State Univ, Coll Liberal Arts & Sci, Tempe, AZ USA. [Viboud, Cecile; Simonsen, Lone; Chowell, Gerardo] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Simonsen, Lone] Univ Copenhagen, Dept Publ Hlth, DK-1168 Copenhagen, Denmark. [Simonsen, Lone] George Washington Univ, Sch Publ Hlth, Milken Inst, Dept Global Hlth, Washington, DC USA. RP Chowell, G (reprint author), 1 Pk Pl,Ste 662 Off 640B, Atlanta, GA 30303 USA. EM gchowell@gsu.edu OI Simonsen, Lone/0000-0003-1535-8526 FU Division of International Epidemiology and Population Studies; Fogarty International Center, US National Institutes of Health (NIH) - Office of Pandemics and Emerging Threats at the US Department of Health and Human Services; National Science Foundation (NSF) as part of the joint NSF-NIH-US Department of Agriculture Ecology and Evolution of Infectious Diseases Program [1414374]; United Kingdom Biotechnology and Biological Sciences Research Council [BB/M008894/1]; United Kingdom Biotechnology and Biological Sciences Research Council (RAPIDD NFS grant) [1518939]; United Kingdom Biotechnology and Biological Sciences Research Council (NSF) [1518529]; United Kingdom Biotechnology and Biological Sciences Research Council (NSF-Division of Information & Intelligent Systems grant) [1518939]; Research and Policy for Infectious Disease Dynamics Program of the US Department of Homeland Security; Lundbeck Foundation, Denmark FX C.V. and G.C. acknowledge financial support from the Division of International Epidemiology and Population Studies, the Fogarty International Center, US National Institutes of Health (NIH), funded in part by the Office of Pandemics and Emerging Threats at the US Department of Health and Human Services. G.C. also acknowledges support from the National Science Foundation (NSF; grant number 1414374) as part of the joint NSF-NIH-US Department of Agriculture Ecology and Evolution of Infectious Diseases Program, United Kingdom Biotechnology and Biological Sciences Research Council (grant number BB/M008894/1; RAPIDD NFS grant number 1518939; and NSF grant number 1518529; and NSF-Division of Information & Intelligent Systems grant number1518939). L.S., C.V., and G.C. acknowledge support from the Research and Policy for Infectious Disease Dynamics Program of the US Department of Homeland Security, and L.S. received support from the Lundbeck Foundation, Denmark. NR 32 TC 6 Z9 6 U1 2 U2 8 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 JAN 1 PY 2016 VL 62 IS 1 BP 24 EP 31 DI 10.1093/cid/civ748 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DB6JO UT WOS:000368621400004 PM 26338786 ER PT J AU Purswani, MU Karalius, B Yao, TJ Schmid, DS Burchett, SK Siberry, GK Patel, K Van Dyke, RB Yogev, R AF Purswani, Murli U. Karalius, Brad Yao, Tzy-Jyun Schmid, D. Scott Burchett, Sandra K. Siberry, George K. Patel, Kunjal Van Dyke, Russell B. Yogev, Ram CA Pediatric HIV AIDS Cohort Study TI Prevalence and Persistence of Varicella Antibodies in Previously Immunized Children and Youth With Perinatal HIV-1 Infection SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE varicella; vaccine; antibodies; HIV; perinatal ID OUTER RETINAL NECROSIS; ACTIVE ANTIRETROVIRAL THERAPY; OF-THE-LITERATURE; ZOSTER-VIRUS; UNITED-STATES; VACCINE; IMMUNOGENICITY; PREVENTION; INJECTIONS; LONGEVITY AB Background. Two doses of live-attenuated varicella-zoster vaccine are recommended for human immunodeficiency virus 1 (HIV-1)infected children with CD4% >= 15%. We determined the prevalence and persistence of antibody in immunized children with perinatal HIV (PHIV) and their association with number of vaccinations, combination antiretroviral therapy (cART), and HIV status. Methods. The Adolescent Master Protocol is an observational study of children with PHIV and perinatally HIV-exposed but uninfected (PHEU) children conducted at 15 US sites. In a cross-sectional analysis, we tested participants' most recent stored sera for varicella antibody using whole-cell and glycoprotein enzyme-linked immunosorbent assay. Seropositivity predictors were identified using multivariable logistic regression models and C statistics. Results. Samples were available for 432 children with PHIV and 221 PHEU children; 82% of children with PHIV and 97% of PHEU children were seropositive (P < .001). Seropositivity after 1 vaccine dose among children with PHIV and PHEU children was 100% at < 3 years (both), 73% and 100% at 3-<7 years (P < .05), and 77% and 97% at >= 7 years (P < .01), respectively. Seropositivity among recipients of 2 vaccine doses was >94% at all intervals. Independent predictors of seropositivity among children with PHIV were receipt of 2 vaccine doses, receipt of 1 dose while on >= 3 months of cART, compared with none (adjusted odds ratio [aOR]: 14.0 and 2.8, respectively; P < .001 for overall dose effect), and in those vaccinated >= 3 years previously, duration of cART (aOR: 1.29 per year increase, P = .02). Conclusions. Humoral immune responses to varicella vaccine are best achieved when children with PHIV receive their first dose >= 3 months after cART initiation and maintained by completion of the 2-dose series and long-term cART use. C1 [Purswani, Murli U.] Bronx Lebanon Hosp Ctr, Albert Einstein Coll Med, Div Pediat Infect Dis, New York, NY USA. [Karalius, Brad; Patel, Kunjal] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Karalius, Brad; Yao, Tzy-Jyun; Patel, Kunjal] Harvard Univ, TH Chan Sch Publ Hlth, Ctr Biostat AIDS Res CBAR, Boston, MA 02115 USA. [Schmid, D. Scott] Ctr Dis Control & Prevent, Div Viral Dis, Atlanta, GA USA. [Burchett, Sandra K.] Boston Childrens Hosp, Boston, MA USA. [Burchett, Sandra K.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Siberry, George K.] NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bldg 10, Bethesda, MD 20892 USA. [Van Dyke, Russell B.] Tulane Univ, Sch Med, Dept Pediat, 1430 Tulane Ave, New Orleans, LA 70112 USA. [Yogev, Ram] Northwestern Univ, Ann & Robert H Lurie Childrens Hosp Chicago, Feinberg Sch Med, Dept Pediat, Evanston, IL 60208 USA. RP Purswani, MU (reprint author), Bronx Lebanon Hosp Ctr, Div Pediat Infect Dis, 1685 Morris Ave,Ste 1G, Bronx, NY 10457 USA. EM mpurswan@bronxleb.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Allergy and Infectious Diseases; Office of AIDS Research; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders; National Heart Lung and Blood Institute; National Institute of Dental and Craniofacial Research; National Institute on Alcohol Abuse and Alcoholism; Harvard T.H. Chan School of Public Health [HD052102]; Tulane University School of Medicine [HD052104] FX The PHACS 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: George Seage; Project Director: Julie Alperen) and the Tulane University School of Medicine (HD052104; Principal Investigator: Russell Van Dyke; Co-Principal Investigator: Kenneth Rich; Project Director: Patrick Davis). Data management services were provided by Frontier Science and Technology Research Foundation (Principal Investigator: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc (Principal Investigator: Julie Davidson). NR 35 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 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JAN 1 PY 2016 VL 62 IS 1 BP 106 EP 114 DI 10.1093/cid/civ734 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DB6JO UT WOS:000368621400018 PM 26385992 ER PT J AU Kim, SJ Lewis, B Steiner, MS Bissa, UV Dose, C Frank, JA AF Kim, Saejeong J. Lewis, Bobbi Steiner, Mark-Steven Bissa, Ursula V. Dose, Christian Frank, Joseph A. TI Superparamagnetic iron oxide nanoparticles for direct labeling of stem cells and in vivo MRI tracking SO CONTRAST MEDIA & MOLECULAR IMAGING LA English DT Article DE superparamagnetic iron oxide nanoparticles; dextran; transfection reagent free or direct labeling; bone marrow stromal cells; neural stem cells; hematopoietic stem ID GENE-THERAPY; REGENERATIVE MEDICINE; STROMAL CELLS; TISSUE-REPAIR; CELLULAR MRI; SINGLE CELLS; PARTICLES; FERUMOXYTOL; QUANTIFICATION; TRANSLATION AB To develop effective stem cell therapies, it is important to track therapeutic cells non-invasively and monitor homing to areas of pathology. The purpose of this study was to design and evaluate the labeling efficiency of commercially available dextran-coated superparamagnetic iron oxide nanoparticles, FeraTrack Direct (FTD), in various stem and immune cells; assess the cytotoxicity and tolerability of the FTD in stem cells; and monitor stem cell homing using FTD-labeled bone-marrow-derived mesenchymal stromal cells (BMSCs) and neural stem cells (NSCs) in a tumor model by in vivo MRI. BMSCs, NSCs, hematopoietic stem cells (HSCs), T-lymphocytes, and monocytes were labeled effectively with FTD without the need for transfection agents, and Prussian blue (PB) staining and transmission electron microscopy (TEM) confirmed intracellular uptake of the agent. The viability, proliferation, and functionality of the labeled cells were minimally or not affected after labeling. When 10(6) FTD-labeled BMSCs or NSCs were injected into C6 glioma bearing nude mice, the cells homing to the tumors were detected as hypointense regions within the tumor using 3 T clinical MRI up to 10 days post injection. Histological analysis confirmed the homing of injected cells to the tumor by the presence of PB positive cells that are not macrophages. Labeling of stem cells or immune cells with FTD was non-toxic, and should facilitate the translation of this agent to clinical trials for evaluation of trafficking of cells by MRI. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Kim, Saejeong J.; Lewis, Bobbi; Frank, Joseph A.] NIH, Frank Lab, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD USA. [Steiner, Mark-Steven; Bissa, Ursula V.; Dose, Christian] Miltenyi Biotec, Bergisch Gladbach, Germany. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, Intramural Res Program, NIH, Bethesda, MD USA. RP Kim, SJ (reprint author), NIH, Frank Lab, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD USA. EM kimsn@mail.nih.gov FU Intramural Research Programs of the NIH Clinical Center; National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health FX This research was funded by the Intramural Research Programs of the NIH Clinical Center and the National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health. NR 44 TC 2 Z9 3 U1 7 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1555-4309 EI 1555-4317 J9 CONTRAST MEDIA MOL I JI Contrast Media Mol. Imaging PD JAN-FEB PY 2016 VL 11 IS 1 BP 55 EP 64 DI 10.1002/cmmi.1658 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DC1VE UT WOS:000369004700007 PM 26234504 ER PT J AU Mallory, M Gogineni, E Jones, GC Greer, L Simone, CB AF Mallory, Matthew Gogineni, Emile Jones, Guy C. Greer, Lester Simone, Charles B., II TI Therapeutic hyperthermia: The old, the new, and the upcoming SO CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY LA English DT Review DE Hyperthermia; Radiation therapy; IMRT; Heat therapy ID PROSPECTIVE RANDOMIZED-TRIAL; REGIONAL DEEP HYPERTHERMIA; ADVANCED PROSTATE-CANCER; ATOMIC-ENERGY AGENCY; SOFT-TISSUE SARCOMAS; DNA STRAND BREAKS; GERM-CELL TUMORS; PLUS HYPERTHERMIA; CERVICAL-CANCER; NEOADJUVANT RADIOCHEMOTHERAPY AB Hyperthermia has long been used for cancer treatment, either alone or in combination with chemotherapy, radiation therapy, or both. Its efficacy and versatility continue to be well demonstrated in randomized trials across a number of primary cancers, but barriers to its widespread adoption persist including effective delivery and verification systems. This article describes hyperthermia, details its biological mechanisms of action and immunological effects, and summarizes select preclinical data and key clinical trials combining hyperthermia with standard cancer treatments. Current challenges and emerging technologies that have the potential to make this translational therapy more accessible to a greater number of patients are also described. Published by Elsevier Ireland Ltd. C1 [Mallory, Matthew] Virginia Commonwealth Univ, Internal Med, Richmond, VA 23298 USA. [Gogineni, Emile] New York Inst Technol, Coll Osteopath Med, Old Westbury, NY 11568 USA. [Jones, Guy C.] NCI, Radiat Oncol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Greer, Lester] Ft Belvoir Community Hosp, Dept Radiat Oncol, 9300 DeWitt Loop, Ft Belvoir, VA 22060 USA. [Simone, Charles B., II] Univ Penn, Dept Radiat Oncol, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. RP Jones, GC (reprint author), NCI, Radiat Oncol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mlm3xe@virginia.edu; gogie42@gmail.com; guy.jones@nih.gov; Lester.l.greer.mil@health.mil; charles.simone@uphs.upenn.edu NR 69 TC 11 Z9 11 U1 6 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1040-8428 EI 1879-0461 J9 CRIT REV ONCOL HEMAT JI Crit. Rev. Oncol./Hematol. PD JAN PY 2016 VL 97 BP 56 EP 64 DI 10.1016/j.critrevonc.2015.08.003 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA DB8CI UT WOS:000368744100006 PM 26315383 ER PT J AU Cadet, JL AF Cadet, Jean Lud TI Dysregulation of Acetylation Enzymes in Animal Models of Psychostimulant use Disorders: Evolving Stories SO CURRENT NEUROPHARMACOLOGY LA English DT Article DE Acetylation; addiction; cocaine; dorsal striatum; epigenetics; gene expression; methamphetamine; nucleus accumbens ID HISTONE DEACETYLASE INHIBITORS; COCAINE-INDUCED PLASTICITY; CREB-BINDING PROTEIN; TRANSCRIPTION FACTOR; NUCLEUS-ACCUMBENS; RAT STRIATUM; EXPRESSION; CBP; ACETYLTRANSFERASE; METHAMPHETAMINE AB Substance use disorders are neuropsychiatric illnesses that have substantial negative biopsychosocial impact. These diseases are defined as compulsive abuse of licit or illicit substances despite adverse medicolegal consequences. Although much research has been conducted to elucidate the pathobiological bases of these disorders, much remains to be done to develop an overarching neurobiological understanding that might be translatable to beneficial pharmacological therapies. Recent advances in epigenetics promise to lead to such an elucidation. Here I provide a brief overview of observations obtained using some models of psychostimulant administration in rodents. The review identifies CREB binding protein (CBP), HDAC1, HDAC2, HADC3, HDAC4, and HDAC5 as important players in the acetylation and deacetylation processes that occur after contingent or non-contingent administration of psychostimulants. These observations are discussed within a framework that suggests a need for better animal models of addiction in order to bring these epigenetic advances to bear on the pharmacological treatment of human addicts. C1 [Cadet, Jean Lud] NIDA Intramural Res Program, Mol Neuropsychiat Res Branch, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Cadet, Jean Lud] NIDA Intramural Res Program, Div & Outreach, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Cadet, Jean Lud] NIDA Intramural Res Program, Addict & Aging, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Cadet, JL (reprint author), NIDA Intramural Res Program, Mol Neuropsychiat Res Branch, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM JCADET@intra.nida.nih.gov NR 72 TC 0 Z9 0 U1 2 U2 2 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1570-159X EI 1875-6190 J9 CURR NEUROPHARMACOL JI Curr. Neuropharmacol. PY 2016 VL 14 IS 1 BP 10 EP 16 DI 10.2174/1570159X13666150121230133 PG 7 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DC0IS UT WOS:000368901000003 ER PT J AU Aghaeepour, N Chattopadhyay, P Chikina, M Dhaene, T Van Gassen, S Kursa, M Lambrecht, BN Malek, M McLachlan, GJ Qian, Y Qiu, P Saeys, Y Stanton, R Tong, D Vens, C Walkowiak, S Wang, K Finak, G Gottardo, R Mosmann, T Nolan, GP Scheuermann, RH Brinkman, RR AF Aghaeepour, Nima Chattopadhyay, Pratip Chikina, Maria Dhaene, Tom Van Gassen, Sofie Kursa, Miron Lambrecht, Bart N. Malek, Mehrnoush McLachlan, G. J. Qian, Yu Qiu, Peng Saeys, Yvan Stanton, Rick Tong, Dong Vens, Celine Walkowiak, Slawomir Wang, Kui Finak, Greg Gottardo, Raphael Mosmann, Tim Nolan, Garry P. Scheuermann, Richard H. Brinkman, Ryan R. TI A benchmark for evaluation of algorithms for identification of cellular correlates of clinical outcomes SO CYTOMETRY PART A LA English DT Article DE flow cytometry; bioinformatics; clustering; classification; data analysis; HIV; clinical outcome; supervised analysis ID FLOW-CYTOMETRY DATA; DENDRITIC CELLS; HIV-INFECTION; DISEASE; PHENOTYPES; HIERARCHY AB The Flow Cytometry: Critical Assessment of Population Identification Methods (FlowCAP) challenges were established to compare the performance of computational methods for identifying cell populations in multidimensional flow cytometry data. Here we report the results of FlowCAP-IV where algorithms from seven different research groups predicted the time to progression to AIDS among a cohort of 384 HIV+ subjects, using antigen-stimulated peripheral blood mononuclear cell (PBMC) samples analyzed with a 14-color staining panel. Two approaches (FlowReMi.1 and flowDensity-flowType-RchyOptimyx) provided statistically significant predictive value in the blinded test set. Manual validation of submitted results indicated that unbiased analysis of single cell phenotypes could reveal unexpected cell types that correlated with outcomes of interest in high dimensional flow cytometry datasets. (c) 2015 International Society for Advancement of Cytometry C1 [Aghaeepour, Nima; Malek, Mehrnoush; Brinkman, Ryan R.] British Columbia Canc Agcy, Terry Fox Lab, 601 W 10th Ave, Vancouver, BC V5Z 1L3, Canada. [Aghaeepour, Nima; Brinkman, Ryan R.] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. [Aghaeepour, Nima; Nolan, Garry P.] Stanford Univ, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Chattopadhyay, Pratip] NIH, ImmunoTechnol Sect, Vaccine Res Ctr, Washington, DC USA. [Chikina, Maria] Univ Pittsburgh, Dept Computat & Syst Biol, Pittsburgh, PA USA. [Dhaene, Tom; Van Gassen, Sofie] Univ Ghent, Dept Informat Technol, iMinds, B-9000 Ghent, Belgium. [Van Gassen, Sofie; Lambrecht, Bart N.; Saeys, Yvan; Vens, Celine] Univ Ghent VIB, Inflammat Res Ctr, Ghent, Belgium. [Van Gassen, Sofie; Lambrecht, Bart N.; Saeys, Yvan; Vens, Celine] Ghent Univ Hosp, Dept Resp Med, Ghent, Belgium. [Kursa, Miron; Walkowiak, Slawomir] Univ Warsaw, Interdisciplinary Ctr Math & Computat Modelling, Warsaw, Poland. [McLachlan, G. J.] Univ Queensland, Dept Stat, Brisbane, Qld 4072, Australia. [Qian, Yu; Stanton, Rick; Scheuermann, Richard H.] J Craig Venter Inst, La Jolla, CA USA. [Qiu, Peng] Georgia Inst Technol, Dept Biomed Engn, Atlanta, GA 30332 USA. [Qiu, Peng] Emory Univ, Atlanta, GA 30322 USA. [Tong, Dong] Nottingham Trent Univ, John Van Geest Canc Res Ctr, Nottingham, England. [Tong, Dong] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland. [Vens, Celine] KU Leuven Kulak, Dept Publ Hlth & Primary Care, Kortrijk, Belgium. [Wang, Kui] Univ Queensland, Dept Math, Brisbane, Qld 4072, Australia. [Wang, Kui] Shihezi Univ, Sch Med, Xinjiang 832000, Peoples R China. [Finak, Greg; Gottardo, Raphael] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. [Mosmann, Tim] Univ Rochester, Med Ctr, David H Smith Ctr Vaccine Biol & Immunol, Rochester, NY 14642 USA. [Scheuermann, Richard H.] Univ Calif San Diego, Dept Pathol, San Diego, CA 92103 USA. RP Brinkman, RR (reprint author), British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. EM rbrinkman@bccrc.ca RI McLachlan, Geoffrey/A-1491-2008; Saeys, Yvan/C-1311-2009; Lambrecht, Bart/K-2484-2014; Brinkman, Ryan/B-1108-2008; OI McLachlan, Geoffrey/0000-0002-5921-3145; Saeys, Yvan/0000-0002-0415-1506; Lambrecht, Bart/0000-0003-4376-6834; Brinkman, Ryan/0000-0002-9765-2990; Finak, Greg/0000-0003-4341-9090; Chattopadhyay, Pratip/0000-0002-5457-9666 FU International Society for Advancement of Cytometry's Scholarship; Ann Schreiber Mentored Investigator Award from the Ovarian Cancer Research Fund [OCRF 292495]; Canadian Institute of Health Research [321510]; Canadian Institute of Health Research Scholarship for Strategic Training in Bioinformatics; University of British Columbia's 4YF Scholarship; Rachford and Carlota A. Harris Professorship; NIH [152175.5041015.0412, 1R33CA183692-01 U19 AI057229, U54CA149145, N01-HV-00242, 1U19AI100627, 5R01AI07372405, 1R33CA18365401, 1R33CA183692, R01CA184968, 1 R33 CA183654, A1073724, CA184968, R33 CA183692]; DOD [W81XWH-12-1-0591]; William Lawrence & Blanche Hughes Foundation; DOD (Department of Defense) [UCD - W81XWH-13-BCRP-BREAKTHROUGH]; Ovarian Cancer Teal Innovator Award (GPN), Entertainment Industry Foundation (NWCRA); Lymphoma Research Foundation; Bill and Melinda Gates Fdn. [OPP 1017093 GF12421137101]; Alliance for Lupus Research; Northrop-Grumman Corp [7500108142]; NIH/NIBIB [EB008400]; NSERC; NIH/NIAID [R24AI054953]; Agency for Innovation by Science and Technology; Research Foundation - Flanders Postdoctoral Fellowship [CVNCI R01CA163481]; Polish National Science Centre [2011/01/N/ST6/07035] FX This work was supported by the International Society for Advancement of Cytometry's Scholarship (NA and PKC), an Ann Schreiber Mentored Investigator Award from the Ovarian Cancer Research Fund OCRF 292495 (NA), a Canadian Institute of Health Research Postdoctoral Fellowship 321510 (NA), a Canadian Institute of Health Research Scholarship for Strategic Training in Bioinformatics (NA), University of British Columbia's 4YF Scholarship (NA), Rachford and Carlota A. Harris Professorship (GPN), and the following grants: NIH 152175.5041015.0412, 1R33CA183692-01 U19 AI057229, U54CA149145, N01-HV-00242, 1U19AI100627, 5R01AI07372405, 1R33CA18365401, 1R33CA183692, R01CA184968, 1 R33 CA183654, A1073724, CA184968, and R33 CA183692 (GPN), DOD W81XWH-12-1-0591 (GPN), William Lawrence & Blanche Hughes Foundation (GPN), DOD (Department of Defense) UCD - W81XWH-13-BCRP-BREAKTHROUGH (GPN), Ovarian Cancer Teal Innovator Award (GPN), Entertainment Industry Foundation (NWCRA) (GPN), Lymphoma Research Foundation (GPN), Bill and Melinda Gates Fdn. OPP 1017093 GF12421137101 (GPN), Alliance for Lupus Research (GPN), Northrop-Grumman Corp 7500108142, NIH/NIBIB EB008400 (RRB, MM, NA, GF, RG, RS), NSERC (RB, MM), NIH/NIAID R24AI054953 (TM) NSERC (RB, MM), Agency for Innovation by Science and Technology Ph.D. grant (SVG), Research Foundation - Flanders Postdoctoral Fellowship (CVNCI R01CA163481 (PQ) Polish National Science Centre grant 2011/01/N/ST6/07035 (MBK). NR 40 TC 3 Z9 3 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4922 EI 1552-4930 J9 CYTOM PART A JI Cytom. Part A PD JAN PY 2016 VL 89A IS 1 SI SI BP 16 EP 21 DI 10.1002/cyto.a.22732 PG 6 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DC2QO UT WOS:000369061600004 PM 26447924 ER PT J AU Cannon, EN Simpson, EA Fox, NA Vanderwert, RE Woodward, AL Ferrari, PF AF Cannon, Erin N. Simpson, Elizabeth A. Fox, Nathan A. Vanderwert, Ross E. Woodward, Amanda L. Ferrari, Pier F. TI Relations between infants' emerging reach-grasp competence and event-related desynchronization in EEG SO DEVELOPMENTAL SCIENCE LA English DT Article ID MU-RHYTHM; BIMANUAL COORDINATION; 14-MONTH-OLD INFANTS; 8-MONTH-OLD INFANTS; INFERIOR PARIETAL; HAND ORIENTATION; MOTOR ACTIVATION; DIFFERENT SIZES; OTHERS ACTIONS; OBJECT SIZE AB Recent reports of similar patterns of brain electrical activity (electroencephalogram: EEG) during action execution and observation, recorded from scalp locations over motor-related regions in infants and adults, have raised the possibility that two foundational abilities - controlling one's own intentional actions and perceiving others' actions - may be integrally related during ontogeny. However, to our knowledge, there are no published reports of the relations between developments in motor skill (i.e. recording actual motor skill performance) and EEG during both action execution and action observation. In the present study we collected EEG from 21 9-month-olds who were given opportunities to reach for toys and who also observed an experimenter reach for toys. Event-related desynchronization (ERD) was computed from the EEG during the reaching events. We assessed infants' reaching-grasping competence, including reach latency, errors, preshaping of the hand, and bimanual reaches, and found that desynchronization recorded in scalp electrodes over motor-related regions during action observation was associated with action competence during execution. Infants who were more competent reachers, compared to less competent reachers, exhibited greater ERD while observing reaching-grasping. These results provide initial evidence for an early emerging neural system integrating one's own actions with the perception of others' actions. C1 [Cannon, Erin N.; Fox, Nathan A.] Univ Maryland, Dept Human Dev & Quantitat Methodol, College Pk, MD 20742 USA. [Simpson, Elizabeth A.; Ferrari, Pier F.] Univ Parma, Dipartimento Neurosci, I-43100 Parma, Italy. [Simpson, Elizabeth A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Poolesville, MD USA. [Vanderwert, Ross E.] Childrens Hosp Boston, Div Dev Med, Labs Cognit Neurosci, Boston, MA USA. [Woodward, Amanda L.] Univ Chicago, Dept Psychol, Chicago, IL 60637 USA. RP Cannon, EN (reprint author), Univ Maryland, Dept Human Dev & Quantitat Methodol, College Pk, MD 20742 USA. EM ecannon@umd.edu OI Vanderwert, Ross/0000-0002-2280-8401; Simpson, Elizabeth/0000-0003-2715-2533 FU NIH [NICHD P01 HD064653] FX This research was supported by an NIH grant (NICHD P01 HD064653) to ALW. We thank L. Brand, T. Tavassolie, and K. Finch for assistance in collecting and coding the data, R. Casstevens for programming of Matlab scripts, and the many undergraduate research assistants at the UMD Child Development Lab. We are especially grateful to the families who participated in this work. NR 73 TC 7 Z9 7 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1363-755X EI 1467-7687 J9 DEVELOPMENTAL SCI JI Dev. Sci. PD JAN PY 2016 VL 19 IS 1 BP 50 EP 62 DI 10.1111/desc.12295 PG 13 WC Psychology, Developmental; Psychology, Experimental SC Psychology GA DC2YH UT WOS:000369084200005 PM 25754667 ER PT J AU Robert-Guroff, M AF Robert-Guroff, Marjorie TI The Yin and Yang of ADCC-Mediating Antibodies SO EBIOMEDICINE LA English DT Editorial Material ID IMMUNODEFICIENCY-VIRUS; HIV-1; CYTOTOXICITY; GP120; CELLS C1 [Robert-Guroff, Marjorie] NCI, Vaccine Branch, 41 Medlars Dr,Bldg 41,Room D804, Bethesda, MD 20892 USA. RP Robert-Guroff, M (reprint author), NCI, Vaccine Branch, 41 Medlars Dr,Bldg 41,Room D804, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-3964 J9 EBIOMEDICINE JI EBioMedicine PD JAN PY 2016 VL 3 BP 10 EP 11 DI 10.1016/j.ebiom.2016.01.003 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DC1ZA UT WOS:000369015800006 PM 26870833 ER PT J AU Hua, X Goedert, JJ Pu, A Yu, GQ Shi, JX AF Hua, Xing Goedert, James J. Pu, Angela Yu, Guoqin Shi, Jianxin TI Allergy associations with the adult fecal microbiota: Analysis of the American Gut Project SO EBIOMEDICINE LA English DT Article DE Human microbiome; Feces; Adults; Hygiene hypothesis; Allergy ID NON-HODGKIN-LYMPHOMA; NUTRITION EXAMINATION SURVEY; CESAREAN-SECTION; ATOPIC ECZEMA; INTESTINAL MICROBIOTA; CHILDHOOD ASTHMA; NATIONAL-HEALTH; BIRTH-ORDER; EARLY-LIFE; T-CELLS AB Background: Alteration of the gut microbial population (dysbiosis) may increase the risk for allergies and other conditions. This study sought to clarify the relationship of dysbiosis with allergies in adults. Methods: Publicly available American Gut Project questionnaire and fecal 16S rRNA sequence data were analyzed. Fecal microbiota richness (number of observed species) and composition (UniFrac) were used to compare adults with versus without allergy to foods (peanuts, tree nuts, shellfish, other) and non-foods (drug, bee sting, dander, asthma, seasonal, eczema). Logistic and Poisson regression models adjusted for potential confounders. Odds ratios and 95% confidence intervals (CI) were calculated for lowest vs highest richness tertile. Taxonomy associations considered 122 non-redundant taxa (of 2379 total taxa) with >= 0.1% mean abundance. Results: Self-reported allergy prevalence among the 1879 participants (mean age, 45.5 years; 46.9% male) was 81.5%, ranging from 2.5% for peanuts to 40.5% for seasonal. Fecal microbiota richness was markedly lower with total allergies (P = 10(-9)) and five particular allergies (P <= 10(-4)). Richness odds ratios were 1.7 (CI 1.3-2.2) with seasonal, 1.8 (CI 1.3-2.5) with drug, and 7.8 (CI 2.3-26.5) with peanut allergy. These allergic participants also had markedly altered microbial community composition (unweighted UniFrac, P = 10-4 to 10-7). Total food and non-food allergies were significantly associated with 7 and 9 altered taxa, respectively. The dysbiosis was most marked with nut and seasonal allergies, driven by higher Bacteroidales and reduced Clostridiales taxa. Interpretation: American adults with allergies, especially to nuts and seasonal pollen, have low diversity, reduced Clostridiales, and increased Bacteroidales in their gut microbiota. This dysbiosis might be targeted to improve treatment or prevention of allergy. Published by Elsevier B.V. C1 [Hua, Xing; Goedert, James J.; Pu, Angela; Yu, Guoqin; Shi, Jianxin] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Goedert, JJ (reprint author), 9609 Med Ctr Dr,Room 6E106 MSC 9767, Bethesda, MD 20892 USA. EM goedertj@mail.nih.gov FU NCI NIH HHS [ZIA CP010214, ZIA-CP-010214] NR 57 TC 10 Z9 10 U1 12 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-3964 J9 EBIOMEDICINE JI EBioMedicine PD JAN PY 2016 VL 3 BP 172 EP 179 DI 10.1016/j.ebiom.2015.11.038 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA DC1ZA UT WOS:000369015800025 PM 26870828 ER PT J AU Espinosa, P Pfeiffer, RM Garcia-Casado, Z Requena, C Landi, MT Kumar, R Nagore, E AF Espinosa, Pablo Pfeiffer, Ruth M. Garcia-Casado, Zaida Requena, Celia Landi, Maria Teresa Kumar, Rajiv Nagore, Eduardo TI Risk factors for keratinocyte skin cancer in patients diagnosed with melanoma, a large retrospective study SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Melanoma; Non-melanoma skin cancer; Risk factors; MC1R; Second malignancy; Keratinocyte skin cancer ID SQUAMOUS-CELL CARCINOMAS; MC1R GENE VARIANTS; CUTANEOUS MELANOMA; BASAL-CELL; MEDITERRANEAN POPULATION; MELANOCYTIC NEVI; SOLAR KERATOSES; HAIR COLOR; RED HAIR; METAANALYSIS AB Background: Melanoma survivors are at an increased risk of developing other malignancies, including keratinocyte skin cancer (KSC). While it is known that many risk factors for melanoma also impact risk of KSC in the general population, no previous study has investigated risk factors for KSC development in melanoma patients. Objective: We assessed associations of personal and clinical characteristics, including skin phenotype and variations in the melanocortin 1 receptor (MC1R) gene, with KSC risk in melanoma patients. Patients and methods: We used prospective follow-up information on 1200 patients treated for melanoma at the Instituto Valenciano de Oncologia, Spain, between 2000 and 2011. We computed hazard ratios and 95% confidence intervals (CIs) for the association of clinical, personal and genetic characteristics with risk of KSC, squamous cell carcinoma (SCC), or basal cell carcinoma (BCC) from Cox proportional hazard models. Five-year cumulative incidence based on competing risk models of SCC, BCC or KSC overall was computed using multivariate subdistribution hazard models. To assess predictive performance of the models, we computed areas under the receiver-operating characteristic curves (AUCs, discriminatory power) using cross-validation. Results: Median follow-up was 57.2 months; a KSC was detected in 163 patients (13.6%). In multivariable Cox models, age, sex, sunburns, chronic sun exposure, past personal history of non-melanoma skin cancer or other non-cutaneous neoplasia, and the MC1R variants p.D294H and p.R163Q were significantly associated with KSC risk. A cumulative incidence model including age, sex, personal history of KSC, and of other non-cutaneous neoplasia had an AUC of 0.76 (95% CI: 0.71-0.80). When p.D294H and p.R163Q variants were added to the model, the AUC increased to 0.81 (95% CI: 0.77-0.84) (p-value for difference <0.0001). Conclusions: In addition to age, sex, skin characteristics, and sun exposure, p.R163Q and p.D294H MC1R variants significantly increased KSC risk among melanoma patients. Our findings may help identify patients who could benefit most from preventive measures. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Espinosa, Pablo; Requena, Celia; Nagore, Eduardo] Inst Valenciano Oncol, Dept Dermatol, C Prof Beltran Baguena 8, Valencia 46009, Spain. [Pfeiffer, Ruth M.] Natl Canc Inst, Div Canc Epidemiol & Genet, Biostat Branch, Rockville, MD USA. [Garcia-Casado, Zaida] Inst Valenciano Oncol, Mol Biol Lab, Valencia, Spain. [Landi, Maria Teresa] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Kumar, Rajiv] German Canc Res Ctr, Mol Genet Epidemiol, Heidelberg, Germany. RP Nagore, E (reprint author), Inst Valenciano Oncol, Dept Dermatol, C Prof Beltran Baguena 8, Valencia 46009, Spain. EM eduardo_nagore@ono.com OI Kumar, Rajiv/0000-0002-6093-0395 NR 32 TC 2 Z9 2 U1 3 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JAN PY 2016 VL 53 BP 115 EP 124 DI 10.1016/j.ejca.2015.10.058 PG 10 WC Oncology SC Oncology GA DB8TI UT WOS:000368789100013 PM 26702765 ER PT J AU Tang, XN Hernandez-Andrade, E Ahn, H Garcia, M Saker, H Korzeniewski, SJ Tarca, AL Yeo, L Hassan, SS Romero, R AF Tang, Xiangna Hernandez-Andrade, Edgar Ahn, Hyunyoung Garcia, Maynor Saker, Homam Korzeniewski, Steven J. Tarca, Adi L. Yeo, Lami Hassan, Sonia S. Romero, Roberto TI Intermediate Diastolic Velocity as a Parameter of Cardiac Dysfunction in Growth-Restricted Fetuses SO FETAL DIAGNOSIS AND THERAPY LA English DT Article DE Small-for-gestational-age fetus; Absent/reversed end-diastolic velocities of the umbilical artery; Perinatal death; Acidemia at birth; E/A ratio; Ductus venosus ID MYOCARDIAL PERFORMANCE INDEX; SPATIOTEMPORAL IMAGE CORRELATION; DUCTUS VENOSUS DOPPLER; BLOOD-FLOW VELOCITY; FOR-GESTATIONAL-AGE; FETAL HEART-RATE; BIOPHYSICAL PROFILE; UMBILICAL ARTERY; TISSUE DOPPLER; M-MODE AB Objective: To evaluate the intermediate intracardiac diastolic velocities in fetuses with growth restriction. Methods: Doppler waveforms of the two atrioventricular valves were obtained. Peak velocities of the E (early) and A (atrial) components, and the lowest intermediate velocity (IDV) between them, were measured in 400 normally grown and in 100 growth-restricted fetuses. The prevalence of abnormal IDV, E/IDV, and A/IDV ratios in fetuses presenting with perinatal death or acidemia at birth (pH <= 7.1) was estimated. Results: IDV was significantly lower and E/IDV ratios significantly higher in the two ventricles of growth-restricted fetuses with reduced diastolic velocities in the umbilical artery (p < 0.05). In 13 fetuses presenting with perinatal death or acidemia at birth, 11 (85%) had either an E/IDV or A/IDV ratio >95th percentile, whereas 5 (38%) showed absent or reversed atrial velocities in the ductus venosus (DV-ARAV; p < 0.04). Fetuses without DV-ARAV but with elevated E/IDV ratios in either ventricle were nearly 7-fold more likely to have perinatal demise or acidemia at birth (OR 6.9, 95% CI 1.4-34) than those with E/IDV ratios <95th percentile. Conclusion: The E/IDV and A/IDV ratios in the two cardiac ventricles might provide information about the risk of perinatal demise or acidemia in growth-restricted fetuses. (C) 2015 S. Karger AG, Basel C1 [Tang, Xiangna; Hernandez-Andrade, Edgar; Ahn, Hyunyoung; Garcia, Maynor; Saker, Homam; Korzeniewski, Steven J.; Yeo, Lami; Hassan, Sonia S.; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Bethesda, MD USA. [Tang, Xiangna; Hernandez-Andrade, Edgar; Ahn, Hyunyoung; Garcia, Maynor; Saker, Homam; Korzeniewski, Steven J.; Tarca, Adi L.; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Korzeniewski, Steven J.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Dept Mol Obstet & Genet, Detroit, MI 48201 USA. RP Hernandez-Andrade, E; Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, Hutzel Womens Hosp, NICHD NIH DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM ehernand@med.wayne.edu; romeror@mail.nih.gov FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH/DHHS); NICHD/NIH/DHHS [HHSN275201300006C]; Perinatal Initiative of the Wayne State University School of Medicine (WSUSOM); Department of Obstetrics and Gynecology of the WSUSOM FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH/DHHS), and, in part, with Federal funds from NICHD/NIH/DHHS under contract No. HHSN275201300006C. A.L.T. was supported by the Perinatal Initiative of the Wayne State University School of Medicine (WSUSOM) and the Department of Obstetrics and Gynecology of the WSUSOM. The ultrasound experience and technical support of senior Registered Diagnostic Medical Sonographers Catherine Ducharme and Denise Haggerty are gratefully acknowledged. NR 113 TC 0 Z9 0 U1 0 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1015-3837 EI 1421-9964 J9 FETAL DIAGN THER JI Fetal Diagn. Ther. PY 2016 VL 39 IS 1 BP 28 EP 39 DI 10.1159/000431321 PG 12 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DC1KD UT WOS:000368974300005 PM 26279291 ER PT J AU Solomon, MZ Vannier, D Chowning, JT Miller, JS Paget, KF AF Solomon, Mildred Z. Vannier, David Chowning, Jeanne Ting Miller, Jacqueline S. Paget, Katherine F. TI The Pedagogical Challenges of Teaching High School Bioethics: Insights from the Exploring Bioethics Curriculum SO HASTINGS CENTER REPORT LA English DT Article AB A belief that high school students have the cognitive ability to analyze and assess moral choices and should be encouraged to do so but have rarely been helped to do so was the motivation for developing Exploring Bioethics, a six-module curriculum and teacher guide for grades nine through twelve on ethical issues in the life sciences. A multidisciplinary team of bioethicists, science educators, curriculum designers, scientists, and high school biology teachers worked together on the curriculum under a contract between the National Institutes of Health and Education Development Center, a nonprofit research and development organization with a long history of innovation in science education. At the NIH, the Department of Bioethics within the Clinical Center and the Office of Science Education within the Office of the Director guided the project.Our overarching goal for Exploring Bioethics was to introduce students to bioethics as a field of inquiry and to enable them to develop ethical reasoning skills so they could move beyond gut reactions to more nuanced positions. C1 [Solomon, Mildred Z.] Harvard Univ, Sch Med, Hastings Ctr, Cambridge, MA 02138 USA. [Solomon, Mildred Z.] Harvard Univ, Sch Med, Anaesthesia, Cambridge, MA 02138 USA. [Vannier, David] NHGRI, Educ & Community Involvement Branch, NIH, Bethesda, MD USA. [Chowning, Jeanne Ting] Rainier Scholars, Seattle, WA USA. [Miller, Jacqueline S.; Paget, Katherine F.] Educ Dev Ctr, Sci & Math Programs, Newton, MA USA. RP Solomon, MZ (reprint author), Harvard Univ, Sch Med, Hastings Ctr, Cambridge, MA 02138 USA.; Solomon, MZ (reprint author), Harvard Univ, Sch Med, Anaesthesia, Cambridge, MA 02138 USA. NR 10 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0093-0334 EI 1552-146X J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD JAN-FEB PY 2016 VL 46 IS 1 BP 11 EP 18 DI 10.1002/hast.532 PG 8 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA DB7WI UT WOS:000368727200008 PM 26786036 ER PT J AU Butman, JA Suga, N AF Butman, John A. Suga, Nobuo TI Synaptic mechanisms shaping delay-tuned combination-sensitivity in the auditory thalamus of mustached bats SO HEARING RESEARCH LA English DT Article DE Echolocation; FM-FM neurons; GABAergic inhibition; Hierarchical processing; NMDAergic facilitation; Non-NMDA-mediated facilitation ID MEDIAL GENICULATE-BODY; NON-NMDA RECEPTORS; MOUSE INFERIOR COLLICULUS; TARGET RANGE; MUSTACHE BAT; CORTICOFUGAL MODULATION; EXCITATORY RESPONSES; IDENTIFIED NEURONS; RETICULAR NUCLEUS; BIOSONAR SIGNALS AB For the processing of target-distance information, delay-tuned auditory neurons of the mustached bat show facilitative responses to a combination of signal elements of a biosonar pulse-echo pair with a specific echo delay. They are initially produced in the inferior colliculus by facilitative responses based on the coincidence of the rebound response following glycinergic inhibition to the first harmonic of the pulse and a short-latency response to the 2nd-4th harmonics of its echo. Here, we report that further facilitative responses to pulse-echo pairs of thalamic delay-tuned neurons are mediated by glutamate receptors (NMDA and non-NMDA receptors), and that GABAergic inhibition shortens the duration of facilitative responses mediated by NMDA-receptors, without changing the delay tuning of thalamic delay-tuned neurons. Different from collicular delay-tuned neurons, thalamic ones respond much more to pulse-echo pairs than individual signal elements. The neural mechanisms involved in shaping thalamic delay-tuning support a model of hierarchical signal processing in the auditory system. Published by Elsevier B.V. C1 [Butman, John A.; Suga, Nobuo] Washington Univ, Dept Biol, One Brookings Dr, St Louis, MO 63130 USA. [Butman, John A.] NIH, MRI Sect, Radiol & Imaging Sci Clin Ctr, Bldg 10 Room 1C373,10 Ctr Dr, Bethesda, MD 20892 USA. RP Suga, N (reprint author), Washington Univ, Dept Biol, One Brookings Dr, St Louis, MO 63130 USA. EM jbutman@nih.gov; sugahn@att.net OI Butman, John/0000-0002-1547-9195 FU National Institute on Deafness and Other Communicative Disorders [DC-00175] FX This research based on J. A. Butman's Ph. D. dissertation (1992) at Washington University in St. Louis was supported by a research grant, DC-00175, of the National Institute on Deafness and Other Communicative Disorders. We thank to Drs. D. Fitzpatrick and K. Fox for their discussion and technical advice. We are also grateful to Drs. David E. Crawley and Kevin K. Ohlemiller for their comments on the current article. NR 73 TC 1 Z9 1 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 EI 1878-5891 J9 HEARING RES JI Hear. Res. PD JAN PY 2016 VL 331 BP 69 EP 82 DI 10.1016/j.heares.2015.10.013 PG 14 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA DC1AN UT WOS:000368949300008 PM 26519094 ER PT J AU Lauro, PM Vanegas-Arroyave, N Huang, L Taylor, PA Zaghloul, KA Lungu, C Saad, ZS Horovitz, SG AF Lauro, Peter M. Vanegas-Arroyave, Nora Huang, Ling Taylor, Paul A. Zaghloul, Kareem A. Lungu, Codrin Saad, Ziad S. Horovitz, Silvina G. TI DBSproc: An Open Source Process for DBS Electrode Localization and Tractographic Analysis SO HUMAN BRAIN MAPPING LA English DT Article DE magnetic resonance imaging (MRI); neurostimulation; deep brain stimulation (DBS); diffusion tensor imaging (DTI); Parkinson's disease (PD) ID DEEP-BRAIN-STIMULATION; SUBTHALAMIC NUCLEUS; PARKINSONS-DISEASE; ESSENTIAL TREMOR; GLOBUS-PALLIDUS; DIFFUSION MRI; IMPEDANCE; ACCURACY; DYSTONIA; TISSUE AB Deep brain stimulation (DBS) is an effective surgical treatment for movement disorders. Although stimulation sites for movement disorders such as Parkinson's disease are established, the therapeutic mechanisms of DBS remain controversial. Recent research suggests that specific white-matter tract and circuit activation mediates symptom relief. To investigate these questions, we have developed a patient-specific open-source software pipeline called 'DBSproc' for (1) localizing DBS electrodes and contacts from postoperative CT images, (2) processing structural and diffusion MRI data, (3) registering all images to a common space, (4) estimating DBS activation volume from patient-specific voltage and impedance, and (5) understanding the DBS contact-brain connectivity through probabilistic tractography. In this paper, we explain our methodology and provide validation with anatomical and tractographic data. This method can be used to help investigate mechanisms of action of DBS, inform surgical and clinical assessments, and define new therapeutic targets. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Lauro, Peter M.; Vanegas-Arroyave, Nora; Huang, Ling; Lungu, Codrin] NINDS, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Vanegas-Arroyave, Nora; Horovitz, Silvina G.] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Taylor, Paul A.] Univ Cape Town, Fac Hlth Sci, Dept Human Biol, MRC UCT Med Imaging Res Unit, ZA-7925 Cape Town, South Africa. [Taylor, Paul A.] African Inst Math Sci, Muizenberg, Western Cape, South Africa. [Zaghloul, Kareem A.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Saad, Ziad S.] NIMH, Stat & Sci Comp Core, NIH, Bethesda, MD 20892 USA. RP Horovitz, SG (reprint author), NINDS, Off Clin Director, NIH, Bethesda, MD 20892 USA.; Horovitz, SG (reprint author), NINDS, NIH, 10 Ctr Dr MSC 1428,Bldg 10,Room 7D37, Bethesda, MD 20892 USA. EM Silvina.horovitz@nih.gov FU Medtronic Deep Brain Stimulation Therapy Fellowship Grant FX Contract grant sponsor: Medtronic Deep Brain Stimulation Therapy Fellowship Grant 2014-2015 (to N.V-A.) NR 40 TC 3 Z9 3 U1 1 U2 4 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 JAN PY 2016 VL 37 IS 1 BP 422 EP 433 DI 10.1002/hbm.23039 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DC3WU UT WOS:000369150500030 PM 26523416 ER PT J AU Brooks, PJ Yang, NN Austin, CP AF Brooks, Philip J. Yang, N. Nora Austin, Christopher P. TI Gene Therapy: The View from NCATS SO HUMAN GENE THERAPY LA English DT Article ID IN-VIVO; MESSENGER-RNA; DELIVERY; VECTORS; CELLS; SUPPRESSION; NUCLEASES; SAFETY; DRUG; STEM C1 [Brooks, Philip J.] Natl Ctr Adv Translat Sci, Div Clin Innovat, NIH, 6701 Democracy Blvd,Room 924, Bethesda, MD 20892 USA. [Brooks, Philip J.] Natl Ctr Adv Translat Sci, Off Rare Dis Res, NIH, 6701 Democracy Blvd,Room 924, Bethesda, MD 20892 USA. [Yang, N. Nora] Natl Ctr Adv Translat Sci, Div Preclin Innovat, NIH, Bethesda, MD USA. [Austin, Christopher P.] Natl Ctr Adv Translat Sci, Off Director, NIH, Bethesda, MD USA. RP Brooks, PJ (reprint author), Natl Ctr Adv Translat Sci, Div Clin Innovat, NIH, 6701 Democracy Blvd,Room 924, Bethesda, MD 20892 USA.; Brooks, PJ (reprint author), Natl Ctr Adv Translat Sci, Off Rare Dis Res, NIH, 6701 Democracy Blvd,Room 924, Bethesda, MD 20892 USA. EM pjbrooks@mail.nih.gov NR 46 TC 0 Z9 0 U1 2 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 EI 1557-7422 J9 HUM GENE THER JI Hum. Gene Ther. PD JAN 1 PY 2016 VL 27 IS 1 BP 7 EP 13 DI 10.1089/hum.2016.29018.pjb PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DB6CC UT WOS:000368599700002 PM 26784641 ER PT J AU Bu, HJ Narisu, N Schlick, B Rainer, J Manke, T Schafer, G Pasqualini, L Chines, P Schweiger, MR Fuchsberger, C Klocker, H AF Bu, Huajie Narisu, Narisu Schlick, Bettina Rainer, Johannes Manke, Thomas Schaefer, Georg Pasqualini, Lorenza Chines, Peter Schweiger, Michal R. Fuchsberger, Christian Klocker, Helmut TI Putative Prostate Cancer Risk SNP in an Androgen Receptor-Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites SO HUMAN MUTATION LA English DT Article DE prostate cancer; risk SNPs; androgen receptor; melanophilin; MLPH; androgen regulation; AR ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; MELANOSOME TRANSPORT; RESPONSE ELEMENT; DNA-SEQUENCES; CELL-LINE; VARIANTS; IDENTIFICATION; TRANSCRIPTION; EXPRESSION AB Genome-wide association studies have identified genomic loci, whose single-nucleotide polymorphisms (SNPs) predispose to prostate cancer (PCa). However, the mechanisms of most of these variants are largely unknown. We integrated chromatin-immunoprecipitation-coupled sequencing and microarray expression profiling in TMPRSS2-ERG gene rearrangement positive DUCaP cells with the GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor-binding sites (ARBSs). Among the 48 GWAS index risk SNPs and 3,917 linked SNPs, 80 were found located in ARBSs. Of these, rs11891426:T>G in an intron of the melanophilin gene (MLPH) was within a novel putative auxiliary AR-binding motif, which is enriched in the neighborhood of canonical androgen-responsive elements. TG exchange attenuated the transcriptional activity of the ARBS in an AR reporter gene assay. The expression of MLPH in primary prostate tumors was significantly lower in those with the G compared with the T allele and correlated significantly with AR protein. Higher melanophilin level in prostate tissue of patients with a favorable PCa risk profile points out a tumor-suppressive effect. These results unravel a hidden link between AR and a functional putative PCa risk SNP, whose allele alteration affects androgen regulation of its host gene MLPH. C1 [Bu, Huajie; Schlick, Bettina; Schaefer, Georg; Pasqualini, Lorenza; Klocker, Helmut] Med Univ Innsbruck, Div Expt Urol, Dept Urol, A-6020 Innsbruck, Austria. [Bu, Huajie] Univ Innsbruck, Res Inst Biomed Aging Res, A-6020 Innsbruck, Austria. [Narisu, Narisu; Chines, Peter] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. [Schlick, Bettina] Ctr Personalized Canc Med, Oncotyrol, Innsbruck, Austria. [Rainer, Johannes] Med Univ Innsbruck, Sect Mol Pathophysiol, Bioctr Innsbruck, A-6020 Innsbruck, Austria. [Rainer, Johannes; Fuchsberger, Christian] EURAC Res, Ctr Biomed, Bolzano, Italy. [Manke, Thomas; Schweiger, Michal R.] Max Planck Inst Mol Genet, Ihnestr 73, D-14195 Berlin, Germany. [Manke, Thomas] Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany. [Schaefer, Georg] Med Univ Innsbruck, Dept Pathol, A-6020 Innsbruck, Austria. [Schweiger, Michal R.] Univ Cologne, Cologne Ctr Genom, D-50931 Cologne, Germany. [Fuchsberger, Christian] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. RP Klocker, H (reprint author), Med Univ Innsbruck, Dept Urol, Anichstr 35, A-6020 Innsbruck, Austria. EM helmut.klocker@i-med.ac.at FU Austrian Science Funds (FWF) [W1101]; Austrian COMET Center Oncotyrol [2.1.3]; Austrian Cancer Aid Tyrol; NHGRI, NIH; Volkswagenstiftung Lichtenberg Program FX Contract grant sponsors: Austrian Science Funds (FWF, project W1101, MCBO); the Austrian COMET Center Oncotyrol (project 2.1.3); the Austrian Cancer Aid Tyrol; NHGRI, NIH (intramural program); Volkswagenstiftung Lichtenberg Program. NR 75 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD JAN PY 2016 VL 37 IS 1 BP 52 EP 64 DI 10.1002/humu.22909 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA DC3ZS UT WOS:000369159900006 PM 26411452 ER PT S AU Samsel, L McCoy, JP AF Samsel, Leigh McCoy, J. Philip, Jr. BE Barteneva, NS Vorobjev, IA TI Detection and Characterization of Rare Circulating Endothelial Cells by Imaging Flow Cytometry SO IMAGING FLOW CYTOMETRY: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Circulating endothelial cells; CECs; Imaging flow cytometry; Rare event flow cytometry; CD146 ID PROGENITOR CELLS; INFLAMMATION; LYMPHOCYTES; PECAM-1; BIOLOGY; MARKERS; CD146; CD34 AB Circulating endothelial cells (CECs) are angiogenic cells that appear in increased numbers in the peripheral circulation either as a result of vascular injury or in response to angiogenic stimuli. Elevated levels of CECs have been correlated with various disease states, indicating the use of CECs as a biomarker of disease. Flow cytometry is a widely accepted method for detecting and quantitating CECs. Flow cytometry provides statistical information on large numbers of cells but no information on morphological characteristics. Imaging flow cytometry combines traditional flow cytometry and microscopy, providing a streamlined, multiparameter approach to characterize the biological properties and morphology of large numbers of cells, and is particularly amenable for rare event analysis such as CECs. This approach for identifying and characterizing CECs allows the morphological characterization of large numbers of live, nucleated, single CECs, and alleviates the need for prior enrichment. C1 [Samsel, Leigh; McCoy, J. Philip, Jr.] NHLBI, Flow Cytometry Core Facil, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Samsel, L (reprint author), NHLBI, Flow Cytometry Core Facil, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 19 TC 1 Z9 1 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-3302-0; 978-1-4939-3300-6 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 BP 249 EP 264 DI 10.1007/978-1-4939-3302-0_18 D2 10.1007/978-1-4939-3302-0 PG 16 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Imaging Science & Photographic Technology SC Biochemistry & Molecular Biology; Imaging Science & Photographic Technology GA BE1ZP UT WOS:000368811100019 ER PT S AU Fertrin, KY Samsel, L van Beers, EJ Mendelsohn, L Kato, GJ McCoy, JP AF Fertrin, Kleber Y. Samsel, Leigh van Beers, Eduard J. Mendelsohn, Laurel Kato, Gregory J. McCoy, J. Philip, Jr. BE Barteneva, NS Vorobjev, IA TI Sickle Cell Imaging Flow Cytometry Assay (SIFCA) SO IMAGING FLOW CYTOMETRY: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Sickle cell disease; Sickling assay; Imaging flow cytometry ID ERYTHROCYTES; DISEASE; BLOOD AB Hemoglobin S polymerization under hypoxic conditions in sickle cell disorders causes characteristic shape changes to human red blood cells. Previous sickling assays used to investigate the efficacy of novel agents to treat these disorders are laborious and observer dependent. Here, we describe a partially automated, high-throughput sickling assay using imaging flow cytometry. C1 [Fertrin, Kleber Y.] Univ Estadual Campinas, Sch Med Sci, Dept Clin Pathol, Campinas, SP, Brazil. [Fertrin, Kleber Y.] Univ Estadual Campinas, Hematol & Hemotherapy Ctr, Hemoctr Campinas, Campinas, SP, Brazil. [Samsel, Leigh; McCoy, J. Philip, Jr.] NHLBI, Flow Cytometry Core Facil, NIH, Bldg 10, Bethesda, MD 20892 USA. [van Beers, Eduard J.] Univ Amsterdam, Acad Med Ctr, Dept Clin Hematol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Mendelsohn, Laurel] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Kato, Gregory J.] Univ Pittsburgh, Vasc Med Inst, Div Hematol Oncol, Pittsburgh, PA USA. RP Fertrin, KY (reprint author), Univ Estadual Campinas, Sch Med Sci, Dept Clin Pathol, Campinas, SP, Brazil.; Fertrin, KY (reprint author), Univ Estadual Campinas, Hematol & Hemotherapy Ctr, Hemoctr Campinas, Campinas, SP, Brazil. RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 NR 7 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-3302-0; 978-1-4939-3300-6 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 BP 279 EP 292 DI 10.1007/978-1-4939-3302-0_20 D2 10.1007/978-1-4939-3302-0 PG 14 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Imaging Science & Photographic Technology SC Biochemistry & Molecular Biology; Imaging Science & Photographic Technology GA BE1ZP UT WOS:000368811100021 ER PT J AU Bornstein, MH Putnick, DL Suwalsky, JTD AF Bornstein, Marc H. Putnick, Diane L. Suwalsky, Joan T. D. TI Infant-Mother and Infant-Caregiver Emotional Relationships: Process Analyses of Interactions in Three Contemporary Childcare Arrangements SO INFANCY LA English DT Article ID MATERNAL EMPLOYMENT; SUBSTITUTE CAREGIVERS; AVAILABILITY; QUALITY; OUTCOMES; PARENTS; LIFE; KINDERGARTEN; SENSITIVITY; ATTACHMENT AB Emotional relationships in infant-mother dyads in families where mothers provided full-time childcare were compared with those of families where mothers used in-home childcare providers and family childcare providers (N=245). Infant relationships with childcare providers were also studied. Emotional relationships were adequate in all three childcare arrangements, but infant-mother dyads in in-home childcare arrangements displayed healthier emotional relationships than infant-mother dyads in mother care arrangements; no differences in the health of emotional relationships with infants emerged among the three types of childcare providers (mother care, in-home childcare, family childcare). Infant-mother dyads in in-home childcare arrangements also displayed healthier emotional relationships than infant-in-home childcare caregiver dyads, but infant-mother and infant-caregiver dyads were comparable in family childcare families. Emotional relationships in infant-mother and infant-caregiver dyads were not correlated, regardless of the type of childcare. C1 [Bornstein, Marc H.; Putnick, Diane L.; Suwalsky, Joan T. D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Bornstein, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov OI Putnick, Diane/0000-0002-6323-749X FU Intramural Research Program of the NIH, NICHD FX This research was supported by the Intramural Research Program of the NIH, NICHD. NR 79 TC 0 Z9 0 U1 6 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1525-0008 EI 1532-7078 J9 INFANCY JI Infancy PD JAN-FEB PY 2016 VL 21 IS 1 BP 8 EP 36 DI 10.1111/infa.12097 PG 29 WC Psychology, Developmental SC Psychology GA DB7TL UT WOS:000368719000002 ER PT J AU Dmello, C Sawant, S Alam, H Gangadaran, P Tiwari, R Dongre, H Rana, N Barve, S Costea, DE Chaukar, D Kane, S Pant, H Vaidya, M AF Dmello, Crismita Sawant, Sharada Alam, Hunain Gangadaran, Prakash Tiwari, Richa Dongre, Harsh Rana, Neha Barve, Sai Costea, Daniela Elena Chaukar, Davendra Kane, Shubhada Pant, Harish Vaidya, Milind TI Vimentin-mediated regulation of cell motility through modulation of beta4 integrin protein levels in oral tumor derived cells SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Article DE Vimentin; OSCC; beta 4 integrin; Cell adhesion; Migration ID INTERMEDIATE-FILAMENT CYTOSKELETON; STRATIFIED EPITHELIAL-CELLS; DOWN-REGULATION; ALPHA-6-BETA-4 INTEGRIN; EPIDERMOLYSIS-BULLOSA; HUMAN KERATINOCYTES; CANCER PROGRESSION; CARCINOMA-CELLS; EXPRESSION; ADHESION AB Vimentin expression correlates well with migratory and invasive potential of the carcinoma cells. The molecular mechanism by which vimentin regulates cell motility is not yet clear. Here, we addressed this issue by depleting vimentin in oral squamous cell carcinoma derived cell line. Vimentin knockdown cells showed enhanced adhesion and spreading to laminin-5. However, we found that they were less invasive as compared to the vector control cells. In addition, signaling associated with adhesion behavior of the cell was increased in vimentin knockdown clones. These findings suggest that the normal function of beta 4 integrin as mechanical adhesive device is enhanced upon vimentin downregulation. As a proof of principle, the compromised invasive potential of vimentin depleted cells could be rescued upon blocking with beta 4 integrin adhesion-blocking (ASC-8) antibody or downregulation of beta 4 integrin in vimentin knockdown background. Interestingly, plectin which associates with alpha 6 beta 4 integrin in the hemidesmosomes, was also found to be upregulated in vimentin knockdown clones. Furthermore, experiments on lysosome and proteasome inhibition revealed that perhaps vimentin regulates the turnover of beta 4 integrin and plectin. Moreover, an inverse association was observed between vimentin expression and beta 4 integrin in oral squamous cell carcinoma (OSCC). Collectively, our results show a novel role of vimentin in modulating cell motility by destabilizing beta 4 integrin-mediated adhesive interactions. Further, vimentin-beta 4 integrin together may prove to be useful markers for prognostication of human oral cancer. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Dmello, Crismita; Sawant, Sharada; Alam, Hunain; Gangadaran, Prakash; Tiwari, Richa; Dongre, Harsh; Rana, Neha; Barve, Sai; Vaidya, Milind] TMC, ACTREC, CRI, Kharghar, Navi Mumbai, India. [Costea, Daniela Elena] Univ Bergen, Inst Clin Med, Gade Lab Pathol, N-5020 Bergen, Norway. [Costea, Daniela Elena] Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway. [Chaukar, Davendra] TMH, Surg Oncol Head & Neck Unit, Mumbai, Maharashtra, India. [Kane, Shubhada] TMH, Dept Pathol, Mumbai, Maharashtra, India. [Pant, Harish] NINDS, NIH, Lab Neurochem, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Alam, Hunain] Univ Texas Houston, MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA. [Gangadaran, Prakash] Kyunpook Natl Univ, Sch Med, Dept Nucl Med, N101, Daegu, South Korea. RP Vaidya, M (reprint author), TMC, ACTREC, CRI, Kharghar, Navi Mumbai, India. EM mvaidya@actrec.gov.in OI Dongre, Harsh/0000-0003-4378-2869; Gangadaran, Prakash/0000-0002-0658-4604 FU Department of Biotechnology [102/IFD/SAN/947]; ACTREC, TMC FX We thank Professor Robert Goldman (Feinberg School of Medicine, Northwestern University, USA) for his generous gift of the emerald vimentin retroviral construct. We thank Dr. Livio Trusolino (Department of Oncology, University of Torino School of Medicine, Italy) for his generous gift of beta 4 integrin shRNA and scrambled shRNA construct. We thank following people from ACTREC, TMC, India for their kind help. Dr. Sorab Dalal for his generous gift of pTU6 PURO vector. Pratik Chaudhari for critically reviewing the manuscript. Indrajit Sahu, Shyam More, Manohar Dange for their valuable experimental suggestions. We are thankful to Mrs. Tejaswinin Modak (Online trainer and instructor for English Writing Skills, Centre for e-learning and Training) for english spelling and grammar. This work was supported by grant from Department of Biotechnology (Grant no. 102/IFD/SAN/947). CD was supported by fellowship from ACTREC, TMC. NR 49 TC 1 Z9 1 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 EI 1878-5875 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD JAN PY 2016 VL 70 BP 161 EP 172 DI 10.1016/j.biocel.2015.11.015 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DB9WX UT WOS:000368869500017 PM 26646105 ER PT J AU Bosomprah, S Tatem, AJ Dotse-Gborgbortsi, W Aboagye, P Matthews, Z AF Bosomprah, Samuel Tatem, Andrew J. Dotse-Gborgbortsi, Winfred Aboagye, Patrick Matthews, Zoe TI Spatial distribution of emergency obstetric and newborn care services in Ghana: Using the evidence to plan interventions SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Article DE Emergency obstetric and newborn care (EmONC); Geospatial analysis; Ghana; Maternal mortality; Needs assessment; Signal functions AB Objective: To provide clear policy directions for gaps in the provision of signal function services and sub-regions requiring priority attention using data from the 2010 Ghana Emergency Obstetric and Newborn Care (EmONC) survey. Methods: Using 2010 survey data, the fraction of facilities with only one or two signal functions missing was calculated for each facility type and EmONC designation. Thematic maps were used to provide insight into inequities in service provision. Results: Of 1159 maternity facilities, 89 provided all the necessary basic or comprehensive EmONC signal functions 3 months prior to the 2010 survey. Only 21% of facility-based births were in fully functioning EmONC facilities, but an additional 30% occurred in facilities missing one or two basic signal functions most often assisted vaginal delivery and removal of retained products. Tackling these missing signal functions would extend births taking place in fully functioning facilities to over 50%. Subnational analyses based on estimated total pregnancies in each district revealed a pattern of inequity in service provision across the country. Conclusion: Upgrading facilities missing only one or two signal functions will allow Ghana to meet international standards for availability of EmONC services. Reducing maternal deaths will require high national priority given to addressing inequities in the distribution of EmONC services. (C) 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Bosomprah, Samuel; Dotse-Gborgbortsi, Winfred] Evidence Act, Accra, Ghana. [Bosomprah, Samuel; Dotse-Gborgbortsi, Winfred] Univ Ghana, Sch Publ Hlth, Legon, Ghana. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Tatem, Andrew J.] Flowminder Fdn, Stockholm, Sweden. [Aboagye, Patrick] Ghana Hlth Serv, Family Hlth Div, Accra, Ghana. [Matthews, Zoe] Univ Southampton, Dept Social Stat & Demog, Southampton, Hants, England. RP Bosomprah, S (reprint author), Univ Ghana, Sch Publ Hlth, Dept Biostat, POB LG13, Legon, Accra, Ghana. EM sbosomprah@gmail.com NR 9 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0020-7292 EI 1879-3479 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD JAN PY 2016 VL 132 IS 1 BP 130 EP 134 DI 10.1016/j.ijgo.2015.11.004 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DC1CQ UT WOS:000368954800029 PM 26725855 ER PT J AU Walls, A Dermody, S Kumaran, R Krishnan, N Harley, EH AF Walls, Andrew Dermody, Sarah Kumaran, Ravindran Krishnan, Nathan Harley, Earl H. TI Characterization of B-Cells in tonsils of patients diagnosed with pediatric autoimmune neuropsychiatric disorder associated streptococcus SO INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY LA English DT Article DE Otolaryngology; PANDAS; Pediatrics; Head and neck surgery; Tonsillectomy ID ACTIVATING FACTOR; PANDAS; INFECTIONS; HYPOTHESIS AB Objective: To determine if Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS) patients demonstrate a significantly different number of B-Cells or markers of activity when compared to recurrent Group A Streptococcus or Obstructive Sleep Apnea patients. Study design: Prospective Cohort Study. Study setting: Academic University Hospital. Methods: Tonsil tissue was collected from twenty-two patients in the operating room and organized into three groups. Ten clinically diagnosed PANDAS, six Group A Streptococcus and six Obstructive Sleep Apnea patients were included in this study. Each tissue sample was extracted with MSD Tris Lysis Buffer and protein lysates were analyzed for CD 19, B-Cell Activating Factor and B-Cell Activating Receptor by western blot methods. Results: Based on ANOVA analysis, there was no significant difference in the expression of B-Cell Activating Factor, B-Cell Activating Receptor or CD 19 when comparing the three study groups by western blot analysis methods. Conclusions: In this prospective cohort study, it appears that PANDAS patients do not demonstrate increased number of B-Cells, expression of B-Cell Activating Factor or B-Cell Activating Receptor when compared to Group A Streptococcus or Obstructive Sleep Apnea cohorts. As a result, further evaluation of the cell-mediated immune system is warranted to provide further insight into the pathophysiology of PANDAS. In addition, we must investigate if PANDAS patients only demonstrate increased B-Cell number or activity when undergoing an acute Tic/OCD exacerbation. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Walls, Andrew; Dermody, Sarah; Kumaran, Ravindran; Krishnan, Nathan; Harley, Earl H.] Georgetown Univ Hosp, Dept Otolaryngol Head & Neck Surg, Washington, DC 20007 USA. [Walls, Andrew; Dermody, Sarah; Krishnan, Nathan; Harley, Earl H.] Georgetown Univ, Sch Med, 3900 Reservoir Rd NW, Washington, DC 20007 USA. [Kumaran, Ravindran] NIA, NIH, Bethesda, MD 20892 USA. RP Walls, A (reprint author), Georgetown Univ, Sch Med, 3900 Reservoir Rd NW, Washington, DC 20007 USA. EM Adw27@georgetown.edu NR 17 TC 2 Z9 3 U1 5 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-5876 EI 1872-8464 J9 INT J PEDIATR OTORHI JI Int. J. Pediatr. Otorhinolaryngol. PD JAN PY 2016 VL 80 IS 1 BP 49 EP 52 DI 10.1016/j.ijporl.2015.11.020 PG 4 WC Otorhinolaryngology; Pediatrics SC Otorhinolaryngology; Pediatrics GA DC1BF UT WOS:000368951100011 PM 26746612 ER PT J AU Renfroe, JB Bradley, MM Okun, MS Bowers, D AF Renfroe, J. B. Bradley, M. M. Okun, M. S. Bowers, D. TI Motivational engagement in Parkinson's disease: Preparation for motivated action SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Article DE CNV; Parkinson's; LPP; Motivation; Incentive; Motor preparation ID STIMULUS-PRECEDING NEGATIVITY; MOVEMENT-RELATED POTENTIALS; BECK DEPRESSION INVENTORY; FEEDBACK STIMULI; MOTOR AREAS; APATHY; EMOTION; REWARD; DISORDERS; SYMPTOMS AB The current study investigated whether motivational dysfunction in Parkinson's patients is related to a deficit in preparing for motivated behavior. Based on previous studies, it was hypothesized that PD patients would show reduced preparation for action specifically when faced with threat (of loss) and that reduced action preparation would relate to self -report of apathy symptoms. The study measured an electrocortical correlate of preparation for action (CNV amplitude) in PD patients and healthy controls, as well as defensive and appetitive activation during emotional perception (LPP amplitude). The sample included 18 non -demented PD patients (tested on dopaminergic medications) and 15 healthy controls who responded as quickly as possible to cues signaling threat of loss or reward, in which the speed of the response determined the outcome. Results indicated that, whereas PD patients showed similar enhanced action preparation with the addition of incentives to controls, PD patients showed generally reduced action preparation, evidenced by reduced CNV amplitude overall. Results suggest that PD patients may have behavioral issues due to globally impaired action preparation but that this deficit is not emotion -specific, and movement preparation may be aided by incentive in PD patients. (C) 2015 Elsevier B.V. All rights reserved. C1 [Renfroe, J. B.; Bowers, D.] Univ Florida, Dept Clin & Hlth Psychol, POB 100165, Gainesville, FL 32610 USA. [Renfroe, J. B.; Bradley, M. M.] Univ Florida, NIMH Ctr Study Emot & Attent, Gainesville, FL 32611 USA. [Okun, M. S.] Univ Florida, Ctr Movement Disorders & Neurorestorat, Gainesville, FL 32611 USA. [Renfroe, J. B.] Med Univ S Carolina, 208 B Rutledge Ave,MSC 108, Charleston, SC 29425 USA. RP Renfroe, JB (reprint author), POB 100165, Gainesville, FL 32610 USA.; Renfroe, JB (reprint author), Med Univ S Carolina, 208 B Rutledge Ave,MSC 108, Charleston, SC 29425 USA. EM jenna.renfroe.phd@gmail.com FU NRSA; NIH National Institute of Neurological Disorders and Stroke (NINDS) [F31 NS 073331-01]; UF INFORM database; NPF center of excellence FX This work was instrumentally supported by an NRSA awarded to the first author (JR) by the NIH National Institute of Neurological Disorders and Stroke (NINDS) (F31 NS 073331-01), as well as the UF INFORM database and NPF center of excellence. NR 68 TC 1 Z9 1 U1 6 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 EI 1872-7697 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD JAN PY 2016 VL 99 BP 24 EP 32 DI 10.1016/j.ijpsycho.2015.11.014 PG 9 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA DC4MA UT WOS:000369193800004 PM 26659013 ER PT J AU Patounakis, G Bergh, E Forman, EJ Tao, X Lonczak, A Franasiak, JM Treff, N Scott, RT AF Patounakis, George Bergh, Eric Forman, Eric J. Tao, Xin Lonczak, Agnieszka Franasiak, Jason M. Treff, Nathan Scott, Richard T., Jr. TI Multiple thrombophilic single nucleotide polymorphisms lack a significant effect on outcomes in fresh IVF cycles: an analysis of 1717 patients SO JOURNAL OF ASSISTED REPRODUCTION AND GENETICS LA English DT Article DE SNP; IVF outcomes; Thrombophilia; Infertility; Pregnancy ID VITRO FERTILIZATION FAILURE; V-LEIDEN MUTATION; INHERITED THROMBOPHILIA; IMPLANTATION FAILURE; EMBRYO-TRANSFER; WOMEN; METAANALYSIS; MISCARRIAGE AB The aim of the study is to determine if thrombophilic single nucleotide polymorphisms (SNPs) affect outcomes in fresh in vitro fertilization (IVF) cycles in a large general infertility population. A prospective cohort analysis was performed at a university-affiliated private IVF center of female patients undergoing fresh non-donor IVF cycles. The effect of the following thrombophilic SNPs on IVF outcomes were explored: factor V (Leiden and H1299R), prothrombin (G20210A), factor XIII (V34L), beta-fibrinogen (-455G -> aEuro parts per thousand A), plasminogen activator inhibitor-1 (4G/5G), human platelet antigen-1 (a/b9L33P), and methylenetetrahydrofolate reductase (C677T and A1298C). The main outcome measures included positive pregnancy test, clinical pregnancy, embryo implantation, live birth, and pregnancy loss. Patients (1717) were enrolled in the study, and a total of 4169 embryos were transferred. There were no statistically significant differences in positive pregnancy test, clinical pregnancy, embryo implantation, live birth, or pregnancy loss in the analysis of 1717 patients attempting their first cycle of IVF. Receiver operator characteristics and logistic regression analyses showed that outcomes cannot be predicted by the cumulative number of thrombophilic mutations present in the patient. Individual and cumulative thrombophilic SNPs do not affect IVF outcomes. Therefore, initial screening for these SNPs is not indicated. C1 [Patounakis, George] NIH, Bldg 10, Bethesda, MD 20892 USA. [Bergh, Eric] Mt Sinai Sch Med, New York, NY USA. [Forman, Eric J.; Tao, Xin; Lonczak, Agnieszka; Franasiak, Jason M.; Treff, Nathan; Scott, Richard T., Jr.] Reprod Med Associates New Jersey, 140 Allen Rd, Morristown, NJ 07920 USA. [Forman, Eric J.; Franasiak, Jason M.; Treff, Nathan; Scott, Richard T., Jr.] Rutgers State Univ, Robert Wood Johnson Med Sch, Piscataway, NJ 08854 USA. RP Scott, RT (reprint author), Reprod Med Associates New Jersey, 140 Allen Rd, Morristown, NJ 07920 USA.; Scott, RT (reprint author), Rutgers State Univ, Robert Wood Johnson Med Sch, Piscataway, NJ 08854 USA. EM rscott@rmanj.com FU Ferring Pharmaceuticals (Saint-Prex, Switzerland) FX Ferring Pharmaceuticals (Saint-Prex, Switzerland) financially supported this study with an unrestricted research grant. The authors greatly appreciated the help of Batsal Devkota and Deanne Taylor for assistance with the database queries. NR 19 TC 2 Z9 2 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1058-0468 EI 1573-7330 J9 J ASSIST REPROD GEN JI J. Assist. Reprod. Genet. PD JAN PY 2016 VL 33 IS 1 BP 67 EP 73 DI 10.1007/s10815-015-0606-z PG 7 WC Genetics & Heredity; Obstetrics & Gynecology; Reproductive Biology SC Genetics & Heredity; Obstetrics & Gynecology; Reproductive Biology GA DB7HW UT WOS:000368686400010 PM 26545911 ER PT J AU Clarridge, K Leitenberg, D Loechelt, B Picard, C Keller, M AF Clarridge, Katherine Leitenberg, David Loechelt, Brett Picard, Capuchine Keller, Michael TI Major Histocompatibility Complex Class II Deficiency due to a Novel Mutation in RFXANK in a Child of Mexican Descent SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Letter C1 [Clarridge, Katherine] NIAID, Immunoregulat Lab, Washington, DC USA. [Clarridge, Katherine; Loechelt, Brett; Keller, Michael] Childrens Natl Hlth Syst, Div Allergy & Immunol, 111 Michigan Ave NW,M7745A, Washington, DC 20010 USA. [Leitenberg, David] Childrens Natl Hlth Syst, Dept Lab Med, Washington, DC USA. [Leitenberg, David] George Washington Univ, Dept Microbiol Immunol & Trop Med, Washington, DC USA. [Picard, Capuchine] Univ Paris 05, Necker Med Sch, Lab Human Genet Infect Dis, Necker Branch,Imagine Inst,INSERM UMR1163, Paris, France. RP Keller, M (reprint author), Childrens Natl Hlth Syst, Div Allergy & Immunol, 111 Michigan Ave NW,M7745A, Washington, DC 20010 USA. EM MKeller@childrensnational.org OI Leitenberg, David/0000-0002-0622-9522 FU NIAID NIH HHS [L40 AI113970]; NICHD NIH HHS [K12 HD001399] NR 4 TC 0 Z9 1 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD JAN PY 2016 VL 36 IS 1 BP 4 EP 5 DI 10.1007/s10875-015-0219-4 PG 2 WC Immunology SC Immunology GA DB7WD UT WOS:000368726600002 PM 26634365 ER PT J AU Mosher, BP Tariq, M Koizumi, H Koshiya, N Zhang, R Smith, J AF Mosher, B. P. Tariq, M. Koizumi, H. Koshiya, N. Zhang, R. Smith, J. TI OPTOGENETIC STUDIES OF RESPIRATORY RHYTHM GENERATION IN TRANSGENIC MICE SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract CT Western Regional Meeting of the American-Federation-for-Medical-Research CY JAN 28-30, 2016 CL Carmel, CA SP Amer Federat Med Res C1 [Mosher, B. P.] Univ Washington, Seattle, WA 98195 USA. [Mosher, B. P.; Tariq, M.; Koizumi, H.; Koshiya, N.; Zhang, R.; Smith, J.] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1081-5589 EI 1708-8267 J9 J INVEST MED JI J. Invest. Med. PD JAN PY 2016 VL 64 IS 1 MA 119 BP 186 EP 186 DI 10.1136/jim-d-15-00013.119 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA DB7MM UT WOS:000368699600129 ER PT J AU Chu, A Williams, C Wadehra, M AF Chu, A. Williams, C. Wadehra, M. TI EPITHELIAL MEMBRANE PROTEIN 2 (EMP2) DEFICIENCY ALTERS PLACENTAL ANGIOGENESIS MIMICKING FEATURES OF INTRAUTERINE GROWTH RESTRICTION SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract CT Western Regional Meeting of the American-Federation-for-Medical-Research CY JAN 28-30, 2016 CL Carmel, CA SP Amer Federat Med Res C1 [Chu, A.; Wadehra, M.] Univ Calif Los Angeles, Los Angeles, CA USA. [Williams, C.] NIH, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1081-5589 EI 1708-8267 J9 J INVEST MED JI J. Invest. Med. PD JAN PY 2016 VL 64 IS 1 MA 285 BP 258 EP 258 DI 10.1136/jim-d-15-00013.285 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA DB7MM UT WOS:000368699600294 ER PT J AU Lu, SY Zhang, Y Kalin, JH Cai, LS Kozikowski, AP Pike, VW AF Lu, Shuiyu Zhang, Yi Kalin, Jay H. Cai, Lisheng Kozikowski, Alan P. Pike, Victor W. TI Exploration of the labeling of [C-11]tubastatin A at the hydroxamic acid site with [C-11]carbon monoxide SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Article DE [C-11]tubastatin A; HDAC6; [C-11]Carbon monoxide; Carbonylation; Hydroxyaminolysis ID ACTIVATED ACYL GROUPS; IN-SITU; ATMOSPHERIC-PRESSURE; CARBON-MONOXIDE; HYDROXYLAMINE; CHEMISTRY; AMINES; PET; SUBSTITUTION; INHIBITOR AB We aimed to label tubastatin A (1) with carbon-11 (t(1/2)=20.4min) in the hydroxamic acid site to provide a potential radiotracer for imaging histone deacetylase 6 in vivo with positron emission tomography. Initial attempts at a one-pot Pd-mediated insertion of [C-11]carbon monoxide between the aryl iodide (2) and hydroxylamine gave low radiochemical yields (<5%) of [C-11]1. Labeling was achieved in useful radiochemical yields (16.1 +/- 5.6%, n=4) through a two-step process based on Pd-mediated insertion of [C-11]carbon monoxide between the aryl iodide (2) and p-nitrophenol to give the [C-11]p-nitrophenyl ester ([C-11]5), followed by ultrasound-assisted hydroxyaminolysis of the activated ester with excess hydroxylamine in a DMSO/THF mixture in the presence of a strong phosphazene base P-1-t-Bu. However, success in labeling the hydroxamic acid group of [C-11]tubastatin A was not transferable to the labeling of three other model hydroxamic acids. C1 [Lu, Shuiyu; Zhang, Yi; Cai, Lisheng; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Kalin, Jay H.; Kozikowski, Alan P.] Univ Illinois, Dept Med Chem & Pharmacognosy, Chicago, IL USA. RP Lu, SY (reprint author), NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. EM Shuiyu.Lu@mail.nih.gov OI Kalin, Jay/0000-0002-8747-6022; Lu, Shuiyu/0000-0003-0310-4318 FU Intramural Research Program of the National Institutes of Health (NIMH) [ZIA-MH002793] FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIMH, ZIA-MH002793). The authors are grateful to the NIH Clinical Center PET Department (Chief, Dr. Peter Herscovitch) for the production of carbon-11 and Dr. Jinsoo Hong for assistance on operation and maintenance of the radiochemistry apparatus. NR 40 TC 1 Z9 1 U1 8 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD JAN PY 2016 VL 59 IS 1 BP 9 EP 13 DI 10.1002/jlcr.3360 PG 5 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DC0YY UT WOS:000368945200002 PM 26647018 ER PT J AU Lally, N An, L Banerjee, D Niciu, MJ Luckenbaugh, DA Richards, EM Roiser, JP Shen, J Zarate, CA Nugent, AC AF Lally, Niall An, Li Banerjee, Dipavo Niciu, Mark J. Luckenbaugh, David A. Richards, Erica M. Roiser, Jonathan P. Shen, Jun Zarate, Carlos A., Jr. Nugent, Allison C. TI Reliability of 7T H-1-MRS Measured Human Prefrontal Cortex Glutamate, Glutamine, and Glutathione Signals Using an Adapted Echo Time Optimized PRESS Sequence: A Between- and Within-Sessions Investigation SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE glutamatergic; intraclass correlation coefficient; point resolved spectroscopy; medial prefrontal cortex (mPFC); proton magnetic resonance spectroscopy; reliability ID MAGNETIC-RESONANCE-SPECTROSCOPY; ANTERIOR CINGULATE; ANXIETY DISORDER; MAJOR DEPRESSION; HUMAN BRAIN; IN-VIVO; KETAMINE; GABA; TESLA; MRS AB Purpose: To ascertain the mechanisms of neuropsychiatric illnesses and their treatment, accurate and reliable imaging techniques are required; proton magnetic resonance spectroscopy (H-1-MRS) can noninvasively measure glutamatergic function. Evidence suggests that aberrant glutamatergic signaling plays a role in numerous psychopathologies. Until recently, overlapping glutamatergic signals (glutamate, glutamine, and glutathione) could not easily be separated. However, the advent of novel pulse sequences and higher field magnetic resonance imaging (MRI) allows more precise resolution of overlapping glutamatergic signals, although the question of signal reliability remains undetermined. Materials and Methods: At 7T MR, we acquired H-1-MRS data from the medial pregenual anterior cingulate cortex of healthy volunteers (n=26) twice on two separate days. An adapted echo time optimized point-resolved spectroscopy sequence, modified with the addition of a J-suppression pulse to attenuate N-acetyl-aspartate multiplet signals at 2.49 ppm, was used to excite and acquire the spectra. In-house software was used to model glutamate, glutamine, and glutathione, among other metabolites, referenced to creatine. Intraclass correlation coefficients (ICCs) were computed for within- and between-session measurements. Results: Within-session measurements of glutamate, glutamine, and glutathione were on average reliable (ICCs 0.7). As anticipated, ICCs for between-session values of glutamate, glutamine, and glutathione were slightly lower but nevertheless reliable (ICC >0.62). A negative correlation was observed between glutathione concentration and age (r((24))=-0.37; P<0.05), and a gender effect was noted on glutamine and glutathione. Conclusion: The adapted sequence provides good reliability to measure glutamate, glutamine, and glutathione signals. C1 [Lally, Niall; Banerjee, Dipavo; Niciu, Mark J.; Luckenbaugh, David A.; Richards, Erica M.; Zarate, Carlos A., Jr.; Nugent, Allison C.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Lally, Niall; Roiser, Jonathan P.] UCL, Inst Cognit Neurosci, London, England. [An, Li; Shen, Jun] NIMH, Magnet Resonance Spect Core Facil, NIH, Bethesda, MD 20892 USA. RP Lally, N (reprint author), 10 Ctr Dr,CRC,Room 7-5340, Bethesda, MD 20892 USA. EM lallynm@mail.nih.gov RI Niciu, Mark/J-1766-2014; OI Niciu, Mark/0000-0002-5612-3021; Lally, Niall/0000-0001-9148-3180; Nugent, Allison/0000-0003-2569-2480 FU Ioline Henter (NIMH) provided excellent editorial assistance; Intramural Research Program of the National Institute of Mental Health; National Institutes of Health; NARSAD Independent Investigator; Brain & Behavior Mood Disorders Research Award; Wellcome Trust-National Institutes of Health joint PhD studentship [WT095465]; [NCT00397111]; [07-M-0021] FX The authors thank the 7SE research unit and staff for their support. Ioline Henter (NIMH) provided excellent editorial assistance. Contract grant sponsor: Intramural Research Program of the National Institute of Mental Health, National Institutes of Health; Contract grant numbers: IRP-NIMH-NIH; NCT00397111, protocol number 07-M-0021; Contract grant sponsor: NARSAD Independent Investigator (to C.A.Z.); Contract grant sponsor: Brain & Behavior Mood Disorders Research Award (to C.A.Z.); Contract grant sponsor: Wellcome Trust-National Institutes of Health joint PhD studentship; Contract grant number: WT095465 (to N.L.). NR 38 TC 3 Z9 3 U1 4 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD JAN PY 2016 VL 43 IS 1 BP 88 EP 98 DI 10.1002/jmri.24970 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DB8BM UT WOS:000368741400007 PM 26059603 ER PT J AU Robins, HI Zhang, PX Gilbert, MR Chakravarti, A de Groot, JF Grimm, SA Wang, F Lieberman, FS Krauze, A Trotti, AM Mohile, N Kee, AYJ Colman, H Cavaliere, R Kesari, S Chmura, SJ Mehta, M AF Robins, H. Ian Zhang, Peixin Gilbert, Mark R. Chakravarti, Arnab de Groot, John F. Grimm, Sean A. Wang, Fen Lieberman, Frank S. Krauze, Andra Trotti, Andy M. Mohile, Nimish Kee, Andrew Y. J. Colman, Howard Cavaliere, Robert Kesari, Santosh Chmura, Steven J. Mehta, Minesh TI A randomized phase I/II study of ABT-888 in combination with temozolomide in recurrent temozolomide resistant glioblastoma: an NRG oncology RTOG group study SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Glioblastoma; ABT-888; Temozolomide; Velparib ID O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE ACTIVITY; II CLINICAL-TRIALS; ADJUVANT TEMOZOLOMIDE; RADIOTHERAPY; BEVACIZUMAB; PROGRESSION; CONCOMITANT; THERAPY AB This study tested the hypothesis that ABT-888 (velparib), a poly (ADP-ribose) polymerase (PARP) inhibitor, can modulate temozolomide (TMZ) resistance in recurrent TMZ refractory glioblastoma patients. The combination regimen (TMZ/ABT-888) was tested using two randomized schedules (5 vs. 21 days), with 6-month progression free survival (PFS6) as the primary endpoint. The maximum tolerated dose (MTD) for TMZ using the 21 day of 28 TMZ schedule, in concert with 40 mg BID ABT-888 was determined in a phase I portion of this study, and previously reported to be 75 mg/m(2) (arm1). The MTD for ABT-888 (40 mg BID) and the 5 of 28 day TMZ (150-200 mg/m(2)) schedule was known from prior trials (arm2). Two cohorts were studied: bevacizumab (BEV) na < ve (n = 151), and BEV refractory (n = 74). Overall ten patients were ineligible. The incidence rate of grade 3/4 myelosuppression over all was 20.0 %. For the BEV refractory cohort, the PFS 6 was 4.4 %; for the BEV na < ve cohort, PFS6 was 17 %. Overall survival was similar for both arms in both the BEV na < ve [median survival time (MST) 10.3 M; 95 % CI 8.4-12] and BEV refractory cohort (MST 4.7 M; 95 %CI 3.5-5.6). The median PFS was essentially the same for both arms and both cohorts at similar to 2.0 M (95 % CI 1.9-2.1). C1 [Robins, H. Ian] Univ Wisconsin, Paul Carbone Comprehens Canc Ctr, 600 Highland Ave, Madison, WI 53792 USA. [Zhang, Peixin] NRG Oncol Stat & Data Management Ctr, Philadelphia, PA USA. [Gilbert, Mark R.] NCI, NIH, Bethesda, MD 20892 USA. [Chakravarti, Arnab; Cavaliere, Robert] Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. [de Groot, John F.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Grimm, Sean A.] Candence Canc Ctr, Warrenville, IL USA. [Wang, Fen] Univ Kansas, Kansas City, KS USA. [Lieberman, Frank S.] UPMC, Shadyside Hosp, Pittsburgh, PA USA. [Krauze, Andra] NCI, Radiat Oncol Branch, Bldg 10, Bethesda, MD 20892 USA. [Trotti, Andy M.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Mohile, Nimish] Univ Rochester, Rochester, NY USA. [Kee, Andrew Y. J.] Legacy Hlth, Portland, OR USA. [Colman, Howard] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [Kesari, Santosh] UC San Diego Hlth Sci, Dept Neurosci, La Jolla, CA USA. [Kesari, Santosh] UC San Diego Hlth Sci, Dept Radiat Med, La Jolla, CA USA. [Kesari, Santosh] UC San Diego Hlth Sci, Dept Appl Sci, La Jolla, CA USA. [Chmura, Steven J.] Univ Chicago, Chicago, IL 60637 USA. [Mehta, Minesh] Univ Maryland Med Syst, Baltimore, MD USA. RP Robins, HI (reprint author), Univ Wisconsin, Paul Carbone Comprehens Canc Ctr, 600 Highland Ave, Madison, WI 53792 USA. EM hirobins@wisc.edu RI Gilbert, Mark/J-7494-2016; OI Gilbert, Mark/0000-0003-2556-9722; mehta, minesh/0000-0002-4812-5713 FU National Cancer Institute (NCI) [U10CA21661, U10CA180868, U10CA180822, U10CA37422, UG1CA189867]; AbbVie FX This project was supported by Grants U10CA21661, U10CA180868, U10CA180822, U10CA37422, and UG1CA189867 from the National Cancer Institute (NCI) and AbbVie. NR 19 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD JAN PY 2016 VL 126 IS 2 BP 309 EP 316 DI 10.1007/s11060-015-1966-z PG 8 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DB7WS UT WOS:000368728300011 PM 26508094 ER PT J AU Spinner, JL Hasenkrug, AM Shannon, JG Kobayashi, SD Hinnebusch, BJ AF Spinner, Justin L. Hasenkrug, Aaron M. Shannon, Jeffrey G. Kobayashi, Scott D. Hinnebusch, B. Joseph TI Role of the Yersinia YopJ protein in suppressing interleukin-8 secretion by human polymorphonuclear leukocytes SO MICROBES AND INFECTION LA English DT Article DE Neutrophil; IL-8; CXCL8; YopJ; Yersinia; Plague ID NF-KAPPA-B; BUBONIC PLAGUE; LYMPH-NODE; SIGNALING RESPONSES; ENTEROCOLITICA O-8; ADAPTIVE IMMUNITY; EPITHELIAL-CELLS; III SECRETION; AIL PROTEIN; RAT MODEL AB Polymorphonuclear leukocytes, in addition to their direct bactericidal activities, produce cytokines involved in the activation and regulation of the innate and adaptive immune response to infection. In this study we evaluated the cytoldne response of human PMNs following incubation with the pathogenic Yersinia species. Yersinia pestis strains with the pCD1 virulence plasmid, which encodes cytotoxic Yop proteins that are translocated into host cells, stimulated little or no cytokine production compared to pCD1-negative strains. In particular, PMNs incubated with pCD1-negative Y. pestis secreted 1000-fold higher levels of interleukin-8 (IL-8 or CXCL8), a proinflammatory chemokine important for PMN recruitment and activation. Deletion of yopE,-H,-T,-M or ypkA had no effect on pCD1-dependent inhibition, whereas deletion of yopJ resulted in significantly increased IL-8 production. Like Y. pestis, the enteropathogenic Yersinia species inhibited IL-8 secretion by PMNs, and strains lacking the virulence plasmid induced high levels of IL-8. Our results show that virulence plasmid-encoded effector Yops, particularly YopJ, prevent IL-8 secretion by human PMNs. Suppression of the chemotactic IL-8 response by Y. pestis may contribute to the delayed PMN recruitment to the infected lymph node that typifies bubonic plague. Published by Elsevier Masson SAS on behalf of Institut Pasteur. C1 [Spinner, Justin L.; Hasenkrug, Aaron M.; Shannon, Jeffrey G.; Hinnebusch, B. Joseph] NIAID, NIH, Lab Zoonot Pathogens, Rocky Mt Labs, 905 S 4th St, Hamilton, MT 59840 USA. [Kobayashi, Scott D.] NIAID, NIH, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, 905 S 4th St, Hamilton, MT 59840 USA. [Spinner, Justin L.] GlaxoSmithKline, 553 Old Corvallis Rd, Hamilton, MT 59840 USA. [Hasenkrug, Aaron M.] New York Med Coll, Valhalla, NY 10595 USA. RP Hinnebusch, BJ (reprint author), NIAID, NIH, Lab Zoonot Pathogens, Rocky Mt Labs, 905 S 4th St, Hamilton, MT 59840 USA. EM jhinnebusch@niaid.nih.gov FU Division of Intramural Research, NIAID, NIH FX This research was supported by the Division of Intramural Research, NIAID, NIH. We thank Frank DeLeo, Addie Porter and Brett Freedman for providing isolated human PMNs and blood samples. We thank Kim Hasenkrug, Natalia Malachowa, and Chris Bosio for critical review of the manuscript. NR 44 TC 3 Z9 3 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 EI 1769-714X J9 MICROBES INFECT JI Microbes Infect. PD JAN PY 2016 VL 18 IS 1 BP 21 EP 29 DI 10.1016/j.micinf.2015.08.015 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DC1DU UT WOS:000368957800003 PM 26361732 ER PT S AU Copeland, WC Kasiviswanathan, R Longley, MJ AF Copeland, William C. Kasiviswanathan, Rajesh Longley, Matthew J. BE McKenzie, M TI Analysis of Translesion DNA Synthesis by the Mitochondrial DNA Polymerase gamma SO MITOCHONDRIAL DNA: METHODS AND PROTOCOLS, 3RD EDITION SE Methods in Molecular Biology LA English DT Article; Book Chapter DE DNA polymerase gamma; Mitochondrial DNA polymerase; DNA replication; Translesion synthesis; DNA repair; Enzyme assays; POLG ID ACCESSORY SUBUNIT; SEQUENTIAL ACTION; BYPASS; ADDUCT; REPLICATION; FIDELITY; DISEASE; DEOXYGUANOSINE; EFFICIENCY; MUTATIONS AB Mitochondrial DNA is replicated by the nuclear-encoded DNA polymerase gamma (pol gamma) which is composed of a single 140 kDa catalytic subunit and a dimeric 55 kDa accessory subunit. Mitochondrial DNA is vulnerable to various forms of damage, including several types of oxidative lesions, UV-induced photoproducts, chemical adducts from environmental sources, as well as alkylation and inter-strand cross-links from chemotherapy agents. Although many of these lesions block DNA replication, pol gamma can bypass some lesions by nucleotide incorporation opposite a template lesion and further extension of the DNA primer past the lesion. This process of translesion synthesis (TLS) by pol gamma can occur in either an error-free or an error-prone manner. Assessment of TLS requires extensive analysis of oligonucleotide substrates and replication products by denaturing polyacrylamide sequencing gels. This chapter presents protocols for the analysis of translesion DNA synthesis. C1 [Copeland, William C.; Kasiviswanathan, Rajesh; Longley, Matthew J.] NIEHS, Mitochondrial DNA Replicat Grp, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Copeland, WC (reprint author), NIEHS, Mitochondrial DNA Replicat Grp, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. FU Intramural NIH HHS [Z01 ES065080-13, Z01 ES065078-15]; NIEHS NIH HHS [Z01 ES065080, Z01 ES065078] NR 26 TC 0 Z9 0 U1 0 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-3040-1; 978-1-4939-3039-5 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1351 BP 19 EP 26 DI 10.1007/978-1-4939-3040-1_2 D2 10.1007/978-1-4939-3040-1 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BE2DX UT WOS:000369077400003 PM 26530671 ER PT J AU Caterino, M Chandler, RJ Sloan, JL Dorko, K Cusmano-Ozog, K Ingenito, L Strom, SC Imperlini, E Scolamiero, E Venditti, CP Ruoppolo, M AF Caterino, Marianna Chandler, Randy J. Sloan, Jennifer L. Dorko, Kenneth Cusmano-Ozog, Kristina Ingenito, Laura Strom, Stephen C. Imperlini, Esther Scolamiero, Emanuela Venditti, Charles P. Ruoppolo, Margherita TI The proteome of methylmalonic acidemia (MMA): the elucidation of altered pathways in patient livers SO MOLECULAR BIOSYSTEMS LA English DT Article ID MITOCHONDRIAL DYSFUNCTION; KIDNEY TRANSPLANTATION; PROPIONIC ACIDURIA; GLOBUS-PALLIDUS; MANAGEMENT; DEFICIENCY; DISEASE; HUMANS AB Methylmalonic acidemia (MMA) is a heterogeneous and severe autosomal recessive inborn error of metabolism most commonly caused by the deficient activity of the vitamin B12 dependent enzyme, methylmalonyl-CoA mutase (MUT). The main treatment for MMA patients is the dietary restriction of propiogenic amino acids and carnitine supplementation. Despite treatment, the prognosis for vitamin B12 non-responsive patients remains poor and is associated with neonatal lethality, persistent morbidity and decreased life expectancy. While multi-organ pathology is a feature of MMA, the liver is severely impacted by mitochondrial dysfunction which likely underlies the metabolic instability experienced by the patients. Liver and/or combined liver/kidney transplantation is therefore sometimes performed in severely affected patients. Using liver specimens from donors and MMA patients undergoing elective liver transplantation collected under a dedicated natural history protocol (clinicaltrials.gov: NCT00078078), we employed proteomics to characterize the liver pathology and impaired hepatic metabolism observed in the patients. Pathway analysis revealed perturbations of enzymes involved in energy metabolism, gluconeogenesis and Krebs cycle anaplerosis. Our findings identify new pathophysiologic and therapeutic targets that could be valuable for designing alternative therapies to alleviate clinical manifestations seen in this disorder. C1 [Caterino, Marianna; Ruoppolo, Margherita] Univ Naples Federico II, Dipartimento Med Mol & Biotecnol Med, Via Pansini 5, I-80131 Naples, Italy. [Caterino, Marianna; Ingenito, Laura; Imperlini, Esther; Scolamiero, Emanuela; Ruoppolo, Margherita] CEINGE Biotecnol Avanzate, Naples, Italy. [Caterino, Marianna; Ruoppolo, Margherita] Assoc Culturale DiSciMuS RCF, I-80026 Naples, Italy. [Chandler, Randy J.; Sloan, Jennifer L.; Venditti, Charles P.] NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Dorko, Kenneth] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66103 USA. [Cusmano-Ozog, Kristina] Childrens Natl Med Ctr, Div Genet & Metab, Washington, DC 20010 USA. [Strom, Stephen C.] Karolinska Inst, Dept Pathol, Dept Lab Med, S-10401 Stockholm, Sweden. RP Ruoppolo, M (reprint author), Univ Naples Federico II, Dipartimento Med Mol & Biotecnol Med, Via Pansini 5, I-80131 Naples, Italy.; Ruoppolo, M (reprint author), CEINGE Biotecnol Avanzate, Naples, Italy.; Ruoppolo, M (reprint author), Assoc Culturale DiSciMuS RCF, I-80026 Naples, Italy.; Venditti, CP (reprint author), NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM venditti@mail.nih.gov RI Imperlini, Esther/K-4513-2016 FU Intramural Research Program of the National Human Genome Research Institute, NIH; Torsten och Ragnar Soderberg Stiftelse; NIGMS/NIH COBRE grant [P20 GM103549]; Vetenskapradet, the Swedish Research Council FX RJC, JLS, and CPV were supported by the Intramural Research Program of the National Human Genome Research Institute, NIH. SS was supported by the Torsten och Ragnar Soderberg Stiftelse. KD was supported by the NIGMS/NIH COBRE grant P20 GM103549. SS was supported by the Torsten och Ragnar Soderberg Stiftelse and the Vetenskapradet, the Swedish Research Council. NR 28 TC 2 Z9 2 U1 2 U2 6 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1742-206X EI 1742-2051 J9 MOL BIOSYST JI Mol. Biosyst. PY 2016 VL 12 IS 2 BP 566 EP 574 DI 10.1039/c5mb00736d PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DB9TD UT WOS:000368858900026 PM 26672496 ER PT J AU Lin, LS Yang, XY Niu, G Song, JB Yang, HH Chen, XY AF Lin, Li-Sen Yang, Xiangyu Niu, Gang Song, Jibin Yang, Huang-Hao Chen, Xiaoyuan TI Dual-enhanced photothermal conversion properties of reduced graphene oxide-coated gold superparticles for light-triggered acoustic and thermal theranostics SO NANOSCALE LA English DT Article ID MESSENGER-RNA DETECTION; THERAPY; NANOPARTICLES; CANCER; NANOCRYSTALS; NANOSHEETS; NANORODS; PLATFORM; NANOCOMPOSITE; NANOVESICLES AB A rational design of highly efficient photothermal agents that possess excellent light-to-heat conversion properties is a fascinating topic in nanotheranostics. Herein, we present a facile route to fabricate size-tunable reduced graphene oxide (rGO)-coated gold superparticles (rGO-GSPs) and demonstrate their dual-enhanced photothermal conversion properties for photoacoustic imaging and photothermal therapy. For the first time, graphene oxide (GO) was directly used as an emulsifying agent for the preparation of gold superparticles (GSPs) with near-infrared absorption by the emulsion method. Moreover, GO spontaneously deposited on the surface of GSPs could also act as the precursor of the rGO shell. Importantly, both the plasmonic coupling of the self-assembled gold nanoparticles and the interaction between GSPs and rGO endow rGO-GSPs with enhanced photothermal conversion properties, allowing rGO-GSPs to be used for sensitive photoacoustic detection and efficient photothermal ablation of tumours in vivo. This study provides a facile approach to prepare colloidal superparticles-graphene hybrid nanostructures and will pave the way toward the design and optimization of photothermal nanomaterials with improved properties for theranostic applications. C1 [Lin, Li-Sen; Yang, Huang-Hao] Fuzhou Univ, Coll Chem, Key Lab Anal & Detect Technol Food Safety MOE, Fuzhou 350108, Peoples R China. [Lin, Li-Sen; Yang, Xiangyu; Niu, Gang; Song, Jibin; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. RP Yang, HH (reprint author), Fuzhou Univ, Coll Chem, Key Lab Anal & Detect Technol Food Safety MOE, Fuzhou 350108, Peoples R China.; Song, JB; Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. EM jibin.song@nih.gov; hhyang@fio.org.cn; shawn.chen@nih.gov FU National Basic Research Program of China [2010CB732403, 2014CB744503]; National Natural Science Foundation of China [21125524, 21475026]; Intramural Research Program (IRP) of the NIBIB, NIH FX This work was supported by the National Basic Research Program of China (no. 2010CB732403, 2014CB744503), the National Natural Science Foundation of China (no. 21125524, 21475026), and the Intramural Research Program (IRP) of the NIBIB, NIH. NR 41 TC 8 Z9 8 U1 23 U2 52 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-3364 EI 2040-3372 J9 NANOSCALE JI Nanoscale PY 2016 VL 8 IS 4 BP 2116 EP 2122 DI 10.1039/c5nr07552a PG 7 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA DB9TX UT WOS:000368860900042 PM 26726809 ER PT J AU Ying, TL Prabakaran, P Dimitrov, DS AF Ying, Tianlei Prabakaran, Ponraj Dimitrov, Dimiter S. TI A systems approach to HIV-1 vaccines SO NATURE BIOTECHNOLOGY LA English DT Editorial Material AB Understanding the full breadth of immune responses that protect against HIV-1 may speed vaccine development. C1 [Ying, Tianlei] Fudan Univ, Sch Basic Med Sci, Minist Educ, Key Lab Med Mol Virol, Shanghai 200433, Peoples R China. [Ying, Tianlei] Fudan Univ, Sch Basic Med Sci, Minist Hlth, Shanghai 200433, Peoples R China. [Prabakaran, Ponraj] Intrexon Corp, Germantown, GA USA. [Dimitrov, Dimiter S.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Dimitrov, DS (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM dimiter.dimitrov@nih.gov NR 11 TC 0 Z9 0 U1 3 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JAN PY 2016 VL 34 IS 1 BP 44 EP 46 PG 3 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DB8HQ UT WOS:000368758200024 PM 26744981 ER PT J AU Elkins, JM Fedele, V Szklarz, M Azeez, KRA Salah, E Mikolajczyk, J Romanov, S Sepetov, N Huang, XP Roth, BL Zen, AA Fourches, D Muratov, E Tropsha, A Morris, J Teicher, BA Kunkel, M Polley, E Lackey, KE Atkinson, FL Overington, JP Bamborough, P Muller, S Price, DJ Willson, TM Drewry, DH Knapp, S Zuercher, WJ AF Elkins, Jonathan M. Fedele, Vita Szklarz, Marta Azeez, Kamal R. Abdul Salah, Eidarus Mikolajczyk, Jowita Romanov, Sergei Sepetov, Nikolai Huang, Xi-Ping Roth, Bryan L. Zen, Ayman Al Haj Fourches, Denis Muratov, Eugene Tropsha, Alex Morris, Joel Teicher, Beverly A. Kunkel, Mark Polley, Eric Lackey, Karen E. Atkinson, Francis L. Overington, John P. Bamborough, Paul Mueller, Susanne Price, Daniel J. Willson, Timothy M. Drewry, David H. Knapp, Stefan Zuercher, William J. TI Comprehensive characterization of the Published Kinase Inhibitor Set SO NATURE BIOTECHNOLOGY LA English DT Article ID DRUG DISCOVERY; PROTEIN-KINASE; POTENT INHIBITORS; INTERACTION MAP; IN-VITRO; SELECTIVITY; KINOME; CANCER; ANGIOGENESIS; SCREEN AB Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein-coupled receptors and in cellular assays of cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome. C1 [Elkins, Jonathan M.; Fedele, Vita; Szklarz, Marta; Azeez, Kamal R. Abdul; Salah, Eidarus; Mueller, Susanne; Knapp, Stefan] Univ Oxford, Nuffield Dept Clin Med, Struct Genom Consortium & Target Discovery Inst, Old Rd Campus, Oxford, England. [Mikolajczyk, Jowita; Romanov, Sergei; Sepetov, Nikolai] Nanosyn Inc, Santa Clara, CA USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, Natl Inst Mental Hlth Psychoact Act Drug Screenin, NIMH PDSP,Dept Pharmacol, Chapel Hill, NC USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, Div Chem Biol & Med Chem, Chapel Hill, NC USA. [Zen, Ayman Al Haj] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, British Heart Fdn Ctr Res Excellence, Oxford, England. [Fourches, Denis; Muratov, Eugene; Tropsha, Alex] Univ N Carolina, Div Chem Biol & Med Chem, UNC Eshelman Sch Pharm, Lab Mol Modeling, Chapel Hill, NC USA. [Morris, Joel; Teicher, Beverly A.; Kunkel, Mark; Polley, Eric] NCI, Div Canc Treatment & Diag, Rockville, MD USA. [Lackey, Karen E.] Med Univ S Carolina, Charleston, SC 29425 USA. [Atkinson, Francis L.; Overington, John P.] EMBL EBI, Wellcome Trust Genome Campus, Cambridge, England. [Bamborough, Paul] GlaxoSmithKline, Chem Sci, Stevenage, Herts, England. [Price, Daniel J.; Willson, Timothy M.; Drewry, David H.; Zuercher, William J.] GlaxoSmithKline, Chem Sci, Res Triangle Pk, NC USA. [Knapp, Stefan] Goethe Univ Frankfurt, Inst Pharmazeut Chem, Georg Voigt Str 14, Frankfurt, Germany. [Knapp, Stefan] Buchmann Inst Mol Life Sci BMLS, Frankfurt, Germany. [Overington, John P.; Willson, Timothy M.; Drewry, David H.; Zuercher, William J.] Novartis Vaccines & Diagnost, Holly Springs, NC USA. [Fourches, Denis] N Carolina State Univ, Dept Chem, Bioinformat Res Ctr, Box 8204, Raleigh, NC 27695 USA. [Overington, John P.] Stratified Med, London, England. [Drewry, David H.] Meryx Pharmaceut, Chapel Hill, NC USA. [Willson, Timothy M.; Zuercher, William J.] Univ N Carolina, UNC Eshelman Sch Pharm, SGC UNC, Div Chem Biol & Med Chem, Chapel Hill, NC USA. RP Drewry, DH; Zuercher, WJ (reprint author), GlaxoSmithKline, Chem Sci, Res Triangle Pk, NC USA.; Knapp, S (reprint author), Goethe Univ Frankfurt, Inst Pharmazeut Chem, Georg Voigt Str 14, Frankfurt, Germany.; Knapp, S (reprint author), Buchmann Inst Mol Life Sci BMLS, Frankfurt, Germany.; Drewry, DH; Zuercher, WJ (reprint author), Novartis Vaccines & Diagnost, Holly Springs, NC USA. EM david.drewry@meryxpharma.com; knapp@pharmchem.uni-frankfurt.de; william.zuercher@unc.edu RI Muratov, Eugene/C-4454-2014; Fachbereich14, Dekanat/C-8553-2015; OI Muratov, Eugene/0000-0003-4616-7036; Elkins, Jon/0000-0003-2858-8929; Knapp, Stefan/0000-0001-5995-6494; Muller-Knapp, Susanne/0000-0003-2402-4157; Overington, John/0000-0002-5859-1064 FU AbbVie; Bayer Pharma AG; Boehringer Ingelheim; Canada Foundation for Innovation; Eshelman Institute for Innovation; Genome Canada; Innovative Medicines Initiative (EU/EFPIA); Janssen; Merck Co.; Novartis Pharma AG; Ontario Ministry of Economic Development and Innovation; Pfizer; Sao Paulo Research Foundation-FAPESP; Takeda; Wellcome Trust; BHF Centre of Research Excellence, Oxford [RE/13/1/30181] FX The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA), Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, Sao Paulo Research Foundation-FAPESP, Takeda, and Wellcome Trust. A.A.H.Z. acknowledges support from the BHF Centre of Research Excellence, Oxford (RE/13/1/30181). NR 49 TC 16 Z9 16 U1 6 U2 20 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JAN PY 2016 VL 34 IS 1 BP 95 EP 103 DI 10.1038/nbt.3374 PG 9 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DB8HQ UT WOS:000368758200033 PM 26501955 ER PT J AU Huang, RL Xia, MH Sakamuru, S Zhao, JH Shahane, SA Attene-Ramos, M Zhao, TG Austin, CP Simeonov, A AF Huang, Ruili Xia, Menghang Sakamuru, Srilatha Zhao, Jinghua Shahane, Sampada A. Attene-Ramos, Matias Zhao, Tongan Austin, Christopher P. Simeonov, Anton TI Modelling the Tox21 10 K chemical profiles for in vivo toxicity prediction and mechanism characterization SO NATURE COMMUNICATIONS LA English DT Article ID ENVIRONMENTAL CHEMICALS; SIGNALING PATHWAY; CELL-LINES; THROUGHPUT; ASSAYS; CYTOTOXICITY; VALIDATION; PLATFORM; RECEPTOR; LIBRARY AB Target-specific, mechanism-oriented in vitro assays post a promising alternative to traditional animal toxicology studies. Here we report the first comprehensive analysis of the Tox21 effort, a large-scale in vitro toxicity screening of chemicals. We test similar to 10,000 chemicals in triplicates at 15 concentrations against a panel of nuclear receptor and stress response pathway assays, producing more than 50 million data points. Compound clustering by structure similarity and activity profile similarity across the assays reveals structure-activity relationships that are useful for the generation of mechanistic hypotheses. We apply structural information and activity data to build predictive models for 72 in vivo toxicity end points using a cluster-based approach. Models based on in vitro assay data perform better in predicting human toxicity end points than animal toxicity, while a combination of structural and activity data results in better models than using structure or activity data alone. Our results suggest that in vitro activity profiles can be applied as signatures of compound mechanism of toxicity and used in prioritization for more in-depth toxicological testing. C1 [Huang, Ruili; Xia, Menghang; Sakamuru, Srilatha; Zhao, Jinghua; Shahane, Sampada A.; Attene-Ramos, Matias; Zhao, Tongan; Austin, Christopher P.; Simeonov, Anton] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA. RP Huang, RL (reprint author), NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM huangru@mail.nih.gov FU Intramural Research Programs of the National Toxicology Program, National Institute of Environmental Health Sciences [Y2-ES-7020-01]; US Environmental Protection Agency [Y3-HG-7026-03]; National Center for Advancing Translational Sciences, National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Toxicology Program (Interagency agreement #Y2-ES-7020-01), National Institute of Environmental Health Sciences, the US Environmental Protection Agency (Interagency Agreement #Y3-HG-7026-03) and the National Center for Advancing Translational Sciences, National Institutes of Health. We also thank Nicole Miller, Samuel Michael and Carleen Klumpp-Thomas for assisting with the screens, Paul Shinn, Misha Itkin and Danielle VanLeer for compound management and William Leister for the Tox21 10K library quality control. NR 39 TC 10 Z9 10 U1 14 U2 19 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 JAN PY 2016 VL 7 AR 10425 DI 10.1038/ncomms10425 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC2BQ UT WOS:000369022600008 PM 26811972 ER PT J AU Lee, B Koo, J Jun, JY Gavrilova, O Lee, Y Seo, AY Taylor-Douglas, DC Adler-Wailes, DC Chen, FY Gardner, R Koutzoumis, D Kazemzadeh, RS Roberson, RB Yanovski, JA AF Lee, Bonggi Koo, Jashin Jun, Joo Yun Gavrilova, Oksana Lee, Yongjun Seo, Arnold Y. Taylor-Douglas, Dezmond C. Adler-Wailes, Diane C. Chen, Faye Gardner, Ryan Koutzoumis, Dimitri Kazemzadeh, Roya Sherafat Roberson, Robin B. Yanovski, Jack A. TI A mouse model for a partially inactive obesity-associated human MC3R variant SO NATURE COMMUNICATIONS LA English DT Article ID MELANOCORTIN-3 RECEPTOR GENE; MESENCHYMAL STEM-CELLS; PROTEIN-COUPLED RECEPTOR; ADIPOSE-TISSUE; INSULIN SENSITIVITY; ADIPONECTIN; RESISTANCE; TRANSLATION; SYSTEM; MICE AB We previously reported children homozygous for two MC3R sequence variants (C17A+G241A) have greater fat mass than controls. Here we show, using homozygous knock-in mouse models in which we replace murine Mc3r with wild-type human (MC3R(hWT/hWT)) and double-mutant (C17A+G241A) human (MC3R(hDM/hDM)) MC3R, that MC3R(hDM/hDM) have greater weight and fat mass, increased energy intake and feeding efficiency, but reduced length and fat-free mass compared with MC3R(hWT/hWT). MC3R(hDM/hDM) mice do not have increased adipose tissue inflammatory cell infiltration or greater expression of inflammatory markers despite their greater fat mass. Serum adiponectin levels are increased in MC3R(hDM/hDM) mice and MC3R(hDM/hDM) human subjects. MC3R(hDM/hDM) bone- and adipose tissue-derived mesenchymal stem cells (MSCs) differentiate into adipocytes that accumulate more triglyceride than MC3R(hWT/hWT) MSCs. MC3R(hDM/hDM) impacts nutrient partitioning to generate increased adipose tissue that appears metabolically healthy. These data confirm the importance of MC3R signalling in human metabolism and suggest a previously-unrecognized role for the MC3R in adipose tissue development. C1 [Lee, Bonggi; Koo, Jashin; Jun, Joo Yun; Taylor-Douglas, Dezmond C.; Adler-Wailes, Diane C.; Chen, Faye; Gardner, Ryan; Koutzoumis, Dimitri; Kazemzadeh, Roya Sherafat; Roberson, Robin B.; Yanovski, Jack A.] NICHD, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. [Gavrilova, Oksana] NIDDK, Mouse Metab Core Lab, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. [Lee, Yongjun] NICHD, Heritable Disorders Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. [Seo, Arnold Y.] NICHD, Cell Biol & Metab Program, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. [Koo, Jashin] KBIO, 123 Osongsaengmyeong Ro, Cheongju 28160, Chungbuk, South Korea. [Adler-Wailes, Diane C.] NICHD, Sect Eukaryot DNA Replicat & Gene Regulat, Program Genom Differentiat, NIH, 6 Ctr Dr, Bethesda, MD 20892 USA. [Lee, Bonggi] Pusan Natl Univ, Coll Pharm, Busan, South Korea. RP Yanovski, JA (reprint author), NICHD, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jy15i@nih.gov FU intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [1ZIAHD000641]; NIH Clinical Center Bench to Bedside Program; National Institute of Minority Health and Health Disparities; intramural research program of NIDDK FX This research was supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), grant 1ZIAHD000641 (to J.A.Y.), with supplemental funding from the NIH Clinical Center Bench to Bedside Program and the National Institute of Minority Health and Health Disparities. Dr Gavrilova is supported by the intramural research program of NIDDK. B.L. and J.A.Y. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The opinions and assertions expressed herein are those of the authors and are not to be construed as reflecting the views of the US Public Health Service, the National Institutes of Health or the US Department of Health and Human Services. We gratefully acknowledge the assistance of Dr Heiner Westphal and Mr Alexander Grinberg (NICHD) in the generation of the MC3R mouse knock-in models and the assistance of Tatyana Chanturiya (NIDDK) for technical support of indirect calorimetry and assays. NR 54 TC 6 Z9 6 U1 3 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JAN PY 2016 VL 7 AR 10522 DI 10.1038/ncomms10522 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC2CJ UT WOS:000369024500001 PM 26818770 ER PT J AU Nakajima, KI Cui, ZZ Li, C Meister, J Cui, YH Fu, O Smith, AS Jain, S Lowell, BB Krashes, MJ Wess, J AF Nakajima, Ken-ichiro Cui, Zhenzhong Li, Chia Meister, Jaroslawna Cui, Yinghong Fu, Ou Smith, Adam S. Jain, Shalini Lowell, Bradford B. Krashes, Michael J. Wess, Juergen TI Gs-coupled GPCR signalling in AgRP neurons triggers sustained increase in food intake SO NATURE COMMUNICATIONS LA English DT Article ID KRUPPEL-LIKE FACTOR; PROTEIN-KINASE-A; GENOME-WIDE ANALYSIS; ARCUATE NUCLEUS; HYPOTHALAMIC NEURONS; RECEPTOR EXPRESSION; DESIGNER RECEPTORS; ENERGY-BALANCE; ACTIVATION; GENE AB Agouti-related peptide (AgRP) neurons of the hypothalamus play a key role in regulating food intake and body weight, by releasing three different orexigenic molecules: AgRP; GABA; and neuropeptide Y. AgRP neurons express various G protein-coupled receptors (GPCRs) with different coupling properties, including G(s)-linked GPCRs. At present, the potential role of G(s)-coupled GPCRs in regulating the activity of AgRP neurons remains unknown. Here we show that the activation of G(s)-coupled receptors expressed by AgRP neurons leads to a robust and sustained increase in food intake. We also provide detailed mechanistic data linking the stimulation of this class of receptors to the observed feeding phenotype. Moreover, we show that this pathway is clearly distinct from other GPCR signalling cascades that are operative in AgRP neurons. Our data suggest that drugs able to inhibit this signalling pathway may become useful for the treatment of obesity. C1 [Nakajima, Ken-ichiro; Cui, Zhenzhong; Meister, Jaroslawna; Cui, Yinghong; Jain, Shalini; Wess, Juergen] Natl Inst Diabet & Digest & Kidney Dis, Bioorgan Chem Lab, Mol Signaling Sect, Bethesda, MD 20892 USA. [Li, Chia; Krashes, Michael J.] Natl Inst Diabet & Digest & Kidney Dis, Diabet Endocrine & Obes Branch, Bethesda, MD 20892 USA. [Nakajima, Ken-ichiro; Fu, Ou] Univ Tokyo, Grad Sch Agr & Life Sci, Dept Appl Biol Chem, Bunkyo Ku, Tokyo 1138657, Japan. [Smith, Adam S.] NIMH, Sect Neural Gene Express, Bethesda, MD 20892 USA. [Lowell, Bradford B.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Endocrinol,Dept Med, Boston, MA 02115 USA. RP Wess, J (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Bioorgan Chem Lab, Mol Signaling Sect, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov OI Smith, Adam/0000-0003-2837-6205 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH; Council for Science, Technology, and Innovation (CSTI, Japan); Cross-ministerial Strategic Innovation Promotion Program (SIP); Technologies for Creating Next-Generation Agriculture, Forestry and Fisheries FX This research was funded by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH. This work was also partially supported by the Council for Science, Technology, and Innovation (CSTI, Japan), Cross-ministerial Strategic Innovation Promotion Program (SIP), Technologies for Creating Next-Generation Agriculture, Forestry and Fisheries (K.N. and O.F.) and the Lotte Shigemitsu Prize (K.N.). GT1-7 cells were kindly provided by Dr Pamela Mellon (UCSD, CA). We are grateful to Drs W. Scott Young (NIMH, NIH) and Oksana Gavrilova (NIDDK, NIH) for advice and helpful discussions. We also thank Dr Bryan Roth (UNC, Chapel Hill, NC) for providing the pAAV-hSyn-DIO hM3Dq-mCherry plasmid. Dr Rebecca Berdeaux (University of Texas Health Science Center, Houston, TX) for providing reagents and helpful advice regarding the luciferase reporter assays, Dr Jeff Reece (NIDDK, NIH) for his help with the confocal microscopy studies, and Dr Pablo Enriori (Monash University, Australia) for providing the protocol for AgRP release assay. NR 53 TC 11 Z9 11 U1 3 U2 8 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 JAN PY 2016 VL 7 AR 10268 DI 10.1038/ncomms10268 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC2AX UT WOS:000369020700003 PM 26743492 ER PT J AU Pattaro, C Teumer, A Gorski, M Chu, AY Li, M Mijatovic, V Garnaas, M Tin, A Sorice, R Li, Y Taliun, D Olden, M Foster, M Yang, Q Chen, MH Pers, TH Johnson, AD Ko, YA Fuchsberger, C Tayo, B Nalls, M Feitosa, MF Isaacs, A Dehghan, A d'Adamo, P Adeyemo, A Dieffenbach, AK Zonderman, AB Nolte, IM van der Most, PJ Wright, AF Shuldiner, AR Morrison, AC Hofman, A Smith, AV Dreisbach, AW Franke, A Uitterlinden, AG Metspalu, A Tonjes, A Lupo, A Robino, A Johansson, A Demirkan, A Kollerits, B Freedman, BI Ponte, B Oostra, BA Paulweber, B Kramer, BK Mitchell, BD Buckley, BM Peralta, CA Hayward, C Helmer, C Rotimi, CN Shaffer, CM Muller, C Sala, C van Duijn, CM Saint-Pierre, A Ackermann, D Shriner, D Ruggiero, D Toniolo, D Lu, YC Cusi, D Czamara, D Ellinghaus, D Siscovick, DS Ruderfer, D Gieger, C Grallert, H Rochtchina, E Atkinson, EJ Holliday, EG Boerwinkle, E Salvi, E Bottinger, EP Murgia, F Rivadeneira, F Ernst, F Kronenberg, F Hu, FB Navis, GJ Curhan, GC Ehret, GB Homuth, G Coassin, S Thun, GA Pistis, G Gambaro, G Malerba, G Montgomery, GW Eiriksdottir, G Jacobs, G Li, G Wichmann, HE Campbell, H Schmidt, H Wallaschofski, H Volzke, H Brenner, H Kroemer, HK Kramer, H Lin, HH Leach, IM Ford, I Guessous, I Rudan, I Prokopenko, I Borecki, I Heid, IM Kolcic, I Persico, I Jukema, JW Wilson, JF Felix, JF Divers, J Lambert, JC Stafford, JM Gaspoz, JM Smith, JA Faul, JD Wang, JJ Ding, JZ Hirschhorn, JN Attia, J Whitfield, JB Chalmers, J Viikari, J Coresh, J Denny, JC Karjalainen, J Fernandes, JK Endlich, K Butterbach, K Keene, KL Lohman, K Portas, L Launer, LJ Lyytikainen, LP Yengo, L Franke, L Ferrucci, L Rose, LM Kedenko, L Rao, M Struchalin, M Kleber, ME Cavalieri, M Haun, M Cornelis, MC Ciullo, M Pirastu, M de Andrade, M McEvoy, MA Woodward, M Adam, M Cocca, M Nauck, M Imboden, M Waldenberger, M Pruijm, M Metzger, M Stumvoll, M Evans, MK Sale, MM Kahonen, M Boban, M Bochud, M Rheinberger, M Verweij, N Bouatia-Naji, N Martin, NG Hastie, N Probst-Hensch, N Soranzo, N Devuyst, O Raitakari, O Gottesman, O Franco, OH Polasek, O Gasparini, P Munroe, PB Ridker, PM Mitchell, P Muntner, P Meisinger, C Smit, JH Kovacs, P Wild, PS Froguel, P Rettig, R Magi, R Biffar, R Schmidt, R Middelberg, RPS Carroll, RJ Penninx, BW Scott, RJ Katz, R Sedaghat, S Wild, SH Kardia, SLR Ulivi, S Hwang, SJ Enroth, S Kloiber, S Trompet, S Stengel, B Hancock, SJ Turner, ST Rosas, SE Stracke, S Harris, TB Zeller, T Zemunik, T Lehtimaki, T Illig, T Aspelund, T Nikopensius, T Esko, T Tanaka, T Gyllensten, U Volker, U Emilsson, V Vitart, V Aalto, V Gudnason, V Chouraki, V Chen, WM Igl, W Marz, W Koenig, W Lieb, W Loos, RJF Liu, YM Snieder, H Pramstaller, PP Parsa, A O'Connell, JR Susztak, K Hamet, P Tremblay, J de Boer, IH Boger, CA Goessling, W Chasman, DI Kottgen, A Kao, WHL Fox, CS AF Pattaro, Cristian Teumer, Alexander Gorski, Mathias Chu, Audrey Y. Li, Man Mijatovic, Vladan Garnaas, Maija Tin, Adrienne Sorice, Rossella Li, Yong Taliun, Daniel Olden, Matthias Foster, Meredith Yang, Qiong Chen, Ming-Huei Pers, Tune H. Johnson, Andrew D. Ko, Yi-An Fuchsberger, Christian Tayo, Bamidele Nalls, Michael Feitosa, Mary F. Isaacs, Aaron Dehghan, Abbas d'Adamo, Pio Adeyemo, Adebowale Dieffenbach, Aida Karina Zonderman, Alan B. Nolte, Ilja M. van der Most, Peter J. Wright, Alan F. Shuldiner, Alan R. Morrison, Alanna C. Hofman, Albert Smith, Albert V. Dreisbach, Albert W. Franke, Andre Uitterlinden, Andre G. Metspalu, Andres Tonjes, Anke Lupo, Antonio Robino, Antonietta Johansson, Asa Demirkan, Ayse Kollerits, Barbara Freedman, Barry I. Ponte, Belen Oostra, Ben A. Paulweber, Bernhard Kraemer, Bernhard K. Mitchell, Braxton D. Buckley, Brendan M. Peralta, Carmen A. Hayward, Caroline Helmer, Catherine Rotimi, Charles N. Shaffer, Christian M. Mueller, Christian Sala, Cinzia van Duijn, Cornelia M. Saint-Pierre, Aude Ackermann, Daniel Shriner, Daniel Ruggiero, Daniela Toniolo, Daniela Lu, Yingchang Cusi, Daniele Czamara, Darina Ellinghaus, David Siscovick, David S. Ruderfer, Douglas Gieger, Christian Grallert, Harald Rochtchina, Elena Atkinson, Elizabeth J. Holliday, Elizabeth G. Boerwinkle, Eric Salvi, Erika Bottinger, Erwin P. Murgia, Federico Rivadeneira, Fernando Ernst, Florian Kronenberg, Florian Hu, Frank B. Navis, Gerjan J. Curhan, Gary C. Ehret, George B. Homuth, Georg Coassin, Stefan Thun, Gian-Andri Pistis, Giorgio Gambaro, Giovanni Malerba, Giovanni Montgomery, Grant W. Eiriksdottir, Gudny Jacobs, Gunnar Li, Guo Wichmann, H-Erich Campbell, Harry Schmidt, Helena Wallaschofski, Henri Voelzke, Henry Brenner, Hermann Kroemer, Heyo K. Kramer, Holly Lin, Honghuang Leach, I. Mateo Ford, Ian Guessous, Idris Rudan, Igor Prokopenko, Inga Borecki, Ingrid Heid, Iris M. Kolcic, Ivana Persico, Ivana Jukema, J. Wouter Wilson, James F. Felix, Janine F. Divers, Jasmin Lambert, Jean-Charles Stafford, Jeanette M. Gaspoz, Jean-Michel Smith, Jennifer A. Faul, Jessica D. Wang, Jie Jin Ding, Jingzhong Hirschhorn, Joel N. Attia, John Whitfield, John B. Chalmers, John Viikari, Jorma Coresh, Josef Denny, Joshua C. Karjalainen, Juha Fernandes, Jyotika K. Endlich, Karlhans Butterbach, Katja Keene, Keith L. Lohman, Kurt Portas, Laura Launer, Lenore J. Lyytikaeinen, Leo-Pekka Yengo, Loic Franke, Lude Ferrucci, Luigi Rose, Lynda M. Kedenko, Lyudmyla Rao, Madhumathi Struchalin, Maksim Kleber, Marcus E. Cavalieri, Margherita Haun, Margot Cornelis, Marilyn C. Ciullo, Marina Pirastu, Mario de Andrade, Mariza McEvoy, Mark A. Woodward, Mark Adam, Martin Cocca, Massimiliano Nauck, Matthias Imboden, Medea Waldenberger, Melanie Pruijm, Menno Metzger, Marie Stumvoll, Michael Evans, Michele K. Sale, Michele M. Kaehoenen, Mika Boban, Mladen Bochud, Murielle Rheinberger, Myriam Verweij, Niek Bouatia-Naji, Nabila Martin, Nicholas G. Hastie, Nick Probst-Hensch, Nicole Soranzo, Nicole Devuyst, Olivier Raitakari, Olli Gottesman, Omri Franco, Oscar H. Polasek, Ozren Gasparini, Paolo Munroe, Patricia B. Ridker, Paul M. Mitchell, Paul Muntner, Paul Meisinger, Christa Smit, Johannes H. Kovacs, Peter Wild, Philipp S. Froguel, Philippe Rettig, Rainer Maegi, Reedik Biffar, Reiner Schmidt, Reinhold Middelberg, Rita P. S. Carroll, Robert J. Penninx, Brenda W. Scott, Rodney J. Katz, Ronit Sedaghat, Sanaz Wild, Sarah H. Kardia, Sharon L. R. Ulivi, Sheila Hwang, Shih-Jen Enroth, Stefan Kloiber, Stefan Trompet, Stella Stengel, Benedicte Hancock, Stephen J. Turner, Stephen T. Rosas, Sylvia E. Stracke, Sylvia Harris, Tamara B. Zeller, Tanja Zemunik, Tatijana Lehtimaeki, Terho Illig, Thomas Aspelund, Thor Nikopensius, Tiit Esko, Tonu Tanaka, Toshiko Gyllensten, Ulf Voelker, Uwe Emilsson, Valur Vitart, Veronique Aalto, Ville Gudnason, Vilmundur Chouraki, Vincent Chen, Wei-Min Igl, Wilmar Maerz, Winfried Koenig, Wolfgang Lieb, Wolfgang Loos, Ruth J. F. Liu, Yongmei Snieder, Harold Pramstaller, Peter P. Parsa, Afshin O'Connell, Jeffrey R. Susztak, Katalin Hamet, Pavel Tremblay, Johanne de Boer, Ian H. Boeger, Carsten A. Goessling, Wolfram Chasman, Daniel I. Koettgen, Anna Kao, W. H. Linda Fox, Caroline S. CA ICBP Consortium AGEN Consortium CARDIOGRAM CHARGe-Heart Failure Grp ECHOGen Consortium TI Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function SO NATURE COMMUNICATIONS LA English DT Article ID GENOME-WIDE ASSOCIATION; FALSE DISCOVERY RATES; STAGE RENAL-DISEASE; SERUM CREATININE; METAANALYSIS; VARIANTS; INDIVIDUALS; POPULATION; RISK; HYPERTENSION AB Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. C1 [Pattaro, Cristian; Taliun, Daniel; Fuchsberger, Christian; Saint-Pierre, Aude; Pramstaller, Peter P.] Med Univ Lubeck, European Acad Bozen Bolzano EURAC, Ctr Biomed, Via Galvani 31, I-39100 Bolzano, Italy. 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[Wichmann, H-Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany. [Wichmann, H-Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany. [Wichmann, H-Erich] Klinikum Grosshadern, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany. [Campbell, Harry; Rudan, Igor; Wilson, James F.; Wild, Sarah H.] Univ Edinburgh, Ctr Populat Hlth Sci, Teviot Pl, Edinburgh EH8 9AG, Midlothian, Scotland. [Schmidt, Helena] Med Univ Graz, Dept Neurol, Inst Mol Biol & Biochem, Austrian Stroke Prevent Study, Harrachgasse 21, A-8010 Graz, Austria. [Wallaschofski, Henri; Nauck, Matthias] Univ Med Greifswald, Inst Clin Chem & Lab Med, Ferdinand Sauerbruch Str, D-17475 Greifswald, Germany. [Wallaschofski, Henri; Voelzke, Henry; Nauck, Matthias; Voelker, Uwe] German Ctr Cardiovasc Res DZHK, Partner Site Greifswald,Ferdinand Sauerbruch St, D-17475 Greifswald, Germany. [Kroemer, Heyo K.] Ernst Moritz Arndt Univ Greifswald, Inst Pharmacol, Friedrich Loeffler Str 23d, D-17487 Greifswald, Germany. [Lin, Honghuang] Boston Univ, Sch Med, 72 East Concord St,B-616, Boston, MA 02118 USA. [Leach, I. Mateo; Verweij, Niek] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, POB 30-001, NL-9700 RB Groningen, Netherlands. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Robertson Ctr, R1122B Level 11,Boyd Orr Bldg, Glasgow G12 8QQ, Lanark, Scotland. [Guessous, Idris; Gaspoz, Jean-Michel] Univ Geneva, Dept Community Med Primary Care & Emergency Med, Div Primary Care Med, Geneva Univ Hosp,Fac Med, CH-1211 Geneva, Switzerland. [Guessous, Idris] Univ Lausanne Hosp, Univ Inst Social & Prevent Med, Community Prevent Unit, Route Corniche 10, CH-1010 Lausanne, Switzerland. [Guessous, Idris] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, 1518 Clifton Rd NE, Atlanta, GA 30322 USA. [Prokopenko, Inga] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London W12 0NN, England. [Kolcic, Ivana; Boban, Mladen; Polasek, Ozren; Zemunik, Tatijana] Univ Split, Sch Med, Croatian Ctr Global Hlth, Soltanska 2, Split 21000, Croatia. [Jukema, J. Wouter; Trompet, Stella] Leiden Univ, Med Ctr, Dept Cardiol, POB 9600, NL-2300 RC Leiden, Netherlands. [Jukema, J. Wouter] Interuniv Cardiol Inst Netherlands ICIN, Moreelsepk 1, NL-3511 EP Utrecht, Netherlands. [Jukema, J. Wouter] Einthoven Lab Expt Vasc Med, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands. [Jukema, J. Wouter] Durrer Ctr Cardiogenet Res, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Divers, Jasmin; Stafford, Jeanette M.] Wake Forest Univ Hlth Sci, Dept Biostat Sci, Div Publ Hlth Sci, 2326 Med Ctr Blvd, Winston Salem, NC 27157 USA. [Lambert, Jean-Charles; Stracke, Sylvia; Chouraki, Vincent] Inst Pasteur, INSERM, U744, 1 Rue Pr, F-59019 Lille, France. [Smith, Jennifer A.; Kardia, Sharon L. R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, 1415 Washington Hts, Ann Arbor, MI 48109 USA. [Faul, Jessica D.] Univ Michigan, Inst Social Res, Survey Res Ctr, 426 Thompson St,3456, Ann Arbor, MI 48104 USA. [Wang, Jie Jin; Mitchell, Paul] Univ Sydney, Westmead Millennium Inst, Ctr Vis Res, Westmead Hosp C24, Sydney, NSW 2145, Australia. [Ding, Jingzhong] Wake Forest Sch Med, Dept Internal Med Geriatr, Med Ctr Blvd, Winston Salem, NC 27157 USA. [Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, 77 Ave Louis Pasteur,NRB 0330, Boston, MA 02115 USA. [Chalmers, John; Woodward, Mark] Univ Sydney, George Inst Global Hlth, Level 10,King George V Bldg,83-117 Missenden Rd, Camperdown, NSW 2050, Australia. [Viikari, Jorma; Woodward, Mark] Univ Turku, Turku Univ Hosp, Dept Med, POB 52, Turku 20521, Finland. [Coresh, Josef; Kao, W. H. Linda] Welch Ctr Prevent Epidemiol & Clin Res, 2024 East Monument St,Suite 2-600, Baltimore, MD 21287 USA. [Denny, Joshua C.; Carroll, Robert J.] Vanderbilt Univ, Sch Med, Eskind Biomed Lib 448, 2209 Garland Ave, Nashville, TN 37212 USA. [Karjalainen, Juha; Franke, Lude] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, POB 72, NL-9700 AB Groningen, Netherlands. [Fernandes, Jyotika K.] Med Univ S Carolina, Div Endocrinol, 171 Ashley Ave, Charleston, SC 29425 USA. [Endlich, Karlhans] Ernst Moritz Arndt Univ Greifswald, Inst Anat & Cell Biol, Friedrich Loeffler Str 23c, D-17487 Greifswald, Germany. [Keene, Keith L.] E Carolina Univ, Dept Biol, Ctr Hlth Dispar, 1001 East 10th St,N209 Howell Sci Complex, Greenville, NC 27858 USA. [Launer, Lenore J.; Harris, Tamara B.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Gateway Bldg,3C309,7201 Winsconsin Ave, Bethesda, MD 20892 USA. [Lyytikaeinen, Leo-Pekka; Lehtimaeki, Terho] Univ Tampere, Sch Med, Dept Clin Chem, Fimlab Labs, Tampere 33520, Finland. [Yengo, Loic; Froguel, Philippe] CNRS, UMR 8199, 1 Rue Prof Calmette, F-59000 Lille, France. [Yengo, Loic; Froguel, Philippe] Lille Pasteur Inst, 1 Rue Prof Calmette, F-59000 Lille, France. [Yengo, Loic; Froguel, Philippe] Univ Lille 2, 42 Rue Paul Duez, F-59000 Lille, France. [Ferrucci, Luigi; Tanaka, Toshiko] NIA, Clin Res Branch, 251 Bayview Blvd, Baltimore, MD 21250 USA. [Struchalin, Maksim] Erasmus Univ, Dept Epidemiol & Biostat, Med Ctr, Dr Molewaterpl, NL-3000 DR Rotterdam, Netherlands. [Struchalin, Maksim] Erasmus Univ, Med Ctr, Dept Forens Mol Biol, Dr Molewaterpl, Rotterdam, Netherlands. [Kleber, Marcus E.] Heidelberg Univ, Med Fac Mannheim, Med Clin 5, Theodor Kutzer Ufer 1-3, D-68167 Mannheim, Germany. [Cavalieri, Margherita; Schmidt, Reinhold] Med Univ Graz, Dept Neurol, Austrian Stroke Prevent Study, Div Special Neurol, Auenbruggerpl 22, A-8036 Graz, Austria. [McEvoy, Mark A.] Univ Newcastle, John Hunter Hosp, Hunter Med Res Inst, Ctr Clin Epidemiol & Biostat,HRMC, Locked Bag 1, Newcastle, NSW 2310, Australia. [Woodward, Mark] Univ Oxford, Nuffield Dept Populat Hlth, George Inst Global Hlth, Old Rd Campus,Roosevelt Dr, Oxford OX3 7LF, England. [Pruijm, Menno] Univ Lausanne Hosp, Serv Nephrol, Rue Bugnon 17, CH-1005 Lausanne, Switzerland. [Metzger, Marie; Stengel, Benedicte] Univ Paris 11, INSERM, UMRS 1018, CESP Team 10, 16 Ave Paul Vaillant Couturier, F-94807 Villejuif, France. [Evans, Michele K.] NIA, Hlth Dispar Res Sect, Clin Res Branch, NIH,Biomed Ctr, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. [Sale, Michele M.; Chen, Wei-Min] Univ Virginia, Dept Med Cardiovasc Med, Ctr Publ Hlth Genom, POB 800717, Charlottesville, VA 22908 USA. [Kaehoenen, Mika] Univ Tampere, Sch Med, Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland. [Bochud, Murielle] Univ Lausanne, CHU Vaudois, Univ Inst Social & Prevent Med, Route Corniche 2, CH-1066 Epalinges, Switzerland. [Bouatia-Naji, Nabila] Paris Cardiovasc Res Ctr PARCC, INSERM, UMR970, 56 Rue Leblanc, F-75015 Paris, France. [Bouatia-Naji, Nabila] Paris Descartes Univ, Fac Med, Sorbonne Paris Cite, 12 Rue Ecole Med, F-75006 Paris, France. [Martin, Nicholas G.] Harvard Univ, Brigham & Womens Hosp, Sch Med, 77 Ave Louis Pasteur, Boston, MA 02115 USA. [Soranzo, Nicole] Wellcome Trust Sanger Inst, Hinxton CB10 1HH, England. [Devuyst, Olivier] Univ Zurich, Inst Physiol, Mech Inherited Kidney Disorders Grp, Winterthurerstr 190, CH-8057 Zurich, Switzerland. [Raitakari, Olli; Aalto, Ville] Univ Turku, Turku Univ Hosp, Dept Clin Physiol, Res Ctr Appl & Prevent Cardiovasc Med, POB 52, Turku 20521, Finland. [Munroe, Patricia B.] Queen Mary Univ London, William Harvey Res Inst, Dept Clin Pharmacol, London EC1M 6BQ, England. [Munroe, Patricia B.] Queen Mary Univ London, NIHR Barts Cardiovasc Biomed Res Unit, London EC1M 6BQ, England. [Ridker, Paul M.; Chasman, Daniel I.] Harvard Univ, Sch Med, 900 Commonwealth Ave Eeast, Boston, MA 02115 USA. [Muntner, Paul] Univ Alabama Birmingham, Dept Med, 1530 3rd Ave, South Birmingham, AL 35294 USA. [Muntner, Paul] Univ Alabama Birmingham, Dept Epidemiol, 1530 3rd Ave, South Birmingham, AL 35294 USA. [Smit, Johannes H.; Penninx, Brenda W.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, AJ Ernststr 1187, NL-1081 HL Amsterdam, Netherlands. [Smit, Johannes H.; Penninx, Brenda W.] Vrije Univ Amsterdam, Med Ctr, EMGO Inst, AJ Ernststr 1187, NL-1081 HL Amsterdam, Netherlands. [Kovacs, Peter] Univ Leipzig, IFB AdiposityDis, Liebigstr 21, D-04103 Leipzig, Germany. [Wild, Philipp S.] Med Univ Ctr Mainz, Langenbeckstr 1, D-55131 Mainz, Germany. [Rettig, Rainer] Ernst Moritz Arndt Univ Greifswald, Inst Physiol, D-17487 Greifswald, Germany. [Biffar, Reiner] Ernst Moritz Arndt Univ Greifswald, Clin Prosthodont Dent Gerostomatol & Mat Sci, Rotgerberstr 8, D-17475 Greifswald, Germany. [Scott, Rodney J.] Univ Newcastle, Sch Biomed Sci & Pharm, Hunter Med Res Inst, John Hunter Hosp,HRMC, Locked Bag 1, Newcastle, NSW 2310, Australia. [Katz, Ronit; de Boer, Ian H.] Univ Washington, Kidney Res Inst, Box 359606,325 9th Ave, Seattle, WA 98104 USA. [Ulivi, Sheila] Inst Maternal & Child Health IRCCS Burlo Garofolo, Via Istria 65, I-34137 Trieste, Italy. [Turner, Stephen T.] Mayo Clin, Dept Internal Med, Div Nephrol & Hypertens, 200 First St SW, Rochester, MN 55905 USA. [Stracke, Sylvia] Ernst Moritz Arndt Univ Greifswald, Clin Internal Med A, Friedrich Loeffler Str 23a, D-17475 Greifswald, Germany. [Emilsson, Valur] Univ Iceland, Fac Pharmaceut Sci, Saemundargata 2, IS-101 Reykjavik, Iceland. [Maerz, Winfried] Synlab Serv GmbH, Synlab Acad, Oberer Eselsberg 45, D-89081 Ulm, Germany. [Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, Albert Einstein Allee 23, D-89081 Ulm, Germany. [Loos, Ruth J. F.] Ichan Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, Via Lorenz Bohler 5, I-39100 Bolzano, Italy. [Pramstaller, Peter P.] Med Univ Lubeck, Dept Neurol, Ratzeburger Allee 160, D-23538 Lubeck, Germany. [Parsa, Afshin] Univ Maryland, Sch Med, Div Nephrol, 685 W Baltimore St,MSTF 314, Baltimore, MD 21201 USA. [Hamet, Pavel; Tremblay, Johanne] Univ Montreal, CHUM Res Ctr, CRCHUM, Technopole Angus, 900 St Denis, Montreal, PQ H2X 0A9, Canada. [Fox, Caroline S.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Endocrinol, 221 Longwood Ave, Boston, MA 02115 USA. RP Pattaro, C (reprint author), Med Univ Lubeck, European Acad Bozen Bolzano EURAC, Ctr Biomed, Via Galvani 31, I-39100 Bolzano, Italy.; Kottgen, A (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St, Baltimore, MD 21205 USA.; Kottgen, A (reprint author), Univ Hosp Freiburg, Dept Internal Med 4, Berliner Allee 29, D-79110 Freiburg, Germany.; Fox, CS (reprint author), NHLBIs Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA.; Fox, CS (reprint author), Ctr Populat Studies, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA.; Fox, CS (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Endocrinol, 221 Longwood Ave, Boston, MA 02115 USA. EM cristian.pattaro@eurac.edu; anna.koettgen@uniklinik-freiburg.de; foxca@nhlbi.nih.gov RI Erdmann, Jeanette/P-7513-2014; Ellinghaus, David/G-4467-2012; Deloukas, Panos/B-2922-2013; Colaus, PsyColaus/K-6607-2013; Verweij, Niek/A-4499-2017; HELMER, Catherine/I-6581-2015; Brenner, Hermann/B-4627-2017; Franke, Andre/B-2151-2010; Lieb, Wolfgang/C-1990-2012; Yengo, Loic/D-2692-2017; Palmer, Lyle/K-3196-2014; Polasek, Ozren/B-6002-2011; Boban, Mladen/E-2777-2017; Kolcic, Ivana/E-2713-2017; Feitosa, Mary/K-8044-2012; ruggiero, daniela/K-5638-2016; Matullo, Giuseppe/K-6383-2016; Onland-Moret, N. Charlotte/G-9185-2011; Bochud, Murielle/A-3981-2010; van der Schouw, Yvonne/F-8327-2014; Ruderfer, Douglas/M-5795-2016; BOUATIA-NAJI, NABILA/D-5863-2013; d'Adamo, Adamo Pio/G-4064-2011; Schwarz, Peter/B-5127-2013; Johnson, Andrew/G-6520-2013; Franke, Lude/P-7036-2016; Karjalainen, Juha/P-8624-2016; Laan, Maris/A-4100-2011; Lyytikainen, Leo-Pekka/C-8544-2016; Aulchenko, Yurii/M-8270-2013; Woodward, Mark/D-8492-2015; Stengel, Benedicte/G-5730-2015; Cossette, Suzanne/I-8008-2016; Lambert, jean-charles/A-9553-2014; Li, Yong/A-6283-2011; Mitchell, Paul/P-1498-2014; Grallert, Harald/B-3424-2013; Waldenberger, Melanie/B-5355-2014; Wang, Jie Jin/P-1499-2014; Singleton, Andrew/C-3010-2009; Kronenberg, Florian/B-1736-2008; Smith, Albert Vernon/K-5150-2015; OI Humphries, Stephen E/0000-0002-8221-6547; Verweij, Niek/0000-0002-4303-7685; Kloiber, Stefan/0000-0002-6838-4114; Cooper, Matthew/0000-0003-1139-3682; Org, Elin/0000-0003-1451-9375; Gieger, Christian/0000-0001-6986-9554; Beckmann, Jacques S /0000-0002-9741-1900; ELOSUA, ROBERTO/0000-0001-8235-0095; Cocca, Massimiliano/0000-0002-1127-7596; Erdmann, Jeanette/0000-0002-4486-6231; Deloukas, Panos/0000-0001-9251-070X; HELMER, Catherine/0000-0002-5169-7421; Brenner, Hermann/0000-0002-6129-1572; Franke, Andre/0000-0003-1530-5811; Yengo, Loic/0000-0002-4272-9305; Palmer, Lyle/0000-0002-1628-3055; Polasek, Ozren/0000-0002-5765-1862; Kolcic, Ivana/0000-0001-7918-6052; Feitosa, Mary/0000-0002-0933-2410; ruggiero, daniela/0000-0003-3898-7827; Bochud, Murielle/0000-0002-5727-0218; van der Schouw, Yvonne/0000-0002-4605-435X; Ruderfer, Douglas/0000-0002-2365-386X; d'Adamo, Adamo Pio/0000-0001-9367-4909; Schwarz, Peter/0000-0001-6317-7880; Franke, Lude/0000-0002-5159-8802; Laan, Maris/0000-0002-8519-243X; Salvi, Erika/0000-0002-2724-2291; Marmot, Michael/0000-0002-2431-6419; Prabhakaran, Dorairaj/0000-0002-3172-834X; Zonderman, Alan B/0000-0002-6523-4778; Mitchell, Braxton/0000-0003-4920-4744; Smith, Jennifer/0000-0002-3575-5468; Lawlor, Debbie A/0000-0002-6793-2262; Tai, E Shyong/0000-0003-2929-8966; Johansson, Asa/0000-0002-2915-4498; Morris, Richard/0000-0001-7240-4563; Kleber, Marcus/0000-0003-0663-7275; Lyytikainen, Leo-Pekka/0000-0002-7200-5455; Aulchenko, Yurii/0000-0002-7899-1575; Lambert, jean-charles/0000-0003-0829-7817; Waldenberger, Melanie/0000-0003-0583-5093; Wang, Jie Jin/0000-0001-9491-4898; Kronenberg, Florian/0000-0003-2229-1120; Dehghan, Abbas/0000-0001-6403-016X; Peters, Annette/0000-0001-6645-0985; Wain, Louise/0000-0003-4951-1867; Li, Yong/0000-0003-2651-8791; Smith, Albert Vernon/0000-0003-1942-5845; Ramachandran, Vasan/0000-0001-7357-5970; Goessling, Wolfram/0000-0001-9972-1569; Enroth, Stefan/0000-0002-5056-9137; Soranzo, Nicole/0000-0003-1095-3852; Chen, Wei-Min/0000-0002-2643-2333; Kumari, Meena/0000-0001-9716-1035; Meisinger, Christa/0000-0002-9026-6544; Jarvelin, Marjo-Riitta/0000-0002-2149-0630 FU NIH [R01DK090311, R24OD017870] FX Study-specific acknowledgements and funding sources for participating studies are reported in Supplementary Note. Zebrafish work was supported by NIH R01DK090311 and R24OD017870 to W.G. NR 48 TC 22 Z9 22 U1 16 U2 30 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 JAN PY 2016 VL 7 AR 10023 DI 10.1038/ncomms10023 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC2FO UT WOS:000369032800001 PM 26831199 ER PT J AU Richardson, BD Saha, K Krout, D Cabrera, E Felts, B Henry, LK Swant, J Zou, MF Newman, AH Khoshbouei, H AF Richardson, Ben D. Saha, Kaustuv Krout, Danielle Cabrera, Elizabeth Felts, Bruce Henry, L. Keith Swant, Jarod Zou, Mu-Fa Newman, Amy Hauck Khoshbouei, Habibeh TI Membrane potential shapes regulation of dopamine transporter trafficking at the plasma membrane SO NATURE COMMUNICATIONS LA English DT Article ID PROTEIN-KINASE-C; DEPENDENT MECHANISM; IN-VITRO; FLUORESCENCE MICROSCOPY; TRANSMEMBRANE SEGMENT; SURFACE EXPRESSION; COCAINE ANALOGS; CROSS-LINKING; AMPHETAMINE; NEURONS AB The dopaminergic system is essential for cognitive processes, including reward, attention and motor control. In addition to DA release and availability of synaptic DA receptors, timing and magnitude of DA neurotransmission depend on extracellular DA-level regulation by the dopamine transporter (DAT), the membrane expression and trafficking of which are highly dynamic. Data presented here from real-time TIRF (TIRFM) and confocal microscopy coupled with surface biotinylation and electrophysiology suggest that changes in the membrane potential alone, a universal yet dynamic cellular property, rapidly alter trafficking of DAT to and from the surface membrane. Broadly, these findings suggest that cell-surface DAT levels are sensitive to membrane potential changes, which can rapidly drive DAT internalization from and insertion into the cell membrane, thus having an impact on the capacity for DAT to regulate extracellular DA levels. C1 [Richardson, Ben D.; Saha, Kaustuv; Cabrera, Elizabeth; Swant, Jarod; Khoshbouei, Habibeh] Univ Florida, Dept Neurosci, Evelyn F & William L McKnight Brain Inst, Gainesville, FL 32610 USA. [Krout, Danielle; Felts, Bruce; Henry, L. Keith] Univ N Dakota, Dept Basic Sci, Sch Med & Hlth Sci, Grand Forks, ND 58203 USA. [Zou, Mu-Fa; Newman, Amy Hauck] NIDA, Med Chem Sect, Intramural Res Program, Baltimore, MD 21224 USA. RP Khoshbouei, H (reprint author), Univ Florida, Dept Neurosci, Evelyn F & William L McKnight Brain Inst, Gainesville, FL 32610 USA. EM habibeh@ufl.edu OI Richardson, Benjamin/0000-0003-0403-4956 FU NIH [DA026947, NS071122, OD020026]; NIDA-IRP FX We thank Dr Min Lin for assistance and direction in preparation of midbrain neuron primary culture and Sean Olson for his assistance in preparing plasmid DNA. This study was funded by NIH grant # DA026947, NS071122, OD020026 and the NIDA-IRP. NR 70 TC 0 Z9 0 U1 7 U2 13 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 JAN PY 2016 VL 7 AR 10423 DI 10.1038/ncomms10423 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC2BQ UT WOS:000369022600006 PM 26804245 ER PT J AU Singh, SR Liu, Y Zhao, JS Zeng, XK Hou, SX AF Singh, Shree Ram Liu, Ying Zhao, Jiangsha Zeng, Xiankun Hou, Steven X. TI The novel tumour suppressor Madm regulates stem cell competition in the Drosophila testis SO NATURE COMMUNICATIONS LA English DT Article ID SELF-RENEWAL; TRANSGENIC RNAI; HEMATOPOIETIC STEM; NICHE OCCUPANCY; ADAPTER PROTEIN; GERM-CELLS; IN-VIVO; GENE; MAINTENANCE; DIVISION AB Stem cell competition has emerged as a mechanism for selecting fit stem cells/progenitors and controlling tumourigenesis. However, little is known about the underlying molecular mechanism. Here we identify Mlf1-adaptor molecule (Madm), a novel tumour suppressor that regulates the competition between germline stem cells (GSCs) and somatic cyst stem cells (CySCs) for niche occupancy. Madm knockdown results in overexpression of the EGF receptor ligand vein (vn), which further activates EGF receptor signalling and integrin expression non-cell autonomously in CySCs to promote their overproliferation and ability to outcompete GSCs for niche occupancy. Conversely, expressing a constitutively activated form of the Drosophila JAK kinase (hop(Tum-l)) promotes Madm nuclear translocation, and suppresses vn and integrin expression in CySCs that allows GSCs to outcompete CySCs for niche occupancy and promotes GSC tumour formation. Tumour suppressor-mediated stem cell competition presented here could be a mechanism of tumour initiation in mammals. C1 [Singh, Shree Ram; Liu, Ying; Zhao, Jiangsha; Zeng, Xiankun; Hou, Steven X.] NCI, Basic Res Lab, NIH, Frederick, MD 21702 USA. RP Hou, SX (reprint author), NCI, Basic Res Lab, NIH, Frederick, MD 21702 USA. EM hous@mail.nih.gov RI Singh, Shree Ram/B-7614-2008; Liu, Ying /K-8883-2016 OI Singh, Shree Ram/0000-0001-6545-583X; FU National Cancer Institute, National Institutes of Health FX We thank Ting Xie, Erika Bach, Soichi Tanda, Jocelyn Donaldson, Amanda Simcox, Kendal Broadie, Amin Ghabrial, Trudi Schupbach, Norbert Perrimon, Hugo Stocker, VDRC, NIG, the Bloomington Stock Centers for fly stocks; Ruth Lehmann, Hugo Stocker, James Skeath and the Developmental Studies Hybridoma Bank for antibodies; and Dr Stephen Lockett and Kimberly Peifley of Optical Microscopy and Analysis Laboratory (OMAL) for help with the confocal microscopy. This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 64 TC 2 Z9 2 U1 3 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JAN PY 2016 VL 7 AR 10473 DI 10.1038/ncomms10473 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC2AJ UT WOS:000369019300001 PM 26792023 ER PT J AU Evans, M Moy, B AF Evans, Michele Moy, Beverly TI Announcing a New Journal Section: Community Outreach SO ONCOLOGIST LA English DT Editorial Material C1 [Evans, Michele] NIA, Hlth Dispar Res Sect, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. [Moy, Beverly] Massachusetts Gen Hosp, Breast Oncol Program, 55 Fruit St,Lawrence House,LRH 304, Boston, MA 02114 USA. RP Moy, B (reprint author), Massachusetts Gen Hosp, Breast Oncol Program, 55 Fruit St,Lawrence House,LRH 304, Boston, MA 02114 USA.; Evans, M (reprint author), NIH, Hlth Dispar Res Sect, Lab Epidemiol & Populat Sci, Biomed Res Ctr, 251 Bayview Blvd,Suite 100,Room 04C222, Baltimore, MD 21224 USA. EM me42v@nih.gov; bmoy@mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD JAN PY 2016 VL 21 IS 1 BP 1 EP 1 DI 10.1634/theoncologist.2015-0494 PG 1 WC Oncology SC Oncology GA DC3RV UT WOS:000369137300001 PM 26712959 ER PT J AU Lee, JM Ivy, SP Kohn, EC AF Lee, Jung-min Ivy, S. Percy Kohn, Elise C. TI Challenges and Opportunities for Immunotherapies in Gynecologic Cancers SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID OVARIAN-CANCER; CERVICAL-CANCER; CELL-DEATH; BLOCKADE; TUMORS; MICROENVIRONMENT; BEVACIZUMAB; THERAPY; TRIAL C1 [Lee, Jung-min; Kohn, Elise C.] NCI, Womens Malignancies Branch, Ctr Canc Res & Canc Therapeut, Bethesda, MD 20892 USA. [Ivy, S. Percy; Kohn, Elise C.] NCI, Evaluat Program, Bethesda, MD 20892 USA. RP Lee, JM (reprint author), NCI, Womens Malignancies Branch, Ctr Canc Res & Canc Therapeut, Bethesda, MD 20892 USA. NR 31 TC 0 Z9 0 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD JAN PY 2016 VL 30 IS 1 BP 67 EP 69 PG 3 WC Oncology SC Oncology GA DB9XS UT WOS:000368871600009 PM 26791847 ER PT J AU Gordon, LA Malati, CY Hadigan, C McLaughlin, M Alfaro, RM Calderon, MM Kovacs, JA Penzak, SR AF Gordon, Lori A. Malati, Christine Y. Hadigan, Colleen McLaughlin, Mary Alfaro, Raul M. Calderon, Monica M. Kovacs, Joseph A. Penzak, Scott R. TI Lack of an Effect of Ritonavir Alone and Lopinavir-Ritonavir on the Pharmacokinetics of Fenofibric Acid in Healthy Volunteers SO PHARMACOTHERAPY LA English DT Article DE hypertriglyceridemia; human immunodeficiency virus; protease inhibitor; fenofibrate; lopinavir-ritonavir; pharmacokinetics ID ANTIRETROVIRAL THERAPY; HIV-1-INFECTED PATIENTS; PROTEASE INHIBITORS; HIV-INFECTION; LIPID PROFILE; IN-VITRO; LOPINAVIR/RITONAVIR; MANAGEMENT; ATAZANAVIR/RITONAVIR; BUPRENORPHINE AB Study ObjectiveBecause we previously observed a significant 41% reduction in gemfibrozil exposure after 2weeks of lopinavir-ritonavir administration, we sought to determine the influence of lopinavir-ritonavir and ritonavir alone on the pharmacokinetics of fenofibric acid, an alternative to gemfibrozil for the treatment of elevated triglyceride levels. DesignOpen-label, single-sequence pharmacokinetic study. SettingClinical Research Center at the National Institutes of Health. SubjectsThirteen healthy adult volunteers. InterventionSubjects received a single oral dose of fenofibrate 145mg during three study phases: before ritonavir administration, after 2weeks of administration of ritonavir 100mg twice/day, and after 2weeks of administration of lopinavir 400mg-ritonavir 100mg twice/day. Measurements and Main ResultsSerial blood samples were collected over 120hours for determination of fenofibric acid concentrations. Fenofibric acid pharmacokinetic parameter values were compared before and after concomitant ritonavir or lopinavir-ritonavir administration. The geometric mean ratios (90% confidence intervals) for fenofibric acid area under the plasma concentration-time curve were 0.89 (0.77-1.01) after 14days of ritonavir alone compared with baseline (p>0.05) and 0.87 (0.69-1.05) after 14days of lopinavir-ritonavir compared with baseline (p>0.05). Study drugs were generally well tolerated; all adverse events were mild or moderate, transient, and resolved without intervention. ConclusionIn contrast to a significant interaction between gemfibrozil and lopinavir-ritonavir, neither lopinavir-ritonavir nor ritonavir alone altered the pharmacokinetics of fenofibric acid in healthy volunteers. These data suggest that fenofibrate remains an important option in human immunodeficiency virus-infected patients receiving common ritonavir-boosted therapy. C1 [Gordon, Lori A.; Malati, Christine Y.; Alfaro, Raul M.; Calderon, Monica M.; Penzak, Scott R.] NIH, Dept Pharm, Ctr Clin, Bethesda, MD USA. [Hadigan, Colleen; McLaughlin, Mary] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Kovacs, Joseph A.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Gordon, LA (reprint author), Xavier Univ, Louisiana Coll Pharm, Div Clin & Adm Sci, 1 Drexel Dr, New Orleans, LA 70125 USA. EM lgordon4@xula.edu FU Intramural NIH HHS NR 31 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-0008 EI 1875-9114 J9 PHARMACOTHERAPY JI Pharmacotherapy PD JAN PY 2016 VL 36 IS 1 BP 49 EP 56 DI 10.1002/phar.1682 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DC0XP UT WOS:000368941600007 PM 26799348 ER PT S AU Cheng, L Pisitkun, T Knepper, MA Hoffert, JD AF Cheng, Lei Pisitkun, Trairak Knepper, Mark A. Hoffert, Jason D. BE VonStechow, L TI Peptide Labeling Using Isobaric Tagging Reagents for Quantitative Phosphoproteomics SO PHOSPHO-PROTEOMICS: METHODS AND PROTOCOLS, 2ND EDITION SE Methods in Molecular Biology LA English DT Article; Book Chapter DE IMAC; Isobaric tags; Isotopic labeling; iTRAQ; LC-MS/MS; Mass spectrometry; Multiplexing; Phosphopeptide; Phosphoproteomics; Reporter ion; TMT ID TANDEM MASS-SPECTROMETRY; PROTEIN-PHOSPHORYLATION; PHOSPHOPEPTIDES; MS/MS; QUANTIFICATION; DISSOCIATION; THROUGHPUT; MIXTURES; 4-PLEX; 8-PLEX AB Isobaric tagging reagents have become an invaluable tool for multiplexed quantitative proteomic analysis. These reagents can label multiple, distinct peptide samples from virtually any source material (e.g., tissue, cell line, purified proteins), allowing users the opportunity to assess changes in peptide abundances across many different time points or experimental conditions. Here, we describe the application of isobaric peptide labeling, specifically 8plex isobaric tags for relative and absolute quantitation (8plex iTRAQ), for quantitative phosphoproteomic analysis of cultured cells or tissue suspensions. For this particular protocol, labeled samples are pooled, fractionated by strong cation exchange chromatography, enriched for phosphopeptides, and analyzed by tandem mass spectrometry (LC-MS/MS) for both peptide identification and quantitation. C1 [Cheng, Lei] Aarhus Univ, Dept Biomed, Aarhus, Denmark. [Cheng, Lei] Aarhus Univ, Ctr Interact Prot Epithelial Transport, Aarhus, Denmark. [Pisitkun, Trairak] Chulalongkorn Univ, Fac Med, Bangkok 10330, Thailand. [Knepper, Mark A.; Hoffert, Jason D.] NHLBI, Epithelial Syst Biol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Cheng, L (reprint author), Aarhus Univ, Dept Biomed, Aarhus, Denmark.; Cheng, L (reprint author), Aarhus Univ, Ctr Interact Prot Epithelial Transport, Aarhus, Denmark. FU Intramural NIH HHS; NHLBI NIH HHS [Z01-HL-001285] NR 28 TC 1 Z9 1 U1 1 U2 7 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-3049-4; 978-1-4939-3048-7 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1355 BP 53 EP 70 DI 10.1007/978-1-4939-3049-4_4 D2 10.1007/978-1-4939-3049-4 PG 18 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BE1XU UT WOS:000368703600005 PM 26584918 ER PT J AU Pilling, LC Joehanes, R Kacprowski, T Peters, M Jansen, R Karasik, D Kiel, DP Harries, LW Teumer, A Powell, J Levy, D Lin, H Lunetta, K Munson, P Bandinelli, S Henley, W Hernandez, D Singleton, A Tanaka, T van Grootheest, G Hofman, A Uitterlinden, AG Biffar, R Glaser, S Homuth, G Malsch, C Volker, U Penninx, B van Meurs, JBJ Ferrucci, L Kocher, T Murabito, J Melzer, D AF Pilling, L. C. Joehanes, R. Kacprowski, T. Peters, M. Jansen, R. Karasik, D. Kiel, D. P. Harries, L. W. Teumer, A. Powell, J. Levy, D. Lin, H. Lunetta, K. Munson, P. Bandinelli, S. Henley, W. Hernandez, D. Singleton, A. Tanaka, T. van Grootheest, G. Hofman, A. Uitterlinden, A. G. Biffar, R. Glaeser, S. Homuth, G. Malsch, C. Voelker, U. Penninx, B. van Meurs, J. B. J. Ferrucci, L. Kocher, T. Murabito, J. Melzer, D. TI Gene transcripts associated with muscle strength: a CHARGE meta-analysis of 7,781 persons SO PHYSIOLOGICAL GENOMICS LA English DT Article DE gene-expression; muscle; strength; blood; human; leukocyte ID HUMAN SKELETAL-MUSCLE; GRIP STRENGTH; EXPRESSION; MASS; AGE; PROTEINS; CELLS; EPIDEMIOLOGY; SARCOPENIA; MORTALITY AB Lower muscle strength in midlife predicts disability and mortality in later life. Blood-borne factors, including growth differentiation factor 11 (GDF11), have been linked to muscle regeneration in animal models. We aimed to identify gene transcripts associated with muscle strength in adults. Meta-analysis of whole blood gene expression (overall 17,534 unique genes measured by microarray) and hand-grip strength in four independent cohorts (n = 7,781, ages: 20-104 yr, weighted mean = 56), adjusted for age, sex, height, weight, and leukocyte subtypes. Separate analyses were performed in subsets (older/younger than 60, men/women). Expression levels of 221 genes were associated with strength after adjustment for cofactors and for multiple statistical testing, including ALAS2 (rate-limiting enzyme in heme synthesis), PRF1 (perforin, a cytotoxic protein associated with inflammation), IGF1R, and IGF2BP2 (both insulin like growth factor related). We identified statistical enrichment for hemoglobin biosynthesis, innate immune activation, and the stress response. Ten genes were associated only in younger individuals, four in men only and one in women only. For example, PIK3R2 (a negative regulator of PI3K/AKT growth pathway) was negatively associated with muscle strength in younger (<60 yr) individuals but not older (>= 60 yr). We also show that 115 genes (52%) have not previously been linked to muscle in NCBI PubMed abstracts. This first large-scale transcriptome study of muscle strength in human adults confirmed associations with known pathways and provides new evidence for over half of the genes identified. There may be age-and sex-specific gene expression signatures in blood for muscle strength. C1 [Pilling, L. C.; Melzer, D.] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Epidemiol & Publ Hlth Grp, Exeter, Devon, England. [Joehanes, R.; Levy, D.; Lin, H.; Lunetta, K.; Munson, P.; Murabito, J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Joehanes, R.; Levy, D.] NHLBI, Populat Studies Branch, Bldg 10, Bethesda, MD 20892 USA. [Kacprowski, T.; Teumer, A.; Homuth, G.; Malsch, C.; Voelker, U.] Univ Med, Interfac Inst Genet & Funct Genom, Dept Funct Genom, Greifswald, Germany. [Kacprowski, T.; Teumer, A.; Homuth, G.; Malsch, C.; Voelker, U.] Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany. [Peters, M.; Uitterlinden, A. G.; van Meurs, J. B. J.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Peters, M.; Hofman, A.; Uitterlinden, A. G.; van Meurs, J. B. J.] NGI NCHA, Leiden, Netherlands. [Jansen, R.; van Grootheest, G.; Penninx, B.] Vrije Univ Amsterdam, Dept Psychiat, Med Ctr, Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Karasik, D.; Kiel, D. P.] Hebrew SeniorLife Inst Aging Res, Boston, MA USA. [Harries, L. W.] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, RNA Mech Complex Dis Grp, Exeter, Devon, England. [Powell, J.] Univ Queensland, Queensland Brain Inst, Ctr Neurogenet & Stat Genom, Brisbane, Qld, Australia. [Lin, H.] Boston Univ, Sch Med, Dept Med, Sect Computat Biomed, Boston, MA 02118 USA. [Lunetta, K.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Munson, P.] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. [Bandinelli, S.] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy. [Henley, W.] Univ Exeter, Sch Med, Inst Hlth Serv Res, Exeter, Devon, England. [Hernandez, D.; Singleton, A.] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. [Tanaka, T.; Ferrucci, L.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Hofman, A.; Uitterlinden, A. G.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Biffar, R.] Univ Med Greifswald, Dept Prosthet Dent Gerostomatol & Dent Mat, Greifswald, Germany. [Glaeser, S.] Ernst Moritz Arndt Univ Greifswald, Dept Internal Med Cardiol Intens Care Pulm Med &, Greifswald, Germany. [Kocher, T.] Univ Med Greifswald, Dept Restorat Dent Periodontol & Endodontol, Unit Periodontol, Greifswald, Germany. [Murabito, J.] Boston Univ, Gen Internal Med Sect, Boston, MA 02215 USA. RP Melzer, D (reprint author), Univ Exeter, Sch Med, Epidemiol & Publ Hlth, Med Res, RILD Level 3,RD&E Wonford,Barrack Rd, Exeter EX2 5DW, Devon, England. EM D.Melzer@exeter.ac.uk RI Singleton, Andrew/C-3010-2009; Kacprowski, Tim/K-8650-2013; OI Kacprowski, Tim/0000-0002-5393-2413; Pilling, Luke/0000-0002-3332-8454; Peters, Marjolein/0000-0003-3167-9063; Kiel, Douglas/0000-0001-8474-0310; Melzer, David/0000-0002-0170-3838; Karasik, David/0000-0002-8826-0530 FU Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD; NIH [R01AG-029451, R01 AR-41398]; NHLBI [N01-HC-25195]; Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD; Wellcome Trust Institutional Strategic Support Award [WT097835MF]; National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula; Geestkracht program of the Netherlands Organisation for Health Research and Development (ZonMw) [10-000-1002]; VU University Medical Center; GGZ inGeest; Arkin; Leiden University Medical Center; GGZ Rivierduinen; University Medical Center Groningen; Lentis; GGZ Friesland; GGZ Drenthe; Scientific Institute for Quality of Healthcare (IQ healthcare); Netherlands Institute for Health Services Research (NIVEL); Netherlands Institute of Mental Health and Addiction (Trimbos Institute); Erasmus Medical Center; Erasmus University; ZonMw; Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly (RIDE2) [014-93-015]; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands; Federal Ministry of Education and Research Grants [01ZZ9603, 01ZZ0103, 01ZZ0403]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; network Greifswald Approach to Individualized Medicine (GANI_MED) - Federal Ministry of Education and Research [03IS2061A]; Rotterdam FX FHS gene expression profiling was funded through the Division of Intramural Research (principal investigator, Daniel Levy), National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD. J. Murabito is supported by NIH Grant R01AG-029451. D. P. Kiel is supported by NIH Grant R01 AR-41398. The Framingham Heart Study is supported by NHLBI contract N01-HC-25195.; The InCHIANTI study was supported in part by the Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD. D. Melzer and L. W. Harries were generously supported by a Wellcome Trust Institutional Strategic Support Award (WT097835MF). W. E. Henley was funded by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health in England.; The infrastructure for the NESDA study (http://www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (ZonMw, Grant 10-000-1002) and is supported by participating universities and mental health care organizations [VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Scientific Institute for Quality of Healthcare (IQ healthcare), Netherlands Institute for Health Services Research (NIVEL), and Netherlands Institute of Mental Health and Addiction (Trimbos Institute)].; The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, ZonMw, the Netherlands Organisation of Scientific Research NWO Investments (175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. The generation and management of RNA-expression array data for the Rotterdam Study were executed and funded by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. We thank Marjolein Peters, Mila Jhamai, Jeannette M. Vergeer-Drop, Bernadette van Ast-Copier, Marijn Verkerk, and Jeroen van Rooij for help in creating the RNA array expression database.; SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research Grants 01ZZ9603, 01ZZ0103, and 01ZZ0403; the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania; and the network Greifswald Approach to Individualized Medicine (GANI_MED) funded by the Federal Ministry of Education and Research (Grant 03IS2061A). The University of Greifswald is a member of the "Center of Knowledge Interchange" program of the Siemens and Cache Campus program of the InterSystems. NR 54 TC 1 Z9 1 U1 1 U2 4 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 JAN 1 PY 2016 VL 48 IS 1 BP 1 EP 11 DI 10.1152/physiolgenomics.00054.2015 PG 11 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA DC3EW UT WOS:000369103400001 PM 26487704 ER PT J AU Weng, LM Taylor, KD Chen, YDI Sopko, G Kelsey, SF Merz, CNB Pepine, CJ Miller, VM Rotter, JI Gulati, M Goodarzi, MO Cooper-DeHoff, RM AF Weng, Liming Taylor, Kent D. Chen, Yii-Der Ida Sopko, George Kelsey, Sheryl F. Merz, C. Noel Bairey Pepine, Carl J. Miller, Virginia M. Rotter, Jerome I. Gulati, Martha Goodarzi, Mark O. Cooper-DeHoff, Rhonda M. TI Genetic loci associated with nonobstructive coronary artery disease in Caucasian women SO PHYSIOLOGICAL GENOMICS LA English DT Article DE genetics; nonobstructive coronary artery disease; cardio-metabochip; sex ID SYNDROME-EVALUATION WISE; ISCHEMIC-HEART-DISEASE; WAIST-HIP RATIO; GENOME-WIDE ASSOCIATION; CARDIOVASCULAR EVENTS; ENDOTHELIAL DYSFUNCTION; SUSCEPTIBILITY LOCI; METABOLIC SYNDROME; NATIONAL-HEART; BLOOD-PRESSURE AB Nonobstructive coronary artery disease (CAD) in women is associated with adverse cardiovascular (CV) outcomes; however, information regarding genetic variants that predispose women to nonobstructive CAD is lacking. Women from the Women's Ischemia Syndrome Evaluation (WISE) Study and the St. James Women Take Heart (WTH) Study were genotyped with the Cardio-MetaboChip. WISE enrolled women with symptoms and signs of ischemia referred for coronary angiography; WTH enrolled asymptomatic, community-based women without heart disease. Analyses were conducted with a case (WISE)-control (WTH) design and multivariate logistic regression models to investigate genetic variation associated with likelihood of nonobstructive CAD. One genetic marker, single nucleotide polymorphism (SNP) rs2301753 on chromosome 6 in RNF39, achieved chip-wide significance for nonobstructive CAD (P < 9.5 x 10(-7)). After adjusting for baseline characteristics, we found no variants achieved chip-wide significance. However, SNP rs2301753 on chromosome 6 in RNF39 was associated with reduced likelihood of nonobstructive CAD [odds ratio (OR) 0.42 and 95% confidence interval (CI) of 0.29 to 0.68], at a nominal level of P = 5.6 x 10(-6), while SNP rs12818945 in the ATP2B1 locus on chromosome 12 was associated with increased odds for nonobstructive CAD (OR 2.38 and 95% CI of 1.63 to 3.45) and nominal P = 5.8 x 10(-6). The functions of RNF39 and ATP2B1 raise the possibility that genes involved in cardio-dysfunction may contribute to nonobstructive CAD in Caucasian women and may provide insights into novel approaches for therapy and prevention. If replicated, incorporation of these genetic variants into diagnostic evaluation may identify women at high risk for nonobstructive CAD. C1 [Weng, Liming; Cooper-DeHoff, Rhonda M.] Univ Florida, Coll Pharm, Dept Pharmacotherapy & Translat Res, Gainesville, FL USA. [Weng, Liming; Cooper-DeHoff, Rhonda M.] Univ Florida, Coll Pharm, Ctr Pharmacogen, Gainesville, FL USA. [Taylor, Kent D.; Chen, Yii-Der Ida; Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Taylor, Kent D.; Chen, Yii-Der Ida; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Taylor, Kent D.; Chen, Yii-Der Ida; Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles BioMed Res Inst, Torrance, CA 90509 USA. [Sopko, George] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Kelsey, Sheryl F.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Merz, C. Noel Bairey] Cedars Sinai Med Ctr, Cedars Sinai Heart Inst, Barbra Streisand Womens Heart Ctr, Los Angeles, CA 90048 USA. [Pepine, Carl J.; Cooper-DeHoff, Rhonda M.] Univ Florida, Coll Med, Div Cardiol, Gainesville, FL USA. [Miller, Virginia M.] Mayo Clin, Dept Surg, Rochester, MN USA. [Miller, Virginia M.] Mayo Clin, Dept Physiol & Biomed Engn, Rochester, MN USA. [Gulati, Martha] Ohio State Univ, Dept Med Cardiol, Columbus, OH 43210 USA. [Goodarzi, Mark O.] Cedars Sinai Med Ctr, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA. RP Cooper-DeHoff, RM (reprint author), Univ Florida, Dept Pharmacotherapy & Translat Res, POB 100486, Gainesville, FL 32610 USA.; Cooper-DeHoff, RM (reprint author), Univ Florida, Div Cardiovasc Med, Coll Pharm, Ctr Pharmacogen, POB 100486, Gainesville, FL 32610 USA.; Cooper-DeHoff, RM (reprint author), Univ Florida, Div Cardiovasc Med, Coll Med, Ctr Pharmacogen, POB 100486, Gainesville, FL 32610 USA. EM dehoff@cop.ufl.edu FU Society for Women's Health Research, Washington, DC; Gerlach Family from Columbus, OH; Ohio State University, Columbus, OH; Bill and Sarah Soter family from Palm Beach, FL; National Institutes of Health [U01 GM-074492, N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, U0164829, U01 HL-649141, U01 HL-649241, T32HL-69751, R01 HL-090957, 1R03AG-032631, MO1-RR-00425, UL1TR-000124, P30 DK-063491]; Gustavus and Louis Pfeiffer Research Foundation, Danville, NJ; Women's Guild of Cedars-Sinai Medical Center, Los Angeles, CA; Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA; QMED, Inc.; Laurence Harbor, NJ; Edythe L. Broad; Constance Austin Women's Heart Research Fellowships, Cedars-Sinai Medical Center, Los Angeles, CA; Barbra Streisand Women's Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, CA; Linda Joy Pollin Women's Heart Health Program; Erika Glazer Women's Heart Health Project, Cedars-Sinai Medical Center, Los Angeles, CA FX This work was supported by grants from the Society for Women's Health Research, Washington, DC (to R. M. Cooper-DeHoff); the Gerlach Translational Award provided by the Gerlach Family from Columbus, OH; the Women & Philanthropy Grant from the Ohio State University, Columbus, OH (to Martha Gulati); and the Bill and Sarah Soter family from Palm Beach, FL; National Institutes of Health contracts and grants as follows: U01 GM-074492, N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV- 68164, U0164829, U01 HL-649141, U01 HL-649241, T32HL-69751, R01 HL-090957, 1R03AG-032631, MO1-RR-00425, UL1TR-000124, P30 DK-063491; and grants from the Gustavus and Louis Pfeiffer Research Foundation, Danville, NJ; The Women's Guild of Cedars-Sinai Medical Center, Los Angeles, CA; The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA; and QMED, Inc., Laurence Harbor, NJ; the Edythe L. Broad and the Constance Austin Women's Heart Research Fellowships, Cedars-Sinai Medical Center, Los Angeles, CA; the Barbra Streisand Women's Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, CA; The Linda Joy Pollin Women's Heart Health Program and the Erika Glazer Women's Heart Health Project, Cedars-Sinai Medical Center, Los Angeles, CA. NR 40 TC 1 Z9 1 U1 0 U2 0 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 JAN 1 PY 2016 VL 48 IS 1 BP 12 EP 20 DI 10.1152/physiolgenomics.00067.2015 PG 9 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA DC3EW UT WOS:000369103400002 PM 26534935 ER PT S AU Sayers, EW Karsch-Mizrachi, I AF Sayers, Eric W. Karsch-Mizrachi, Ilene BE Edwards, D TI Using GenBank SO PLANT BIOINFORMATICS: METHODS AND PROTOCOLS, 2ND EDITION SE Methods in Molecular Biology LA English DT Article; Book Chapter DE NCBI; Entrez; DNA Sequence; BLAST; MegaBLAST ID DATABASE; INFORMATION; ARCHIVE; BLAST; IMPROVEMENTS; SYSTEM AB GenBank (R) is a comprehensive database of publicly available DNA sequences for 300,000 named organisms, more than 110,000 within the embryophyta, obtained through submissions from individual laboratories and batch submissions from large-scale sequencing projects. Daily data exchange with the European Nucleotide Archive (ENA) in Europe and the DNA Data Bank of Japan ensures worldwide coverage. GenBank is accessible through the NCBI Entrez retrieval system that integrates data from the major DNA and protein sequence databases with taxonomy, genome, mapping, protein structure and domain information, as well as the biomedical journal literature in PubMed. BLAST provides sequence similarity searches of GenBank and other sequence databases. Complete bimonthly releases and daily updates of the GenBank database are available by FTP. GenBank usage scenarios ranging from local analyses of the data available via FTP to online analyses supported by the NCBI web-based tools are discussed. To access GenBank and its related retrieval and analysis services, go to the NCBI home page at www.ncbi.nlm.nih.gov C1 [Sayers, Eric W.; Karsch-Mizrachi, Ilene] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. RP Sayers, EW (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 20 TC 0 Z9 0 U1 3 U2 16 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-3167-5; 978-1-4939-3166-8 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1374 BP 1 EP 22 DI 10.1007/978-1-4939-3167-5_1 D2 10.1007/978-1-4939-3167-5 PG 22 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Plant Sciences; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Plant Sciences; Mathematical & Computational Biology GA BE2ES UT WOS:000369091900002 PM 26519398 ER PT S AU Danan, C Manickavel, S Hafner, M AF Danan, Charles Manickavel, Sudhir Hafner, Markus BE Dassi, E TI PAR-CLIP: A Method for Transcriptome-Wide Identification of RNA Binding Protein Interaction Sites SO POST-TRANSCRIPTIONAL GENE REGULATION, 2ND EDITION SE Methods in Molecular Biology LA English DT Article; Book Chapter DE RNA-binding protein (RBP); RNA; Photoactivatable ribonucleoside enhanced cross-linking and immunoprecipitation (PAR-CLIP); Cross-linking and immunoprecipitation (CLIP); Posttranscriptional gene regulation (PTGR); RNA recognition element (RRE); Noncoding RNA; mRNA; Binding site ID DROSOPHILA-MELANOGASTER; COMPUTATIONAL APPROACH; TARGET SITES; MOTIF FINDER; DISEASE; TRANSLATION; DATABASE; SEQ AB During post-transcriptional gene regulation (PTGR), RNA binding proteins (RBPs) interact with all classes of RNA to control RNA maturation, stability, transport, and translation. Here, we describe Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immuno precipitation (PAR-CLIP), a transcriptome-scale method for identifying RBP binding sites on target RNAs with nucleotide-level resolution. This method is readily applicable to any protein directly contacting RNA, including RBPs that are predicted to bind in a sequence-or structure-dependent manner at discrete RNA recognition elements (RREs), and those that are thought to bind transiently, such as RNA polymerases or helicases. C1 [Danan, Charles; Manickavel, Sudhir; Hafner, Markus] NIAMS, Lab Muscle Stem Cells & Gene Regulat, Bethesda, MD USA. RP Danan, C (reprint author), NIAMS, Lab Muscle Stem Cells & Gene Regulat, Bethesda, MD USA. FU Intramural NIH HHS [Z99 AR999999] NR 34 TC 2 Z9 2 U1 2 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-3067-8; 978-1-4939-3066-1 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1358 BP 153 EP 173 DI 10.1007/978-1-4939-3067-8_10 D2 10.1007/978-1-4939-3067-8 PG 21 WC Genetics & Heredity SC Genetics & Heredity GA BE1XT UT WOS:000368702400011 PM 26463383 ER PT J AU Biradavolu, M Jia, YJ Withers, K Kapetanovic, S AF Biradavolu, Monica Jia, Yujiang Withers, Keenan Kapetanovic, Suad TI Factors Influencing the Delivery of HIV-Related Services to Severely Mentally Ill Individuals: The Provider's Perspective SO PSYCHOSOMATICS LA English DT Article ID ILLNESS; ADULTS AB Background: Individuals with severe mental illnesses (SMI) are disproportionately vulnerable to HIV infection but are not consistently engaged in HIV related services. Objective: To understand factors influencing implementation of HIV-related services to individuals with SMI, we conducted a series of focus groups with multidisciplinary clinicians and staff serving individuals with SMI in outpatient, emergency, acute inpatient, and chronic inpatient levels of care. Method: Six focus groups with 30 participants were conducted, audiotaped, and transcribed Our qualitative analysis drew on Grounded Theory. Using NVivo Version 9, coding was conducted by the first and senior authors; interrater reliability was verified by running Coding Comparison queries. Results: The providers' narratives highlighted (1) patient-related factors, (2) stigma, and (3) administrative factors as themes particularly relevant to the delivery of HIV-related services to individuals with SMI. The reported relevance of these factors ranged across levels of care, from creating multiple barriers in the outpatient care to relatively seamless and effective delivery of full continuum of HIV-related services in the chronic inpatient environment, where adequate structural support is provided. Conclusion: Providers' narratives suggest that effective delivery of HIV-related services for individuals with SMI requires sustained structural support that is coordinated across levels of psychiatric care and tailored to individual patient's needs. The narratives also suggest that such support is currently not available. C1 [Biradavolu, Monica] Amer Univ, Dept Sociol, Washington, DC 20016 USA. [Jia, Yujiang] Washington DC HIV AIDS Hepatitis STD & TB Adm, Washington, DC USA. [Withers, Keenan; Kapetanovic, Suad] NIMH, NIH, Bethesda, MD 20892 USA. [Kapetanovic, Suad] Univ So Calif, Keck Sch Med, Dept Psychiat & Behav Sci, 2250 Alcazar St, Los Angeles, CA 90033 USA. RP Kapetanovic, S (reprint author), Univ So Calif, Keck Sch Med, Dept Psychiat & Behav Sci, 2250 Alcazar St, Los Angeles, CA 90033 USA. EM kapetano@usc.edu FU Intramural NIH HHS [Z99 MH999999] NR 10 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD JAN-FEB PY 2016 VL 57 IS 1 BP 64 EP 70 PG 7 WC Psychiatry; Psychology SC Psychiatry; Psychology GA DC2JB UT WOS:000369041900008 PM 26688187 ER PT J AU Rucci, M McGraw, PV Krauzlis, RJ AF Rucci, Michele McGraw, Paul V. Krauzlis, Richard J. TI Fixational eye movements and perception SO VISION RESEARCH LA English DT Editorial Material ID SUPERIOR COLLICULUS; IMAGE STABILIZATION; COVERT ATTENTION; VISUAL-ACUITY; MICROSACCADES C1 [Rucci, Michele] Boston Univ, Dept Psychol & Brain Sci, Boston, MA 02215 USA. [McGraw, Paul V.] Univ Nottingham, Sch Psychol, Nottingham NG7 2RD, England. [Krauzlis, Richard J.] NEI, Sensorimotor Res Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Rucci, M (reprint author), Boston Univ, Dept Psychol & Brain Sci, Boston, MA 02215 USA.; McGraw, PV (reprint author), Univ Nottingham, Sch Psychol, Nottingham NG7 2RD, England.; Krauzlis, RJ (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM mrucci@bu.edu; paul.mcgraw@nottingham.ac.uk; richard.krauzlis@nih.gov OI McGraw, Paul/0000-0001-9484-8560 NR 49 TC 1 Z9 1 U1 6 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 EI 1878-5646 J9 VISION RES JI Vision Res. PD JAN PY 2016 VL 118 SI SI BP 1 EP 4 DI 10.1016/j.visres.2015.12.001 PG 4 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA DC1HY UT WOS:000368968600001 PM 26686666 ER PT J AU Felsenstein, KM Saunders, LB Simmons, JK Leon, E Calabrese, DR Zhang, SL Michalowski, A Gareiss, P Mock, BA Schneekloth, JS AF Felsenstein, Kenneth M. Saunders, Lindsey B. Simmons, John K. Leon, Elena Calabrese, David R. Zhang, Shuling Michalowski, Aleksandra Gareiss, Peter Mock, Beverly A. Schneekloth, John S., Jr. TI Small Molecule Microarrays Enable the Identification of a Selective, Quadruplex-Binding Inhibitor of MYC Expression SO ACS CHEMICAL BIOLOGY LA English DT Article ID PROMOTER G-QUADRUPLEX; DIVERSE SMALL MOLECULES; STRUCTURE-BASED DESIGN; C-MYC; CATIONIC PORPHYRIN; DOWN-REGULATION; TUMOR-GROWTH; HUMAN GENOME; DNA; TELOMERASE AB The transcription factor MYC plays a pivotal role in cancer initiation, progression, and maintenance. However, it has proven difficult to develop small molecule inhibitors of MYC. One attractive route to pharmacological inhibition of MYC has been the prevention of its expression through small molecule-mediated stabilization of the G-quadruplex (G4) present in its promoter. Although molecules that bind globally to quadruplex DNA and influence gene expression are well-known, the identification of new chemical scaffolds that selectively modulate G4-driven genes remains a challenge. Here, we report an approach for the identification of G4-binding small molecules using small molecule microarrays (SMMs). We use the SMM screening platform to identify a novel G4-binding small molecule that inhibits MYC expression in cell models, with minimal impact on the expression of other G4-associated genes. Surface plasmon resonance (SPR) and thermal melt assays demonstrated that this molecule binds reversibly to the MYC G4 with single digit micromolar affinity, and with weaker or no measurable binding to other G4s. Biochemical and cell-based assays demonstrated that the compound effectively silenced MYC transcription and translation via a G4-dependent mechanism of action. The compound induced G1 arrest and was selectively toxic to MYC-driven cancer cell lines containing the G4 in the promoter but had minimal effects in peripheral blood mononucleocytes or a cell line lacking the G4 in its MYC promoter. As a measure of selectivity, gene expression analysis and qPCR experiments demonstrated that MYC and several MYC target genes were downregulated upon treatment with this compound, while the expression of several other G4-driven genes was not affected. In addition to providing a novel chemical scaffold that modulates MYC expression through G4 binding, this work suggests that the SMM screening approach may be broadly useful as an approach for the identification of new G4-binding small molecules. C1 [Felsenstein, Kenneth M.; Simmons, John K.; Leon, Elena; Zhang, Shuling; Michalowski, Aleksandra; Mock, Beverly A.] NCI, Lab Canc Biol & Genet, Bldg 37,Room 3146, Bethesda, MD 20892 USA. [Felsenstein, Kenneth M.; Leon, Elena] NCI, JHU Mol Targets & Drug Discovery Program, Baltimore, MD USA. [Saunders, Lindsey B.; Calabrese, David R.; Schneekloth, John S., Jr.] NCI, Biol Chem Lab, Bldg 376,Room 225C,POB B, Frederick, MD 21702 USA. [Gareiss, Peter] Yale Ctr Mol Discovery, West Haven, CT USA. [Felsenstein, Kenneth M.] Univ Colorado Med Scientist Training Program, Aurora, CO USA. RP Mock, BA (reprint author), NCI, Lab Canc Biol & Genet, Bldg 37,Room 3146, Bethesda, MD 20892 USA.; Schneekloth, JS (reprint author), NCI, Biol Chem Lab, Bldg 376,Room 225C,POB B, Frederick, MD 21702 USA. EM mockb@mail.nih.gov; schneeklothjs@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, Center for Cancer Research; National Cancer Institute (NCI), National Institutes of Health [1 ZIA BC011585 01] FX We thank members of the Chemical Biology Laboratory for helpful comments and suggestions. We gratefully acknowledge Dr. A. Stephen, K. Worthy, Dr. M. O'Neill, Dr. T. Anderson, and the Protein Chemistry Laboratory (Advanced Technology Program, Frederick National Laboratory for Cancer Research) for their invaluable expertise and assistance in conducting the surface plasmon resonance experiments. We thank J.-Q., Chen and M. A. Herrmann for performing the MYC immunoassays with Protein Simple technology. We thank G. Tosato (Center for Cancer Research) for the CA46 cells. We also thank J. Merkel for helpful discussions regarding microarray analysis. This work was supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, and the National Cancer Institute (NCI), National Institutes of Health (1 ZIA BC011585 01). K.F. obtained his M.S., and E.L. is working on her M.S. as NCI/Johns Hopkins University Molecular Targets and Drug Discovery Fellows. J.K.S. is a Multiple Myeloma Research Foundation fellow. NR 62 TC 12 Z9 12 U1 3 U2 23 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 EI 1554-8937 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD JAN PY 2016 VL 11 IS 1 BP 139 EP 148 DI 10.1021/acschembio.5b00577 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DB5OC UT WOS:000368562500016 PM 26462961 ER PT J AU Park, JK Taubenberger, JK AF Park, Jae-Keun Taubenberger, Jeffery K. TI Universal Influenza Vaccines: To Dream the Possible Dream? SO ACS INFECTIOUS DISEASES LA English DT Editorial Material ID CHALLENGE AB Influenza viruses are a significant public health threat, causing both annually circulating epidemics and unpredictable pandemics. Vaccination is the best means of control against individual cases of influenza and also for decreasing epidemic spread in the population. However, rapid influenza virus evolution requires continual reformulation of vaccines for annual influenza epidemics, and because pandemics cannot be accurately predicted, no current vaccine strategy can induce broad protection against all subtypes of influenza viruses. Recent work has suggested that such broadly protective, or "universal", influenza virus vaccines might be achievable using vaccine strategies that target conserved B- and T-cell epitopes. C1 [Park, Jae-Keun; Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Taubenberger, JK (reprint author), NIAID, Viral Pathogenesis Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000986-01] NR 11 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 2373-8227 J9 ACS INFECT DIS JI ACS Infect. Dis. PD JAN PY 2016 VL 2 IS 1 BP 5 EP 7 DI 10.1021/acsinfecdis.5b00146 PG 3 WC Chemistry, Medicinal; Infectious Diseases SC Pharmacology & Pharmacy; Infectious Diseases GA DB4DU UT WOS:000368464500003 PM 26977452 ER PT J AU Starling, RC Stehlik, J Baran, DA Armstrong, B Stone, JR Ikle, D Morrison, Y Bridges, ND Putheti, P Strom, TB Bhasin, M Guleria, I Chandraker, A Sayegh, M Daly, KP Briscoe, DM Heeger, PS AF Starling, R. C. Stehlik, J. Baran, D. A. Armstrong, B. Stone, J. R. Ikle, D. Morrison, Y. Bridges, N. D. Putheti, P. Strom, T. B. Bhasin, M. Guleria, I. Chandraker, A. Sayegh, M. Daly, K. P. Briscoe, D. M. Heeger, P. S. CA CTOT-05 Consortium TI Multicenter Analysis of Immune Biomarkers and Heart Transplant Outcomes: Results of the Clinical Trials in Organ Transplantation-05 Study SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article ID CARDIAC ALLOGRAFT VASCULOPATHY; CORONARY-ARTERY-DISEASE; ANTIBODY-MEDIATED REJECTION; ENDOTHELIAL GROWTH-FACTOR; INTRAVASCULAR ULTRASOUND ASSESSMENT; ACUTE CELLULAR REJECTION; ALLOMAP GENE-EXPRESSION; LONG-TERM SURVIVAL; REACTIVE T-CELLS; INTERNATIONAL SOCIETY AB Identification of biomarkers that assess posttransplant risk is needed to improve long-term outcomes following heart transplantation. The Clinical Trials in Organ Transplantation (CTOT)-05 protocol was an observational, multicenter, cohort study of 200 heart transplant recipients followed for the first posttransplant year. The primary endpoint was a composite of death, graft loss/retransplantation, biopsy-proven acute rejection (BPAR), and cardiac allograft vasculopathy (CAV) as defined by intravascular ultrasound (IVUS). We serially measured anti-HLA-and auto-antibodies, angiogenic proteins, peripheral blood allo-reactivity, and peripheral blood gene expression patterns. We correlated assay results and clinical characteristics with the composite endpoint and its components. The composite endpoint was associated with older donor allografts (p < 0.03) and with recipient anti-HLA antibody (p < 0.04). Recipient CMV-negativity (regardless of donor status) was associated with BPAR (p < 0.001), and increases in plasma vascular endothelial growth factor-C (OR 20; 95%CI:1.9-218) combined with decreases in endothelin-1 (OR 0.14; 95%CI:0.02-0.97) associated with CAV. The remaining biomarkers showed no relationships with the study endpoints. While suboptimal endpoint definitions and lower than anticipated event rates were identified as potential study limitations, the results of this multicenter study do not yet support routine use of the selected assays as noninvasive approaches to detect BPAR and/or CAV following heart transplantation. C1 [Starling, R. C.] Cleveland Clin, Kaufman Ctr Heart Failure, Cleveland, OH 44106 USA. [Starling, R. C.] Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA. [Stehlik, J.] Univ Utah, Hlth Sci Ctr, Div Cardiovasc Med, Salt Lake City, UT USA. [Baran, D. A.] Newark Beth Israel Med Ctr, Transplant Ctr, Newark, NJ USA. [Armstrong, B.; Ikle, D.] Rho, Chapel Hill, NC USA. [Stone, J. R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Morrison, Y.; Bridges, N. D.] NIAID, Transplantat Branch, NIH, Rockville, MD USA. [Putheti, P.; Strom, T. B.; Bhasin, M.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med, Boston, MA 02115 USA. [Bhasin, M.] Beth Israel Deaconess Med Ctr, Genom Prot Bioinformat & Syst Biol Ctr, Boston, MA 02215 USA. [Guleria, I.; Chandraker, A.; Sayegh, M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Schuster Family Transplantat Res Ctr,Dept Med, Boston, MA 02115 USA. [Guleria, I.; Briscoe, D. M.] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Med, Boston, MA USA. [Guleria, I.; Daly, K. P.; Briscoe, D. M.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Daly, K. P.] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Cardiol, Boston, MA USA. [Heeger, P. S.] Icahn Sch Med Mt Sinai, Inst Immunol, Translat Transplant Res Ctr, Dept Med, New York, NY 10029 USA. [Heeger, P. S.] Icahn Sch Med Mt Sinai, Recanati Miller Transplant Inst, New York, NY 10029 USA. RP Heeger, PS (reprint author), Icahn Sch Med Mt Sinai, Inst Immunol, Translat Transplant Res Ctr, Dept Med, New York, NY 10029 USA.; Heeger, PS (reprint author), Icahn Sch Med Mt Sinai, Recanati Miller Transplant Inst, New York, NY 10029 USA. EM peter.heeger@mssm.edu OI Daly, Kevin/0000-0003-4327-1532 FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [U01AI063594, AI063623] FX This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under U01AI063594 awarded to P.H. and AI063623 awarded to M. S. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 85 TC 6 Z9 6 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JAN PY 2016 VL 16 IS 1 BP 121 EP 136 DI 10.1111/ajt.13422 PG 16 WC Surgery; Transplantation SC Surgery; Transplantation GA DB4TW UT WOS:000368507300017 PM 26260101 ER PT J AU Lan, CW Fiellin, DA Barry, DT Bryant, KJ Gordon, AJ Edelman, EJ Gaither, JR Maisto, SA Marshall, BDL AF Lan, Chiao-Wen Fiellin, David A. Barry, Declan T. Bryant, Kendall J. Gordon, Adam J. Edelman, E. Jennifer Gaither, Julie R. Maisto, Stephen A. Marshall, Brandon D. L. TI The Epidemiology of Substance Use Disorders in US Veterans: A Systematic Review and Analysis of Assessment Methods SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; VA HEALTH-CARE; RANDOMIZED CLINICAL-TRIAL; MAJOR DEPRESSIVE DISORDER; AMERICAN-INDIAN VETERANS; HAZARDOUS ALCOHOL-USE; SPINAL-CORD-INJURY; PSYCHIATRIC-DISORDERS; BIPOLAR DISORDER; DRUG-USE AB Background: Substance use disorders (SUDs), which encompass alcohol and drug use disorders (AUDs, DUDs), constitute a major public health challenge among US veterans. SUDs are among the most common and costly of all health conditions among veterans. Objectives: This study sought to examine the epidemiology of SUDs among US veterans, compare the prevalence of SUDs in studies using diagnostic and administrative criteria assessment methods, and summarize trends in the prevalence of SUDs reported in studies sampling US veterans over time. Methods: Comprehensive electronic database searches were conducted. A total of 3,490 studies were identified. We analyzed studies sampling US veterans and reporting prevalence, distribution, and examining AUDs and DUDs. Results: Of the studies identified, 72 met inclusion criteria. The studies were published between 1995 and 2013. Studies using diagnostic criteria reported higher prevalence of AUDs (32% vs. 10%) and DUDs (20% vs. 5%) than administrative criteria, respectively. Regardless of assessment method, both the lifetime and past year prevalence of AUDs in studies sampling US veterans has declined gradually over time. Conclusion: The prevalence of SUDs reported in studies sampling US veterans are affected by assessment method. Given the significant public health problems of SUDs among US veterans, improved guidelines for clinical screening using validated diagnostic criteria to assess AUDs and DUDs in US veteran populations are needed. Scientific Significance: These findings may inform VA and other healthcare systems in prevention, diagnosis, and intervention for SUDs among US veterans. C1 [Lan, Chiao-Wen] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Community Hlth Sci, Los Angeles, CA USA. [Fiellin, David A.; Edelman, E. Jennifer] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Barry, Declan T.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Barry, Declan T.] APT Fdn Inc, Pain Treatment Serv, New Haven, CT USA. [Bryant, Kendall J.] NIAAA, NIH, Bethesda, MD USA. [Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA. [Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Mental Hlth Res Educ & Clin Ctr, Pittsburgh, PA USA. [Gordon, Adam J.] Univ Pittsburgh, Ctr Res Hlth Care, Pittsburgh, PA USA. [Gaither, Julie R.] Yale Univ, Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT USA. [Maisto, Stephen A.] Syracuse Univ, Dept Psychol, Syracuse, NY USA. [Marshall, Brandon D. L.] Brown Univ, Dept Epidemiol, Sch Publ Hlth, 121 South Main St,Box G-S-121-2, Providence, RI 02912 USA. RP Marshall, BDL (reprint author), Brown Univ, Dept Epidemiol, 121 South Main St,Box G-S-121-2, Providence, RI 02912 USA. EM brandon_marshall@brown.edu OI Fiellin, David/0000-0002-4006-010X FU National Institute on Alcohol Abuse and Alcoholism (NIAAA) [U24-AA022000]; Yale Drug Abuse, Addiction and HIV Research Scholars (DAHRS) Program [K12-DA-33312-03]; Brown University; [K05-AA16928] FX This work was supported in part by grant U24-AA022000 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Dr. Edelman is funded by the Yale Drug Abuse, Addiction and HIV Research Scholars (DAHRS) Program (K12-DA-33312-03). Dr. Maisto is supported by grant K05-AA16928 (NIAAA). Dr. Marshall is supported by a Richard B. Salomon Faculty Research Award from Brown University. NR 113 TC 1 Z9 1 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 EI 1521-0391 J9 AM J ADDICTION JI Am. J. Addict. PD JAN PY 2016 VL 25 IS 1 BP 7 EP 24 DI 10.1111/ajad.12319 PG 18 WC Substance Abuse SC Substance Abuse GA DB4TS UT WOS:000368506900001 PM 26693830 ER PT S AU Birnbaum, LS AF Birnbaum, Linda S. BE Insel, PA TI My Winding Road: From Microbiology to Toxicology and Environmental Health SO ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 56 SE Annual Review of Pharmacology and Toxicology LA English DT Review; Book Chapter DE autobiography; Birnbaum; EPA; NIEHS; NTP; Linda S. Birnbaum ID DOSE-RESPONSE RELATIONSHIPS; AGE-RELATED-CHANGES; DIBENZO-P-DIOXINS; LONG-EVANS RATS; MIXED-FUNCTION OXIDASES; CYP1A2 ENZYME-ACTIVITY; SPRAGUE-DAWLEY RATS; FEMALE B6C3F1 MICE; C57BL/6N MICE; PHARMACOKINETIC MODEL C1 [Birnbaum, Linda S.] NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. RP Birnbaum, LS (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM birnbaumls@niehs.nih.gov NR 116 TC 0 Z9 0 U1 4 U2 14 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 0362-1642 BN 978-0-8243-0456-0 J9 ANNU REV PHARMACOL JI Annu. Rev. Pharmacol. Toxicol. PY 2016 VL 56 BP 1 EP 17 DI 10.1146/annurev-pharmtox-010715-103255 PG 17 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA BE1PJ UT WOS:000368345700001 PM 26514198 ER PT S AU Insel, PA Amara, SG Blaschke, TF Meyer, UA AF Insel, Paul A. Amara, Susan G. Blaschke, Terrence F. Meyer, Urs A. BE Insel, PA TI Introduction to the Theme "Cancer Pharmacology" SO ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 56 SE Annual Review of Pharmacology and Toxicology LA English DT Editorial Material; Book Chapter C1 [Insel, Paul A.] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. [Insel, Paul A.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Amara, Susan G.] NIMH, Bethesda, MD 20892 USA. [Blaschke, Terrence F.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Blaschke, Terrence F.] Stanford Univ, Sch Med, Dept Mol Pharmacol, Stanford, CA 94305 USA. [Meyer, Urs A.] Univ Basel, Div Pharmacol & Neurobiol, CH-4056 Basel, Switzerland. RP Insel, PA (reprint author), Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA.; Insel, PA (reprint author), Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. NR 14 TC 2 Z9 2 U1 2 U2 11 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 0362-1642 BN 978-0-8243-0456-0 J9 ANNU REV PHARMACOL JI Annu. Rev. Pharmacol. Toxicol. PY 2016 VL 56 BP 19 EP 22 DI 10.1146/annurev-pharmtox-102015-123106 PG 4 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA BE1PJ UT WOS:000368345700002 PM 26551200 ER PT S AU Gottesman, MM Lavi, O Hall, MD Gillet, JP AF Gottesman, Michael M. Lavi, Orit Hall, Matthew D. Gillet, Jean-Pierre BE Insel, PA TI Toward a Better Understanding of the Complexity of Cancer Drug Resistance SO ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 56 SE Annual Review of Pharmacology and Toxicology LA English DT Review; Book Chapter DE ABCB1; P-glycoprotein; chemotherapy; platinum compounds; multidrug resistance ID CELL LUNG-CANCER; CHRONIC MYELOID-LEUKEMIA; HUMAN OVARIAN-CARCINOMA; TISSUE PLATINUM CONCENTRATION; TYROSINE KINASE INHIBITORS; MULTIDRUG-RESISTANCE; COPPER TRANSPORTER; BCR-ABL; INTRATUMORAL HETEROGENEITY; COLLATERAL SENSITIVITY AB Resistance to anticancer drugs is a complex process that results from alterations in drug targets; development of alternative pathways for growth activation; changes in cellular pharmacology, including increased drug efflux; regulatory changes that alter differentiation pathways or pathways for response to environmental adversity; and/or changes in the local physiology of the cancer, such as blood supply, tissue hydrodynamics, behavior of neighboring cells, and immune system response. All of these specific mechanisms are facilitated by the intrinsic hallmarks of cancer, such as tumor cell heterogeneity, redundancy of growth-promoting pathways, increased mutation rate and/or epigenetic alterations, and the dynamic variation of tumor behavior in time and space. Understanding the relative contribution of each of these factors is further complicated by the lack of adequate in vitro models that mimic clinical cancers. Several strategies to use current knowledge of drug resistance to improve treatment of cancer are suggested. C1 [Gottesman, Michael M.; Lavi, Orit; Hall, Matthew D.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Gillet, Jean-Pierre] Univ Namur, Namur Res Inst Life Sci NARILIS, Mol Physiol Res Unit URPhyM, Lab Mol Canc Biol,Fac Med, B-5000 Namur, Belgium. RP Gottesman, MM; Lavi, O; Hall, MD (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA.; Gillet, JP (reprint author), Univ Namur, Namur Res Inst Life Sci NARILIS, Mol Physiol Res Unit URPhyM, Lab Mol Canc Biol,Fac Med, B-5000 Namur, Belgium. EM mgottesman@nih.gov; lavio@mail.nih.gov; hallma@mail.nih.gov; jean-pierre.gillet@unamur.be FU Intramural NIH HHS NR 122 TC 13 Z9 13 U1 12 U2 53 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 0362-1642 BN 978-0-8243-0456-0 J9 ANNU REV PHARMACOL JI Annu. Rev. Pharmacol. Toxicol. PY 2016 VL 56 BP 85 EP 102 DI 10.1146/annurev-pharmtox-010715-103111 PG 18 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA BE1PJ UT WOS:000368345700006 PM 26514196 ER PT J AU Horwitz, BN Reynolds, CA Walum, H Ganiban, J Spotts, EL Reiss, D Lichtenstein, P Neiderhiser, JM AF Horwitz, Briana N. Reynolds, Chandra A. Walum, Hasse Ganiban, Jody Spotts, Erica L. Reiss, David Lichtenstein, Paul Neiderhiser, Jenae M. TI Understanding The Role of Mate Selection Processes in Couples' Pair-Bonding Behavior SO BEHAVIOR GENETICS LA English DT Article DE Assortative mating; Mate selection; Marital quality; Pair-bonding behavior; Phenotypic assortment; Social homogamy ID SPOUSE SIMILARITY; FLUID ABILITY; ADJUSTMENT; ASSORTMENT; QUALITY; PEOPLE; MODELS; TWINS; GENE AB Couples are similar in their pair-bonding behavior, yet the reasons for this similarity are often unclear. A common explanation is phenotypic assortment, whereby individuals select partners with similar heritable characteristics. Alternatively, social homogamy, whereby individuals passively select partners with similar characteristic due to shared social backgrounds, is rarely considered. We examined whether phenotypic assortment and/or social homogamy can contribute to mate similarity using a twin-partner design. The sample came from the Twin and Offspring Study in Sweden, which included 876 male and female monozygotic and same-sex dizygotic twins plus their married or cohabitating partners. Results showed that variance in pair-bonding behavior was attributable to genetic and nonshared environmental factors. Furthermore, phenotypic assortment accounted for couple similarity in pair-bonding behavior. This suggests that individuals' genetically based characteristics are involved in their selection of mates with similar pair-bonding behavior. C1 [Horwitz, Briana N.] Calif State Univ Fullerton, Dept Psychol, H-710I Humanities Bldg, Fullerton, CA 92831 USA. [Reynolds, Chandra A.] Univ Calif Riverside, Dept Psychol, Riverside, CA 92521 USA. [Walum, Hasse] Emory Univ, Ctr Behav Neurosci, Atlanta, GA 30322 USA. [Ganiban, Jody] George Washington Univ, Dept Psychol, Washington, DC 20052 USA. [Spotts, Erica L.] Natl Inst Hlth, Off Behav Sci & Social Res, Bethesda, MD USA. [Reiss, David] Yale Univ, Ctr Child Study, New Haven, CT 06520 USA. [Lichtenstein, Paul] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Neiderhiser, Jenae M.] Penn State Univ, Dept Psychol, University Pk, PA 16802 USA. RP Horwitz, BN (reprint author), Calif State Univ Fullerton, Dept Psychol, H-710I Humanities Bldg, Fullerton, CA 92831 USA. EM bhorwitz@fullerton.edu FU National Institute of Mental Health [R01MH54601]; National Institute on Aging [F32 AG039165] FX We thank the principle investigators and families of the Twin and Offspring Study in Sweden (TOSS. Funding for TOSS was provided by the National Institute of Mental Health Grant R01MH54601. Additional funding was provided by the National Institute on Aging (F32 AG039165). NR 31 TC 0 Z9 0 U1 6 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 EI 1573-3297 J9 BEHAV GENET JI Behav. Genet. PD JAN PY 2016 VL 46 IS 1 SI SI BP 143 EP 149 DI 10.1007/s10519-015-9766-y PG 7 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA DB7UP UT WOS:000368722300012 PM 26573626 ER PT J AU Collier, AC Chun, TW Maenza, J Coombs, RW Tapia, K Chang, M Stevens, CE Justement, JS Murray, D Stekler, JD Mullins, JI Holte, SE AF Collier, Ann C. Chun, Tae-Wook Maenza, Janine Coombs, Robert W. Tapia, Kenneth Chang, Ming Stevens, Claire E. Justement, J. Shawn Murray, Danielle Stekler, Joanne D. Mullins, James I. Holte, Sarah E. TI A Pilot Study of Raltegravir Plus Combination Antiretroviral Therapy in Early Human Immunodeficiency Virus Infection: Challenges and Lessons Learned SO BIORESEARCH OPEN ACCESS LA English DT Article DE antiretroviral therapy; integrase inhibitor; primary HIV; reservoir ID PRIMARY HIV-1 INFECTION; T-CELL-ACTIVATION; DECAY CHARACTERISTICS; CONTROLLED-TRIAL; OPEN-LABEL; INTENSIFICATION; DNA; INDIVIDUALS; RESERVOIR; IMPACT AB Availability of integrase strand transfer inhibitors created interest in determining whether their use would decrease persistently infected cell numbers. This study hypothesized that adding raltegravir (RAL) to standard antiretroviral therapy (ART) would decrease human immunodeficiency virus (HIV)-infected CD4(+) T cells more than standard combination ART. This was a pilot, randomized study comparing open-label standard triple ART to standard triple ART plus RAL over 96 weeks in ART-naive adults with early HIV infection. The primary objective was to compare quantity and trajectory of HIV DNA. Eighty-two persons were referred. A diverse set of reasons precluded the enrollment of all but 10. Those who enrolled and completed the study had an estimated median duration of HIV infection of 74 days at ART start. The groups had similar baseline characteristics. The RAL group had more rapid first phase plasma HIV RNA decay (0.67log(10) copies/mL/day) than with combination ART (0.34log(10)copies/mL/day), p=0.037. Second phase HIV RNA decay, residual viremia, cell-associated RNA, HIV DNA, CD4(+) T-cells with replication-competent virus, and 2LTR circle levels did not differ between groups. Among those with entry plasma HIV RNA levels above the median, 2LTR circles were significantly lower over time than in those with lower entry HIV RNA levels (p=0.02). Our results suggest homogeneity of responses in cell-associated RNA, HIV DNA, CD4(+) T-cells with replication-competent virus, and 2LTR circles with early HIV in both ART groups. The kinetics of 2LTR DNA did not reflect the kinetics of plasma HIV RNA decline following ART initiation. C1 [Collier, Ann C.; Maenza, Janine; Coombs, Robert W.; Stekler, Joanne D.; Mullins, James I.] Univ Washington, Div Infect Dis, Dept Med, Seattle, WA USA. [Chun, Tae-Wook; Justement, J. Shawn; Murray, Danielle] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Coombs, Robert W.; Chang, Ming; Mullins, James I.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Tapia, Kenneth] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Stevens, Claire E.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Mullins, James I.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Holte, Sarah E.] Univ Washington, Div Fred Hutch, Dept Biostat, Program Biostat & Biomath, Seattle, WA 98195 USA. [Collier, Ann C.] Univ Washington, Harborview Med Ctr, Dept Med Infect Dis, Box 359929,325 9th Ave, Seattle, WA 98104 USA. RP Collier, AC (reprint author), Univ Washington, Div Infect Dis, Dept Med, Seattle, WA USA.; Collier, AC (reprint author), Univ Washington, Harborview Med Ctr, Dept Med Infect Dis, Box 359929,325 9th Ave, Seattle, WA 98104 USA. EM acollier@uw.edu NR 19 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2164-7844 EI 2164-7860 J9 BIORESEARCH OPEN ACC JI BioResearch Open Access PD JAN 1 PY 2016 VL 5 IS 1 BP 15 EP 21 DI 10.1089/biores.2015.0038 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DB3WN UT WOS:000368444100001 PM 26862469 ER PT J AU Arora, A Abdel-Fatah, TMA Agarwal, D Doherty, R Croteau, DL Moseley, PM Hameed, K Green, A Aleskandarany, MA Rakha, EA Patterson, K Ball, G Chan, SYT Ellis, IO Bohr, VA Bryant, HE Madhusudan, S AF Arora, Arvind Abdel-Fatah, Tarek M. A. Agarwal, Devika Doherty, Rachel Croteau, Deborah L. Moseley, Paul M. Hameed, Khalid Green, Andrew Aleskandarany, Mohammed A. Rakha, Emad A. Patterson, Karl Ball, Graham Chan, Stephen Y. T. Ellis, Ian O. Bohr, Vilhelm A. Bryant, Helen E. Madhusudan, Srinivasan TI Clinicopathological and prognostic significance of RECQL5 helicase expression in breast cancers SO CARCINOGENESIS LA English DT Article ID CHINESE HAN POPULATION; HUMAN RECQ5-BETA; DNA HELICASES; SUSCEPTIBILITY; TRANSCRIPTION; ASSOCIATION; REPAIR; GENE; POLYMORPHISMS; OSTEOSARCOMA AB RECQL5 is a member of the RecQ family of DNA helicases and has key roles in homologous recombination, base excision repair, replication and transcription. The clinicopathological significance of RECQL5 expression in breast cancer is unknown. In this study, we have evaluated RECQL5 mRNA expression in 1977 breast cancers, and RECQL5 protein level in 1902 breast cancers [Nottingham Tenovus series (n = 1650) and ER- cohort (n = 252)]. Expression levels were correlated to aggressive phenotypes and survival outcomes. High RECQL5 mRNA expression was significantly associated with high histological grade (P = 0.007), HER2 overexpression (P = 0.032), ER+/HER2-/high proliferation genefu subtype (P < 0.0001), integrative molecular clusters (intClust 1and 9) (P < 0.0001) and poor survival (P < 0.0001). In subgroup analysis, high RECQL5 mRNA level remains significantly associated with poor BCSS in ER+ cohort (P < 0.0001) but not in ER- cohort (P = 0.116). At the protein level, in tumours with low RAD51, high RECQL5 level was significantly associated with high histological grade (P < 0.0001), higher mitotic index (P = 0.008), dedifferentiation (P = 0.025), pleomorphism (P = 0.027) and poor survival (P = 0.003). In subgroup analysis, high RECQL5/low RAD51 remains significantly associated with poor BCSS in ER+ cohort (P = 0.010), but not in ER-cohort (P = 0.628). In multivariate analysis, high RECQL5 mRNA and high RECQL5/low RAD51 nuclear protein coexpression independently influenced survival (P = 0.022) in whole cohort and in the ER+ subgroup. Preclinically, we show that exogenous expression of RECQL5 in MCF10A cells can drive proliferation supporting an oncogenic function for RECQL5 in breast cancer. We conclude that RECQL5 is a promising biomarker in breast cancer. C1 [Arora, Arvind; Doherty, Rachel; Madhusudan, Srinivasan] Univ Nottingham, Sch Med, Div Canc & Stem Cells, Acad Unit Oncol, Nottingham NG5 1PB, England. [Arora, Arvind; Abdel-Fatah, Tarek M. A.; Moseley, Paul M.; Hameed, Khalid; Chan, Stephen Y. T.; Madhusudan, Srinivasan] Univ Nottingham Hosp, Dept Oncol, Nottingham NG5 1PB, England. [Agarwal, Devika; Ball, Graham] Nottingham Trent Univ, Sch Sci & Technol, Clifton Campus, Nottingham NG11 8NS, England. [Croteau, Deborah L.; Ellis, Ian O.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Green, Andrew; Aleskandarany, Mohammed A.; Rakha, Emad A.] Univ Nottingham, Sch Med, Dept Pathol, Nottingham NG5 1PB, England. [Patterson, Karl; Bryant, Helen E.] Univ Sheffield, Sheffield Canc Res Ctr, Sch Med, Dept Oncol,Acad Unit Mol Oncol, Sheffield S10 2RX, S Yorkshire, England. RP Madhusudan, S (reprint author), Univ Nottingham, Sch Med, Div Canc & Stem Cells, Acad Unit Oncol, Nottingham NG5 1PB, England. EM srinivasan.madhusudan@nottingham.ac.uk OI Doherty, Rachel/0000-0002-3979-961X; Agarwal, Devika/0000-0002-5203-307X; Madhusudan, Srinivasan/0000-0002-5354-5480 NR 36 TC 3 Z9 3 U1 2 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 JAN PY 2016 VL 37 IS 1 BP 63 EP 71 DI 10.1093/carcin/bgv163 PG 9 WC Oncology SC Oncology GA DB3LK UT WOS:000368412900009 PM 26586793 ER PT J AU Phipps, AI Passarelli, MN Chan, AT Harrison, TA Jeon, J Hutter, CM Berndt, SI Brenner, H Caan, BJ Campbell, PT Chang-Claude, J Chanock, SJ Cheadle, JP Curtis, KR Duggan, D Fisher, D Fuchs, CS Gala, M Giovannucci, EL Hayes, RB Hoffmeister, M Hsu, L Jacobs, EJ Jansen, L Kaplan, R Kap, EJ Maughan, TS Potter, JD Schoen, RE Seminara, D Slattery, ML West, H White, E Peters, U Newcomb, PA AF Phipps, Amanda I. Passarelli, Michael N. Chan, Andrew T. Harrison, Tabitha A. Jeon, Jihyoun Hutter, Carolyn M. Berndt, Sonja I. Brenner, Hermann Caan, Bette J. Campbell, Peter T. Chang-Claude, Jenny Chanock, Stephen J. Cheadle, Jeremy P. Curtis, Keith R. Duggan, David Fisher, David Fuchs, Charles S. Gala, Manish Giovannucci, Edward L. Hayes, Richard B. Hoffmeister, Michael Hsu, Li Jacobs, Eric J. Jansen, Lina Kaplan, Richard Kap, Elisabeth J. Maughan, Timothy S. Potter, John D. Schoen, Robert E. Seminara, Daniela Slattery, Martha L. West, Hannah White, Emily Peters, Ulrike Newcomb, Polly A. TI Common genetic variation and survival after colorectal cancer diagnosis: a genome-wide analysis SO CARCINOGENESIS LA English DT Article ID FATTY LIVER-DISEASE; INTESTINAL-CELL KINASE; SUSCEPTIBILITY LOCI; COLON-CANCER; NURSES HEALTH; ASSOCIATION; RISK; METAANALYSIS; POLYMORPHISMS; TRIAL AB Genome-wide association studies have identified several germline single nucleotide polymorphisms (SNPs) significantly associated with colorectal cancer (CRC) incidence. Common germline genetic variation may also be related to CRC survival. We used a discovery-based approach to identify SNPs related to survival outcomes after CRC diagnosis. Genome-wide genotyping arrays were conducted for 3494 individuals with invasive CRC enrolled in six prospective cohort studies (median study-specific follow-up = 4.2-8.1 years). In pooled analyses, we used Cox regression to assess SNP-specific associations with CRC-specific and overall survival, with additional analyses stratified by stage at diagnosis. Top findings were followed-up in independent studies. A P value threshold of P < 5x10(-8) in analyses combining discovery and follow-up studies was required for genome-wide significance. Among individuals with distant-metastatic CRC, several SNPs at 6p12.1, nearest the LOVL5 gene, were statistically significantly associated with poorer survival, with the strongest associations noted for rs209489 [hazard ratio (HR) = 1.8, P = 7.6x10(-10) and HR = 1.8, P = 3.7x10(-9) for CRC-specific and overall survival, respectively). No SNPs were statistically significantly associated with survival among all cases combined or in cases without distant-metastases. SNPs in 6p12.1/ELOVL5 were associated with survival outcomes in individuals with distant-metastatic CRC, and merit further follow-up for functional significance. Findings from this genome-wide association study highlight the potential importance of genetic variation in CRC prognosis and provide clues to genomic regions of potential interest. C1 [Phipps, Amanda I.; Passarelli, Michael N.; Potter, John D.; White, Emily; Peters, Ulrike; Newcomb, Polly A.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Phipps, Amanda I.; Passarelli, Michael N.; Harrison, Tabitha A.; Jeon, Jihyoun; Hutter, Carolyn M.; Curtis, Keith R.; Hsu, Li; Potter, John D.; White, Emily; Peters, Ulrike; Newcomb, Polly A.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Chan, Andrew T.; Fuchs, Charles S.; Giovannucci, Edward L.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Berndt, Sonja I.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Brenner, Hermann; Jansen, Lina] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany. [Brenner, Hermann; Hoffmeister, Michael] German Canc Consortium DKTK, D-69120 Heidelberg, Germany. [Caan, Bette J.] Kaiser Permanente Med Care Program Northern Calif, Div Res, Oakland, CA 94612 USA. [Campbell, Peter T.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA. [Chang-Claude, Jenny; Jacobs, Eric J.; Kap, Elisabeth J.] German Canc Res Ctr, Div Canc Epidemiol, Unit Genet Epidemiol, D-69120 Heidelberg, Germany. [Cheadle, Jeremy P.; West, Hannah] Cardiff Univ, Sch Med, Inst Canc & Genet, Cardiff CF14 4XN, S Glam, Wales. [Duggan, David] Translat Genom Res Inst, Phoenix, AZ 85004 USA. [Fisher, David] UCL, MRC Clin Trials Unit, London WC2B 6NH, England. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Gala, Manish; Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. [Hayes, Richard B.] NYU, Sch Med, Dept Populat Hlth, Div Epidemiol, New York, NY 10016 USA. [Hsu, Li] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Maughan, Timothy S.] Univ Oxford, Gray Inst Radiat Oncol & Biol, Oxford OX3 7DQ, England. [Potter, John D.] Massey Univ, Ctr Publ Hlth Res, Wellington 6140, New Zealand. [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Dept Med & Epidemiol, Pittsburgh, PA 15213 USA. [Seminara, Daniela] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Slattery, Martha L.] Univ Utah, Hlth Sci Ctr, Dept Internal Med, Salt Lake City, UT 84132 USA. RP Phipps, AI (reprint author), Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.; Phipps, AI (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. EM aiphipps@u.washington.edu RI Jansen, Lina/D-7255-2016; Brenner, Hermann/B-4627-2017; OI Jansen, Lina/0000-0001-8004-4940; Brenner, Hermann/0000-0002-6129-1572; Hayes, Richard/0000-0002-0918-661X; Hoffmeister, Michael/0000-0002-8307-3197 FU National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services [U01CA137088, R01CA059045, R25CA094880, T32CA009168, K07CA172298, K05CA152715, R01 CA176272]; Cancer Research UK; Medical Research Council; Bobby Moore Fund from Cancer Research UK, Tenovus; Kidani Trust; National Institute for Social Care and Health Research Cancer Genetics Biomedical Research Unit; CORECT: National Cancer Institute, National Institutes of Health [CA-09-002, U19CA148107]; CPS-II: The American Cancer Society; DACHS: German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; DALS: National Institutes of Health [R01 CA48998]; HPFS: National Institutes of Health [P01CA055075, UM1CA167552, R01CA137178, P50CA127003, K24DK098311]; NHS: National Institutes of Health [R01CA137178, P50CA127003, K24DK098311, P01CA087969]; PHS: National Institutes of Health [K24DK098311, R01CA42182]; PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; WHI: National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C] FX National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01CA137088 to U.P., R01CA059045 to U.P., R25CA094880, T32CA009168, K07CA172298 to A.I.P., K05CA152715 to P.A.N., R01 CA176272 to P.A.N. and A.T.C.). The COIN trial was funded by Cancer Research UK and the Medical Research Council, and its associated translational studies are supported by the Bobby Moore Fund from Cancer Research UK, Tenovus, the Kidani Trust and the National Institute for Social Care and Health Research Cancer Genetics Biomedical Research Unit. Additional funding support for individual studies is provided below:; CORECT: National Cancer Institute, National Institutes of Health under RFA # CA-09-002 (U19CA148107). 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.; CPS-II: The American Cancer Society funds the creation, maintenance and updating of the Cancer Prevention Study-II (CPS-II) cohort. This study was conducted with Institutional Review Board approval.; 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: National Institutes of Health (P01CA055075, UM1CA167552, R01CA137178, P50CA127003, K24DK098311).; NHS: National Institutes of Health (R01CA137178, P01CA087969, P50CA127003, K24DK098311).; PHS: National Institutes of Health (R01CA42182, K24DK098311).; 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.; VITAL: National Institutes of Health (K05CA154337 to E.W.).; WHI: National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C. Supplementary Tables 1-4 and Figures 1-8 can be found at http://carcin.oxfordjournals.org/ NR 50 TC 0 Z9 0 U1 0 U2 5 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 JAN PY 2016 VL 37 IS 1 BP 87 EP 95 DI 10.1093/carcin/bgv161 PG 9 WC Oncology SC Oncology GA DB3LK UT WOS:000368412900012 PM 26586795 ER PT J AU Kachuri, L Amos, CI Mckay, JD Johansson, M Vineis, P Bueno-De-Mesquita, HB Boutron-Ruault, MC Johansson, M Quiros, JR Sieri, S Travis, RC Weiderpass, E Le Marchand, L Henderson, BE Wilkens, L Goodman, GE Chen, C Doherty, JA Christiani, DC Wei, YY Su, L Tworoger, S Zhang, XH Kraft, P Zaridze, D Field, JK Marcus, MW Davies, MPA Hyde, R Caporaso, NE Landi, MT Severi, G Giles, GG Liu, G McLaughlin, JR Li, YF Xiao, XJ Fehringer, G Zong, XC Denroche, RE Zuzarte, PC McPherson, JD Brennan, P Hung, RJ AF Kachuri, Linda Amos, Christopher I. Mckay, James D. Johansson, Mattias Vineis, Paolo Bueno-de-Mesquita, H. Bas Boutron-Ruault, Marie-Christine Johansson, Mikael Quiros, J. Ramon Sieri, Sabina Travis, Ruth C. Weiderpass, Elisabete Le Marchand, Loic Henderson, Brian E. Wilkens, Lynne Goodman, Gary E. Chen, Chu Doherty, Jennifer A. Christiani, David C. Wei, Yongyue Su, Li Tworoger, Shelley Zhang, Xuehong Kraft, Peter Zaridze, David Field, John K. Marcus, Michael W. Davies, Michael P. A. Hyde, Russell Caporaso, Neil E. Landi, Maria Teresa Severi, Gianluca Giles, Graham G. Liu, Geoffrey McLaughlin, John R. Li, Yafang Xiao, Xiangjun Fehringer, Gord Zong, Xuchen Denroche, Robert E. Zuzarte, Philip C. McPherson, John D. Brennan, Paul Hung, Rayjean J. TI Fine mapping of chromosome 5p15.33 based on a targeted deep sequencing and high density genotyping identifies novel lung cancer susceptibility loci SO CARCINOGENESIS LA English DT Article ID GENOME-WIDE ASSOCIATION; TELOMERE LENGTH; NEVER-SMOKERS; LYSOPHOSPHATIDYLCHOLINE ACYLTRANSFERASE; GENETIC-VARIATION; PROSTATE-CANCER; RISK; POPULATION; VARIANTS; EXPRESSION AB Chromosome 5p15.33 has been identified as a lung cancer susceptibility locus, however the underlying causal mechanisms were not fully elucidated. Previous fine-mapping studies of this locus have relied on imputation or investigated a small number of known, common variants. This study represents a significant advance over previous research by investigating a large number of novel, rare variants, as well as their underlying mechanisms through telomere length. Variants for this fine-mapping study were identified through a targeted deep sequencing (average depth of coverage greater than 4000x) of 576 individuals. Subsequently, 4652 SNPs, including 1108 novel SNPs, were genotyped in 5164 cases and 5716 controls of European ancestry. After adjusting for known risk loci, rs2736100 and rs401681, we identified a new, independent lung cancer susceptibility variant in LPCAT1: rs139852726 (OR = 0.46, P = 4.73x10(-9)), and three new adenocarcinoma risk variants in TERT: rs61748181 (OR = 0.53, P = 2.64x10(-6)), rs112290073 (OR = 1.85, P = 1.27x10(-5)), rs138895564 (OR = 2.16, P = 2.06x10(-5); among young cases, OR = 3.77, P = 8.41x10(-4)). In addition, we found that rs139852726 (P = 1.44x10(-3)) was associated with telomere length in a sample of 922 healthy individuals. The gene-based SKAT-O analysis implicated TERT as the most relevant gene in the 5p15.33 region for adenocarcinoma (P = 7.84x10(-7)) and lung cancer (P = 2.37x10(-5)) risk. In this largest fine-mapping study to investigate a large number of rare and novel variants within 5p15.33, we identified novel lung and adenocarcinoma susceptibility loci with large effects and provided support for the role of telomere length as the potential underlying mechanism. C1 [Kachuri, Linda; McLaughlin, John R.; Fehringer, Gord; Zong, Xuchen; Hung, Rayjean J.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5T 3L9, Canada. [Kachuri, Linda; Liu, Geoffrey; Hung, Rayjean J.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON M5T 3M7, Canada. [Amos, Christopher I.; Severi, Gianluca; Xiao, Xiangjun] Dartmouth Coll, Geisel Sch Med, Ctr Genom Med, Dept Community & Family Med, Lebanon, NH 03766 USA. [Mckay, James D.; Johansson, Mattias; Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Vineis, Paolo; Severi, Gianluca] Human Genet Fdn HuGeF, I-10126 Turin, Italy. [Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, Norfolk Pl, London W2 1PG, England. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Dept Determinants Chron Dis DCD, NL-3721 MA Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr, Dept Gastroenterol & Hepatol, NL-3584 CX Utrecht, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London SW7 2AZ, England. [Bueno-de-Mesquita, H. Bas] Univ Malaya, Fac Med, Dept Social & Prevent Med, Kuala Lumpur 50603, Malaysia. [Boutron-Ruault, Marie-Christine; Severi, Gianluca] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, Lifestyle Genes & Hth Integrat Trans Generat Epid, U1018, F-94805 Villejuif, France. [Boutron-Ruault, Marie-Christine; Severi, Gianluca] Univ Paris 11, UMRS 1018 94805, Villejuif, France. [Boutron-Ruault, Marie-Christine; Severi, Gianluca] Inst Gustave Roussy, F-94805 Villejuif, France. [Johansson, Mikael] Umea Univ, Dept Radiat Sci, SE-90187 Umea, Sweden. [Quiros, J. Ramon] Publ Hlth Directorate Asturias, Oviedo 33006, Spain. [Sieri, Sabina] Fdn IRCCS Ist Nazl Tumori, Epidemiol & Prevent Unit, I-20133 Milan, Italy. [Travis, Ruth C.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford OX3 7LF, England. [Weiderpass, Elisabete] Univ Tromso, Fac Hlth Sci, Dept Community Med, Arctic Univ Norway, N-9037 Tromso, Norway. [Weiderpass, Elisabete] Canc Registry Norway, Dept Res, N-0379 Oslo, Norway. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Le Marchand, Loic; Henderson, Brian E.; Wilkens, Lynne] Univ Hawaii, Ctr Canc, Honolulu, HI 96813 USA. [Goodman, Gary E.; Chen, Chu] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Christiani, David C.; Wei, Yongyue; Su, Li; Tworoger, Shelley] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Christiani, David C.; Wei, Yongyue; Su, Li] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Christiani, David C.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Christiani, David C.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Tworoger, Shelley; Zhang, Xuehong] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Tworoger, Shelley; Zhang, Xuehong] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Zaridze, David] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Zaridze, David] Russian Canc Res Ctr, Moscow 115478, Russia. [Field, John K.; Marcus, Michael W.; Davies, Michael P. A.; Hyde, Russell] Univ Liverpool, Canc Res Ctr Inst Translat Med Univ, Roy Castle Lung Canc Res Programme, Liverpool L69 3BX, Merseyside, England. [Caporaso, Neil E.; Landi, Maria Teresa] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Severi, Gianluca; Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3004, Australia. [Severi, Gianluca; Giles, Graham G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia. [Giles, Graham G.] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. [Liu, Geoffrey] Princess Margaret Canc Ctr, Ontario Canc Inst, Toronto, ON M5G 0A3, Canada. [McLaughlin, John R.] Publ Hlth Ontario, Toronto, ON M5G 1V2, Canada. [Denroche, Robert E.; Zuzarte, Philip C.; McPherson, John D.] Ontario Inst Canc Res, Genome Technol, Toronto, ON M5G 0A3, Canada. RP Hung, RJ (reprint author), Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5T 3L9, Canada.; Hung, RJ (reprint author), Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON M5T 3M7, Canada. EM rayjean.hung@lunenfeld.ca RI Hung, Rayjean/A-7439-2013; Sieri, Sabina/K-4667-2016; Weiderpass, Elisabete/M-4029-2016; Liu, Geoffrey/N-4421-2016; McPherson, John/D-2633-2017; OI Sieri, Sabina/0000-0001-5201-172X; Weiderpass, Elisabete/0000-0003-2237-0128; McPherson, John/0000-0001-8049-9347; Giles, Graham/0000-0003-4946-9099 FU National Institutes of Health [U19CA148127, CA092824, CA074386, CA090578, UM1 CA164973]; Cancer Care Ontario Research Chair of Population Studies; Canadian Cancer Society Research Institute [020214]; CIHR Research Doctoral Award-Frederick Banting; Charles Best Canada Graduate Scholarships FX This work was supported by: the National Institutes of Health grant U19CA148127 (PI: Amos), the data harmonization was supported by Cancer Care Ontario Research Chair of Population Studies to Rayjean J. Hung. The MSH-PMH study was supported by Canadian Cancer Society Research Institute (no. 020214, PI: Hung). The Harvard Lung Cancer Study was funded by the National Institutes of Health grants: CA092824, CA074386, CA090578 (PI: Christiani). The Multiethnic Cohort Study was supported by the National Institutes of Health grant UM1 CA164973. Linda Kachuri is a trainee in the Canadian Institutes of Health Research (CIHR) Strategic Training for Advanced Genetic Epidemiology (STAGE) Program, and is supported by the CIHR Research Doctoral Award-Frederick Banting and Charles Best Canada Graduate Scholarships. NR 48 TC 3 Z9 3 U1 1 U2 8 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 JAN PY 2016 VL 37 IS 1 BP 96 EP 105 DI 10.1093/carcin/bgv165 PG 10 WC Oncology SC Oncology GA DB3LK UT WOS:000368412900013 PM 26590902 ER PT J AU Rawal, S Hoffman, HJ Bainbridge, KE Huedo-Medina, TB Duffy, VB AF Rawal, Shristi Hoffman, Howard J. Bainbridge, Kathleen E. Huedo-Medina, Tania B. Duffy, Valerie B. TI Prevalence and Risk Factors of Self-Reported Smell and Taste Alterations: Results from the 2011-2012 US National Health and Nutrition Examination Survey (NHANES) SO CHEMICAL SENSES LA English DT Article DE dry mouth; dysgeusia; head injury; health status; phantosmia ID QUALITY-OF-LIFE; OLFACTORY DYSFUNCTION; ADULT-POPULATION; OLDER-ADULTS; IMPAIRMENT; AGE; SENSITIVITY; DISEASE; ASSOCIATION; UNAWARENESS AB Chemosensory problems challenge health through diminished ability to detect warning odors, consume a healthy diet, and maintain quality of life. We examined the prevalence and associated risk factors of self-reported chemosensory alterations in 3603 community-dwelling adults (aged 40+ years), from the nationally representative, US National Health and Nutrition Examination Survey (NHANES) 2011-2012. In this new NHANES component, technicians surveyed adults in the home about perceived smell and taste problems, distortions, and diminished abilities since age 25 (termed "alterations"), and chemosensory-related health risks and behaviors. The prevalence of self-reported smell alteration was 23%, including phantosmia at 6%; taste was 19%, including dysgeusia at 5%. Prevalence rates increased progressively with age, highest in those aged 80+ years (smell, 32%; taste, 27%). In multivariable logistic regression, controlling for sociodemographics, health behaviors, and chemosensory-related conditions, the strongest independent risk factor for smell alteration was sinonasal symptoms (odds ratio [OR] = 2.06; 95% confidence interval [CI]: 1.63-2.61), followed by heavy drinking, loss of consciousness from head injury, family income a parts per thousand currency sign110% poverty threshold, and xerostomia. For taste, the strongest risk factor was xerostomia (OR = 2.65; 95% CI: 1.97-3.56), followed by nose/facial injury, lower educational attainment, and fair/poor health. Self-reported chemosensory alterations are prevalent in US adults, supporting increased attention to decreasing their modifiable risks, managing safety/health consequences, and expanding chemosensory screening/testing and treatments. C1 [Rawal, Shristi; Huedo-Medina, Tania B.; Duffy, Valerie B.] Univ Connecticut, Dept Allied Hlth Sci, 358 Mansfield Rd,Unit 1101, Storrs, CT 06269 USA. [Hoffman, Howard J.; Bainbridge, Kathleen E.] NIDCD, Epidemiol & Stat Program, NIH, Bethesda, MD 20892 USA. RP Duffy, VB (reprint author), Univ Connecticut, Dept Allied Hlth Sci, 358 Mansfield Rd,Unit 1101, Storrs, CT 06269 USA. EM valerie.duffy@uconn.edu FU National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH) [Y1-DC-0013]; National Center for Health Statistics (NCHS), Centers for Disease Control and Prevention (CDC) FX This work was supported by an Interagency Agreement [Y1-DC-0013] between the National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH) and the National Center for Health Statistics (NCHS), Centers for Disease Control and Prevention (CDC). NR 46 TC 9 Z9 9 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0379-864X EI 1464-3553 J9 CHEM SENSES JI Chem. Senses PD JAN PY 2016 VL 41 IS 1 BP 69 EP 76 DI 10.1093/chemse/bjv057 PG 8 WC Behavioral Sciences; Food Science & Technology; Neurosciences; Physiology SC Behavioral Sciences; Food Science & Technology; Neurosciences & Neurology; Physiology GA DB3MU UT WOS:000368416600007 PM 26487703 ER PT J AU Lerit, DA Poulton, JS AF Lerit, Dorothy A. Poulton, John S. TI Centrosomes are multifunctional regulators of genome stability SO CHROMOSOME RESEARCH LA English DT Review DE Centrosome; Genome stability; Chromosomal instability; Mitosis; DNA damage; p53; Acentrosomal; Cell cycle; PCM; Aneuploidy; Interphase; Centrosome separation; Asymmetric division ID CELL-CYCLE PROGRESSION; SPINDLE-ASSEMBLY CHECKPOINT; NEURAL STEM-CELLS; DNA-DAMAGE; CHROMOSOMAL INSTABILITY; DROSOPHILA-NEUROBLASTS; CAENORHABDITIS-ELEGANS; CENTRIOLE DUPLICATION; DAUGHTER CENTROSOME; SELF-ORGANIZATION AB The maintenance of genome stability is critical for proper cell function, and loss of this stability contributes to many human diseases and developmental disorders. Therefore, cells have evolved partially redundant mechanisms to monitor and protect the genome. One subcellular organelle implicated in the maintenance of genome stability is the centrosome, best known as the primary microtubule organizing center of most animal cells. Centrosomes serve many different roles throughout the cell cycle, and many of those roles, including mitotic spindle assembly, nucleation of the interphase microtubule array, DNA damage response, and efficient cell cycle progression, have been proposed to help maintain genome stability. As a result, the centrosome is itself a highly regulated entity. Here, we review evidence concerning the significance of the centrosome in promoting genome integrity. Recent advances permitting acute and persistent centrosome removal suggest we still have much to learn regarding the specific function and actual importance of centrosomes in different contexts, as well as how cells may compensate for centrosome dysfunction to maintain the integrity of the genome. Although many animal cells survive and proliferate in the absence of centrosomes, they do so aberrantly. Based on these and other studies, we conclude that centrosomes serve as critical, multifunctional organelles that promote genome stability. C1 [Lerit, Dorothy A.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Poulton, John S.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Lerit, Dorothy A.] NIH, 50 South Dr,Bldg 50,Room 2122, Bethesda, MD 20892 USA. [Poulton, John S.] Univ N Carolina, Fordham 519,CB 3280, Chapel Hill, NC 27599 USA. RP Lerit, DA (reprint author), NIH, 50 South Dr,Bldg 50,Room 2122, Bethesda, MD 20892 USA.; Poulton, JS (reprint author), Univ N Carolina, Fordham 519,CB 3280, Chapel Hill, NC 27599 USA. EM dorothy.lerit@nih.gov; poultonj@email.unc.edu FU Lenfant Biomedical Postdoctoral Fellowship; NHLBI Career Transition Award [1K22HL126922]; Peifer lab grant [NIH R01GM067236] FX We thank Nasser M. Rusan, Mark Peifer, and Erich Kushner for critical comments. DAL is supported by a Lenfant Biomedical Postdoctoral Fellowship and a NHLBI Career Transition Award (1K22HL126922). JSP is supported by the Peifer lab grant NIH R01GM067236. NR 95 TC 1 Z9 1 U1 2 U2 9 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0967-3849 EI 1573-6849 J9 CHROMOSOME RES JI Chromosome Res. PD JAN PY 2016 VL 24 IS 1 SI SI BP 5 EP 17 DI 10.1007/s10577-015-9506-4 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DB8YS UT WOS:000368803700002 PM 26658800 ER PT J AU Garimella, PS Katz, R Patel, KV Kritchevsky, SB Parikh, CR Ix, JH Fried, LF Newman, AB Shlipak, MG Harris, TB Sarnak, MJ AF Garimella, Pranav S. Katz, Ronit Patel, Kushang V. Kritchevsky, Stephen B. Parikh, Chirag R. Ix, Joachim H. Fried, Linda F. Newman, Anne B. Shlipak, Michael G. Harris, Tamara B. Sarnak, Mark J. CA Hlth ABC Study TI Association of Serum Erythropoietin With Cardiovascular Events, Kidney Function Decline, and Mortality The Health Aging and Body Composition Study SO CIRCULATION-HEART FAILURE LA English DT Article DE cardiovascular outcomes; chronic kidney disease; death; erythropoietin; heart failure ID CONGESTIVE-HEART-FAILURE; EPOETIN-ALPHA; ENDOGENOUS ERYTHROPOIETIN; DARBEPOETIN-ALPHA; OLDER-ADULTS; CYSTATIN-C; INFLAMMATORY MARKERS; DISEASE; ANEMIA; RISK AB Background Studies suggest that in patients with heart failure (HF), high serum erythropoietin is associated with risk of recurrent HF and mortality. Trials of erythropoietin-stimulating agents in persons with kidney disease have also suggested an increased incidence of adverse clinical events. No large studies of which we are aware have evaluated the association of endogenous erythropoietin levels with clinical outcomes in the community-living older adults. Methods and Results Erythropoietin concentration was measured in 2488 participants aged 70-79 years in the Health, Aging and Body Composition Study. Associations of erythropoietin with incident HF, coronary heart disease, stroke, mortality, and 30% decline in estimated glomerular filtration rate were examined using Cox proportional hazards and logistic regression over 10.7 years of follow-up. Mean (SD) age was 75 (3) years and median (quartile 1, quartile 3) erythropoietin was 12.3 (9.0, 17.2) mIU/mL. There were 503 incident HF events, and each doubling of serum erythropoietin was associated with a 25% increased risk of incident HF 1.25 (95% confidence interval 1.13, 1.48) after adjusting for demographics, prevalent cardiovascular disease, cardiovascular disease risk factors, kidney function, and serum hemoglobin. There was no interaction of serum erythropoietin with chronic kidney disease or anemia (P>0.50). There were 330 incident coronary heart disease events, 161 strokes, 1112 deaths, and 698 outcomes of 30% decline in estimated glomerular filtration rate. Serum erythropoietin was not significantly associated with these outcomes. Conclusions Higher levels of endogenous erythropoietin are associated with incident HF in older adults. Studies need to elucidate the mechanisms through which endogenous erythropoietin levels associate with specific outcomes. C1 [Garimella, Pranav S.; Sarnak, Mark J.] Tufts Med Ctr, Dept Med, Div Nephrol, Boston, MA 02111 USA. [Katz, Ronit] Univ Washington, Kidney Res Inst, Seattle, WA 98195 USA. [Patel, Kushang V.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Kritchevsky, Stephen B.] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Parikh, Chirag R.] Yale Univ, Sch Med, Dept Med, Nephrol Sect, New Haven, CT 06510 USA. [Ix, Joachim H.] Univ Calif San Diego, Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA 92103 USA. [Ix, Joachim H.] Univ Calif San Diego, Div Nephrol & Prevent Med, San Diego, CA 92103 USA. [Fried, Linda F.] Univ Pittsburgh, VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA 15260 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol Biostat & Med, San Francisco, CA 94143 USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, Dept Gen Internal Med, San Francisco, CA USA. [Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. RP Sarnak, MJ (reprint author), Tufts Med Ctr, Div Nephrol, 800 Washington St,Box 391, Boston, MA 02111 USA. EM msarnak@tuftsmedicalcenter.org RI Newman, Anne B./C-6408-2013 OI Newman, Anne B./0000-0002-0106-1150 FU Intramural Research Program of the National Institutes of Health (NIH); National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, 5R01AG027002]; NINR [R01-NR012459]; American Heart Association [14EIA18560026]; National Center on Minority Health and Health Disparities, NIH [MD-07-080] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH) and the National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, and NINR grant R01-NR012459. Drs Shlipak, Sarnak, Ix, and Katz were supported by NIA grant 5R01AG027002, Dr Ix by an American Heart Association Award #14EIA18560026, and Dr Patel was supported by National Center on Minority Health and Health Disparities, NIH grant MD-07-080. The study sponsors had no role in study design; collection, analysis, and interpretation of the data; writing the report; and the decision to submit the report for publication. NR 44 TC 3 Z9 3 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD JAN PY 2016 VL 9 IS 1 AR e002124 DI 10.1161/CIRCHEARTFAILURE.115.002124 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DB6HN UT WOS:000368615500001 PM 26721912 ER PT J AU Saito, Y Stamp, LK Caudle, KE Hershfield, MS McDonagh, EM Callaghan, JT Tassaneeyakul, W Mushiroda, T Kamatani, N Goldspiel, BR Phillips, EJ Klein, TE Lee, MTM AF Saito, Y. Stamp, L. K. Caudle, K. E. Hershfield, M. S. McDonagh, E. M. Callaghan, J. T. Tassaneeyakul, W. Mushiroda, T. Kamatani, N. Goldspiel, B. R. Phillips, E. J. Klein, T. E. Lee, M. T. M. TI Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for human leukocyte antigen B (HLA-B) genotype and allopurinol dosing: 2015 update SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article AB The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA-B*58:01 Genotype and Allopurinol Dosing was originally published in February 2013. We reviewed the recent literature and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplemental Material and included additional resources for applying CPIC guidelines into the electronic health record. Up-to-date information can be found at PharmGKB (). C1 [Saito, Y.] Natl Inst Hlth Sci, Div Med Safety Sci, Setagaya Ku, Tokyo, Japan. [Stamp, L. K.] Univ Otago, Dept Med, Christchurch, New Zealand. [Caudle, K. E.] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, 332 N Lauderdale St, Memphis, TN 38105 USA. [Hershfield, M. S.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Hershfield, M. S.] Duke Univ, Sch Med, Dept Biochem, Durham, NC USA. [McDonagh, E. M.; Klein, T. E.] Stanford Univ, Med Ctr, Dept Genet, Stanford, CA 94305 USA. [Callaghan, J. T.] Dept Vet Affairs Med Ctr, ACOS Res, Indianapolis, IN USA. [Callaghan, J. T.] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Callaghan, J. T.] Indiana Univ Sch Med, Dept Pharmacol Toxicol, Indianapolis, IN 46202 USA. [Tassaneeyakul, W.] Khon Kaen Univ, Fac Med, Dept Pharmacol, Res & Diagnost Ctr Emerging Infect Dis, Khon Kaen, Thailand. [Mushiroda, T.] RIKEN, Lab Pharmacogenet, Ctr Genom Med, Yokohama, Kanagawa, Japan. [Kamatani, N.] StaGen, Inst Data Anal, Tokyo, Japan. [Goldspiel, B. R.] NIH, Dept Pharm, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Phillips, E. J.] Murdoch Univ, Inst Immunol & Infect Dis, Div Infect Dis, Murdoch, WA 6150, Australia. [Phillips, E. J.] Vanderbilt Univ, Med Ctr, Div Infect Dis, Nashville, TN USA. [Lee, M. T. M.] RIKEN Ctr Integrat Med Sci, Lab Int Alliance Genom Res, Yokohama, Kanagawa, Japan. [Lee, M. T. M.] Acad Sinica, Inst Biomed Sci, Natl Ctr Genome Med, Taipei, Taiwan. [Lee, M. T. M.] China Med Univ, Sch Chinese Med, Taichung, Taiwan. RP Lee, MTM (reprint author), RIKEN Ctr Integrat Med Sci, Lab Int Alliance Genom Res, Yokohama, Kanagawa, Japan.; Lee, MTM (reprint author), Acad Sinica, Inst Biomed Sci, Natl Ctr Genome Med, Taipei, Taiwan.; Lee, MTM (reprint author), China Med Univ, Sch Chinese Med, Taichung, Taiwan. EM mikelee@src.riken.jp OI McDonagh, Ellen/0000-0001-5806-6174 FU NHLBI NIH HHS [U01 HL0105198, U01 HL105198]; NIGMS NIH HHS [R24 GM061374, R24 GM115264, R24 GM61374, U01 GM092666, UO1 GM92666] NR 0 TC 10 Z9 10 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD JAN PY 2016 VL 99 IS 1 BP 36 EP 37 DI 10.1002/cpt.161 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB8YL UT WOS:000368803000020 PM 26094938 ER PT J AU Flechsig, P Choyke, P Kratochwil, C Warth, A Antoch, G Holland-Letz, T Rath, D Eichwald, V Huber, PE Kauczor, HU Haberkorn, U Giesel, FL AF Flechsig, Paul Choyke, Peter Kratochwil, Clemens Warth, Arne Antoch, Gerald Holland-Letz, Tim Rath, Daniel Eichwald, Viktoria Huber, Peter E. Kauczor, Hans-Ulrich Haberkorn, Uwe Giesel, Frederik L. TI Increased x-ray attenuation in malignant vs. benign mediastinal nodes in an orthotopic model of lung cancer SO DIAGNOSTIC AND INTERVENTIONAL RADIOLOGY LA English DT Article ID LYMPH-NODES; FDG-PET/CT; CT; TOMOGRAPHY; METAANALYSIS; METASTASES AB PURPOSE Staging of lung cancer is typically performed with fluorodeoxyglucose-positron emission tomography-computed tomography (FDG-PET/CT); however, false positive PET scans can occur due to inflammatory disease. The CT scan is used for anatomic registration and attenuation correction. Herein, we evaluated x-ray attenuation (XRA) within nodes on CT and correlated this with the presence of malignancy in an orthotopic lung cancer model in rats. METHODS 1x106 NCI-H460 cells were injected transthoracically in six National Institutes of Health nude rats and six animals served as controls. After two weeks, animals were sacrificed; lymph nodes were extracted and scanned with a micro-CT to determine their XRA prior to histologic analysis. RESULTS Median CT density in malignant lymph nodes (n=20) was significantly higher than benign lymph nodes (n=12; P=0.018). Short-axis diameter of metastatic lymph nodes was significantly different than benign nodes (3.4 mm vs. 2.4 mm; P=0.025). Area under the curve for malignancy was higher for density-based lymph node analysis compared with size measurements (0.87 vs. 0.7). CONCLUSION XRA of metastatic mediastinal lymph nodes is significantly higher than benign nodes in this lung cancer model. This suggests that information on nodal density may be useful when used in combination with the results of FDG-PET in determining the likelihood of malignant adenopathy. C1 [Flechsig, Paul; Kauczor, Hans-Ulrich] Univ Heidelberg Hosp, Dept Diagnost & Intervent Radiol, Heidelberg, Germany. [Kratochwil, Clemens; Rath, Daniel; Haberkorn, Uwe; Giesel, Frederik L.] Univ Heidelberg Hosp, Dept Nucl Med, Heidelberg, Germany. [Warth, Arne] Univ Heidelberg Hosp, Inst Pathol, Heidelberg, Germany. [Choyke, Peter] NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Antoch, Gerald] Univ Dusseldorf, Sch Med, Dept Diagnost & Intervent Radiol, Dusseldorf, Germany. [Holland-Letz, Tim] German Canc Res Ctr, Core Facil Stat, Heidelberg, Germany. [Eichwald, Viktoria] German Canc Res Ctr, Core Facil Small Anim Imaging, Heidelberg, Germany. [Huber, Peter E.] German Canc Res Ctr, Mol Radiat Oncol, Heidelberg, Germany. Univ Hosp Ctr Heidelberg, Heidelberg, Germany. [Kauczor, Hans-Ulrich; Giesel, Frederik L.] Translat Lung Res Ctr Heidelberg, Heidelberg, Germany. RP Giesel, FL (reprint author), Univ Heidelberg Hosp, Dept Nucl Med, Heidelberg, Germany. EM frederik@egiesel.com NR 24 TC 1 Z9 1 U1 0 U2 1 PU TURKISH SOC RADIOLOGY PI ANKARA PA HOSDERE CAD, GUZELKENT SOK, CANKAYA EVLERI, F-2, ANKARA, 06540, TURKEY SN 1305-3825 EI 1305-3612 J9 DIAGN INTERV RADIOL JI Diagn. Interv. Radiol. PD JAN PY 2016 VL 22 IS 1 BP 35 EP 39 DI 10.5152/dir.2015.15220 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DB9ON UT WOS:000368845900005 PM 26611258 ER PT J AU Kiluk, BD Carroll, KM Duhig, A Falk, DE Kampman, K Lai, SG Litten, RZ McCann, DJ Montoya, ID Preston, KL Skolnick, P Weisner, C Woody, G Chandler, R Detke, MJ Dunn, K Dworkin, RH Fertig, J Gewandter, J Moeller, FG Ramey, T Ryan, M Silverman, K Strain, EC AF Kiluk, Brian D. Carroll, Kathleen M. Duhig, Amy Falk, Daniel E. Kampman, Kyle Lai, Shengan Litten, Raye Z. McCann, David J. Montoya, Ivan D. Preston, Kenzie L. Skolnick, Phil Weisner, Constance Woody, George Chandler, Redonna Detke, Michael J. Dunn, Kelly Dworkin, Robert H. Fertig, Joanne Gewandter, Jennifer Moeller, F. Gerard Ramey, Tatiana Ryan, Megan Silverman, Kenneth Strain, Eric C. TI Measures of outcome for stimulant trials: ACTTION recommendations and research agenda SO DRUG AND ALCOHOL DEPENDENCE LA English DT Review DE Stimulant use disorders; Outcome measures; Clinical trials ID ADDICTION SEVERITY INDEX; ALCOHOL CLINICAL-TRIALS; FOLLOW-UP RATES; COCAINE-DEPENDENCE; DRUG-USE; MISSING DATA; USE DISORDERS; URINE; VALIDITY; DRINKING AB Background: The development and approval of an efficacious pharmacotherapy for stimulant use disorders has been limited by the lack of a meaningful indicator of treatment success, other than sustained abstinence. Methods: In March, 2015, a meeting sponsored by Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) was convened to discuss the current state of the evidence regarding meaningful outcome measures in clinical trials for stimulant use disorders. Attendees included members of academia, funding and regulatory agencies, pharmaceutical companies, and healthcare organizations. The goal was to establish a research agenda for the development of a meaningful outcome measure that may be used as an endpoint in clinical trials for stimulant use disorders. Results and conclusions: Based on guidelines for the selection of clinical trial endpoints, the lessons learned from prior addiction clinical trials, and the process that led to identification of a meaningful indicator of treatment success for alcohol use disorders, several recommendations for future research were generated. These include a focus on the validation of patient reported outcome measures of functioning, the exploration of patterns of stimulant abstinence that may be associated with physical and/or psychosocial benefits, the role of urine testing for validating self-reported measures of stimulant abstinence, and the operational definitions for reduction-based measures in terms of frequency rather than quantity of stimulant use. These recommendations may be useful for secondary analyses of clinical trial data, and in the design of future clinical trials that may help establish a meaningful indicator of treatment success. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Kiluk, Brian D.; Carroll, Kathleen M.] Yale Univ, Sch Med, West Haven, CT 06516 USA. [Duhig, Amy] Xcenda, Palm Harbor, FL USA. [Falk, Daniel E.; Litten, Raye Z.; Fertig, Joanne; Ryan, Megan] NIAAA, Bethesda, MD USA. [Kampman, Kyle] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Lai, Shengan; Dunn, Kelly; Silverman, Kenneth; Strain, Eric C.] Johns Hopkins Sch Med, Baltimore, MD USA. [McCann, David J.; Montoya, Ivan D.; Preston, Kenzie L.; Skolnick, Phil; Chandler, Redonna; Ramey, Tatiana] NIDA, Bethesda, MD 20892 USA. [Weisner, Constance] Univ Calif San Francisco, Div Res, Kaiser Permanente, San Francisco, CA 94143 USA. [Woody, George] Univ Penn, Philadelphia, PA 19104 USA. [Woody, George] Treatment Res Inst, Philadelphia, PA USA. [Detke, Michael J.] Indiana Univ Sch Med, Embera Neurotherapeut, Carmel, CA USA. [Dworkin, Robert H.; Gewandter, Jennifer] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Moeller, F. Gerard] Virginia Commonwealth Univ, Richmond, VA USA. RP Kiluk, BD (reprint author), Yale Univ, Sch Med, West Haven, CT 06516 USA. EM brian.kiluk@yale.edu OI Silverman, Kenneth/0000-0003-2724-1413 FU NIDA Intramural Research Program; NIDA [P50-DA09241, K24-DA023186] FX The work of authors who are NIH Intramural staff was supported in part by the NIDA Intramural Research Program. The work of authors Kiluk and Carroll was supported in part by NIDA grant P50-DA09241 (Carroll, PI). Author Strain was supported in part by NIDA grant K24-DA023186. The funding sources had no further role in the writing of this report. NR 58 TC 3 Z9 3 U1 2 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JAN 1 PY 2016 VL 158 BP 1 EP 7 DI 10.1016/j.drugalcdep.2015.11.004 PG 7 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DB5PN UT WOS:000368566200001 PM 26652899 ER PT J AU Siciliano, CA Calipari, ES Yorgason, JT Mateo, Y Helms, CM Lovinger, DM Grant, KA Jones, SR AF Siciliano, Cody A. Calipari, Erin S. Yorgason, Jordan T. Mateo, Yolanda Helms, Christa M. Lovinger, David M. Grant, Kathleen A. Jones, Sara R. TI Chronic ethanol self-administration in macaques shifts dopamine feedback inhibition to predominantly D2 receptors in nucleus accumbens core SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Autoreceptor; Nucleus accumbens; Macaque; Monkey; D3; Caudate ID VENTRAL TEGMENTAL AREA; ADDICTION; STRIATUM; NEURONS; SUPERSENSITIVITY; ADAPTATIONS; ALCOHOLICS; INDUCTION; MONKEYS; REWARD AB Background: Given the high level of homology between nonhuman primates and humans in regard to anatomy, physiology and ethanol drinking patterns, nonhuman primates represent an unparalleled preclinical model for examining the neurobiological basis of ethanol abuse. Methods: Here we examined the neurochemical consequences of chronic daily ethanol use using fast-scan cyclic voltammetry in brain slices containing the nucleus accumbens core or dorsolateral caudate taken from male cynomolgus macaques following ethanol drinking. Results: We found that in both regions the ability of ethanol to decrease dopamine release was unchanged, indicating that ethanol self-administration does not produce tolerance or sensitization to ethanol effects on dopamine release at the dopamine terminal at this time point. We also found that in the nucleus accumbens core, autoregulation of dopamine release was shifted from equal D2 and D3 receptor involvement in control animals to primarily D2 receptor-mediated in drinkers. Specifically, the effect quinpirole, a D2/D3 receptor agonist, on dopamine release was equal across groups; however, dopamine signals were reversed to a greater extent by the selective D3 receptor antagonist SB-277,011A in control animals, indicating a greater contribution of D2 receptors in quinpirole-induced inhibition following ethanol self administration. In the dorsolateral caudate, the effects of quinpirole and reversal with SB-277,011A was not different between ethanol and control slices. Conclusions: This work provides novel insight into the dopaminergic adaptations resulting from chronic ethanol use in nonhuman primates and indicates that alterations in D2/D3 dopamine autoreceptor signaling may be an important neurochemical adaptation to ethanol consumption during early use. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Siciliano, Cody A.; Calipari, Erin S.; Yorgason, Jordan T.; Jones, Sara R.] Wake Forest Sch Med, Dept Physiol & Pharmacol, Winston Salem, NC 27157 USA. [Mateo, Yolanda; Lovinger, David M.] NIAAA, Lab Integrat Neurosci, Sect Synapt Pharmacol, NIH, Rockville, MD 20852 USA. [Helms, Christa M.; Grant, Kathleen A.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Neurosci, Beaverton, OR 97006 USA. RP Jones, SR (reprint author), Wake Forest Sch Med, Dept Physiol & Pharmacol, Winston Salem, NC 27157 USA. EM srjones@wakehealth.edu OI Siciliano, Cody/0000-0001-9871-2089 FU NIH [U01 AA014091, P01 AA021099, F31 DA031533, F31 DA037710, T32 AA007565, F31 AA020439, U01 OD011092, R24 AA019431, P60 AA10760]; Division of Intramural Clinical and Biomedical Research NIAAA; Integrative Neuroscience Initiative on Alcoholism [AA 13510]; OHSU Administration Core [AA 13641] FX This work was funded by NIH grants U01 AA014091, P01 AA021099 (SRJ), F31 DA031533 (ESC), F31 DA037710, T32 AA007565 (CAS), F31 AA020439 (JTY), U01 OD011092, R24 AA019431, P60 AA10760 (KAG), Division of Intramural Clinical and Biomedical Research NIAAA (DML), Integrative Neuroscience Initiative on Alcoholism AA 13510 (KAG) and OHSU Administration Core AA 13641 (KAG). NR 31 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 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JAN 1 PY 2016 VL 158 BP 159 EP 163 DI 10.1016/j.drugalcdep.2015.10.031 PG 5 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DB5PN UT WOS:000368566200021 PM 26627912 ER PT S AU Rausch, JW Sztuba-Solinska, J Lusvarghi, S Le Grice, SFJ AF Rausch, Jason W. Sztuba-Solinska, Joanna Lusvarghi, Sabrina Le Grice, Stuart F. J. BE Prasad, VR Kalpana, GV TI Novel Biochemical Tools for Probing HIV RNA Structure SO HIV PROTOCOLS, 3RD EDITION SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Ensemble SHAPE; In-gel SHAPE; Methidiumpropyl-EDTA; ATCUN; Chemical probing; HIV RNA ID REV-RESPONSE ELEMENT; SECONDARY STRUCTURE; FOOTPRINTING ANALYSIS; SHAPE CHEMISTRY; SOFTWARE; CLEAVAGE; REVEALS; REGIONS; SWITCH AB Functional analysis of viral RNA requires knowledge of secondary structure arrangements and tertiary base interactions. Thus, high-throughput and comprehensive methods for assessing RNA structure are highly desirable. Selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) has proven highly useful for modeling the secondary structures of HIV and other retroviral RNAs in recent years. This technology is not without its limitations however, as SHAPE data can be severely compromised when the RNA under study is structurally heterogeneous. In addition, the method reveals little information regarding the three-dimensional (3D) organization of an RNA. This chapter outlines four detailed SHAPE-related methodologies that circumvent these limitations. "Ensemble" and "in-gel" variations of SHAPE permit structural analysis of individual conformers within structurally heterogeneous mixtures of RNA, while probing strategies that utilize "through-space" cleavage reagents such as methidiumpropyl-EDTA (MPE) and peptides appended with an ATCUN (amino terminal copper/nickel binding motif) can provide insight into 3D organization. Combinational application of these techniques provides a formidable arsenal for exploring the structures of HIV RNAs and associated nucleoprotein complexes. C1 [Rausch, Jason W.; Sztuba-Solinska, Joanna; Le Grice, Stuart F. J.] Frederick Natl Lab Canc Res, Reverse Transcriptase Biochem Sect, HIV Drug Resistance Program, Frederick, MD USA. [Lusvarghi, Sabrina] Natl Inst Diabet & Digest & Kidney Dis, Bioorgan Chem Lab, NIH, Bethesda, MD USA. RP Rausch, JW (reprint author), Frederick Natl Lab Canc Res, Reverse Transcriptase Biochem Sect, HIV Drug Resistance Program, Frederick, MD USA. FU Intramural NIH HHS NR 26 TC 1 Z9 1 U1 2 U2 7 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-3046-3; 978-1-4939-3045-6 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1354 BP 91 EP 117 DI 10.1007/978-1-4939-3046-3_7 D2 10.1007/978-1-4939-3046-3 PG 27 WC Immunology; Virology SC Immunology; Virology GA BE1XH UT WOS:000368688500008 PM 26714707 ER PT S AU Johnson, TP Nath, A AF Johnson, Tory P. Nath, Avindra BE Prasad, VR Kalpana, GV TI Protocol for Detection of HIV-Tat Protein in Cerebrospinal Fluid by a Sandwich Enzyme-Linked Immunosorbent Assay SO HIV PROTOCOLS, 3RD EDITION SE Methods in Molecular Biology LA English DT Article; Book Chapter DE HIV; Transactivator of transcription; Tat; ELISA; Protein detection; CSF; Cell lysates ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELLS; FUSION PROTEINS; INTERNALIZATION; ACTIVATION; SECRETION; APOPTOSIS; MEMBRANE; NEURONS; DOMAIN AB The human immunodeficiency virus (HIV) transactivator of transcription (Tat) is a virally produced protein that is required for efficient viral replication. Once formed inside an infected cell, Tat is secreted into the extracellular space where it has pathophysiological consequences on cells it interacts with. Tat has been demonstrated to be neurotoxic and is produced even under the pressures of anti-retroviral therapy; therefore Tat is suspected to contribute to the development of HIV-associated neurocognitive disorders. In this chapter, we describe a sandwich enzyme-linked immunosorbent assay protocol for the detection of Tat from cerebrospinal fluid samples. C1 [Johnson, Tory P.; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Johnson, TP (reprint author), NINDS, Sect Infect Nervous Syst, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 29 TC 0 Z9 0 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-3046-3; 978-1-4939-3045-6 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1354 BP 343 EP 352 DI 10.1007/978-1-4939-3046-3_23 D2 10.1007/978-1-4939-3046-3 PG 10 WC Immunology; Virology SC Immunology; Virology GA BE1XH UT WOS:000368688500024 PM 26714723 ER PT J AU Huang, YF Paul, WE AF Huang, Yuefeng Paul, William E. TI Inflammatory group 2 innate lymphoid cells SO INTERNATIONAL IMMUNOLOGY LA English DT Review DE IL-25; IL-33; iILC2; ILC plasticity; nILC2 ID TRANSCRIPTION FACTOR GATA3; NATURAL HELPER-CELLS; CD4(+) T-CELLS; ALTERNATIVELY ACTIVATED MACROPHAGES; TYPE-2 IMMUNE-RESPONSE; LUNG INFLAMMATION; AIRWAY INFLAMMATION; CYTOKINE PRODUCTION; HELMINTH EXPULSION; ADAPTIVE IMMUNITY AB Inflammatory ILC2.Group 2 innate lymphoid cells (ILC2 cells) are able to produce type 2 cytokines and to mediate type 2 immune protection and tissue homeostasis. ILC2 cells have often been considered to be a single set of cells that respond to IL-33 and/or IL-25. Recent evidence now indicates that ILC2 cells can be grouped into two distinct subsets: homeostatic or natural ILC2s (nILC2 cells); and inflammatory ILC2 cells (iILC2 cells). nILC2 cells reside in barrier tissues and primarily respond to IL-33. They play critical roles not only in immune protection but also in tissue repair and beige fat biogenesis. iILC2 cells are not present in peripheral tissues in the steady state but can be elicited at many sites by helminth infection or IL-25 treatment. IL-25-elicited ilLC2 cells act as transient ILC progenitors with multipotency. They can be mobilized by distinct types of infections to develop into nILC2-like or ILC3-like cells, functioning in corresponding immune responses. The demonstration of the existence of iILC2 cells adds to our understanding of the complexity of ILC2 biology and makes necessary an analysis of the relationship between nILC2 cells and iILC2 cells. C1 [Huang, Yuefeng; Paul, William E.] NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Huang, YF (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM yuefeng.huang@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health FX Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. NR 64 TC 6 Z9 6 U1 3 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 EI 1460-2377 J9 INT IMMUNOL JI Int. Immunol. PD JAN PY 2016 VL 28 IS 1 BP 23 EP 28 DI 10.1093/intimm/dxv044 PG 6 WC Immunology SC Immunology GA DB7FO UT WOS:000368680400004 PM 26232596 ER PT J AU Karargyris, A Siegelman, J Tzortzis, D Jaeger, S Candemir, S Xue, ZY Santosh, KC Vajda, S Antani, S Folio, L Thoma, GR AF Karargyris, Alexandros Siegelman, Jenifer Tzortzis, Dimitris Jaeger, Stefan Candemir, Sema Xue, Zhiyun Santosh, K. C. Vajda, Szilard Antani, Sameer Folio, Les Thoma, George R. TI Combination of texture and shape features to detect pulmonary abnormalities in digital chest X-rays SO INTERNATIONAL JOURNAL OF COMPUTER ASSISTED RADIOLOGY AND SURGERY LA English DT Article DE Tuberculosis; Screen; Software; Remote; Telemedicine ID TUBERCULOSIS; RADIOGRAPHS AB To improve detection of pulmonary and pleural abnormalities caused by pneumonia or tuberculosis (TB) in digital chest X-rays (CXRs). A method was developed and tested by combining shape and texture features to classify CXRs into two categories: TB and non-TB cases. Based on observation that radiologist interpretation is typically comparative: between left and right lung fields, the algorithm uses shape features to describe the overall geometrical characteristics of the lung fields and texture features to represent image characteristics inside them. Our algorithm was evaluated on two different datasets containing tuberculosis and pneumonia cases. Using our proposed algorithm, we were able to increase the overall performance, measured as area under the (ROC) curve (AUC) by 2.4 % over our previous work. C1 [Karargyris, Alexandros; Jaeger, Stefan; Candemir, Sema; Xue, Zhiyun; Santosh, K. C.; Vajda, Szilard; Antani, Sameer; Thoma, George R.] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Commun Engn Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Siegelman, Jenifer] Brigham & Womens Hosp, Dept Radiol, Div Emergency Radiol, 75 Francis St, Boston, MA 02115 USA. [Siegelman, Jenifer] Harvard Univ, Sch Med, Ctr Evidence Based Imaging, Boston, MA USA. [Tzortzis, Dimitris] Gen Hosp Athens KAT, Ugeianet Diagnost Ctr, Athens, Greece. [Folio, Les] NIH, Ctr Clin, Dept Radiol, Bethesda, MD 20892 USA. RP Karargyris, A (reprint author), Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Commun Engn Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM akarargyris@gmail.com OI Santosh, K.C./0000-0003-4176-0236 NR 10 TC 1 Z9 1 U1 1 U2 4 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1861-6410 EI 1861-6429 J9 INT J COMPUT ASS RAD JI Int. J. Comput. Assist. Radiol. Surg. PD JAN PY 2016 VL 11 IS 1 BP 99 EP 106 DI 10.1007/s11548-015-1242-x PG 8 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging; Surgery SC Engineering; Radiology, Nuclear Medicine & Medical Imaging; Surgery GA DB7IQ UT WOS:000368688600009 PM 26092662 ER PT J AU Subramaniam, S Kuhlbrandt, W Henderson, R AF Subramaniam, Sriram Kuehlbrandt, Werner Henderson, Richard TI CryoEM at IUCrJ: a new era SO IUCRJ LA English DT Article DE electron cryomicroscopy; electron tomography; single particle; cryoEM; overview ID TRANSMISSION ELECTRON-MICROSCOPY; ANGSTROM RESOLUTION; ATOMIC-STRUCTURE; PHASE-CONTRAST; CRYOMICROSCOPY; CRYSTALLOGRAPHY; ARCHITECTURE; VIRUS; RECONSTRUCTION; TOMOGRAPHY AB In this overview, we briefly outline recent advances in electron cryomicroscopy (cryoEM) and explain why the journal IUCrJ, published by the International Union of Crystallography, could provide a natural home for publications covering many present and future developments in the cryoEM field. C1 [Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Kuehlbrandt, Werner] Max Planck Inst Biophys, Dept Biol Struct, D-60538 Frankfurt, Germany. [Henderson, Richard] MRC, Mol Biol Lab, Francis Crick Ave, Cambridge CB2 0QH, England. RP Henderson, R (reprint author), MRC, Mol Biol Lab, Francis Crick Ave, Cambridge CB2 0QH, England. EM rh15@mrc-lmb.cam.ac.uk FU Medical Research Council [MC_U105184322] NR 34 TC 10 Z9 10 U1 2 U2 11 PU INT UNION CRYSTALLOGRAPHY PI CHESTER PA 2 ABBEY SQ, CHESTER, CH1 2HU, ENGLAND SN 2052-2525 J9 IUCRJ JI IUCrJ PD JAN PY 2016 VL 3 BP 3 EP 7 DI 10.1107/S2052252515023738 PN 1 PG 5 WC Chemistry, Multidisciplinary; Crystallography; Materials Science, Multidisciplinary SC Chemistry; Crystallography; Materials Science GA DB5YV UT WOS:000368590900002 PM 26870375 ER PT J AU Treibel, TA Fontana, M Maestrini, V Castelletti, S Rosmini, S Simpson, J Nasis, A Bhuva, AN Bulluck, H Abdel-Gadir, A White, SK Manisty, C Spottiswoode, BS Wong, TC Piechnik, SK Kellman, P Robson, MD Schelbert, EB Moon, JC AF Treibel, Thomas A. Fontana, Marianna Maestrini, Viviana Castelletti, Silvia Rosmini, Stefanie Simpson, Joanne Nasis, Arthur Bhuva, Anish N. Bulluck, Heerajnarain Abdel-Gadir, Amna White, Steven K. Manisty, Charlotte Spottiswoode, Bruce S. Wong, Timothy C. Piechnik, Stefan K. Kellman, Peter Robson, Matthew D. Schelbert, Erik B. Moon, James C. TI Automatic Measurement of the Myocardial Interstitium Synthetic Extracellular Volume Quantification Without Hematocrit Sampling SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE collagen; ECV; magnetic resonance imaging; mortality; myocardial fibrosis ID CARDIOVASCULAR MAGNETIC-RESONANCE; LONGITUDINAL RELAXATION-TIME; SPIN-LATTICE-RELAXATION; OXYGEN-SATURATION; EUROPEAN-SOCIETY; WORKING GROUP; HUMAN BLOOD; T1; FIBROSIS; HEART AB OBJECTIVES The authors sought to generate a synthetic extracellutar volume fraction (ECV) from the relationship between hematocrit and longitudinal relaxation rate of blood. BACKGROUND ECV quantification by cardiac magnetic resonance (CMR) measures diagnostically and prognostically relevant changes in the extraceltutar space. Current methodologies require blood hematocrit (Hct) measurement-a complication to easy clinical appLication. We hypothesized that the relationship between Hct and Longitudinal relaxation rate of blood (R1 =1/T1(blood)) could be calibrated and used to generate a synthetic ECV without Hct that was valid, user-friendly, and prognostic. METHODS Proof-of-concept: 427 subjects with a wide range of health and disease were divided into derivation (n = 214) and validation (n = 213) cohorts. Histology cohort: 18 patients with severe aortic stenosis with histology obtained during valve replacement. Outcome cohort: For comparison with external outcome data, we applied synthetic ECV to 1,172 consecutive patients (median follow-up 1.7 years; 74 deaths). ALL underwent CMR scanning at 1.5-T with ECV calculation from pre- and post-contrast T1 (blood and myocardium) and venous Hct. RESULTS Proof-of-concept: In the derivation cohort, native R1(bLood) and Hct showed a linear relationship (R-2 = 0.51; p < 0.001), which was used to create synthetic Hct and ECV. Synthetic ECV correlated well with conventional ECV (R2 = 0.97; p < 0.001) without bias. These results were maintained in the validation cohort. Histology cohort: Synthetic and conventional ECV both correlated well with collagen volume fraction measured from histology (R-2 = 0.61 and 0.69, both p < 0.001) with no statistical difference (p = 0.70). Outcome cohort: Synthetic ECV related to all-cause mortality (hazard ratio 1.90; 95% confidence interval 1.55 to 2.31; for every 5% increase in ECV). Finally, we engineered a synthetic ECV tool, generating automatic ECV maps during image acquisition. CONCLUSIONS Synthetic ECV provides validated noninvasive quantification of the myocardial extracellular space without blood sampling and is associated with cardiovascular outcomes. (J Am Coll Cardiol Img 2016;9:54-63) (C) 2016 by the American College of Cardiology Foundation. C1 [Treibel, Thomas A.; Fontana, Marianna; Maestrini, Viviana; Castelletti, Silvia; Rosmini, Stefanie; Simpson, Joanne; Nasis, Arthur; Bhuva, Anish N.; Bulluck, Heerajnarain; Abdel-Gadir, Amna; White, Steven K.; Manisty, Charlotte; Moon, James C.] St Bartholomews Hosp, Barts Heart Ctr, 2nd Floor,King George V Block, London EC1A 7BE, England. [Treibel, Thomas A.; Fontana, Marianna; Castelletti, Silvia; Rosmini, Stefanie; Bhuva, Anish N.; Bulluck, Heerajnarain; Abdel-Gadir, Amna; White, Steven K.; Manisty, Charlotte; Moon, James C.] UCL, Inst Cardiovasc Sci, London, England. [Maestrini, Viviana] Univ Roma La Sapienza, Dept Cardiovasc Resp Nephrol Anesthesiol & Geriat, Piazzale Aldo Moro 5, I-00185 Rome, Italy. [Spottiswoode, Bruce S.] Siemens Healthcare, Chicago, IL USA. [Wong, Timothy C.; Schelbert, Erik B.] Univ Pittsburgh, UPMC Heart & Vasc Inst, Pittsburgh, PA USA. [Piechnik, Stefan K.; Robson, Matthew D.] Univ Oxford, John Radcliffe Hosp, Div Cardiovasc Med, Raddiffe Dept Med, Oxford OX3 9DU, England. [Kellman, Peter] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Moon, JC (reprint author), St Bartholomews Hosp, Barts Heart Ctr, 2nd Floor,King George V Block, London EC1A 7BE, England.; Moon, JC (reprint author), St Bartholomews Hosp, Heart Hosp Imaging Ctr, 2nd Floor,King George V Block, London EC1A 7BE, England. EM j.moon@ucl.ac.uk RI Castelletti, Silvia/J-8926-2016; OI Castelletti, Silvia/0000-0001-9693-4083; moon, james/0000-0001-8071-1491; Bulluck, Heerajnarain/0000-0002-1985-1783 FU U.K. National Institute of Health Research; British Heart Foundation; Agency for Healthcare Research and Quality; MLR Oxford Biomedical Research Centre, Oxford University Hospitals Trust, University of Oxford; Pittsburgh Foundation; American Heart Association Scientist Development fund FX Drs. Treibel and Fontana are supported by doctoral research fellowships by the U.K. National Institute of Health Research and British Heart Foundation, respectively. Dr. Spottiswoode is an employee of Siemens Medical Solutions USA, Inc. Dr. Wong was supported by a grant from the Agency for Healthcare Research and Quality. Drs. Piechnik and Robson are supported by the MLR Oxford Biomedical Research Centre, Oxford University Hospitals Trust, University of Oxford. Dr. Schelbert was supported by grants from The Pittsburgh Foundation, and the American Heart Association Scientist Development fund; he has accepted contrast material from Bracco Diagnostics for research purposes beyond the scope of this work. Prof. Moon is directly and indirectly supported by the University College London Hospitals NIHR Biomedical Research Centre and Biomedical Research Unit at Barts Hospital, respectively. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 44 TC 2 Z9 3 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X EI 1876-7591 J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD JAN PY 2016 VL 9 IS 1 SI SI BP 54 EP 63 DI 10.1016/j.jcmg.2015.11.008 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DB4GD UT WOS:000368470600009 PM 26762875 ER PT J AU Bluemke, DA Kawel-Boehm, N AF Bluemke, David A. Kawel-Boehm, Nadine TI Can a MR Imaging Scanner Accurately Measure Hematocrit to Determine ECV Fraction? SO JACC-CARDIOVASCULAR IMAGING LA English DT Editorial Material DE collagen; ECV; magnetic resonance imaging; mortality; myocardial fibrosis ID CARDIOVASCULAR MAGNETIC-RESONANCE; DIFFUSE MYOCARDIAL FIBROSIS; EXTRACELLULAR VOLUME; BLOOD; DISEASE; CARDIOMYOPATHY; EXPANSION; VALUES C1 [Bluemke, David A.; Kawel-Boehm, Nadine] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Bluemke, DA (reprint author), NIH, Radiol & Imaging Sci, Ctr Clin, 10 Ctr Dr,Bldg 10,Rm 1C355, Bethesda, MD 20892 USA. EM bluemked@nih.gov; nadine.kawel@gmx.de OI Bluemke, David/0000-0002-8323-8086 NR 20 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X EI 1876-7591 J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD JAN PY 2016 VL 9 IS 1 SI SI BP 64 EP 66 DI 10.1016/j.jcmg.2015.11.009 PG 3 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DB4GD UT WOS:000368470600010 PM 26762876 ER PT J AU Gergen, PJ Teach, SJ Togias, A Busse, WW AF Gergen, Peter J. Teach, Stephen J. Togias, Alkis Busse, William W. TI Reducing Exacerbations in the Inner City: Lessons from the Inner-City Asthma Consortium (ICAC) SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Review DE Asthma; Exacerbations; Children; Inner-City Asthma Consortium; Control ID ENVIRONMENTAL INTERVENTION; COCKROACH ALLERGEN; CHILDREN; MORBIDITY; TRIAL; EXPOSURE; NCICAS; HOMES AB Asthma exacerbations are important components of asthma morbidity. The Inner-City Asthma Consortium was established in the early 1990s to identify risk factors for and to evaluate treatments to reduce asthma symptoms and exacerbations. Early studies identified atopy and inadequate treatment as important drivers of asthma morbidity. Later studies demonstrated that good adherence to guidelines-based asthma care could virtually eliminate symptoms and reduce but not eliminate exacerbations. Looking at exacerbations by season, risk factors were found to vary across the different seasons. Of the 7 factors identified, allergic status and pulmonary functions were found to be important for exacerbations in all seasons, but allergy had its strongest effect in the fall season. Therefore, additional therapy directed at reducing the role of allergy was evaluated and found to significantly reduce exacerbations even in participants with good symptom control when receiving guidelines-based therapy. Despite this year around aggressive therapy, exacerbations remain albeit at a lower level and with less seasonal variation. Another strategy, the short term use of therapy aimed at reducing the role of allergy begun before the fall season and focused on individuals at high risk for exacerbations, was found to be an effective approach to minimize exacerbations and to limit the amount of therapy necessary. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology C1 [Gergen, Peter J.; Togias, Alkis] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Teach, Stephen J.] Childrens Natl Hlth Syst, Washington, DC USA. [Busse, William W.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. RP Gergen, PJ (reprint author), NIAID, Div Allergy Immunol & Transplantat, 5601 Fishers Lane,Rm 6B58, Rockville, MD 20892 USA. EM pgergen@niaid.nih.gov FU Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [UM1AI114271] FX This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under grant no. UM1AI114271 NR 30 TC 2 Z9 2 U1 2 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD JAN-FEB PY 2016 VL 4 IS 1 BP 22 EP 26 DI 10.1016/j.jaip.2015.07.024 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA DB7AT UT WOS:000368667500003 PM 26589178 ER PT J AU Miller, TA Zak, V Shrader, P Ravishankar, C Pemberton, VL Newburger, JW Shillingford, AJ Dagincourt, N Cnota, JF Lambert, LM Sananes, R Richmond, ME Hsu, DT Miller, SG Zyblewski, SC Williams, RV AF Miller, Thomas A. Zak, Victor Shrader, Peter Ravishankar, Chitra Pemberton, Victoria L. Newburger, Jane W. Shillingford, Amanda J. Dagincourt, Nicholas Cnota, James F. Lambert, Linda M. Sananes, Renee Richmond, Marc E. Hsu, Daphne T. Miller, Stephen G. Zyblewski, Sinai C. Williams, Richard V. CA Pediat Heart Network Investigators TI Growth Asymmetry, Head Circumference, and Neurodevelopmental Outcomes in Infants with Single Ventricles SO JOURNAL OF PEDIATRICS LA English DT Article ID CEREBRAL-BLOOD-FLOW; FETAL CEREBROVASCULAR RESISTANCE; INTRAUTERINE GROWTH; PRETERM INFANTS; DISEASE; IMPACT; TRIAL; RESTRICTION; CHILDREN; FETUSES AB Objective To assess the variability in asymmetric growth and its association with neurodevelopment in infants with single ventricle (SV). Study design We analyzed weight-for-age z-score minus head circumference-for-age z-score (HCAZ), relative head growth (cm/kg), along with individual growth variables in subjects prospectively enrolled in the Infant Single Ventricle Trial. Associations between growth indices and scores on the Psychomotor Developmental Index (PDI) and Mental Developmental Index (MDI) of the Bayley Scales of Infant Development-II (BSID-II) at 14 months were assessed. Results Of the 230 subjects enrolled in the Infant Single Ventricle trial, complete growth data and BSID-II scores were available in 168 (73%). Across the cohort, indices of asymmetric growth varied widely at enrollment and before superior cavopulmonary connection (SCPC) surgery. BSID-II scores were not associated with these asymmetry indices. In bivariate analyses, greater pre-SCPC HCAZ correlated with higher MDI (r = 0.21; P = .006) and PDI (r = 0.38; P < .001) and a greater HCAZ increase from enrollment to pre-SCPC with higher PDI (r = 0.15; P = .049). In multivariable modeling, pre-SCPC HCAZ was an independent predictor of PDI (P = .03), but not MDI. Conclusion In infants with SV, growth asymmetry was not associated with neurodevelopment at 14 months, but pre-SCPC HCAZ was associated with PDI. Asymmetric growth, important in other high-risk infants, is not a brain-sparing adaptation in infants with SV. C1 [Miller, Thomas A.; Williams, Richard V.] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [Zak, Victor; Shrader, Peter; Dagincourt, Nicholas] New England Res Inst, 9 Galen St, Watertown, MA 02172 USA. [Ravishankar, Chitra] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Pemberton, Victoria L.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Newburger, Jane W.] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA. [Newburger, Jane W.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Shillingford, Amanda J.] Childrens Hosp Wisconsin, Dept Pediat, Milwaukee, WI 53201 USA. [Cnota, James F.] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA. [Lambert, Linda M.] Univ Utah, Dept Surg, Salt Lake City, UT USA. [Sananes, Renee] Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada. [Richmond, Marc E.] Columbia Univ, Dept Pediat, Med Ctr, New York, NY 10027 USA. [Hsu, Daphne T.] Childrens Hosp Montefiore, Albert Einstein Coll Med, Dept Pediat, New York, NY USA. [Miller, Stephen G.] Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. [Zyblewski, Sinai C.] Med Univ S Carolina, Dept Pediat, 171 Ashley Ave, Charleston, SC 29425 USA. [Miller, Thomas A.] 81 N Mario Capecchi Dr, Salt Lake City, UT 84113 USA. RP Miller, TA (reprint author), 81 N Mario Capecchi Dr, Salt Lake City, UT 84113 USA. EM thomas.a.miller@hsc.utah.edu FU National Heart, Lung, and Blood Institute (NHLBI) [HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057, HL109781, HL109737]; US Food and Drug Administration's Office of Orphan Products Development FX Supported by the National Heart, Lung, and Blood Institute (NHLBI; HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057, HL109781, HL109737) and the US Food and Drug Administration's Office of Orphan Products Development. The contents of this report are solely the responsibility of the authors and do not necessarily represent the official views of NHLBI or the National Institutes of Health. The authors declare no conflicts of interest. NR 36 TC 1 Z9 1 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JAN PY 2016 VL 168 BP 220 EP + DI 10.1016/j.jpeds.2015.09.041 PG 7 WC Pediatrics SC Pediatrics GA DB5ZK UT WOS:000368592500045 PM 26490132 ER PT J AU Plank-Bazinet, JL Kornstein, SG Clayton, JA McCaskill-Stevens, W Wood, L Cook, N Tajuddin, SM Brown, GM Harris, T Evans, MK Begg, L Brooks, CE Miller, LR Mistretta, AC Cornelison, TL AF Plank-Bazinet, Jennifer L. Kornstein, Susan G. Clayton, Janine Austin McCaskill-Stevens, Worta Wood, Lauren Cook, Nakela Tajuddin, Salman M. Brown, Gina M. Harris, Tamara Evans, Michele K. Begg, Lisa Brooks, Claudette E. Miller, Leah R. Mistretta, Amy Caroline Cornelison, Terri L. TI A Report of the Women's Health Congress Workshop on The Health of Women of Color: A Critical Intersection at the Corner of Sex/Gender and Race/Ethnicity SO JOURNAL OF WOMENS HEALTH LA English DT Article ID IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS; GENOME-WIDE ASSOCIATION; AFRICAN-AMERICAN WOMEN; INTIMA-MEDIA THICKNESS; HEART-FAILURE; RACIAL-DIFFERENCES; CHARGE CONSORTIUM; SEX-DIFFERENCES; RISK BEHAVIOR; BREAST-CANCER AB Women of color face unique health challenges that differ significantly from those of other women and men of color. To bring these issues to light, the National Institutes of Health (NIH) Office of Research on Women's Health sponsored a preconference workshop at the 23rd Annual Women's Health Congress, which was held in Washington, DC, in April 2015. The workshop featured presentations by NIH intramural and extramural scientists who provided insight on the disparities of a wide range of conditions, including cancer, cardiovascular disease, the risk of HIV infection, and disability in an aging population. In this study, we highlight the major points of each presentation and the ensuing discussion. C1 [Plank-Bazinet, Jennifer L.; Clayton, Janine Austin; Begg, Lisa; Brooks, Claudette E.; Miller, Leah R.; Mistretta, Amy Caroline; Cornelison, Terri L.] NIH, Off Res Womens Hlth, Bethesda, MD 20817 USA. [Kornstein, Susan G.] Virginia Commonwealth Univ, Inst Womens Hlth, Dept Psychiat, Richmond, VA USA. [McCaskill-Stevens, Worta] NCI, Community Oncol & Prevent Trials Res Grp, NIH, Bethesda, MD 20892 USA. [Wood, Lauren] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Cook, Nakela] NHLBI, Off Director, Div Cardiovasc Dis, NIH, Bethesda, MD 20892 USA. [Tajuddin, Salman M.; Evans, Michele K.] NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. [Brown, Gina M.] NIH, Off AIDS Res, Bethesda, MD 20817 USA. [Harris, Tamara] NIA, Lab Epidemiol Demog & Biometry, NIH, Baltimore, MD 21224 USA. RP Cornelison, TL (reprint author), NIH, Off Res Womens Hlth, 6707 Democracy Blvd,Suite 400, Bethesda, MD 20817 USA. EM cornelit@od.nih.gov OI Tajuddin, Salman M./0000-0002-7919-8528 NR 37 TC 0 Z9 0 U1 0 U2 3 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 JAN 1 PY 2016 VL 25 IS 1 BP 4 EP 10 DI 10.1089/jwh.2015.5666 PG 7 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 DB4YX UT WOS:000368520700003 PM 26771559 ER PT J AU Perera, S Patel, KV Rosano, C Rubin, SM Satterfield, S Harris, T Ensrud, K Orwoll, E Lee, CG Chandler, JM Newman, AB Cauley, JA Guralnik, JM Ferrucci, L Studenski, SA AF Perera, Subashan Patel, Kushang V. Rosano, Caterina Rubin, Susan M. Satterfield, Suzanne Harris, Tamara Ensrud, Kristine Orwoll, Eric Lee, Christine G. Chandler, Julie M. Newman, Anne B. Cauley, Jane A. Guralnik, Jack M. Ferrucci, Luigi Studenski, Stephanie A. TI Gait Speed Predicts Incident Disability: A Pooled Analysis SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Gait speed; Disability; Mortality; Mobility; Performance ID PHYSICAL PERFORMANCE; OLDER PERSONS; OSTEOPOROTIC FRACTURES; ADL DISABILITY; WALKING SPEED; SELF-REPORT; MOBILITY; DECLINE; ADULTS; HEALTH AB Functional independence with aging is an important goal for individuals and society. Simple prognostic indicators can inform health promotion and care planning, but evidence is limited by heterogeneity in measures of function. We performed a pooled analysis of data from seven studies of 27,220 community-dwelling older adults aged 65 or older with baseline gait speed, followed for disability and mortality. Outcomes were incident inability or dependence on another person in bathing or dressing; and difficulty walking A1/4 - A1/2 mile or climbing 10 steps within 3 years. Participants with faster baseline gait had lower rates of incident disability. In subgroups (defined by 0.2 m/s-wide intervals from < 0.4 to a parts per thousand yen1.4 m/s) with increasingly greater gait speed, 3-year rates of bathing or dressing dependence trended from 10% to 1% in men, and from 15% to 1% in women, while mobility difficulty trended from 47% to 4% in men and 40% to 6% in women. The age-adjusted relative risk ratio per 0.1 m/s greater speed for bathing or dressing dependence in men was 0.68 (0.57-0.81) and in women: 0.74 (0.66-0.82); for mobility difficulty, men: 0.75 (0.68-0.82), women: 0.73 (0.67-0.80). Results were similar for combined disability and mortality. Effects were largely consistent across subgroups based on age, gender, race, body mass index, prior hospitalization, and selected chronic conditions. In the presence of multiple other risk factors for disability, gait speed significantly increased the area under the receiver operator characteristic curve. In older adults, gait speed predicts 3 year incidence of bathing or dressing dependence, mobility difficulty, and a composite outcome of disability and mortality. C1 [Perera, Subashan] Univ Pittsburgh, Div Geriatr Med, Pittsburgh, PA 15213 USA. [Patel, Kushang V.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Rosano, Caterina; Newman, Anne B.; Cauley, Jane A.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Rubin, Susan M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Satterfield, Suzanne] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Harris, Tamara] NIA, Geriatr Epidemiol Sect, Bethesda, MD 20892 USA. [Ensrud, Kristine] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Ensrud, Kristine] Minneapolis VA Hlth Care System, Minneapolis, MN USA. [Orwoll, Eric] Oregon Hlth & Sci Univ, Div Endocrinol Diabet Clin Nutr, Portland, OR 97201 USA. [Lee, Christine G.] Vet Affairs Hlth Care Syst, Res Serv, Portland, OR USA. [Chandler, Julie M.] Merck & Co Inc, Dept Pharmacoepidemiol, Kenilworth, NJ USA. [Guralnik, Jack M.] Univ Maryland, Dept Epidemiol & Publ Hlth, College Pk, MD 20742 USA. [Ferrucci, Luigi; Studenski, Stephanie A.] NIA, Longitudinal Studies Sect, Baltimore, MD 21224 USA. RP Perera, S (reprint author), Univ Pittsburgh, Div Geriatr Med, 3471 Fifth Ave,Suite 500, Pittsburgh, PA 15213 USA. EM ksp9@pitt.edu RI Cauley, Jane/N-4836-2015; Newman, Anne B./C-6408-2013 OI Cauley, Jane/0000-0003-0752-4408; Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010; Newman, Anne B./0000-0002-0106-1150 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01AG023629, R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576]; NIA [R01-AG028050]; NINR [R01-NR012459]; Intramural Research Program of the NIH, National Institute on Aging; National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295]; National Institute of Neurological Disorders and Stroke (NINDS); National Institutes of Health; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Center for Advancing Translational Sciences (NCATS); NIH Roadmap for Medical Research [U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, UL1 TR000128]; VA Clinical Science Research and Development Career Development Award [5IK2CW000729-02] FX The pooling of data from individual studies was supported by Pittsburgh Claude D. Pepper Older Americans Independence Center (NIA P30 AG024827) and a contract from Merck Research Laboratories. This research was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050 and NINR grant R01-NR012459. This research was also supported in part by the Intramural Research Program of the NIH, National Institute on Aging.; This research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grant U01HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org.; The Osteoporotic Fractures in Men (MrOS) study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128.; The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576.; C.G.L. receives support from a VA Clinical Science Research and Development Career Development Award, Project number 5IK2CW000729-02. NR 43 TC 15 Z9 15 U1 4 U2 9 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 JAN PY 2016 VL 71 IS 1 BP 63 EP 71 DI 10.1093/gerona/glv126 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DB2UZ UT WOS:000368366900007 PM 26297942 ER PT J AU Pedone, C Costanzo, L Cesari, M Bandinelli, S Ferrucci, L Incalzi, RA AF Pedone, Claudio Costanzo, Luisa Cesari, Matteo Bandinelli, Stefania Ferrucci, Luigi Incalzi, Raffaele Antonelli TI Are Performance Measures Necessary to Predict Loss of Independence in Elderly People? SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Frailty; Disability; Mortality; Predictive value; Sensitivity and specificity ID OLDER-ADULTS; FRAILTY INDEXES; WOMENS HEALTH; DISABILITY; PHENOTYPE; MORTALITY; PREVALENCE; FRACTURES; CONSENSUS; ACCURACY AB The frailty phenotype (FP) proposed by Fried and colleagues (Fried LP, Tangen CM, Walston J, et al.; Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56:M146-M156.) requires the administration of performance tests (gait speed, handgrip strength) not always feasible in routine clinical practice. Furthermore, the discriminative capacity of the instrument has been rarely investigated. Aim of this study was to evaluate the discriminative capacity of the FP and compare it with a modified version including only anamnestic information. Data are from 890 participants of the InCHIANTI study without impairment in activities of daily living (ADL) at baseline (mean age 74 years, women 55%). Frailty was defined by (a) the presence of a parts per thousand yen3 criteria of the FP, and (b) having a parts per thousand yen2 criteria of an anamnestic FP (AFP), not including gait speed and handgrip strength. Sensitivity, specificity, positive and negative predictive values (PPV, NPV) were used to evaluate the discriminative capacity of both definitions for incident disability (ie, loss of at least one ADL), incidence of "accelerated" disability (loss of > 2 ADL) over a 6-year follow-up, and 5-years mortality. FP and AFP yielded a frailty prevalence of 6.4% and 6.5%, respectively; only 32 patients were considered frail by both indices (kappa: .53). For incident disability, FP showed sensitivity = .194, specificity = .963, PPV = .400, and NPV = .903. Similarly, AFP had sensitivity = .129, specificity = .949, PPV = .245, and NPV = .894. Consistent results were found for accelerated disability and mortality. In our sample, both FP and AFP showed low sensitivity in identifying older people who would die or develop disability, but they could well discriminate people who would not experience adverse outcomes. C1 [Pedone, Claudio; Costanzo, Luisa; Incalzi, Raffaele Antonelli] Univ Campus Biomed, Area Geriatr, I-00128 Rome, Italy. [Cesari, Matteo] Univ Toulouse, Inst Vieillissement, Toulouse, France. [Bandinelli, Stefania] Azienda Sanit Firenze, Florence, Italy. [Ferrucci, Luigi] NIA, NIH, Baltimore, MD 21224 USA. [Incalzi, Raffaele Antonelli] Fdn S Raffaele, Cittadella Carita, Taranto, Italy. RP Costanzo, L (reprint author), Univ Campus Biomed Roma, Area Geriatr, Via Alvaro del Portillo 21, I-00128 Rome, Italy. EM l.costanzo@unicampus.it RI Cesari, Matteo/A-4649-2008 OI Cesari, Matteo/0000-0002-0348-3664 NR 28 TC 1 Z9 1 U1 0 U2 4 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 JAN PY 2016 VL 71 IS 1 BP 84 EP 89 DI 10.1093/gerona/glv096 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DB2UZ UT WOS:000368366900010 PM 26273019 ER PT J AU Semba, RD Ferrucci, L Sun, K Simonsick, E Turner, R Miljkovic, I Harris, T Schwartz, AV Asao, K Kritchevsky, S Newman, AB AF Semba, Richard D. Ferrucci, Luigi Sun, Kai Simonsick, Eleanor Turner, Randi Miljkovic, Iva Harris, Tamara Schwartz, Ann V. Asao, Keiko Kritchevsky, Stephen Newman, Anne B. CA Hlth ABC Study TI Low Plasma Klotho Concentrations and Decline of Knee Strength in Older Adults SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Aging; Klotho; Skeletal muscle strength; Sarcopenia ID TRANSCRIPTS ENCODING MEMBRANE; ENDOTHELIAL DYSFUNCTION; MUSCLE STRENGTH; SKELETAL-MUSCLE; ALPHA-KLOTHO; PROTEIN; GENE; MICE; REGULATOR; STRESS AB Although the "anti-aging hormone" klotho is associated with sarcopenia in mice, the relationship between klotho and muscle strength in older adults is not well known. Plasma klotho concentrations were measured in 2,734 older adults, aged 71-80 years, who participated in the Health, Aging and Body Composition Study, a prospective observational cohort study conducted in Memphis, TN and Pittsburgh, PA. Knee extension strength was measured using isokinetic dynamometry at baseline and follow-up 2 and 4 years later. Knee extension strength was normalized for weight. At baseline, participants in the highest tertile of plasma klotho had higher knee extension strength (beta = .72, standard error [SE] = .018,p < .0001) compared with those in the lowest tertile in a multivariable linear regression model adjusting for age, sex, race, smoking, study site, C-reactive protein, interleukin-6, and diabetes. Participants in the highest tertile of plasma klotho at baseline had less of a decline in knee strength over 4 years of follow-up (beta = -.025,SE = .011, p = .02) compared with those in the lowest tertile in a multivariable linear regression model adjusting for the same covariates above. Plasma klotho concentrations were an independent predictor of changes in knee strength over time in older adults. Further studies are needed to identify the biological mechanisms by which circulating klotho could modify skeletal muscle strength. C1 [Semba, Richard D.; Sun, Kai; Turner, Randi] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21287 USA. [Ferrucci, Luigi; Simonsick, Eleanor] NIA, NIH, Baltimore, MD 21224 USA. [Miljkovic, Iva; Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Harris, Tamara] NIA, Intramural Res Program, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. [Schwartz, Ann V.] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Asao, Keiko] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Kritchevsky, Stephen] Wake Forest Univ, Sticht Ctr Aging, Winston Salem, NC 27109 USA. RP Semba, RD (reprint author), Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Smith Bldg,M015,400 North Broadway, Baltimore, MD 21287 USA. EM rdsemba@jhmi.edu RI Newman, Anne B./C-6408-2013; OI Newman, Anne B./0000-0002-0106-1150; Miljkovic, Iva/0000-0002-3155-9777 FU National Institutes of Health [R01 AG27012, R01 AG028050, R01 HL094507, R21 HL112662]; National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NINR [R01 NR012459]; Intramural Research Program of the National Institutes of Health FX This work was supported by National Institutes of Health grants R01 AG27012, R01 AG028050, R01 HL094507, and R21 HL112662, National Institute on Aging contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106, NINR grant R01 NR012459, and the Intramural Research Program of the National Institutes of Health. NR 25 TC 4 Z9 4 U1 1 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 JAN PY 2016 VL 71 IS 1 BP 103 EP 108 DI 10.1093/gerona/glv077 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DB2UZ UT WOS:000368366900013 PM 26359247 ER PT J AU Tian, Q Studenski, SA Resnick, SM Davatzikos, C Ferrucci, L AF Tian, Qu Studenski, Stephanie A. Resnick, Susan M. Davatzikos, Christos Ferrucci, Luigi TI Midlife and Late-Life Cardiorespiratory Fitness and Brain Volume Changes in Late Adulthood: Results From the Baltimore Longitudinal Study of Aging SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Cardiovascular; Epidemiology; Neuroimaging ID WHITE-MATTER INTEGRITY; AEROBIC FITNESS; OLDER-ADULTS; PERIRHINAL CORTEX; ALZHEIMER-DISEASE; EXERCISE; HIPPOCAMPUS; ATROPHY; HUMANS; MEMORY AB Higher cardiorespiratory fitness (CRF) is cross-sectionally associated with more conserved brain volume in older age, but longitudinal studies are rare. This study examined whether higher midlife CRF was prospectively associated with slower atrophy, which in turn was associated with higher late-life CRF. Brain volume by magnetic resonance imaging was determined annually from 1994 to 2003 in 146 participants (M (baseline age) = 69.6 years). Peak oxygen uptake on a treadmill yielded estimated midlife CRF in 138 and late-life CRF in 73 participants. Higher midlife CRF was associated with greater middle temporal gyrus, perirhinal cortex, and temporal and parietal white matter, but was not associated with atrophy progression. Slower atrophy in middle frontal and angular gyri was associated with higher late-life CRF, independent of CRF at baseline magnetic resonance imaging. Higher midlife CRF may play a role in preserving middle and medial temporal volumes in late adulthood. Slower atrophy in middle frontal and angular gyri may predict late-life CRF. C1 [Tian, Qu; Studenski, Stephanie A.; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Resnick, Susan M.] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. [Davatzikos, Christos] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. RP Tian, Q (reprint author), 251 Bayview Blvd,Suite 100,Room 04B316, Baltimore, MD 21224 USA. EM qu.tian@nih.gov FU Intramural Research Program of the National Institute on Aging; National Institutes of Health [R01AG149-71] FX This research was supported by the Intramural Research Program of the National Institute on Aging. C.D. was supported in part by National Institutes of Health grant R01AG149-71. NR 37 TC 0 Z9 0 U1 3 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 JAN PY 2016 VL 71 IS 1 BP 124 EP 130 DI 10.1093/gerona/glv041 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DB2UZ UT WOS:000368366900016 PM 25896993 ER PT J AU Van Elderen, SSGC Zhang, Q Sigurdsson, S Haight, TJ Lopez, O Eiriksdottir, G Jonsson, P de Jong, L Harris, TB Garcia, M Gudnason, V van Buchem, MA Launer, LJ AF Van Elderen, Saskia S. G. C. Zhang, Qian Sigurdsson, Sigudur Haight, Thaddeus J. Lopez, Oscar Eiriksdottir, Gudny Jonsson, Palmi de Jong, Laura Harris, Tamara B. Garcia, Melissa Gudnason, Vilmundar van Buchem, Mark A. Launer, Lenore J. TI Brain Volume as an Integrated Marker for the Risk of Death in a Community-Based Sample: Age Gene/Environment Susceptibility-Reykjavik Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Brain aging; Epidemiology; Neuroimaging; Mortality risking ID CARDIOVASCULAR HEALTH; WORKING-MEMORY; TISSUE VOLUMES; SURVIVAL; ATROPHY; POPULATION; MORTALITY; ATTENTION; DEMENTIA; MRI AB Total brain volume is an integrated measure of health and may be an independent indicator of mortality risk independent of any one clinical or subclinical disease state. We investigate the association of brain volume to total and cause-specific mortality in a large nondemented stroke-free community-based cohort. The analysis includes 3,543 men and women (born 1907-1935) participating in the Age, Gene, Environment Susceptibility-Reykjavik Study. Participants with a known brain-related high risk for mortality (cognitive impairment or stroke) were excluded from these analyses. Quantitative estimates of total brain volume, white matter, white matter lesions, total gray matter (GM; cortical GM and subcortical GM separately), and focal cerebral vascular disease were generated from brain magnetic resonance imaging. Brain atrophy was expressed as brain tissue volume divided by total intracranial volume, yielding a percentage. Mean follow-up duration was 7.2 (0-10) years, with 647 deaths. Cox regression was used to analyze the association of mortality to brain atrophy, adjusting for demographics, cardiovascular risk factors, and cerebral vascular disease. Reduced risk of mortality was significantly associated with higher total brain volume (hazard ratio, 95% confidence interval = 0.71, 0.65-0.78), white matter (0.85, 0.78-0.93), total GM (0.74, 0.68-0.81), and cortical GM (0.78, 0.70-0.87). Overall, the associations were similar for cardiovascular and noncardiovascular-related deaths. Independent of multiple risk factors and cerebral vascular damage, global brain volume predicts mortality in a large nondemented stroke-free community-dwelling older cohort. Total brain volume may be an integrated measure reflecting a range of health and with further investigation could be a useful clinical tool when assessing risk for mortality. C1 [Van Elderen, Saskia S. G. C.; de Jong, Laura; van Buchem, Mark A.] Leiden Univ, Med Ctr, Dept Radiol, NL-2300 RA Leiden, Netherlands. [Zhang, Qian; Haight, Thaddeus J.; Harris, Tamara B.; Garcia, Melissa; Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Sigurdsson, Sigudur; Eiriksdottir, Gudny; Gudnason, Vilmundar] Icelandic Heart Assoc, Kopavogur, Iceland. [Lopez, Oscar] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Jonsson, Palmi] Landspitali Hosp, Reykjavik, Iceland. RP Launer, LJ (reprint author), LEPS NIA NIH, 7201 Wisconsin Ave, Bethesda, MD 20892 USA. EM launerl@nia.nih.gov FU NIH [N01-AG-12100]; NIH/NIA Intramural Research Program; Hjartavernd (Icelandic Heart Association); Althingi (Icelandic Parliament); University of Iceland Research Fund FX This work was supported by NIH contract N01-AG-12100, the NIH/NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), the Althingi (the Icelandic Parliament), and the University of Iceland Research Fund. NR 25 TC 2 Z9 2 U1 0 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 JAN PY 2016 VL 71 IS 1 BP 131 EP 137 DI 10.1093/gerona/glu192 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DB2UZ UT WOS:000368366900017 PM 25359930 ER PT J AU Xiong, JH Hou, J AF Xiong, Jianhua Hou, Jian TI Apical Resection Mouse Model to Study Early Mammalian Heart Regeneration SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Medicine; Issue 107; Heart regeneration; apical resection; survival surgery; heart disease; mouse model; hypothermia anesthesia; neonatal mouse; cardiomyocyte ID APEX RESECTION; CARDIAC REGENERATION; ADULT AB Cardiovascular disease plagues the whole world due to intensive lifestyle changes. Heart regeneration holds great promise for repairing and restoring cardiomyocytes lost due to injury and disease. In contrast to the robust cardiac regeneration of certain lower vertebrates, adult mammalian hearts typically show minimal capacity for heart regeneration and repair. However, recent studies have sparked considerable scientific interest with the finding that, between postnatal day 1 to 7 (P1 to P7), the neonatal mouse heart retains significant regenerative potential after apical resection (i.e., surgical amputation and exposure of left ventricular apex). One major controversy over this finding might be due to the diverse surgery-related procedures used in efforts to replicate or expand upon this important finding. These instructions dynamically present the materials and methodology for apical resection in a mouse model. The salient steps of this rodent survival surgery involve hypothermia anesthesia, thoracotomy, surgical amputation of heart ventricular apex, and suture and recovery of mice. The approach described could expand the application of the apical resection mouse model for cardiovascular research. C1 [Xiong, Jianhua] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Hou, Jian] China Agr Univ, Coll Biol Sci, State Key Lab Agrobiotechnol, Beijing, Peoples R China. RP Xiong, JH (reprint author), NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. EM jianhua.xiong@nih.gov RI Xiong, Jianhua/D-6099-2015 OI Xiong, Jianhua/0000-0002-2740-4027 FU Fine Science Tools FX Publication fees for this article were sponsored by a gift from Fine Science Tools to Dr. Jian Hou. NR 16 TC 0 Z9 0 U1 0 U2 1 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 JAN PY 2016 IS 107 AR e53488 DI 10.3791/53488(2016) PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB5TV UT WOS:000368577400032 PM 26862937 ER PT J AU Pavkov, ME Weil, EJ Fufaa, GD Nelson, RG Lemley, KV Knowler, WC Niewczas, MA Krolewski, AS AF Pavkov, Meda E. Weil, E. Jennifer Fufaa, Gudeta D. Nelson, Robert G. Lemley, Kevin V. Knowler, William C. Niewczas, Monika A. Krolewski, Andrzej S. TI Tumor necrosis factor receptors 1 and 2 are associated with early glomerular lesions in type 2 diabetes SO KIDNEY INTERNATIONAL LA English DT Article DE diabetic nephropathy; endothelium; kidney biopsy ID STRUCTURAL-FUNCTIONAL RELATIONSHIPS; TNF-ALPHA SYSTEM; ENDOTHELIAL-CELL; KIDNEY-DISEASE; RENAL-FUNCTION; NEPHROPATHY; MELLITUS; ALBUMINURIA; PROTEINURIA; PROGRESSION AB Elevated serum tumor necrosis factor receptor 1 (TNFR1) and 2 (TNFR2) concentrations are strongly associated with increased risk of end-stage renal disease in type 2 diabetes. However, little is known about the early glomerular structural lesions that develop in patients when these markers are elevated. Here, we examined the relationships between TNFRs and glomerular structure in 83 American Indians with type 2 diabetes. Serum TNFRs and glomerular filtration rate (GFR, iothalamate) were measured during a research exam performed within a median of 0.9 months from a percutaneous kidney biopsy. Associations of TNFRs with glomerular structural variables were quantified by Spearman's correlations and by multivariable linear regression after adjustment for age, gender, diabetes duration, hemoglobin A1c, body mass index, and mean arterial pressure. The baseline mean age was 46 years, median GFR 130 ml/min, median albumin/creatinine ratio 26 mg/g, median TNFR1 1500 pg/ml, and median TNFR2 3284 pg/ml. After multivariable adjustment, TNFR1 and TNFR2 significantly correlated inversely with the percentage of endothelial cell fenestration and the total filtration surface per glomerulus. There were significant positive correlations with mesangial fractional volume, glomerular basement membrane width, podocyte foot process width, and percentage of global glomerular sclerosis. Thus, TNFRs may be involved in the pathogenesis of early glomerular lesions in diabetic nephropathy. C1 [Pavkov, Meda E.] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. [Weil, E. Jennifer; Fufaa, Gudeta D.; Nelson, Robert G.; Knowler, William C.] NIDDK, Diabet Epidemiol & Clin Res Sect, NIH, Phoenix, AZ 85014 USA. [Lemley, Kevin V.] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Dept Pediat, Los Angeles, CA 90033 USA. [Niewczas, Monika A.; Krolewski, Andrzej S.] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Niewczas, Monika A.; Krolewski, Andrzej S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Nelson, RG (reprint author), NIDDK, Diabet Epidemiol & Clin Res Sect, NIH, 1550 East Indian Sch Rd, Phoenix, AZ 85014 USA. EM rnelson@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; American Diabetes Association (Clinical Science Award) [1-08-CR-42]; National Institutes of Health: DRC [P30DK036836, DK41526, DK67638] FX This study was supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, by the American Diabetes Association (Clinical Science Award 1-08-CR-42), and by grants from the National Institutes of Health: DRC P30DK036836 to MAN; DK41526 and DK67638 to ASK. Parts of this study were presented in abstract form at the American Society of Nephrology annual meeting and scientific exposition in Philadelphia, Pennsylvania, 13-16 November 2014. NR 35 TC 3 Z9 3 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD JAN PY 2016 VL 89 IS 1 BP 226 EP 234 DI 10.1038/ki.2015.278 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA DB2EO UT WOS:000368321300032 PM 26398493 ER PT J AU Steiner, JP Bachani, M Wolfson-Stofko, B Lee, MH Wang, TG Li, GH Li, WX Strayer, D Haughey, NJ Nath, A AF Steiner, Joseph P. Bachani, Muznabanu Wolfson-Stofko, Brett Lee, Myoung-Hwa Wang, Tongguang Li, Guanhan Li, Wenxue Strayer, David Haughey, Norman J. Nath, Avindra TI Interaction of Paroxetine with Mitochondrial Proteins Mediates Neuroprotection (vol 12, pg 200, 2015) SO NEUROTHERAPEUTICS LA English DT Correction C1 [Steiner, Joseph P.; Wolfson-Stofko, Brett; Haughey, Norman J.; Nath, Avindra] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA. [Steiner, Joseph P.; Bachani, Muznabanu; Wang, Tongguang; Nath, Avindra] NINDS, Translat Neurosci Ctr, Natl Bldg 10,Room 7C-105,10 Ctr Dr, Bethesda, MD 20892 USA. [Lee, Myoung-Hwa; Li, Guanhan; Li, Wenxue; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bldg 10,Room 7C103,10 Ctr Dr, Bethesda, MD 20892 USA. [Strayer, David] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. RP Steiner, JP; Nath, A (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA.; Steiner, JP; Nath, A (reprint author), NINDS, Translat Neurosci Ctr, Natl Bldg 10,Room 7C-105,10 Ctr Dr, Bethesda, MD 20892 USA.; Nath, A (reprint author), NINDS, Sect Infect Nervous Syst, NIH, Bldg 10,Room 7C103,10 Ctr Dr, Bethesda, MD 20892 USA. EM steinerjp@ninds.nih.gov; natha@ninds.nih.gov FU NIDA NIH HHS [R01 DA040390]; NIMH NIH HHS [R01 MH110246, P01 MH105280, P30 MH075673, R01 MH077542, R01 MH096636, R03 MH103985] NR 1 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 JAN PY 2016 VL 13 IS 1 BP 237 EP 237 DI 10.1007/s13311-015-0406-2 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DB5SU UT WOS:000368574700021 PM 26692391 ER PT J AU Yin, ZH Li, H Cui, ZG Ren, YW Li, XL Wu, W Guan, P Qian, BY Rothman, N Lan, Q Zhou, BS AF Yin, Zhihua Li, Hang Cui, Zhigang Ren, Yangwu Li, Xuelian Wu, Wei Guan, Peng Qian, Biyun Rothman, Nathaniel Lan, Qing Zhou, Baosen TI Polymorphisms in pre-miRNA genes and cooking oil fume exposure as well as their interaction on the risk of lung cancer in a Chinese nonsmoking female population SO ONCOTARGETS AND THERAPY LA English DT Article DE lung cancer; microRNA; single nucleotide polymorphism; cooking oil fume; interaction ID CELL-GROWTH; NASOPHARYNGEAL CARCINOMA; SIGNALING PATHWAY; BLADDER-CANCER; BREAST-CANCER; MIR-26A; WOMEN; EZH2; TUMORIGENESIS; ASSOCIATION AB Background: MicroRNAs (miRNAs) are suggested to be very important in the development of lung cancer. This study assesses the association between polymorphisms in miRNA-related (miR)-26a-1, miR-605, and miR-16-1 genes and risk of lung cancer, as well as the effect of gene-environment interaction between miRNA polymorphisms and cooking fume exposure on lung cancer. Methods: A case-control study including 268 diagnosed nonsmoking female lung cancer patients and 266 nonsmoking female controls was carried out. Three miRNA polymorphisms (miR-26a-1 rs7372209, miR-605 rs2043556, and miR-16-1 rs1022960) were analyzed. Both additive and multiplicative interactions were assessed. Results: MiR-16-1 rs1022960 may be associated with the risk of lung cancer. Carriers with TT genotype of miR-16-1 rs1022960 were observed to have a decreased risk of lung cancer compared with CC and CT genotype carriers (odds ratio = 0.550, 95% confidence intervaly= 0.308-0.983, P= 0.044). MiR-26a-1 rs7372209 and miR-605 rs2043556 showed no statistically significant associations with lung cancer risk. There were no significant associations between the three single nucleotide polymorphisms and lung adenocarcinoma. People with exposure to both risk genotypes of miR-26a-1 rs7372209 and cooking oil fumes were more likely to develop lung cancer than those with only genetic risk factor or cooking oil fumes (odds ratios were 2.136, 1.255, and 1.730, respectively). The measures of biological interaction and logistic models indicate that gene-environment interactions were not statistically significant on additive scale or multiplicative scale. Conclusion: MiR-16-1 rs1022960 may be associated with the risk of lung cancer in a Chinese nonsmoking female population. The interactions between miRNA polymorphisms (miR-26a-1 rs7372209, miR-605 rs2043556, and miR-16-1 rs1022960) and cooking oil fumes were not statistically significant. C1 [Yin, Zhihua; Li, Hang; Ren, Yangwu; Li, Xuelian; Wu, Wei; Guan, Peng; Zhou, Baosen] China Med Univ, Sch Publ Hlth, Dept Epidemiol, Shenyang 110122, Peoples R China. [Yin, Zhihua; Li, Hang; Ren, Yangwu; Li, Xuelian; Wu, Wei; Guan, Peng; Zhou, Baosen] Univ Liaoning Prov, Key Lab Canc Etiol & Intervent, Shenyang, Peoples R China. [Cui, Zhigang] China Med Univ, Shenyang 110122, Peoples R China. [Qian, Biyun] Shanghai Jiao Tong Univ, Sch Publ Hlth, Dept Epidemiol, Shanghai 200030, Peoples R China. [Rothman, Nathaniel; Lan, Qing] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Zhou, BS (reprint author), China Med Univ, Sch Publ Hlth, Dept Epidemiol, Shenyang North New Area, 77 Puhe Rd, Shenyang 110122, Peoples R China. EM bszhou@mail.cmu.edu.cn FU National Natural Science Foundation of People's Republic of China [81102194] FX The authors would like to thank all the patients for their participation and the personnel at the hospitals. This study was supported by the National Natural Science Foundation of People's Republic of China (No 81102194). NR 27 TC 3 Z9 3 U1 1 U2 5 PU DOVE MEDICAL PRESS LTD PI ALBANY PA PO BOX 300-008, ALBANY, AUCKLAND 0752, NEW ZEALAND SN 1178-6930 J9 ONCOTARGETS THER JI OncoTargets Ther. PY 2016 VL 9 BP 395 EP 401 DI 10.2147/OTT.S96870 PG 7 WC Biotechnology & Applied Microbiology; Oncology SC Biotechnology & Applied Microbiology; Oncology GA DB3II UT WOS:000368403500006 PM 26855588 ER PT S AU Jang, H Arce, FT Lee, J Gillman, AL Ramachandran, S Kagan, BL Lal, R Nussinov, R AF Jang, Hyunbum Arce, Fernando Teran Lee, Joon Gillman, Alan L. Ramachandran, Srinivasan Kagan, Bruce L. Lal, Ratnesh Nussinov, Ruth BE Eliezer, D TI Computational Methods for Structural and Functional Studies of Alzheimer's Amyloid Ion Channels SO PROTEIN AMYLOID AGGREGATION: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Amyloid channel; beta-Sheet channel; Lipid bilayer; Molecular dynamics simulations; CHARMM; NAMD ID MOLECULAR-DYNAMICS SIMULATIONS; ATOMIC-FORCE MICROSCOPY; ALL-D-ENANTIOMER; BETA-PROTEIN; LIPID-BILAYERS; A-BETA; GRAMICIDIN CHANNEL; CALCIUM-CHANNELS; 3D STRUCTURE; DISEASE AB Aggregation can be studied by a range of methods, experimental and computational. Aggregates form in solution, across solid surfaces, and on and in the membrane, where they may assemble into unregulated leaking ion channels. Experimental probes of ion channel conformations and dynamics are challenging. Atomistic molecular dynamics (MD) simulations are capable of providing insight into structural details of amyloid ion channels in the membrane at a resolution not achievable experimentally. Since data suggest that late stage Alzheimer's disease involves formation of toxic ion channels, MD simulations have been used aiming to gain insight into the channel shapes, morphologies, pore dimensions, conformational heterogeneity, and activity. These can be exploited for drug discovery. Here we describe computational methods to model amyloid ion channels containing the beta-sheet motif at atomic scale and to calculate toxic pore activity in the membrane. C1 [Jang, Hyunbum] NCI, Canc & Infl ammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Arce, Fernando Teran; Gillman, Alan L.; Ramachandran, Srinivasan; Lal, Ratnesh] Univ Calif San Diego, Mat Sci Program, Dept Bioengn, La Jolla, CA 92093 USA. [Arce, Fernando Teran; Lee, Joon; Ramachandran, Srinivasan; Lal, Ratnesh] Univ Calif San Diego, Dept Mech & Aerosp Engn, Mat Sci Program, La Jolla, CA 92093 USA. [Kagan, Bruce L.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, David Geffen Sch Med, Dept Psychiat, Los Angeles, CA 90024 USA. [Nussinov, Ruth] NCI, Canc & Infl ammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. RP Jang, H (reprint author), NCI, Canc & Infl ammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. FU Intramural NIH HHS; PHS HHS [HHSN261200800001E] NR 91 TC 1 Z9 1 U1 2 U2 21 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-2978-8; 978-1-4939-2977-1 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1345 BP 251 EP 268 DI 10.1007/978-1-4939-2978-8_16 D2 10.1007/978-1-4939-2978-8 PG 18 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BE1SA UT WOS:000368439400017 PM 26453217 ER PT S AU Scherpelz, KP Lu, JX Tycko, R Meredith, SC AF Scherpelz, Kathryn P. Lu, Jun-Xia Tycko, Robert Meredith, Stephen C. BE Eliezer, D TI Preparation of Amyloid Fibrils Seeded from Brain and Meninges SO PROTEIN AMYLOID AGGREGATION: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE beta-Amyloid; Alzheimer's disease; Solid-state NMR; Fibril structure; Fibril polymorphism; Protein aggregation; Protein aggregation diseases; Neuritic plaques; Cerebral amyloid angiopathy ID SOLID-STATE NMR; ALZHEIMERS-DISEASE; EXPERIMENTAL CONSTRAINTS; STRUCTURAL BASIS; BETA-SHEET; POLYMORPHISM AB Seeding of amyloid fi brils into fresh solutions of the same peptide or protein in disaggregated form leads to the formation of replicate fi brils [1], with close structural similarity or identity to the original fi brillar seeds. Here we describe procedures for isolating fi brils composed mainly of beta-amyloid (A beta) from human brain and from leptomeninges, a source of cerebral blood vessels, for investigating Alzheimer's disease and cerebral amyloid angiopathy. We also describe methods for seeding isotopically labeled, disaggregated A beta peptide solutions for study using solid-state NMR and other techniques. These methods should be applicable to other types of amyloid fi brils, to A beta fi brils from mice or other species, tissues other than brain, and to some non-fi brillar aggregates. These procedures allow for the examination of authentic amyloid fi brils and other protein aggregates from biological tissues without the need for labeling the tissue. C1 [Scherpelz, Kathryn P.] Univ Chicago, Dept Biochem & Mol Biol, 920 E 58Th St, Chicago, IL 60637 USA. [Lu, Jun-Xia; Tycko, Robert] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Meredith, Stephen C.] Univ Chicago, Dept Pathol Biochem & Mol Biol, Chicago, IL 60637 USA. RP Scherpelz, KP (reprint author), Univ Chicago, Dept Biochem & Mol Biol, 920 E 58Th St, Chicago, IL 60637 USA. FU Intramural NIH HHS; NINDS NIH HHS [R01 NS042852] NR 20 TC 1 Z9 1 U1 3 U2 20 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-2978-8; 978-1-4939-2977-1 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1345 BP 299 EP 312 DI 10.1007/978-1-4939-2978-8_20 D2 10.1007/978-1-4939-2978-8 PG 14 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BE1SA UT WOS:000368439400021 PM 26453221 ER PT J AU McGinty, EE Baller, J Azrin, ST Juliano-Bult, D Daumit, GL AF McGinty, Emma E. Baller, Julia Azrin, Susan T. Juliano-Bult, Denise Daumit, Gail L. TI Interventions to Address Medical Conditions and Health-Risk Behaviors Among Persons With Serious Mental Illness: A Comprehensive Review SO SCHIZOPHRENIA BULLETIN LA English DT Article DE intervention; schizophrenia; medical; somatic; obesity; tobacco ID RANDOMIZED CONTROLLED-TRIAL; INDUCED WEIGHT-GAIN; PLACEBO-CONTROLLED TRIAL; LIFE-STYLE INTERVENTION; OLANZAPINE-TREATED PATIENTS; BUPROPION SUSTAINED-RELEASE; CONTROLLED CLINICAL-TRIAL; TYPE-2 DIABETES-MELLITUS; OBSTRUCTIVE SLEEP-APNEA; QUALITY-OF-LIFE AB People with serious mental illness (SMI) have mortality rates 2 to 3 times higher than the overall US population, largely due to cardiovascular disease. The prevalence of cardiovascular risk factors such as obesity and diabetes mellitus and other conditions, such as HIV/AIDS, is heightened in this group. Based on the recommendations of a National Institute of Mental Health stakeholder meeting, we conducted a comprehensive review examining the strength of the evidence surrounding interventions to address major medical conditions and health-risk behaviors among persons with SMI. Peer-reviewed studies were identified using 4 major research databases. Randomized controlled trials and observational studies testing interventions to address medical conditions and risk behaviors among persons with schizophrenia and bipolar disorder between January 2000 and June 2014 were included. Information was abstracted from each study by 2 trained reviewers, who also rated study quality using a standard tool. Following individual study review, the quality of the evidence (high, medium, low) and the effectiveness of various interventions were synthesized. 108 studies were included. The majority of studies examined interventions to address overweight/obesity (n = 80). The strength of the evidence was high for 4 interventions: metformin and behavioral interventions had beneficial effects on weight loss; and bupropion and varenicline reduced tobacco smoking. The strength of the evidence was low for most other interventions reviewed. Future studies should test long-term interventions to cardiovascular risk factors and health-risk behaviors. In addition, future research should study implementation strategies to effectively translate efficacious interventions into real-world settings. C1 [McGinty, Emma E.; Baller, Julia] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, 624 N Broadway,Room 359, Baltimore, MD 21205 USA. [McGinty, Emma E.; Baller, Julia] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Azrin, Susan T.; Juliano-Bult, Denise] NIMH, Bethesda, MD 20892 USA. [Daumit, Gail L.] Johns Hopkins Med Inst, Div Gen Internal Med, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. RP McGinty, EE (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, 624 N Broadway,Room 359, Baltimore, MD 21205 USA. EM bmcginty@jhu.edu FU National Institute of Mental Health FX This study was commissioned and supported by the National Institute of Mental Health (to G.L.D.). NR 187 TC 16 Z9 16 U1 13 U2 22 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 JAN PY 2016 VL 42 IS 1 BP 96 EP 124 DI 10.1093/schbul/sbv101 PG 29 WC Psychiatry SC Psychiatry GA DB6ML UT WOS:000368629000014 PM 26221050 ER PT J AU Tseng, WL Thomas, LA Harkins, E Pine, DS Leibenluft, E Brotman, MA AF Tseng, Wan-Ling Thomas, Laura A. Harkins, Elizabeth Pine, Daniel S. Leibenluft, Ellen Brotman, Melissa A. TI Neural correlates of masked and unmasked face emotion processing in youth with severe mood dysregulation SO SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE LA English DT Article DE irritability; severe mood dysregulation; functional neuroimaging; backward masking; face emotion processing ID POSTTRAUMATIC-STRESS-DISORDER; BIPOLAR DISORDER; FACIAL EXPRESSIONS; AMYGDALA REACTIVITY; CHILDHOOD PSYCHOPATHOLOGY; CHRONIC IRRITABILITY; HEALTHY-VOLUNTEERS; PREFRONTAL CORTEX; LABELING DEFICITS; ANGRY FACES AB Reproducibility of results is important in improving the robustness of conclusions drawn from research, particularly in functional magnetic resonance imaging (fMRI). In this study, we aim to replicate a previous study on the neural correlates of face emotion processing above and below awareness level using an independent sample of youth with severe mood dysregulation (SMD) and healthy volunteers (HV). We collected fMRI data in 17 SMD and 20 HV, using an affective priming paradigm with masked (17 ms) and unmasked (187 ms) faces (angry, happy, neutral, blank oval). When processing masked and unmasked angry faces, SMD patients exhibited increased activation in the parahippocampal gyrus (PHG) and superior temporal gyrus relative to HV. When processing masked and unmasked happy faces, SMD patients showed decreased activation in the insula, PHG and thalamus compared with HV. During masked face processing in general across emotions, youth with SMD showed greater ventromedial prefrontal cortex (vmPFC) activation relative to HV. Perturbed activation in emotion processing areas (e.g. insula, PHG, superior temporal gyrus and thalamus) manifests as hyper-sensitivity toward negative emotions and hypo-sensitivity toward positive emotions may be important in the etiology and maintenance of irritability, aggression and depressive symptoms in SMD. vmPFC dysfunction may mediate over-reactivity to face emotions associated with irritability. C1 [Tseng, Wan-Ling; Harkins, Elizabeth; Pine, Daniel S.; Leibenluft, Ellen; Brotman, Melissa A.] NIMH, Emot & Dev Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Thomas, Laura A.] Vet Affairs Med Ctr, War Related Illness & Injury Study Ctr, 50 Irving St NW, Washington, DC 20422 USA. RP Tseng, WL (reprint author), Bldg 15,Room 208,15K North Dr, Bethesda, MD 20892 USA. EM wan-ling.tseng@nih.gov RI Brotman, Melissa/H-7409-2013 FU National Institute of Mental Health (NIMH), National Institutes of Health (NIH) [ZIAMH002786] FX This research was supported by the Intramural Research Program of the National Institute of Mental Health (NIMH), National Institutes of Health (NIH; ZIAMH002786) and it was conducted under NIH Clinical Study Protocol 02-M-0021 (ClinicalTrials.gov ID: NCT00025935). NR 74 TC 4 Z9 4 U1 6 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 EI 1749-5024 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD JAN PY 2016 VL 11 IS 1 BP 78 EP 88 DI 10.1093/scan/nsv087 PG 11 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA DB6MH UT WOS:000368628600008 PM 26137973 ER PT J AU Wiggins, JL Adleman, NE Kim, P Oakes, AH Hsu, D Reynolds, RC Chen, G Pine, DS Brotman, MA Leibenluft, E AF Wiggins, Jillian Lee Adleman, Nancy E. Kim, Pilyoung Oakes, Allison H. Hsu, Derek Reynolds, Richard C. Chen, Gang Pine, Daniel S. Brotman, Melissa A. Leibenluft, Ellen TI Developmental differences in the neural mechanisms of facial emotion labeling SO SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE LA English DT Article DE face; emotion; brain; adolescence; development ID BIPOLAR DISORDER; BRAIN-FUNCTION; FACE-NETWORK; EXPRESSIONS; CHILDREN; RECOGNITION; ADOLESCENTS; DEFICITS; CORTEX; RISK AB Adolescence is a time of increased risk for the onset of psychological disorders associated with deficits in face emotion labeling. We used functional magnetic resonance imaging (fMRI) to examine age-related differences in brain activation while adolescents and adults labeled the emotion on fearful, happy and angry faces of varying intensities [0% (i.e. neutral), 50%, 75%, 100%]. Adolescents and adults did not differ on accuracy to label emotions. In the superior temporal sulcus, ventrolateral prefrontal cortex and middle temporal gyrus, adults show an inverted-U-shaped response to increasing intensities of fearful faces and a U-shaped response to increasing intensities of happy faces, whereas adolescents show the opposite patterns. In addition, adults, but not adolescents, show greater inferior occipital gyrus activation to negative (angry, fearful) vs positive (happy) emotions. In sum, when subjects classify subtly varying facial emotions, developmental differences manifest in several 'ventral stream' brain regions. Charting the typical developmental course of the brain mechanisms of socioemotional processes, such as facial emotion labeling, is an important focus for developmental psychopathology research. C1 [Wiggins, Jillian Lee; Adleman, Nancy E.; Kim, Pilyoung; Oakes, Allison H.; Hsu, Derek; Pine, Daniel S.; Brotman, Melissa A.; Leibenluft, Ellen] NIMH, Emot & Dev Branch, NIH, Bldg 15K,MSC-2670, Bethesda, MD 20892 USA. [Adleman, Nancy E.] Catholic Univ Amer, Dept Psychol, Washington, DC 20064 USA. [Kim, Pilyoung] Univ Denver, Dept Psychol, Denver, CO 80208 USA. [Reynolds, Richard C.; Chen, Gang] NIMH, Sci & Stat Comp Core, NIH, Bethesda, MD 20892 USA. RP Wiggins, JL (reprint author), NIMH, Emot & Dev Branch, NIH, Bldg 15K,MSC-2670, Bethesda, MD 20892 USA. EM jillian.wiggins@nih.gov RI Brotman, Melissa/H-7409-2013 FU National Institute of Mental Health, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, conducted under NIH Clinical Study Protocol 00-M-0198 (NCT000006177). NR 47 TC 2 Z9 2 U1 4 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 EI 1749-5024 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD JAN PY 2016 VL 11 IS 1 BP 172 EP 181 DI 10.1093/scan/nsv101 PG 10 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA DB6MH UT WOS:000368628600017 PM 26245836 ER PT J AU Zhang, K Liu, WL Locatis, C Ackerman, M AF Zhang, Kai Liu, Wei-Li Locatis, Craig Ackerman, Michael TI Mobile Videoconferencing Apps for Telemedicine SO TELEMEDICINE AND E-HEALTH LA English DT Article DE technology; telemedicine; mobile health; telecommunications ID VIDEO; FEASIBILITY; ULTRASOUND; TRANSMISSION; PHONE AB Introduction:The quality and performance of several videoconferencing applications (apps) tested on iOS (Apple, Cupertino, CA) and Android (Google, Mountain View, CA) mobile platforms using Wi-Fi (802.11), third-generation (3G), and fourth-generation (4G) cellular networks are described.Materials and Methods:The tests were done to determine how well apps perform compared with videoconferencing software installed on computers or with more traditional videoconferencing using dedicated hardware. The rationale for app assessment and the testing methodology are described.Results:Findings are discussed in relation to operating system platform (iOS or Android) for which the apps were designed and the type of network (Wi-Fi, 3G, or 4G) used. The platform, network, and apps interact, and it is impossible to discuss videoconferencing experienced on mobile devices in relation to one of these factors without referencing the others.Conclusions:Apps for mobile devices can vary significantly from other videoconferencing software or hardware. App performance increased over the testing period due to improvements in network infrastructure and how apps manage bandwidth. C1 [Zhang, Kai; Liu, Wei-Li; Locatis, Craig; Ackerman, Michael] Natl Lib Med, Off High Performance Comp & Commun, Bethesda, MD 20894 USA. RP Zhang, K (reprint author), Natl Lib Med, Off High Performance Comp & Commun, Bldg 38A,Room B1N30,8600 Rockville Pike, Bethesda, MD 20894 USA. EM zhangkai@mail.nih.gov FU National Institutes of Health; National Library of Medicine FX The research reported was supported by the Intramural Research Program of the National Institutes of Health and the National Library of Medicine. NR 20 TC 1 Z9 1 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-5627 EI 1556-3669 J9 TELEMED E-HEALTH JI Telemed. e-Health PD JAN 1 PY 2016 VL 22 IS 1 BP 56 EP 62 DI 10.1089/tmj.2015.0027 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DB3YE UT WOS:000368448900009 PM 26204322 ER PT J AU Henriquez, C Riquelme, TT Vera, D Julio-Kalajzic, F Ehrenfeld, P Melvin, JE Figueroa, CD Sarmiento, J Flores, CA AF Henriquez, C. Riquelme, T. T. Vera, D. Julio-Kalajzic, F. Ehrenfeld, P. Melvin, J. E. Figueroa, C. D. Sarmiento, J. Flores, C. A. TI The calcium-activated potassium channel KCa3.1 plays a central role in the chemotactic response of mammalian neutrophils SO ACTA PHYSIOLOGICA LA English DT Article DE chemotaxis; KCa3.1; neutrophil ID CA2+-ACTIVATED K+ CHANNEL; INTERMEDIATE-CONDUCTANCE; ION CHANNELS; CELL-MIGRATION; BLOOD-PRESSURE; NADPH OXIDASE; MICE LACKING; INFLUX; KCNN4; ENDOTHELIUM AB Aim: Neutrophils are the first cells to arrive at sites of injury. Nevertheless, many inflammatory diseases are characterized by an uncontrolled infiltration and action of these cells. Cell migration depends on volume changes that are governed by ion channel activity, but potassium channels in neutrophil have not been clearly identified. We aim to test whether KCa3.1 participates in neutrophil migration and other relevant functions of the cell. Methods: Cytometer and confocal measurements to determine changes in cell volume were used. Cells isolated from human, mouse and horse were tested for KCa3.1-dependent chemotaxis. Chemokinetics, calcium handling and release of reactive oxygen species were measured to determine the role of KCa3.1 in those processes. A mouse model was used to test for neutrophil recruitment after acute lung injury in vivo. Results: We show for the first time that KCa3.1 is expressed in mammalian neutrophils. When the channel is inhibited by a pharmacological blocker or by genetic silencing, it profoundly affects cell volume regulation, and chemotactic and chemokinetic properties of the cells. We also demonstrated that pharmacological inhibition of KCa3.1 did not affect calcium entry or reactive oxygen species production in neutrophils. Using a mouse model of acute lung injury, we observed that Kca3.1(-/-) mice are significantly less effective at recruiting neutrophils into the site of inflammation. Conclusions: These results demonstrate that KCa3.1 channels are key actors in the migration capacity of neutrophils, and its inhibition did not affect other relevant cellular functions. C1 [Henriquez, C.] Univ Austral Chile, Fac Med Vet, Inst Farmacol, Valdivia, Chile. [Riquelme, T. T.; Vera, D.; Julio-Kalajzic, F.; Flores, C. A.] Ctr Estudios Cient, Valdivia, Chile. [Julio-Kalajzic, F.] Pontificia Univ Catolica Valparaiso, Valparaiso, Chile. [Ehrenfeld, P.; Figueroa, C. D.] Univ Austral Chile, Inst Anat Histol & Patol, Valdivia, Chile. [Melvin, J. E.] Natl Inst Dent & Craniofacial Res, Secretory Mech & Dysfunct Sect, NIH, Bethesda, MD USA. [Sarmiento, J.] Univ Austral Chile, Fac Med, Inst Fisiol, Valdivia, Chile. RP Flores, CA (reprint author), Ctr Estudios Cient, Arturo Prat 514, Valdivia, Chile. EM cflores@cecs.cl FU Fondecyt [11100408, 1110464, 11090292]; Centers of Excellence Base Financing Program of Conicyt FX This research was supported by Fondecyt grants 11100408 (C.A.F.), 1110464 (C.D.F.) and 11090292 (P.E.). The Centro de Estudios Cientificos (CECs) is funded by the Centers of Excellence Base Financing Program of Conicyt. NR 54 TC 1 Z9 1 U1 3 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1748-1708 EI 1748-1716 J9 ACTA PHYSIOL JI Acta Physiol. PD JAN PY 2016 VL 216 IS 1 BP 132 EP 145 DI 10.1111/apha.12548 PG 14 WC Physiology SC Physiology GA DA6XD UT WOS:000367948100011 PM 26138196 ER PT J AU Vanpouille, C Introini, A Morris, SR Margolis, L Daar, ES Dube, MP Little, SJ Smith, DM Lisco, A Gianella, S AF Vanpouille, Christophe Introini, Andrea Morris, Sheldon R. Margolis, Leonid Daar, Eric S. Dube, Michael P. Little, Susan J. Smith, David M. Lisco, Andrea Gianella, Sara TI Distinct cytokine/chemokine network in semen and blood characterize different stages of HIV infection SO AIDS LA English DT Article DE antiretroviral therapy; blood; chemokine; cytokine; HIV-1; semen ID MALE GENITAL-TRACT; T-CELLS; CYTOKINE; INFLAMMATION; ACTIVATION; FLUID; HERPESVIRUSES; THERAPEUTICS; PATHOGENESIS; RECOVERY AB Objective:The cytokine/chemokine network is used by the innate and adaptive immune system to orchestrate effective immune responses. Here, we describe the cross-sectional association between cytokine levels and stage of HIV infection to gain novel insights into HIV-1 immunopathogenesis and identify novel therapeutic targets.Design:Concentrations of 31cytokine/chemokines were retrospectively measured in blood and seminal plasma collected from 252 individuals enrolled in four well characterized cohorts: HIV-uninfected, untreated HIV-infected in early phase of infection, untreated HIV-infected in late phase of infection, and HIV-infected on antiretroviral therapy with undetectable HIV RNA levels in blood (<50 copies/ml).Methods:Cytokine/chemokine levels were measured by multiplex-bead array. Comparisons between groups were performed by Mann-Whitney U-test and P values were adjusted for multiple comparisons using the Benjamini-Hochberg method.Results:Presence of HIV-infection skewed the cytokine/chemokine network towards a pro-inflammatory response in both blood and semen compared to HIV-uninfected controls. Such changes emerged within the first weeks of infection and were maintained thereafter: Among untreated HIV-infected individuals, none of the 31 measured cytokines were significantly different between early and later stages of infection. Suppression of plasma HIV RNA with ART did not result in normalization of the levels of pro-inflammatory cytokines in blood. In semen, several pro-inflammatory cytokines were even further upregulated in ART-treated compared with HIV-uninfected and HIV-untreated individuals.Conclusion:A profound disruption in the cytokine/chemokine network is evident in blood and semen from the earliest stage of HIV infection shortly after the first detection of systemic viremia. These changes are maintained throughout the chronic phase of the infection and do not normalize despite ART and suppression of plasma HIV RNA. C1 [Vanpouille, Christophe; Introini, Andrea; Margolis, Leonid] NICHHD, NIH, Bethesda, MD 20892 USA. [Morris, Sheldon R.; Little, Susan J.; Smith, David M.; Gianella, Sara] Univ Calif San Diego, La Jolla, CA 92093 USA. [Daar, Eric S.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Dube, Michael P.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Smith, David M.] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Lisco, Andrea] NIAID, NIH, Bethesda, MD 20892 USA. RP Gianella, S (reprint author), Univ Calif San Diego, 9500 Gilman Dr MC 0679, La Jolla, CA 92093 USA. EM gianella@ucsd.edu; gianella@ucsd.edu OI Introini, Andrea/0000-0002-9929-8964 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH; Department of Veterans Affairs; James Pendleton Charitable Trust; amfAR grant [108537]; FAIR; U.S. NIH [P30-AI027763, R24AI106039, AI69432, AI043638, MH62512, MH083552, MH101012, AI100665, AI077304, AI36214, AI047745, AI74621, GM093939, AI080353, AI306214, AI27670, AI43638, 7-UM1 AI068636-07]; CTRI [UL1TR000100]; California HIV/AIDS Research Program [RN07-SD-702, MC08-SD-700, EI-11-SD-005]; National Center for Advancing Translational Sciences through UCLA CTSI Grant [UL1TR000124]; National Institute of General Medical Sciences [GM093939] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH; by the Department of Veterans Affairs; by the James Pendleton Charitable Trust; by amfAR grant 108537 with support from FAIR; by U.S. NIH awards P30-AI027763 (CNIHR), R24AI106039, AI69432, AI043638, MH62512, MH083552, MH101012, AI100665, AI077304, AI36214, AI047745, AI74621, GM093939, AI080353, AI306214 (CFAR), AI27670 (ACTU), AI43638, and 7-UM1 AI068636-07; by CTRI grant: UL1TR000100; by California HIV/AIDS Research Program RN07-SD-702, MC08-SD-700 and EI-11-SD-005; by the National Center for Advancing Translational Sciences through UCLA CTSI Grant UL1TR000124; and by National Institute of General Medical Sciences grant GM093939. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 3 Z9 3 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JAN PY 2016 VL 30 IS 2 BP 193 EP 201 DI 10.1097/QAD.0000000000000964 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DA7VJ UT WOS:000368012500002 PM 26558730 ER PT J AU Townsend, K Petersen, T Gordon, LA Kohli, A Nelson, A Seamon, C Gross, C Tang, L Osinusi, A Polis, MA Masur, H Kottilil, S AF Townsend, Kerry Petersen, Tess Gordon, Lori A. Kohli, Anita Nelson, Amy Seamon, Cassie Gross, Chloe Tang, Lydia Osinusi, Anu Polis, Michael A. Masur, Henry Kottilil, Shyam TI Effect of HIV co-infection on adherence to a 12-week regimen of hepatitis C virus therapy with ledipasvir and sofosbuvir SO AIDS LA English DT Article DE adherence; directly acting antivirals; hepatitis C virus; medication event monitoring system ID GENOTYPE 1 INFECTION; PLUS RIBAVIRIN; COMBINATION; HIV/HCV AB Objective:As the treatment of hepatitis C virus (HCV) infection has evolved to directly acting antiviral agents, the impact of these directly acting antiviral-only regimens on improving adherence to HCV treatment in HIV/HCV coinfected populations has not been evaluated. The study compared adherence to ledipasvir/sofosbuvir (LDV/SOF) in HCV monoinfected and HIV/HCV coinfected individuals.Design:Adherence was measured from participants in two phase 2 open-label studies (NCT01805882 and NCT01878799).Methods:HCV treatment-naive, genotype 1 study individuals [HCV monoinfected participants (N=20) and HIV/HCV coinfected participants, antiretroviral untreated (N = 13) or on combination antiretroviral therapy (N=37)] were treated with LDV (90mg) and SOF (400mg) administered as one tablet once daily for 12 weeks. Adherence was measured using three tools: medication event monitoring system cap, pill count, and patient report.Results:Participants were predominately African American (83%) and male (73%), with a median age of 59 years. Participants had prompt HCV viral load decline and high adherence rates (970.5% by medication event monitoring system). Participant adherence decreased significantly from early (baseline week 4) as compared with late (weeks 8-12) in therapy in all three groups - HCV monoinfected (P=0.01), HIV/HCV antiretroviral untreated (P=0.02), and HIV/HCV antiretroviral treated participants (P=0.01).Conclusion:Adherence to LDV/SOF in this urban population was high and comparable between HCV monoinfected and HIV/HCV coinfected participants regardless of antiretroviral use. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Townsend, Kerry; Nelson, Amy; Polis, Michael A.] Natl Inst Hlth Clin Ctr, Immunoregulat Lab, Bethesda, MD USA. [Petersen, Tess; Kohli, Anita; Seamon, Cassie; Osinusi, Anu; Masur, Henry] Natl Inst Hlth Clin Ctr, Dept Crit Care Med, Bethesda, MD USA. [Gordon, Lori A.] NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. [Gordon, Lori A.] Xavier Univ, Coll Pharm, New Orleans, LA 70125 USA. [Kohli, Anita; Gross, Chloe] Frederick Natl Lab Canc Res, Clin Monitoring Res Program, Leidos Biomed Res Inc, Clin Res Directorate,SAIC Frederick Inc, Frederick, MD USA. [Kohli, Anita] Creighton Univ, Div Hepatol, St Josephs Hosp & Med Ctr, Phoenix, AZ USA. [Nelson, Amy; Tang, Lydia; Osinusi, Anu; Kottilil, Shyam] Univ Maryland, Inst Human Virol, Div Infect Dis, Sch Med, Baltimore, MD 21201 USA. [Osinusi, Anu] Gilead Sci Inc, Foster City, CA 94404 USA. RP Kottilil, S (reprint author), Univ Maryland, Inst Human Virol, Div Clin Care & Res, Sch Med, 725W Lombard St,Room S222, Baltimore, MD 21201 USA. EM skottilil@ihv.umaryland.edu FU Regulatory Compliance and Human Subjects Protection Branch of the National Institute of Allergy and Infectious Diseases (NIAID); National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases; NIH; Gilead Sciences FX the Regulatory Compliance and Human Subjects Protection Branch of the National Institute of Allergy and Infectious Diseases (NIAID) served as the study sponsor. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. This research was supported in part by the National Institute of Allergy and Infectious Diseases. The study was partially funded by a Collaborative Research and Development Agreement between NIH and Gilead Sciences. NR 23 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JAN PY 2016 VL 30 IS 2 BP 261 EP 266 DI 10.1097/QAD.0000000000000903 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DA7VQ UT WOS:000368013300001 PM 26691547 ER PT J AU Freeman, RC AF Freeman, Robert C. TI Toward Development of Enhanced Preventive Interventions for HIV Sexual Risk among Alcohol-Using Populations: Confronting the 'Mere Pause from Thinking' SO AIDS AND BEHAVIOR LA English DT Article DE Alcohol; HIV/AIDS; Prevention; Intervention; Behavioral research ID INTIMATE PARTNER VIOLENCE; RANDOMIZED CONTROLLED-TRIAL; SHORT MESSAGE SERVICE; ECOLOGICAL MOMENTARY ASSESSMENT; NATIONAL EPIDEMIOLOGIC SURVEY; SUBSTANCE USE DISORDERS; GENDER-BASED VIOLENCE; FEMALE BAR DRINKERS; TOWN SOUTH-AFRICA; UNITED-STATES AB The papers in this issue detail state-of-the science knowledge regarding the role of alcohol use in HIV/AIDS risk, as well as offer suggestions for ways forward for behavioral HIV prevention for at-risk alcohol-using populations. In light of recent evidence suggesting that the anticipated uptake of the newer biomedical HIV prevention approaches, prominently including pre-exposure prophylaxis, has been stalled owing to a host of barriers, it has become ever more clear that behavioral prevention avenues must continue to receive due consideration as a viable HIV/AIDS prevention approach. The papers collected here make a valuable contribution to "combination prevention" efforts to curb HIV spread. C1 [Freeman, Robert C.] NIAAA, Div Epidemiol & Prevent Res, NIH, Bethesda, MD 20892 USA. RP Freeman, RC (reprint author), NIAAA, Div Epidemiol & Prevent Res, NIH, 5635 Fishers Lane,Room 2073 MSC 9304, Bethesda, MD 20892 USA. EM rfreeman@mail.nih.gov NR 261 TC 0 Z9 0 U1 4 U2 8 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD JAN PY 2016 VL 20 SU 1 BP S1 EP S18 DI 10.1007/s10461-015-1179-7 PG 18 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DB0FM UT WOS:000368184000001 PM 26362168 ER PT J AU Enoch, MA Hodgkinson, CA Shen, PH Gorodetsky, E Marietta, CA Roy, A Goldman, D AF Enoch, Mary-Anne Hodgkinson, Colin A. Shen, Pei-Hong Gorodetsky, Elena Marietta, Cheryl A. Roy, Alec Goldman, David TI GABBR1 and SLC6A1, Two Genes Involved in Modulation of GABA Synaptic Transmission, Influence Risk for Alcoholism: Results from Three Ethnically Diverse Populations SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE GABBR1; GABAB Receptor Subunit; SLC6A1; GAT1; Alcohol Use Disorders ID HLA-G; RECEPTOR; ACTIVATION; SELECTION; BACLOFEN; BEHAVIOR; LINKAGE; REGION; BRAIN; FOCUS AB Background: Animal and human studies indicate that GABBR1, encoding the GABAB1 receptor subunit, and SLC6A1, encoding the neuronal gamma-aminobutyric acid (GABA) transporter GAT1, play a role in addiction by modulating synaptic GABA. Therefore, variants in these genes might predict risk/resilience for alcoholism. Methods: This study included 3 populations that differed by ethnicity and alcoholism phenotype: African American (AA) men: 401 treatment-seeking inpatients with single/comorbid diagnoses of alcohol and drug dependence, 193 controls; Finnish Caucasian men: 159 incarcerated alcoholics, half with comorbid antisocial personality disorder, 181 controls; and a community sample of Plains Indian (PI) men and women: 239 alcoholics, 178 controls. Seven GABBR1 tag single nucleotide polymorphisms were genotyped in the AA and Finnish samples; rs29220 was genotyped in the PI for replication. Also, a uniquely African, functional SLC6A1 insertion promoter polymorphism (IND) was genotyped in the AAs. Results: We found a significant and congruent association between GABBR1 rs29220 and alcoholism in all 3 populations. The major genotype (heterozygotes in AAs, Finns) and the major allele in PIs were significantly more common in alcoholics. Moreover, SLC6A1 IND was more abundant in controls, that is, the major genotype predicted alcoholism. An analysis of combined GABBR1 rs29220 and SLC6A1 IND genotypes showed that rs29220 heterozygotes, irrespective of their IND status, had an increased risk for alcoholism, whereas carriers of the IND allele and either rs29220 homozygote were more resilient. Conclusions: Our results show that with both GABBR1 and SLC6A1, the minor genotypes/alleles were protective against risk for alcoholism. Finally, GABBR1 rs29220 might predict treatment response/adverse effects for baclofen, a GABAB receptor agonist. C1 [Enoch, Mary-Anne; Hodgkinson, Colin A.; Shen, Pei-Hong; Gorodetsky, Elena; Marietta, Cheryl A.; Goldman, David] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. [Roy, Alec] New Jersey VA Hlth Care Syst, Dept Vet Affairs, Psychiat Serv, E Orange, NJ USA. RP Enoch, MA (reprint author), NIAAA, NIH, DICBR, LNG, 5625 Fishers Lane,Room 3S32,MSC 9412, Bethesda, MD 20892 USA. EM maenoch@niaaa.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH; National Institute of Drug Abuse, NIH [RO1 DA 10336-02] FX This research was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH, and in part by grant RO1 DA 10336-02 to AR from the National Institute of Drug Abuse, NIH. NR 31 TC 0 Z9 0 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JAN PY 2016 VL 40 IS 1 BP 93 EP 101 DI 10.1111/acer.12929 PG 9 WC Substance Abuse SC Substance Abuse GA DA9PD UT WOS:000368140900010 PM 26727527 ER PT J AU Alderman, MH Davis, BR Piller, LB Ford, CE Baraniuk, MS Pressel, SL Assadi, MA Einhorn, PT Haywood, LJ Ilamathi, E Oparil, S Retta, TM AF Alderman, Michael H. Davis, Barry R. Piller, Linda B. Ford, Charles E. Baraniuk, M. Sarah Pressel, Sara L. Assadi, Mahshid A. Einhorn, Paula T. Haywood, L. Julian Ilamathi, Ekambaram Oparil, Suzanne Retta, Tamrat M. CA ALLHAT Collaborative Res Grp TI Should Antihypertensive Treatment Recommendations Differ in Patients With and Without Coronary Heart Disease? (from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CONVERTING-ENZYME-INHIBITOR; CALCIUM-CHANNEL BLOCKER; CARDIOVASCULAR EVENTS; BLOOD-PRESSURE; HYPERTENSION; MORBIDITY; MORTALITY; OUTCOMES; FAILURE; INTERVENTION AB Thiazide-type diuretics have been recommended for initial treatment of hypertension in most patients, but should this recommendation differ for patients with and without coronary heart disease (CHD)? The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized, -double-blind hypertension treatment trial in 42,418 participants with high risk of combined cardiovascular disease (CVD) (25% with preexisting CHD). This post hoc analysis compares long-term major clinical outcomes in those assigned amlodipine (n = 9048) or lisinopril (n = 9,054) with those assigned chlorthalidone (n = 15,255), stratified by CHD status. After 4 to 8 years, randomized treatment was discontinued. Total follow-up (active treatment + passive surveillance using national databases for deaths and hospitalizations) was 8 to 13 years. For most CVD outcomes, endstage renal disease, and total mortality, there were no differences across randomized treatment arms regardless of baseline CHD status. In-trial rates of CVD were significantly higher for lisinopril compared with chlorthalidone, and rates of heart failure were significantly higher for arnlodipine compared with chlorthalidone in those with and without CHD (overall hazard ratios [HRs] 1.10, p < 0.001, and 1.38, p < 0.001, respectively). During extended followup, significant outcomes according to GM status interactions (p = 0.012) were noted in amlodipine versus chlorthalidone comparison for CVD and CHD mortality (HR 0.88, p = 0.04, and 0.84, p = 0.04, respectively) in those with CHD at baseline (HR 1.06, p = 0.15, and 1.08, p = 0.17) and in those without. The results of the overall increased stroke mortality in lisinopril compared with chlorthalidone (HR 1.2; p = 0.03) and hospitalized heart failure in amlodipine compared with chlorthalidone (HR 1.12; p = 0.01) during extended follow-up did not differ by baseline CHD status. In conclusion, these results provide no reason to alter our previous recommendation to include a properly dosed diuretic (such as chlorthalidone 12.5 to 25 mg/day) in the initial antihypertensive regimen for most hypertensive patients. (c) 2016 Elsevier Inc. C1 [Alderman, Michael H.] Albert Einstein Coll Med, Dept Med Gen Internal Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Davis, Barry R.; Piller, Linda B.; Ford, Charles E.; Baraniuk, M. Sarah; Pressel, Sara L.] Univ Texas Houston, Sch Publ Hlth, Coordinating Ctr Clin Trials, Houston, TX 77021 USA. [Assadi, Mahshid A.] SUNY Hlth Sci Ctr, Brooklyn, NY USA. [Einhorn, Paula T.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Haywood, L. Julian] Univ So Calif, Keck Sch Med, LAC USC Med Ctr, Los Angeles, CA 90033 USA. [Ilamathi, Ekambaram] Suffolk Nephrol Consultants, Stony Brook, NY USA. [Oparil, Suzanne] Univ Alabama Birmingham, Dept Med & Physiol & Biophys, Birmingham, AL USA. [Retta, Tamrat M.] Howard Univ, Coll Med, Dept Med, Washington, DC USA. RP Piller, LB (reprint author), Univ Texas Houston, Sch Publ Hlth, Coordinating Ctr Clin Trials, Houston, TX 77021 USA. EM Linda.B.Piller@uth.tmc.edu FU National Heart, Lung, and Blood Institute [NO1-HC-35130, HHSN268201100036 C]; Pfizer FX ALLHAT was supported by contracts NO1-HC-35130 and HHSN268201100036 C with the National Heart, Lung, and Blood Institute. It received contributions of study medications supplied by Pfizer (New York, NY) (amlodipine and doxazosin), AstraZeneca (London, United Kingdom) (atenolol and lisinopril), and Bristol-Meyers Squibb (New York, NY) (pravastatin). National Heart, Lung, and Blood Institute also received financial support of ALLHAT provided by Pfizer. NR 25 TC 0 Z9 0 U1 0 U2 7 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD JAN 1 PY 2016 VL 117 IS 1 BP 105 EP 115 DI 10.1016/j.amjcard.2015.10.012 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DA8IS UT WOS:000368048900016 PM 26589819 ER PT J AU Sponholtz, TR Sandler, DP Parks, CG Applebaum, KM AF Sponholtz, Todd R. Sandler, Dale P. Parks, Christine G. Applebaum, Katie M. TI Occupational Exposures and Chronic Kidney Disease: Possible Associations With Endotoxin and Ultrafine Particles SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE kidney disease; occupational exposures; heavy metals; silica; particulates; nephritis ID STAGE RENAL-DISEASE; INDUSTRIAL SAND WORKERS; BLOOD LEAD LEVELS; UNITED-STATES; CRYSTALLINE SILICA; RISK-FACTORS; LUNG-CANCER; FOLLOW-UP; MORTALITY; COHORT AB Background Chronic kidney disease (CKD) carries a high public health burden yet there is limited research on occupational factors, which are examined in this retrospective case-control study. Methods Newly diagnosed cases of CKD (n = 547) and controls (n = 508) from North Carolina provided detailed work histories in telephone interviews. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results There was heterogeneity in the association of CKD and agricultural work, with crop production associated with increased risk and work with livestock associated with decreased risk. Work with cutting/cooling/lubricating oils was associated with a reduced risk. CKD risk was increased for working in dusty conditions. Conclusions CKD risk was reduced in subjects with occupational exposures previously reported to involve endotoxin exposure. Further, exposure to dusty conditions was consistently associated with increased risk of glomerulonephritis across industry, suggesting that research on CKD and ultrafine particulates is needed. (C) 2015 Wiley Periodicals, Inc. C1 [Sponholtz, Todd R.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Sandler, Dale P.; Parks, Christine G.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Applebaum, Katie M.] George Washington Univ, Dept Environm & Occupat Hlth, Milken Inst, Sch Publ Hlth, Washington, DC USA. [Applebaum, Katie M.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. RP Sandler, DP (reprint author), NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. EM sandler@niehs.nih.gov OI Parks, Christine/0000-0002-5734-3456; Sandler, Dale/0000-0002-6776-0018 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01-ES-049028] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-049028). NR 60 TC 0 Z9 0 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0271-3586 EI 1097-0274 J9 AM J IND MED JI Am. J. Ind. Med. PD JAN PY 2016 VL 59 IS 1 BP 1 EP 11 DI 10.1002/ajim.22541 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DA7UQ UT WOS:000368010400001 PM 26572099 ER PT J AU Fleming, L Lemmon, M Beck, N Johnson, M Mu, WY Murdock, D Bodurtha, J Hoover-Fong, J Cohn, R Bosemani, T Baranano, K Hamosh, A AF Fleming, Leah Lemmon, Monica Beck, Natalie Johnson, Maria Mu, Weiyi Murdock, David Bodurtha, Joann Hoover-Fong, Julie Cohn, Ronald Bosemani, Thangamadhan Baranano, Kristin Hamosh, Ada TI Genotype-Phenotype Correlation of Congenital Anomalies in Multiple Congenital Anomalies Hypotonia Seizures Syndrome (MCAHS1)/PIGN-Related Epilepsy SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE epilepsy; intractable; spasms; infantile; PIGN; GPI ethanolamine phosphate transferase 1; human; glycosylphosphatidylinositol anchors; hypotonia; genotype-phenotype association; congenital disorders of glycosylation ID MENTAL-RETARDATION SYNDROME; ANCHORED PROTEINS; MUTATIONS; GLYCOSYLPHOSPHATIDYLINOSITOL; HYPERPHOSPHATASIA; DISORDERS; PIGN; GLYCOSYLATION; DEFICIENCY; YEAST AB Mutations in PIGN, resulting in multiple congenital anomalies-hypotonia-seizures syndrome, a glycosylphosphatidylinositol anchor deficiency, have been published in four families to date. We report four patients from three unrelated families with epilepsy and hypotonia in whom whole exome sequencing yielded compound heterozygous variants in PIGN. As with previous reports Patients 1 and 2 (full siblings) have severe global developmental delay, gastroesophageal reflux disease, and minor dysmorphic features, including high palate, bitemporal narrowing, depressed nasal bridge, and micrognathia; Patient 3 had early global developmental delay with later progressive spastic quadriparesis, intellectual disability, and intractable generalized epilepsy; Patient 4 had bilateral narrowing as well but differed by the presence of hypertelorism, markedly narrow palpebral fissures, and long philtrum, had small distal phalanges of fingers 2, 3, and 4, absent distal phalanx of finger 5 and similar toe anomalies, underdeveloped nails, unusual brain anomalies, and a more severe early clinical course. These patients expand the known clinical spectrum of the disease. The severity of the presentations in conjunction with the patients' mutations suggest a genotype-phenotype correlation in which congenital anomalies are only seen in patients with biallelic loss-of-function. In addition, PIGN mutations appear to be panethnic and may be an underappreciated cause of epilepsy. (C) 2015 Wiley Periodicals, Inc. C1 [Fleming, Leah; Murdock, David] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Lemmon, Monica; Baranano, Kristin] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Beck, Natalie; Mu, Weiyi; Bodurtha, Joann; Hoover-Fong, Julie; Hamosh, Ada] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Beck, Natalie; Hoover-Fong, Julie] Johns Hopkins Univ, Greenberg Ctr Skeletal Dysplasia, Baltimore, MD USA. [Johnson, Maria] Univ Minnesota, Dept Neurol, Minneapolis, MN 55455 USA. [Cohn, Ronald] Univ Toronto, Hosp Sick Children Clin & Metab Genet, Toronto, ON, Canada. [Bosemani, Thangamadhan] Johns Hopkins Univ, Div Pediat Radiol, Sect Pediat Neuroradiol, Baltimore, MD USA. [Baranano, Kristin] Kennedy Krieger Inst, Div Neurogenet, Baltimore, MD USA. RP Fleming, L (reprint author), St Lukes Hlth Syst, Genet & Metab, Boise, ID 83712 USA. EM flemingl@slhs.org FU NCI NIH HHS [P30 CA006973]; NIGMS NIH HHS [T32 GM007471] NR 25 TC 5 Z9 6 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JAN PY 2016 VL 170 IS 1 BP 77 EP 86 DI 10.1002/ajmg.a.37369 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DA6RT UT WOS:000367933600011 PM 26394714 ER PT J AU Janecke, AR Li, B Boehm, M Krabichler, B Rohrbach, M Muller, T Fuchs, I Golas, G Katagiri, Y Ziegler, SG Gahl, WA Wilnai, Y Zoppi, N Geller, HM Giunta, C Slavotinek, A Steinmann, B AF Janecke, Andreas R. Li, Ben Boehm, Manfred Krabichler, Birgit Rohrbach, Marianne Mueller, Thomas Fuchs, Irene Golas, Gretchen Katagiri, Yasuhiro Ziegler, Shira G. Gahl, William A. Wilnai, Yael Zoppi, Nicoletta Geller, Herbert M. Giunta, Cecilia Slavotinek, Anne Steinmann, Beat TI The Phenotype of the Musculocontractural Type of Ehlers-Danlos Syndrome due to CHST14 Mutations SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE dermatan sulfate; deficiency; dermatan sulfate epimerase; N-acetylgalactosamine 4-O-sulfotransferase; connective tissue; Ehlers-Danlos syndrome; adducted thumb; clubfoot; proteoglycan; arthrogryposis; myopathy ID THUMB-CLUBFOOT SYNDROME; DERMATAN SULFATE BIOSYNTHESIS; LYSYL HYDROXYLASE-ACTIVITY; ADDUCTED THUMB; FOOT SYNDROME; EXTRACELLULAR-MATRIX; GENE; PROTEOGLYCANS; CONTRACTURES; FIBROBLASTS AB The musculocontractural type of Ehlers-Danlos syndrome (MC-EDS) has been recently recognized as a clinical entity. MC-EDS represents a differential diagnosis within the congenital neuromuscular and connective tissue disorders spectrum. Thirty-one and three patients have been reported with MC-EDS so far with biallelic mutations identified in CHST14 and DSE, respectively, encoding two enzymes necessary for dermatan sulfate (DS) biosynthesis. We report seven additional patients with MC-EDS from four unrelated families, including the follow-up of a sib-pair originally reported with the kyphoscoliotic type of EDS in 1975. Brachycephaly, a characteristic facial appearance, an asthenic build, hyperextensible and bruisable skin, tapering fingers, instability of large joints, and recurrent formation of large subcutaneous hematomas are always present. Three of seven patients hadmildly elevated serum creatine kinase. The oldest patient was blind due to retinal detachment at 45 years and died at 59 years from intracranial bleeding; her affected brother died at 28 years from fulminant endocarditis. All patients in this series harbored homozygous, predicted loss-of-function CHST14 mutations. Indeed, DS was not detectable in fibroblasts from two unrelated patients with homozygous mutations. Patient fibroblasts produced higher amounts of chondroitin sulfate, showed intracellular retention of collagen types Iand III, andlacked decorin and thrombospondin fibrils compared with control. A great proportion of collagen fibrils were not integrated into fibers, and fiber bundles were dispersed into the ground substance in one patient, all of which is likely to contribute to the clinical phenotype. This report should increase awareness for MC-EDS. (C) 2015 Wiley Periodicals, Inc. C1 [Janecke, Andreas R.; Mueller, Thomas; Fuchs, Irene] Med Univ Innsbruck, Dept Pediat 1, A-6020 Innsbruck, Austria. [Janecke, Andreas R.; Krabichler, Birgit] Med Univ Innsbruck, Div Human Genet, A-6020 Innsbruck, Austria. [Li, Ben; Slavotinek, Anne] Univ Calif San Francisco, Div Genet, Dept Pediat, San Francisco, CA 94143 USA. [Boehm, Manfred] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Rohrbach, Marianne; Giunta, Cecilia; Steinmann, Beat] Univ Childrens Hosp, Div Metab, Connect Tissue Unit, Zurich, Switzerland. [Rohrbach, Marianne; Giunta, Cecilia; Steinmann, Beat] Univ Childrens Hosp, Childrens Res Ctr, Zurich, Switzerland. [Golas, Gretchen; Ziegler, Shira G.; Gahl, William A.] NHGRI, NIH Undiagnosed Dis Program, Common Fund, Off Director,NIH, Bethesda, MD 20892 USA. [Golas, Gretchen; Ziegler, Shira G.; Gahl, William A.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Katagiri, Yasuhiro; Geller, Herbert M.] NHLBI, Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Wilnai, Yael] Stanford Univ, Med Ctr, Dept Pediat, Div Med Genet, Stanford, CA 94305 USA. [Zoppi, Nicoletta] Univ Brescia, Fac Med, Dept Mol & Translat Med, Div Biol & Genet, Brescia, Italy. RP Janecke, AR (reprint author), Med Univ Innsbruck, Dept Pediat 1, Anichstr 35, A-6020 Innsbruck, Austria. EM Andreas.Janecke@i-med.ac.at OI Geller, Herbert/0000-0002-7048-6144; Giunta, Cecilia/0000-0002-9313-8257; Rohrbach, Marianne/0000-0002-4013-6012 FU SNF [310030_138288]; NIH; National Human Genome Research Institute FX Grant sponsor: SNF; Grant number: 310030_138288; Grant sponsor: NIH Common Fund; Grant sponsor: National Human Genome Research Institute. NR 36 TC 3 Z9 3 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JAN PY 2016 VL 170 IS 1 BP 103 EP 115 DI 10.1002/ajmg.a.37383 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA DA6RT UT WOS:000367933600014 PM 26373698 ER PT J AU Donkervoort, S Bonnemann, CG Loeys, B Jungbluth, H Voermans, NC AF Donkervoort, S. Bonnemann, C. G. Loeys, B. Jungbluth, H. Voermans, N. C. TI The Neuromuscular Differential Diagnosis of Joint Hypermobility (vol 169, pg 23, 2015) SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Correction C1 [Donkervoort, S.; Bonnemann, C. G.] NINDS, NIH, Neurogenet Branch, Neuromuscular & Neurogenet Disorders Childhood Se, Bethesda, MD 20892 USA. [Loeys, B.] Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, NL-6500 HB Nijmegen, Netherlands. [Loeys, B.] Univ Antwerp Hosp, Ctr Med Genet, Antwerp, Belgium. [Loeys, B.] Univ Antwerp, B-2020 Antwerp, Belgium. [Jungbluth, H.] Guys & St Thomas NHS Fdn Trust, Evelina Childrens Hosp, Neuromuscular Serv, Dept Paediat Neurol, London, England. [Jungbluth, H.] Kings Coll London, Randall Div Cell & Mol Biophys, Muscle Signalling Sect, London, England. [Jungbluth, H.] Kings Coll London, Inst Psychiat Psychol & Neurosci IoPPN, Dept Basic & Clin Neurosci, London, England. [Voermans, N. C.] Radboud Univ Nijmegen, Dept Neurol, Med Ctr, NL-6500 HB Nijmegen, Netherlands. RP Voermans, NC (reprint author), Radboud Univ Nijmegen, Dept Neurol, Med Ctr, POB 9101, NL-6500 HB Nijmegen, Netherlands. EM nicol.voermans@radboudumc.nl RI Jungbluth, Heinz/B-8893-2012 NR 5 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JAN PY 2016 VL 170 IS 1 BP 285 EP 286 DI 10.1002/ajmg.a.37244 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA DA6RT UT WOS:000367933600044 ER PT J AU Gomez-Lopez, N Romero, R Plazyo, O Panaitescu, B Furcron, AE Miller, D Roumayah, T Flom, E Hassan, SS AF Gomez-Lopez, Nardhy Romero, Roberto Plazyo, Olesya Panaitescu, Bogdan Furcron, Amy E. Miller, Derek Roumayah, Tamara Flom, Emily Hassan, Sonia S. TI Intra-Amniotic Administration of HMGB1 Induces Spontaneous Preterm Labor and Birth SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Article DE Alarmins; DAMPs; danger signals; parturition; prematurity; sterile intra-amniotic inflammation ID AMNIOTIC-FLUID; ALARMIN HMGB1; INFLAMMATION; MEMBRANES; PROTEIN; DAMAGE; DAMPS; CHORIOAMNIONITIS; PARTURITION; STERILE AB Problem Sterile intra-amniotic inflammation is associated with spontaneous preterm labor. Alarmins are proposed to mediate this inflammatory process. The aim of this study was to determine whether intra-amniotic administration of an alarmin, HMGB1, could induce preterm labor/birth. Method of Study Pregnant B6 mice were intra-amniotically or intraperitoneally injected with HMGB1 or PBS (control). Following injection, the gestational age and the rates of preterm birth and pup mortality were recorded. Results Intra-amniotic injection of HMGB1 led to preterm labor/birth [HMGB1 57% (4/7) versus PBS 0% (0/6); P = 0.049) and a high rate of pup mortality at week 1 [HMGB1 60.9 +/- 11.7% (25/41) versus PBS 28.9 +/- 12.6% (11/38); P = 0.001). Intraperitoneal injection of HMGB1 did not induce preterm labor/birth. Conclusion Intra-amniotic administration of HMGB1 induces preterm labor/birth. C1 [Gomez-Lopez, Nardhy; Romero, Roberto; Plazyo, Olesya; Furcron, Amy E.; Miller, Derek; Roumayah, Tamara; Flom, Emily; Hassan, Sonia S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NICHD,NIH,DHHS, Bethesda, MD USA. [Gomez-Lopez, Nardhy; Romero, Roberto; Plazyo, Olesya; Furcron, Amy E.; Miller, Derek; Roumayah, Tamara; Flom, Emily; Hassan, Sonia S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NICHD,NIH,DHHS, Detroit, MI USA. [Gomez-Lopez, Nardhy; Plazyo, Olesya; Furcron, Amy E.; Miller, Derek; Hassan, Sonia S.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Gomez-Lopez, Nardhy; Miller, Derek] Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Detroit, MI 48201 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Panaitescu, Bogdan] Wayne State Univ, Sch Med, Dept Pediat, Div Neonatol, Detroit, MI 48201 USA. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM romeror@mail.nih.gov RI Gomez-Lopez, Nardhy/R-7664-2016 OI Gomez-Lopez, Nardhy/0000-0002-3406-5262 FU Intramural NIH HHS [ZIA HD002400-25] NR 17 TC 8 Z9 8 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1046-7408 EI 1600-0897 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD JAN PY 2016 VL 75 IS 1 BP 3 EP 7 DI 10.1111/aji.12443 PG 5 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA DA7UM UT WOS:000368009900001 PM 26781934 ER PT J AU Soper, SA Rasooly, A AF Soper, Steven A. Rasooly, Avraham TI Cancer: a global concern that demands new detection technologies SO ANALYST LA English DT Editorial Material C1 [Soper, Steven A.] Univ N Carolina, Chapel Hill, NC 27514 USA. [Rasooly, Avraham] NCI, NIH, Bethesda, MD 20892 USA. RP Soper, SA (reprint author), Univ N Carolina, Chapel Hill, NC 27514 USA. FU NIBIB NIH HHS [P41-EB020594, P41 EB020594] NR 5 TC 0 Z9 0 U1 2 U2 5 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 0003-2654 EI 1364-5528 J9 ANALYST JI Analyst PY 2016 VL 141 IS 2 BP 367 EP 370 DI 10.1039/c5an90101d PG 4 WC Chemistry, Analytical SC Chemistry GA DB0GB UT WOS:000368185500001 PM 26688866 ER PT J AU Serrano, KJ Yu, M Riley, WT Patel, V Hughes, P Marchesini, K Atienza, AA AF Serrano, Katrina J. Yu, Mandi Riley, William T. Patel, Vaishali Hughes, Penelope Marchesini, Kathryn Atienza, Audie A. TI Willingness to Exchange Health Information via Mobile Devices: Findings From a Population-Based Survey SO ANNALS OF FAMILY MEDICINE LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-of-Behavioral-Medicine CY APR 22-25, 2015 CL San Antonio, TX SP Soc Behav Med DE mobile health; health information exchange; patient/consumer attitudes; cell phones; electronic mail ID LOW-INCOME; RECORDS; ATTITUDES; PATIENT; PERCEPTIONS; OUTCOMES; TRUST AB PURPOSE The rapid proliferation of mobile devices offers unprecedented opportunities for patients and health care professionals to exchange health information electronically, but little is known about patients' willingness to exchange various types of health information using these devices. We examined willingness to exchange different types of health information via mobile devices, and assessed whether sociodemographic characteristics and trust in clinicians were associated with willingness in a nationally representative sample. METHODS We analyzed data for 3,165 patients captured in the 2013 Health Information National Trends Survey. Multinomial logistic regression analysis was conducted to test differences in willingness. Ordinal logistic regression analysis assessed correlates of willingness to exchange 9 types of information separately. RESULTS Participants were very willing to exchange appointment reminders (odds ratio [OR] = 6.66; 95% CI, 5.68-7.81), general health tips (OR = 2.03; 95% CI, 1.74-2.38), medication reminders (OR = 2.73; 95% CI, 2.35-3.19), laboratory/test results (OR = 1.76; 95% CI, 1.62-1.92), vital signs (OR = 1.63; 95% CI, 1.48-1.80), lifestyle behaviors (OR = 1.40; 95% CI, 1.24-1.58), and symptoms (OR = 1.62; 95% CI, 1.46-1.79) as compared with diagnostic information. Older adults had lower odds of being more willing to exchange any type of information. Education, income, and trust in health care professional information correlated with willingness to exchange certain types of information. CONCLUSIONS Respondents were less willing to exchange via mobile devices information that may be considered sensitive or complex. Age, socioeconomic factors, and trust in professional information were associated with willingness to engage in mobile health information exchange. Both information type and demographic group should be considered when developing and tailoring mobile technologies for patient-clinician communication. C1 [Serrano, Katrina J.; Yu, Mandi; Riley, William T.; Atienza, Audie A.] NCI, NIH, Rockville, MD USA. [Patel, Vaishali; Hughes, Penelope; Marchesini, Kathryn] US Dept HHS, Off Natl Coordinator Hlth Informat Technol, Washington, DC 20201 USA. RP Serrano, KJ (reprint author), NCI, Sci Res & Technol Branch, Behav Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,3E538, Bethesda, MD 20892 USA. EM katrina.serrano@nih.gov NR 30 TC 6 Z9 6 U1 4 U2 10 PU ANNALS FAMILY MEDICINE PI LEAWOOD PA 11400 TOMAHAWK CREEK PARKWAY, LEAWOOD, KS 66211-2672 USA SN 1544-1709 EI 1544-1717 J9 ANN FAM MED JI Ann. Fam. Med. PD JAN-FEB PY 2016 VL 14 IS 1 BP 34 EP 40 DI 10.1370/afm.1888 PG 7 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA DA8UT UT WOS:000368082600007 PM 26755781 ER PT J AU Korn, EL Sachs, MC McShane, LM AF Korn, E. L. Sachs, M. C. McShane, L. M. TI Statistical controversies in clinical research: assessing pathologic complete response as a trial-level surrogate end point for early-stage breast cancer SO ANNALS OF ONCOLOGY LA English DT Article DE breast cancer; pathologic complete response; surrogate end point; trial-level surrogate end point; randomized clinical trial; screening trials ID PHASE-3 TRIAL; OPEN-LABEL; MULTICENTER; TRASTUZUMAB; LAPATINIB; NEOALTTO AB A trial-level surrogate end point for a randomized clinical trial may allow assessment of the relative benefits of the treatment to be performed at an earlier time point and potentially with a smaller sample size. However, determining whether an end point is a reliable trial-level surrogate based on results of previous trials is not straightforward. The question of trial-level surrogacy is easily confused with the question of individual-level surrogacy, and this confusion can lead to controversy. A recent example concerns the evaluation of pathologic complete response (pCR) as a surrogate for event-free survival (EFS) and overall survival (OS) in early-stage breast cancer. The differences between individual-level surrogacy (i.e. for patients receiving a specific treatment, the surrogate end point predicts the definitive end point) and trial-level surrogacy (the results of the trial for the surrogate end point predict the results of the trial for the definitive end point) are discussed. Trial-level data used in two previous meta-analyses evaluating pCR as a trial-level surrogate for EFS and OS were re-analyzed using methods that appropriately account for the variability in pCR rates as well as the variability in the hazard ratios for EFS and OS. There is no evidence that pCR is a trial-level surrogate for EFS or OS, nor is there evidence that pCR could be used reliably to screen out nonpromising agents from further drug development. At present, neoadjuvant RCTs should continue to follow patients to observe EFS and OS to assess clinical benefit, and they should be designed with sufficient sample size to reliably assess EFS. However, one cannot rule out the possibility that future meta-analyses involving more trials and in which the patient population or class of treatments is restricted could suggest the validity of pCR as a trial-level surrogate for EFS or OS in some focused settings. C1 [Korn, E. L.; Sachs, M. C.; McShane, L. M.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Korn, EL (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, MSC 9735, Bethesda, MD 20892 USA. EM korne@ctep.nci.nih.gov NR 18 TC 7 Z9 7 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD JAN PY 2016 VL 27 IS 1 BP 10 EP 15 DI 10.1093/annonc/mdv507 PG 6 WC Oncology SC Oncology GA DB2QR UT WOS:000368354600003 PM 26489443 ER PT J AU Ripley, RT Sarkaria, IS Grosser, R Sima, CS Bains, MS Jones, DR Adusumilli, PS Huang, J Finley, DJ Rusch, VW Rizk, NP AF Ripley, R. Taylor Sarkaria, Inderpal S. Grosser, Rachel Sima, Camelia S. Bains, Manjit S. Jones, David R. Adusumilli, Prasad S. Huang, James Finley, David J. Rusch, Valerie W. Rizk, Nabil P. TI Pretreatment Dysphagia in Esophageal Cancer Patients May Eliminate the Need for Staging by Endoscopic Ultrasonography SO ANNALS OF THORACIC SURGERY LA English DT Article ID GASTROESOPHAGEAL JUNCTION; ULTRASOUND; ADENOCARCINOMA AB Background. Neoadjuvant therapy is commonly administered to patients with localized disease who have T3-4 esophageal disease as staged by endoscopic ultrasound (EUS). Previously, we noted that patients who present with dysphagia have a higher EUS T stage. We hypothesized that the presence of dysphagia is predictive of EUS T3-4 disease and that staging EUS could be forgone for esophageal cancer patients with dysphagia. Methods. We performed a prospective, intent-to-treat, single-cohort study in which patients with potentially resectable esophageal cancer completed a standardized four-tier dysphagia score survey. EUS was performed as part of our standard evaluation. To determine whether the presence of dysphagia predicted EUS T3-4 disease, the dysphagia score was compared with EUS T stage. Results. The study enrolled 114 consecutive patients between August 2012 and February 2014: 77% (88 of 114) received neoadjuvant therapy, 18% (20 of 114) did not, and 5% (6 of 114) pursued treatment elsewhere. In total, 70% (80 of 114) underwent esophagectomy; of these, 54% (61 of 114) had dysphagia and 46% (53 of 114) did not. Dysphagia scores were 66% (40 of 61) grade 1, 25% (15 of 61) grade 2, and 10% (6 of 61) grade 3 to 4. Among patients with dysphagia, 89% (54 of 61) had T3-4 disease by EUS; among those without dysphagia, only 53% (28 of 53) had T3-4 disease by EUS (p < 0.001). Conclusions. The presence of dysphagia in patients with esophageal cancer was highly predictive of T3-4 disease by EUS. On the basis of this finding, approximately 50% of patients currently undergoing staging EUS at our institution could potentially forgo EUS before neoadjuvant therapy. Patients without dysphagia, however, should still undergo EUS. (C) 2016 by The Society of Thoracic Surgeons C1 [Ripley, R. Taylor; Sarkaria, Inderpal S.; Grosser, Rachel; Sima, Camelia S.; Bains, Manjit S.; Jones, David R.; Adusumilli, Prasad S.; Huang, James; Finley, David J.; Rusch, Valerie W.; Rizk, Nabil P.] Mem Sloan Kettering Canc Ctr, Dept Surg, Thorac Serv, New York, NY 10021 USA. RP Ripley, RT (reprint author), NCI, Thorac & GI Oncol Branch, CCR, Bldg 10,4-3952 10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM taylor.ripley@nih.gov OI Huang, James/0000-0001-5495-3577 FU NIH/NCI Cancer Center Support Grant [P30 CA008748] FX Financial Support was provided by NIH/NCI Cancer Center Support Grant P30 CA008748. NR 10 TC 2 Z9 2 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD JAN PY 2016 VL 101 IS 1 BP 226 EP 230 DI 10.1016/j.athoracsur.2015.06.062 PG 5 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DB0FP UT WOS:000368184300040 PM 26603024 ER PT J AU Lange-Maia, BS Newman, AB Cauley, JA Boudreau, RM Jakicic, JM Caserotti, P Glynn, NW Harris, TB Kritchevsky, SB Schwartz, AV Satterfield, S Simonsick, EM Vinik, AI Zivkovic, S Strotmeyer, ES AF Lange-Maia, Brittney S. Newman, Anne B. Cauley, Jane A. Boudreau, Robert M. Jakicic, John M. Caserotti, Paolo Glynn, Nancy W. Harris, Tamara B. Kritchevsky, Stephen B. Schwartz, Ann V. Satterfield, Suzanne Simonsick, Eleanor M. Vinik, Aaron I. Zivkovic, Sasa Strotmeyer, Elsa S. CA Health Aging Body TI Sensorimotor Peripheral Nerve Function and the Longitudinal Relationship With Endurance Walking in the Health, Aging and Body Composition Study SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Aged; Motor neurons; Peripheral nerves; Physical endurance; Rehabilitation; Sensation; Walking ID OLDER-ADULTS; DIABETES-MELLITUS; GAIT CHARACTERISTICS; QUADRICEPS STRENGTH; PHYSICAL-FITNESS; NEUROPATHY; MOBILITY; FALLS; AGE; DISEASE AB Objectives: To determine whether lower extremity sensorimotor peripheral nerve deficits are associated with reduced walking endurance in older adults. Design: Prospective cohort study with 6 years of follow-up. Setting: Two university research clinics. Participants: Community-dwelling older adults enrolled in the Health, Aging and Body Composition Study from the 2000-2001 annual clinical examination (N=2393; mean age +/- SD, 76.5 +/- 2.9y; 48.2% men; 38.2% black) and a subset with longitudinal data (n=1178). Interventions: Not applicable. Main Outcome Measures: Participants underwent peripheral nerve function examination in 2000-2001, including peroneal motor nerve conduction amplitude and velocity, vibration perception threshold, and monofilament testing. Symptoms of lower extremity peripheral neuropathy included numbness or tingling and sudden stabbing, burning, pain, or aches in the feet or legs. The Long Distance Corridor Walk (LDCW) (400m) was administered in 2000-2001 and every 2 years afterward for 6 years to assess endurance walking performance over time. Results: In separate, fully adjusted linear mixed models, poor vibration threshold (>130 mu m), 10-g and 1.4-g monofilament insensitivity were each associated with a slower 400-m walk completion time (16.0s, 14.4s, and 6.9s slower, respectively; P<.05 for each). Poor motor amplitude (<1mV), poor vibration perception threshold, and 10-g monofilament insensitivity were related to greater slowing per year (4.7, 4.2, and 3.8 additional seconds per year, respectively; P<.05), although poor motor amplitude was not associated with initial completion time. Conclusions: Poorer sensorimotor peripheral nerve function is related to slower endurance walking and greater slowing longitudinally. Interventions to reduce the burden of sensorimotor peripheral nerve function impairments should be considered to help older adults maintain walking endurance-a critical component for remaining independent in the community. (C) 2016 by the American Congress of Rehabilitation Medicine C1 [Lange-Maia, Brittney S.; Newman, Anne B.; Cauley, Jane A.; Boudreau, Robert M.; Glynn, Nancy W.; Strotmeyer, Elsa S.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Jakicic, John M.] Univ Pittsburgh, Sch Educ, Dept Hlth & Phys Act, Pittsburgh, PA 15213 USA. [Caserotti, Paolo] Univ Southern Denmark, Dept Sports Sci & Clin Biomech, Odense, Denmark. [Harris, Tamara B.] NIA, Intramural Res Program, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. [Kritchevsky, Stephen B.] Wake Forest Sch Med, Dept Internal Med, Div Gerontol & Geriatr Med, Winston Salem, NC USA. [Schwartz, Ann V.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Simonsick, Eleanor M.] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Vinik, Aaron I.] Eastern Virginia Med Sch, Dept Neurobiol, Norfolk, VA 23501 USA. [Zivkovic, Sasa] Univ Pittsburgh, Med Ctr, Dept Neurol, Pittsburgh, PA 15213 USA. RP Strotmeyer, ES (reprint author), Univ Pittsburgh, Dept Epidemiol, 130 N Bellefield Ave,Room 515, Pittsburgh, PA 15213 USA. EM StrotmeyerE@edc.pitt.edu RI Cauley, Jane/N-4836-2015; OI Cauley, Jane/0000-0003-0752-4408; Boudreau, Robert/0000-0003-0162-5187; Strotmeyer, Elsa/0000-0002-4093-6036; Glynn, Nancy/0000-0003-2265-0162 FU National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, 1-R01-AG 028050]; National Institute of Nursing Research [R01-NR012459]; University of Pittsburgh Claude D. Pepper Older Americans Independence Center [P30-AG024827]; National Institutes of Health, National Institute on Aging FX Supported by the National Institute on Aging (contract nos. N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106; grant no. 1-R01-AG 028050), the National Institute of Nursing Research (grant no. R01-NR012459), the University of Pittsburgh Claude D. Pepper Older Americans Independence Center (pilot grant no. P30-AG024827), and in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 43 TC 2 Z9 2 U1 3 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 EI 1532-821X J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD JAN PY 2016 VL 97 IS 1 BP 45 EP 52 DI 10.1016/j.apmr.2015.08.423 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA DA7CZ UT WOS:000367963500006 PM 26343170 ER PT J AU Jindra, PT Conway, SE Ricklefs, SM Porcella, SF Anzick, SL Haagenson, M Wang, T Spellman, S Milford, E Kraft, P McDermott, DH Abdi, R AF Jindra, Peter T. Conway, Susan E. Ricklefs, Stacy M. Porcella, Stephen F. Anzick, Sarah L. Haagenson, Mike Wang, Tao Spellman, Stephen Milford, Edgar Kraft, Peter McDermott, David H. Abdi, Reza TI Analysis of a Genetic Polymorphism in the Costimulatory Molecule TNFSF4 with Hematopoietic Stem Cell Transplant Outcomes SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Gene polymorphism; Costimulation; Hematopoietic stem cell transplantation; Outcomes; Infection; GVHD ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; C-MYB; OX40 LIGAND; FUNCTIONAL SNPS; SIBLING DONORS; T-CELLS; GRAFT; EXPRESSION; DIFFERENTIATION AB Despite stringent procedures to secure the best HLA matching between donors and recipients, life-threatening complications continue to occur after hematopoietic stem cell transplantation (HSCT). Studying single nucleotide polymorphism (SNP) in genes encoding costimulatory molecules could help identify patients at risk for post-HSCT complications. In a stepwise approach we selected SNPs in key costimulatory molecules including CD274, CD40, CD154, CD28, and TNFSF4 and systematically analyzed their association with post-HSCT outcomes. Our discovery cohort analysis of 1157 HLA-A, -B, -C, -DRB1, and -DQB1 matched cases found that patients with donors homozygous for the C variant of rs10912564 in TNFSF4 (48%) had better disease-free survival (P =.029) and overall survival (P =.009) with less treatment-related mortality (P =.006). Our data demonstrate the TNFSF4C variant had a higher affinity for the nuclear transcription factor Myb and increased percentage of TNFSF4-positive B cells after stimulation compared with CT or TT genotypes. However, these associations were not validated in a more recent cohort, potentially because of changes in standard of practice or absence of a true association. Given the discovery cohort, functional data, and importance of TNFSF4 in infection clearance, TNFSF4C may associate with outcomes and warrants future studies. (C) 2016 American Society for Blood and Marrow Transplantation. C1 [Jindra, Peter T.; Conway, Susan E.; Milford, Edgar; Abdi, Reza] Brigham & Womens Hosp, Div Renal, Transplant Res Ctr, Boston, MA 02115 USA. [Jindra, Peter T.; Conway, Susan E.; Milford, Edgar; Abdi, Reza] Childrens Hosp, Boston, MA 02115 USA. [Ricklefs, Stacy M.; Porcella, Stephen F.; Anzick, Sarah L.] NIAID, Genom Unit, Res Technol Branch, NIH, Hamilton, MT USA. [Haagenson, Mike; Spellman, Stephen] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Wang, Tao] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [McDermott, David H.] NIAID, Mol Signaling Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Abdi, R (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Transplantat Res Ctr, Longwood Ave, Boston, MA 02115 USA. EM rabdi@rics.bwh.harvard.edu OI Haagenson, Michael/0000-0002-6800-0037; Jindra, Peter/0000-0002-0137-0527 FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; Public Health Service from National Cancer Institute (NCI) [U24-CA76518]; National Heart, Lung and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases; NHLBI [5U01HL069294]; NCI; Health Resources and Services Administration [HHSH234200637015C]; Altos, Inc.; Amgen, Inc.; Angioblast; Office of Naval Research [N00014-12-1-0142, N00014-13-1-0039]; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Buchanan Family Foundation; Caridian BCT; Celgene Corporation; CellGenix, GmbH; Children's Leukemia Research Association; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Genzyme Corporation; GlaxoSmithKline; HistoGenetics, Inc.; Kiadis Pharma; Leukemia & Lymphoma Society; Medical College of Wisconsin; Merck Co, Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; RemedyMD; Sanofi; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; Teva Neuroscience, Inc.; THERAKOS, Inc.; Wellpoint, Inc. FX This work was partly supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland. The Center for International Blood and Marrow Transplant Research is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases; Grant/Cooperative Agreement 5U01HL069294 from the NHLBI and NCI; a contract (HHSH234200637015C) with the Health Resources and Services Administration; 2 grants (N00014-12-1-0142 and N00014-13-1-0039) from the Office of Naval Research; and grants from Altos, Inc.; Amgen, Inc.; Angioblast; Anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Buchanan Family Foundation; Caridian BCT; Celgene Corporation; CellGenix, GmbH; Children's Leukemia Research Association; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Genzyme Corporation; GlaxoSmithKline; HistoGenetics, Inc.; Kiadis Pharma; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; RemedyMD; Sanofi; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; Teva Neuroscience, Inc.; THERAKOS, Inc.; and Wellpoint, Inc. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services and mention of trade names, commercial products, or organizations does not imply endorsement by the US Government. NR 56 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JAN PY 2016 VL 22 IS 1 BP 27 EP 36 DI 10.1016/j.bbmt.2015.08.037 PG 10 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DB0SW UT WOS:000368218800007 PM 26348892 ER PT J AU Jacoby, E Chen, A Loeb, DM Gamper, CJ Zambidis, E Llosa, NJ Huo, J Cooke, KR Jones, R Fuchs, E Luznik, L Symons, HJ AF Jacoby, Elad Chen, Allen Loeb, David M. Gamper, Christopher J. Zambidis, Elias Llosa, Nicolas J. Huo, Jeffrey Cooke, Kenneth R. Jones, Rick Fuchs, Ephraim Luznik, Leo Symons, Heather J. TI Single-Agent Post-Transplantation Cyclophosphamide as Graft-versus-Host Disease Prophylaxis after Human Leukocyte Antigen-Matched Related Bone Marrow Transplantation for Pediatric and Young Adult Patients with Hematologic Malignancies SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Cyclophosphamide; Pediatric bone marrow transplantation; Graft-versus-host disease prophylaxis; Hematologic malignancies ID STEM-CELL TRANSPLANTATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; TOTAL-BODY IRRADIATION; HEPATIC VENOOCCLUSIVE DISEASE; HLA-HAPLOIDENTICAL BMT; HEMORRHAGIC CYSTITIS; T-CELLS; ALLOGENEIC MARROW; GVHD PROPHYLAXIS; CHILDREN AB High-dose cyclophosphamide given after HLA-matched related and unrelated allogeneic bone marrow transplantation (BMT) for patients with hematologic malignancies is effective single-agent graft-versus-host disease (GVHD) prophylaxis in adults. Data describing outcomes for pediatric and young adult patients have not been reported. Between the years 2007 and 2013, 29 pediatric and young adult patients ages <= 21 years of age treated at our institution for high-risk hematologic malignancies underwent myeloablative HLA-matched related T cell-replete BMT. Eleven patients received post-transplantation cyclophosphamide (PTCy) as single-agent GVHD prophylaxis and were followed prospectively. Eighteen patients received calcineurin inhibitor (CNI)-based standard GVHD prophylaxis and were studied retrospectively as a control group. No acute GVHD (aGVHD) developed in patients receiving PTCy, whereas patients receiving CNI-based GVHD prophylaxis had cumulative incidences of grades II to IV and grades III and IV aGVHD of 27% and 5%, respectively. No patients receiving PTCy developed chronic GHVD, compared to 1 in the control group. Two-year overall survival was similar between the 2 groups (54% PTCy versus 58% CNI-based prophylaxis), as was event-free survival (42% PTCy versus 47% CNI-based). The 5-year cumulative incidence of relapse was 58% for PTCy and 42% for CNI-based GVHD prophylaxis (P = .45). These results suggest that PTCy is a safe and efficacious method of GVHD prophylaxis after an HLA-matched related BMT in the pediatric and young adult population that affords patients to be off all post-transplantation immunosuppression on day +5. (C) 2016 American Society for Blood and Marrow Transplantation. C1 [Jacoby, Elad; Chen, Allen; Loeb, David M.; Gamper, Christopher J.; Zambidis, Elias; Llosa, Nicolas J.; Huo, Jeffrey; Cooke, Kenneth R.; Symons, Heather J.] Johns Hopkins Univ, Sch Med, Dept Oncol, Div Pediat Oncol, Baltimore, MD 21287 USA. [Jacoby, Elad] NIH, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Jones, Rick; Fuchs, Ephraim; Luznik, Leo] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD 21287 USA. RP Symons, HJ (reprint author), Johns Hopkins Univ, Ctr Oncol, Dept Oncol, Div Pediat Oncol, 1650 Orleans St,CRB 1,Rm 2M52, Baltimore, MD 21287 USA. EM Hsymons2@jhmi.edu OI Gamper, Christopher/0000-0003-0253-2177 FU National Institutes of Health, National Cancer Institute [P01 CA015396, P30 CA006973]; Giant Food Children's Cancer Research Fund; joint American Physicians Fellowship/Israel Medical Association Fellowship Grant FX This work was supported by National Institutes of Health, National Cancer Institute grants P01 CA015396 and P30 CA006973, and the Giant Food Children's Cancer Research Fund. E.J. was also supported by the joint American Physicians Fellowship/Israel Medical Association Fellowship Grant. NR 55 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JAN PY 2016 VL 22 IS 1 BP 112 EP 118 DI 10.1016/j.bbmt.2015.08.034 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DB0SW UT WOS:000368218800017 PM 26343947 ER PT J AU Wood, WA Le-Rademacher, J Syrjala, KL Jim, H Jacobsen, PB Knight, JM Abidi, MH Wingard, JR Majhail, NS Geller, NL Rizzo, JD Fei, MW Wu, J Horowitz, MM Lee, SJ AF Wood, William A. Le-Rademacher, Jennifer Syrjala, Karen L. Jim, Heather Jacobsen, Paul B. Knight, Jennifer M. Abidi, Muneer H. Wingard, John R. Majhail, Navneet S. Geller, Nancy L. Rizzo, J. Douglas Fei, Mingwei Wu, Juan Horowitz, Mary M. Lee, Stephanie J. TI Patient-reported physical functioning predicts the success of hematopoietic cell transplantation (BMT CTN 0902) SO CANCER LA English DT Article DE hematopoietic stem cell transplantation; outcome assessment; physical fitness; quality of life; risk adjustment ID QUALITY-OF-LIFE; GERIATRIC ASSESSMENT; PERFORMANCE STATUS; COMORBIDITY INDEX; MULTIPLE-MYELOMA; CLINICAL-TRIALS; CANCER-PATIENTS; MARROW TRANSPLANTATION; PSYCHOSOCIAL FACTORS; PROGNOSTIC VALUE AB BACKGROUNDIn hematopoietic cell transplantation (HCT), current risk adjustment strategies are based on clinical and disease-related variables. Although patient-reported outcomes (PROs) predict mortality in multiple cancers, they have been less well studied within HCT. Improvements in risk adjustment strategies in HCT would inform patient selection, patient counseling, and quality reporting. The objective of the current study was to determine whether pre-HCT PROs, in particular physical health, predict survival among patients undergoing autologous or allogeneic transplantation. METHODSIn this secondary analysis, the authors studied pre-HCT PROs that were reported by 336 allogeneic and 310 autologous HCT recipients enrolled in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0902 protocol, a study with broad representation of patients who underwent transplantation in the United States. RESULTSAmong allogeneic HCT recipients, the pre-HCT Medical Outcomes Study Short Form-36 Health Survey (SF-36) physical component summary (PCS) scale independently predicted overall mortality (hazards ratio, 1.40 per 10-point decrease; P<.001) and performed at least as well as currently used, non-PRO risk indices. Survival probability estimates at 1 year for the first, second, third, and fourth quartiles of the baseline PCS were 50%, 65%, 75%, and 83%, respectively. Early post-HCT decreases in PCS were associated with higher overall and treatment-related mortality. When adjusted for patient variables included in the US Stem Cell Therapeutic Outcomes Database model for transplant center-specific reporting, the SF-36 PCS retained independent prognostic value. CONCLUSIONSPROs have the potential to improve prognostication in HCT. The authors recommend the routine collection of PROs before HCT, and consideration of the incorporation of PROs into risk adjustment for quality reporting. Cancer 2016;122:91-98. (c) 2015 American Cancer Society. C1 [Wood, William A.] Univ N Carolina, Div Hematol Oncol, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Le-Rademacher, Jennifer; Knight, Jennifer M.; Rizzo, J. Douglas; Fei, Mingwei; Horowitz, Mary M.] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Div Biostat Psychiat & Behav Med, Milwaukee, WI 53226 USA. [Syrjala, Karen L.; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Jim, Heather; Jacobsen, Paul B.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Hlth Outcomes & Behav, Tampa, FL 33612 USA. [Abidi, Muneer H.] Wayne State Univ, Sch Med, Karmanos Canc Inst, Dept Med Oncol, Detroit, MI USA. [Wingard, John R.] Univ Florida, Dept Med, Div Hematol Oncol, Gainesville, FL USA. [Majhail, Navneet S.] Cleveland Clin, Taussig Canc Inst, Blood & Marrow Transplant Program, Cleveland, OH 44106 USA. [Geller, Nancy L.] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. [Wu, Juan] Blood & Marrow Transplant Clin Trials Network, Milwaukee, WI USA. RP Wood, WA (reprint author), Univ N Carolina, Div Hematol Oncol, Phys Off Bldg,170 Manning Dr,3rd Fl, Chapel Hill, NC 27599 USA. EM wawood@med.unc.edu OI Abidi, Muneer/0000-0002-9936-6031 FU National Heart, Lung, and Blood Institute; National Cancer Institute [U10HL069294] FX Supported by the National Heart, Lung, and Blood Institute and the National Cancer Institute (grant U10HL069294). NR 45 TC 7 Z9 7 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JAN 1 PY 2016 VL 122 IS 1 BP 91 EP 98 DI 10.1002/cncr.29717 PG 8 WC Oncology SC Oncology GA DA7LF UT WOS:000367984900014 PM 26439325 ER PT J AU Jang, S Zheng, CY Tsai, HT Fu, AZ Barac, A Atkins, MB Freedman, AN Minasian, L Potosky, AL AF Jang, Sekwon Zheng, Chaoyi Tsai, Huei-Ting Fu, Alex Z. Barac, Ana Atkins, Michael B. Freedman, Andrew N. Minasian, Lori Potosky, Arnold L. TI Cardiovascular toxicity after antiangiogenic therapy in persons older than 65 years with advanced renal cell carcinoma SO CANCER LA English DT Article DE cardiovascular toxicity; renal cell carcinoma; sorafenib; stroke; sunitinib ID SUNITINIB; CANCER; RISK AB BACKGROUNDSorafenib and sunitinib are oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) approved in 2005 and 2006, respectively, for the treatment of patients with renal cell carcinoma (RCC). A population-based, observational cohort study of the cardiovascular risk of VEGFR TKI therapy in elderly RCC patients was conducted. METHODSUsing the Surveillance, Epidemiology, and End Results-Medicare database, this study analyzed patients who were 66 years old or older and were diagnosed with RCC from 2000 to 2009. The incidence of cardiovascular adverse events, including congestive heart failure and cardiomyopathy (CHF/CM), acute myocardial infarction (AMI), stroke, and cardiovascular deaths, was examined through December 2010. A Cox proportional hazards model was created to calculate the hazard ratio (HR), and adjustments were made for age, sex, comorbidity, and the use of other systemic therapy. RESULTSA total of 171 of 670 patients who received sunitinib or sorafenib had cardiovascular events. The incidence rates for CHF/CM, AMI, and stroke were 0.87, 0.14, and 0.14 per 1000 person-days, respectively. Sunitinib or sorafenib use was associated with an increased risk of cardiovascular events (HR, 1.38; 95% confidence interval [CI], 1.02-1.87) and especially stroke (HR, 2.84; 95% CI, 1.52-5.31) in comparison with 788 patients diagnosed with advanced RCC from 2007 to 2009 who were eligible for Part D but did not receive either agent. In subgroup analyses, patients who were 66 to 74 years old at diagnosis had the highest increased risk of stroke associated with the use of either or both drugs. CONCLUSIONSSunitinib and sorafenib might be associated with an increased risk of cardiovascular events and particularly stroke. Cancer 2016;122:124-130. (c) 2015 American Cancer Society. C1 [Jang, Sekwon] Inova Dwight & Martha Schar Canc Inst, Div Oncol, Fairfax, VA USA. [Zheng, Chaoyi] Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Biostat Bioinformat & Biomath, Washington, DC USA. [Tsai, Huei-Ting; Fu, Alex Z.; Atkins, Michael B.; Potosky, Arnold L.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC USA. [Barac, Ana] MedStar Washington Hosp Ctr, Div Cardiol, Washington, DC USA. [Freedman, Andrew N.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Minasian, Lori] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Jang, S (reprint author), Inova Comprehens Canc & Res Inst, Div Oncol, 8505 Arlington Blvd,Suite 100, Fairfax, VA 22031 USA. EM sekwon.jang@inova.org FU National Cancer Institute of the National Institutes of Health [P30CA051008, HHSN261201200362P] FX This study was supported in part by the National Cancer Institute of the National Institutes of Health (award P30CA051008 and contract HHSN261201200362P). NR 15 TC 4 Z9 4 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JAN 1 PY 2016 VL 122 IS 1 BP 124 EP 130 DI 10.1002/cncr.29728 PG 7 WC Oncology SC Oncology GA DA7LF UT WOS:000367984900018 PM 26439451 ER PT J AU DellaValle, CT Deziel, NC Jones, RR Colt, JS De Roos, AJ Cerhan, JR Cozen, W Severson, RK Flory, AR Morton, LM Ward, MH AF DellaValle, Curt T. Deziel, Nicole C. Jones, Rena R. Colt, Joanne S. De Roos, Anneclaire J. Cerhan, James R. Cozen, Wendy Severson, Richard K. Flory, Abigail R. Morton, Lindsay M. Ward, Mary H. TI Polycyclic aromatic hydrocarbons: determinants of residential carpet dust levels and risk of non-Hodgkin lymphoma SO CANCER CAUSES & CONTROL LA English DT Article DE Polycyclic aromatic hydrocarbons; Non-Hodgkin lymphoma; T cell lymphoma; Dust; Case-control study ID IN-HOUSE DUST; EPIDEMIOLOGY CONSORTIUM INTERLYMPH; CIGARETTE-SMOKING; CANCER-RISK; TOBACCO-SMOKE; EXPOSURE; SUBTYPES; WORKERS; MICE; CLASSIFICATION AB Purpose To investigate the risk of non-Hodgkin lymphoma (NHL) associated with residential carpet dust measurements of polycyclic aromatic hydrocarbons (PAHs). Methods We evaluated the relationship between residential carpet dust PAH concentrations (benz(a)anthracene, benzo(a)pyrene, benzo(b)fluoranthene, benzo(k)fluoranthene, chrysene, dibenz(a,h)anthracene, and indeno(1,2,3-c,d)pyrene, and their sum) and risk of NHL (676 cases, 511 controls) in the National Cancer Institute Surveillance Epidemiology and End Results multicenter case-control study. As a secondary aim, we investigated determinants of dust PAH concentrations. We computed odds ratios (OR) and 95 % confidence interval (CI) for associations between NHL and concentrations of individual and summed PAHs using unconditional logistic regression, adjusting for age, gender, and study center. Determinants of natural log-transformed PAHs were investigated using multivariate least-squares regression. Results We observed some elevated risks for NHL overall and B cell lymphoma subtypes in association with quartiles or tertiles of PAH concentrations, but without a monotonic trend, and there was no association comparing the highest quartile or tertile to the lowest. In contrast, risk of T cell lymphoma was significantly increased among participants with the highest tertile of summed PAHs (OR = 3.04; 95 % CI, 1.09-8.47) and benzo(k)fluoranthene (OR = 3.20; 95 % CI, 1.13-9.11) compared with the lowest tertile. Predictors of PAH dust concentrations in homes included ambient air PAH concentrations and the proportion of developed land within 2 km of a residence. Older age, more years of education, and white race were also predictive of higher levels in homes. Conclusion Our results suggest a potential link between PAH exposure and risk of T cell lymphoma and demonstrate the importance of analyzing risk by NHL histologic type. C1 [DellaValle, Curt T.; Jones, Rena R.; Colt, Joanne S.; Ward, Mary H.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Deziel, Nicole C.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [De Roos, Anneclaire J.] Drexel Univ, Dept Environm & Occupat Hlth, Sch Publ Hlth, Philadelphia, PA 19104 USA. [Cerhan, James R.] Mayo Clin, Div Epidemiol, Rochester, MN USA. [Cozen, Wendy] Univ So Calif, Los Angeles, CA USA. [Severson, Richard K.] Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI USA. [Flory, Abigail R.] Westat Corp, Rockville, MD USA. [Morton, Lindsay M.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Ward, MH (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 9609 Med Ctr Dr,Room 6E138 MSC 9771, Bethesda, MD 20892 USA. EM wardm@mail.nih.gov FU Intramural Research Program of the National Institutes of Health/National Cancer Institute; [N01-CN-67008]; [N01-CN-67010]; [N01-PC-65064]; [N01-PC-67009]; [N02-CP-19114]; [N02-CP-71105] FX This study was funded by the Intramural Research Program of the National Institutes of Health/National Cancer Institute and contracts N01-CN-67008, N01-CN-67010, N01-PC-65064, N01-PC-67009, N02-CP-19114, and N02-CP-71105. NR 48 TC 1 Z9 1 U1 2 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JAN PY 2016 VL 27 IS 1 BP 1 EP 13 DI 10.1007/s10552-015-0660-y PG 13 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DA9TD UT WOS:000368151600001 PM 26573845 ER PT J AU Schuler, F Baumgartner, F Klepsch, V Chamson, M Muller-Holzner, E Watson, CJ Oh, S Hennighausen, L Tymoszuk, P Doppler, W Villunger, A AF Schuler, F. Baumgartner, F. Klepsch, V. Chamson, M. Mueller-Holzner, E. Watson, C. J. Oh, S. Hennighausen, L. Tymoszuk, P. Doppler, W. Villunger, A. TI The BH3-only protein BIM contributes to late-stage involution in the mouse mammary gland SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID PROGRAMMED CELL-DEATH; IN-VIVO; ACCELERATED APOPTOSIS; TRANSGENIC MICE; MOTOR COMPLEX; BREAST-CANCER; 1ST STAGE; TGF-BETA; C-MYC; BCL-2 AB After cessation of lactation, involution of the mouse mammary gland proceeds in two distinct phases, a reversible and an irreversible one, which leads to the death and removal of alveolar cells. Cell death is preceded by the loss of STAT5 activity, which abrogates cell differentiation and gain of STAT3 activity. Despite early observations implicating BCL2 (B cell lymphoma 2) family proteins in this process, recent evidence suggests that STAT3-controlled cathepsin activity is most critical for cell death at the early stage of involution. Somewhat surprisingly, this cell death associates with but does not depend on the activation of pro-apoptotic effector caspases. However, transgenic overexpression of BCL2, that blocks caspase activation, delays involution while conditional deletion of BclX accelerates this process, suggesting that BCL2 family proteins are needed for the effective execution of involution. Here, we report on the transcriptional induction of multiple pro-apoptotic BCL2 family proteins of the 'BH3-only' subgroup during involution and the rate-limiting role of BIM in this process. Loss of Bim delayed epithelial cell clearance during involution after forced weaning in mice, whereas the absence of related Bmf had minor and loss of Bad or Noxa no impact on this process. Consistent with a contribution of BCL2 family proteins to the second wave of cell death during involution, loss of Bim reduced the number of apoptotic cells in this irreversible phase. Notably, the expression changes observed within the BCL2 family did not depend on STAT3 signalling, in line with its initiating role early in the process, but rather appear to result from relief of repression by STAT5. Our findings support the existence of a signalling circuitry regulating the irreversible phase of involution in mice by engaging BH3-only protein-driven mitochondrial apoptosis. C1 [Schuler, F.; Baumgartner, F.; Klepsch, V.; Villunger, A.] Med Univ Innsbruck, Bioctr, Div Dev Immunol, A-6020 Innsbruck, Austria. [Chamson, M.; Mueller-Holzner, E.] Med Univ Innsbruck, Dept Obstet & Gynecol, A-6020 Innsbruck, Austria. [Watson, C. J.] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. [Oh, S.; Hennighausen, L.] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. [Tymoszuk, P.; Doppler, W.] Med Univ Innsbruck, Div Med Biochem, Bioctr, A-6020 Innsbruck, Austria. RP Villunger, A (reprint author), Med Univ Innsbruck, Bioctr, Div Dev Immunol, A-6020 Innsbruck, Austria. EM andreas.villunger@i-med.ac.at FU 'Tiroler Krebshilfe'; graduate school Molecular Cell Biology and Oncology (MCBO) - Austrian Science Fund (FWF) [W1101]; Integrated Center for Research and Therapy (IFTZ) of the Medical University Innsbruck; Austrian Academy of Science (OAW); NIDDK/NIH FX We thank A Strasser, L Huber and D Huang for mice and/or reagents; I Gaggl for mouse genotyping, C Soratroi and S Faserl for technical assistance, K Rossi and B Rieder for animal care. This work was supported by grants from the 'Tiroler Krebshilfe' to FB, as well as the graduate school Molecular Cell Biology and Oncology (MCBO) funded by the Austrian Science Fund (FWF; W1101) and the Integrated Center for Research and Therapy (IFTZ) of the Medical University Innsbruck. FS is recipient of a DOC fellowship of the Austrian Academy of Science (OAW). SO and LH were funded by the intramural research program (IRP) of the NIDDK/NIH. SO is a member of the NIH/Dankook Graduate Partnership Program. NR 59 TC 3 Z9 3 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD JAN PY 2016 VL 23 IS 1 BP 41 EP 51 DI 10.1038/cdd.2015.61 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DA8NM UT WOS:000368062000014 PM 26045049 ER PT J AU Waickman, AT Park, JY Park, JH AF Waickman, Adam T. Park, Joo-Young Park, Jung-Hyun TI The common gamma-chain cytokine receptor: tricks-and-treats for T cells SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE Alternative splicing; JAK3; Homeostasis; Signaling; Survival ID SEVERE COMBINED IMMUNODEFICIENCY; DEFECTIVE LYMPHOID DEVELOPMENT; THYMIC STROMAL LYMPHOPOIETIN; ACUTE LYMPHOBLASTIC-LEUKEMIA; MEMBRANE-PROXIMAL REGION; FOLLICULAR-HELPER-CELLS; JAK-3 JANUS KINASE; MICE LACKING JAK3; IL-2 RECEPTOR; INTERLEUKIN-2 RECEPTOR AB Originally identified as the third subunit of the high-affinity IL-2 receptor complex, the common gamma-chain (gamma c) also acts as a non-redundant receptor subunit for a series of other cytokines, collectively known as gamma c family cytokines. gamma c plays essential roles in T cell development and differentiation, so that understanding the molecular basis of its signaling and regulation is a critical issue in T cell immunology. Unlike most other cytokine receptors, gamma c is thought to be constitutively expressed and limited in its function to the assembly of high-affinity cytokine receptors. Surprisingly, recent studies reported a series of findings that unseat gamma c as a simple housekeeping gene, and unveiled gamma c as a new regulatory molecule in T cell activation and differentiation. Cytokine-independent binding of gamma c to other cytokine receptor subunits suggested a pre-association model of gamma c with proprietary cytokine receptors. Also, identification of a gamma c splice isoform revealed expression of soluble gamma c proteins (s gamma c). s gamma c directly interacted with surface IL-2R beta to suppress IL-2 signaling and to promote pro-inflammatory Th17 cell differentiation. As a result, endogenously produced s gamma c exacerbated autoimmune inflammatory disease, while the removal of endogenous s gamma c significantly ameliorated disease outcome. These data provide new insights into the role of both membrane and soluble gamma c in cytokine signaling, and open new venues to interfere and modulate gamma c signaling during immune activation. These unexpected discoveries further underscore the perspective that gamma c biology remains largely uncharted territory that invites further exploration. C1 [Waickman, Adam T.; Park, Joo-Young; Park, Jung-Hyun] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Park, JH (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 5B17,10 Ctr Dr, Bethesda, MD 20892 USA. EM parkhy@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank Drs. Alfred Singer and Xuguang Tai for critical review of this manuscript. We also thank Douglas Joubert, NIH Library Writing Center, for manuscript editing assistance. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 140 TC 2 Z9 3 U1 1 U2 10 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD JAN PY 2016 VL 73 IS 2 BP 253 EP 269 DI 10.1007/s00018-015-2062-4 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DA8TB UT WOS:000368077900002 PM 26468051 ER PT J AU Peay, HL Scharff, H Tibben, A Wilfond, B Bowie, J Johnson, J Nagaraju, K Escolar, D Piacentino, J Biesecker, BB AF Peay, Holly L. Scharff, Hadar Tibben, Aad Wilfond, Benjamin Bowie, Janice Johnson, Joanna Nagaraju, Kanneboyina Escolar, Diana Piacentino, Jonathan Biesecker, Barbara B. TI "Watching time tick by...": Decision making for Duchenne muscular dystrophy trials SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Duchenne muscular dystrophy; Clinical trial; Consent; Proxy decision making ID INFORMED-CONSENT; CLINICAL-TRIALS; CHILDREN; PARTICIPATION; THERAPIES; BENEFITS; IMPACT AB Objective: This interview study explored clinicians' perspectives and parents' decision making about children's participation in Duchenne muscular dystrophy (DMD) clinical trials. Methods: Data from semi-structured interviews conducted with clinicians and parents in U.S. or Canada were assessed using thematic analysis. Results: Eleven clinicians involved in ten trials and fifteen parents involved in six trials were interviewed. Parents described benefit-risk assessments using information from advocacy, peers, professionals, and sponsors. Strong influence was attributed to the progressive nature of DMD. Most expected direct benefit. Few considered the possibility of trial failure. Most made decisions to participate before the informed consent (IC) process, but none-the-less perceived informed choice with little to lose for potential gain. Clinicians described more influence on parental decisions than attributed by parents. Clinicians felt responsible to facilitate IC while maintaining hope. Both clinicians and parents reported criticisms about the IC process and regulatory barriers. Conclusions: The majority of parents described undertaking benefit-risk assessments that led to informed choices that offered psychological and potential disease benefits. Parents' high expectations influenced their decisions while also reflecting optimism. Clinicians felt challenged in balancing parents' expectations and likely outcomes. Prognosis-related pressures coupled with decision making prior to IC suggest an obligation to ensure educational materials are understandable and accurate, and to consider an expanded notion of IC timeframes. Anticipatory guidance about potential trial failure might facilitate parents' deliberations while aiding clinicians in moderating overly-optimistic motivations. Regulators and industry should appreciate special challenges in progressive disorders, where doing nothing was equated with doing harm. (C) 2015 Elsevier Inc. All rights reserved. C1 [Peay, Holly L.; Scharff, Hadar; Johnson, Joanna; Piacentino, Jonathan] Parent Project Muscular Dystrophy, Hackensack, NJ USA. [Peay, Holly L.; Tibben, Aad] Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands. [Wilfond, Benjamin] Seattle Childrens Res Inst, Treuman Katz Ctr Pediat Bioeth, Seattle, WA USA. [Bowie, Janice] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Behav & Soc, Baltimore, MD USA. [Nagaraju, Kanneboyina] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Escolar, Diana] Kennedy Krieger Inst, Baltimore, MD USA. [Biesecker, Barbara B.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. RP Peay, HL (reprint author), RTI Int, 3040 E Cornwallis Rd, Res Triangle Pk, NC 27709 USA. EM hpeay@rti.org OI Scharff, Hadar/0000-0002-8165-6428 FU National Institute of Neurological Disorders and Stroke [R21NS077286] FX We are indebted to the study participants for sharing their experiences. Benjamin Cumbo, a self-advocate, participated as a CBPR advisor for the project. Kathryn Porter, JD, MPH contributed to editing the manuscript. The project described was supported by Grant Number R21NS077286 from the National Institute of Neurological Disorders and Stroke. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health. NR 25 TC 0 Z9 0 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD JAN PY 2016 VL 46 BP 1 EP 6 DI 10.1016/j.cct.2015.11.006 PG 6 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA DB0NH UT WOS:000368204300001 PM 26546066 ER PT J AU Wu, LT Brady, KT Spratt, SE Dunham, AA Heidenfelder, B Batch, BC Lindblad, R VanVeldhuisen, P Rusincovitch, SA Killeen, TK Ghitza, UE AF Wu, Li-Tzy Brady, Kathleen T. Spratt, Susan E. Dunham, Ashley A. Heidenfelder, Brooke Batch, Bryan C. Lindblad, Robert VanVeldhuisen, Paul Rusincovitch, Shelley A. Killeen, Therese K. Ghitza, Udi E. TI Using electronic health record data for substance use Screening, Brief Intervention, and Referral to Treatment among adults with type 2 diabetes: Design of a National Drug Abuse Treatment Clinical Trials Network study SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Diabetes; Home-based primary care; Medical comorbidity; Referral to treatment; Substance use disorder; Substance use screening ID ALCOHOL-USE DISORDERS; PRIMARY-CARE; AUDIT-C; RISK; POPULATION; METAANALYSIS; MANAGEMENT; MELLITUS AB Background: The Affordable Care Act encourages healthcare systems to integrate behavioral and medical healthcare, as well as to employ electronic health records (EHRs) for health information exchange and quality improvement. Pragmatic research paradigms that employ EHRs in research are needed to produce clinical evidence in real-world medical settings for informing learning healthcare systems. Adults with comorbid diabetes and substance use disorders (SUDS) tend to use costly inpatient treatments; however, there is a lack of empirical data on implementing behavioral healthcare to reduce health risk in adults with high-risk diabetes. Given the complexity of high-risk patients' medical problems and the cost of conducting randomized trials, a feasibility project is warranted to guide practical study designs. Methods: We describe the study design, which explores the feasibility of implementing substance use Screening, Brief Intervention, and Referral to Treatment (SBIRT) among adults with high-risk type 2 diabetes mellitus (T2DM) within a home-based primary care setting. Our study includes the development of an integrated EHR datamart to identify eligible patients and collect diabetes healthcare data, and the use of a geographic health information system to understand the social context in patients' communities. Analysis will examine recruitment, proportion of patients receiving brief intervention and/or referrals, substance use, SUD treatment use, diabetes outcomes, and retention. Discussion: By capitalizing on an existing T2DM project that uses home-based primary care, our study results will provide timely clinical information to inform the designs and implementation of future SBIRT studies among adults with multiple medical conditions. (C) 2015 The Authors. Published by Elsevier Inc. C1 [Wu, Li-Tzy] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27708 USA. [Wu, Li-Tzy] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Brady, Kathleen T.] Med Univ S Carolina, South Carolina Clin & Translat Res Inst, Charleston, SC 29425 USA. [Spratt, Susan E.; Batch, Bryan C.] Duke Univ, Med Ctr, Div Endocrinol, Durham, NC USA. [Dunham, Ashley A.; Heidenfelder, Brooke; Rusincovitch, Shelley A.] Duke Univ, Med Ctr, Duke Translat Res Inst, Durham, NC USA. [Lindblad, Robert; VanVeldhuisen, Paul] EMMES Corp, Rockville, MD USA. [Killeen, Therese K.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Ghitza, Udi E.] NIDA, Bethesda, MD 20892 USA. RP Wu, LT (reprint author), Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Box 3903, Durham, NC 27708 USA. EM Litzy.wu@duke.edu FU National Institute on Drug Abuse of the National Institutes of Health [U10DA013727, UG1DA040317, HHSN271200522071C, HHSN271201200017C, N01DA-12-2229, HHSN271201400028C, N01DA-14-223]; Centers for Medicare and Medicaid Services [1C1CMS331018]; Bristol-Myers Squibb Foundation; NIH [R01MD007658, R01DA019623, R33DA027503, R01DA019901] FX This work was made possible by research support from the National Institute on Drug Abuse of the National Institutes of Health (U10DA013727; UG1DA040317; HHSN271200522071C; HHSN271201200017C, N01DA-12-2229; HHSN271201400028C, N01DA-14-223), the Centers for Medicare and Medicaid Services (1C1CMS331018), and the Bristol-Myers Squibb Foundation. LT Wu also received support from the following NIH grants: R01MD007658, R01DA019623, R01DA019901, and R33DA027503. The sponsoring agencies have no further role in the study design and analysis, the writing of the report, or the decision to submit the paper for publication. The opinions expressed in this paper are solely those of the authors and do not represent the official position of the U.S. government and the Bristol-Myers Squibb Foundation. NR 56 TC 1 Z9 1 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD JAN PY 2016 VL 46 BP 30 EP 38 DI 10.1016/j.cct.2015.11.009 PG 9 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA DB0NH UT WOS:000368204300006 PM 26563446 ER PT J AU Tamura, RN Krischer, JP Pagnoux, C Micheletti, R Grayson, PC Chen, YF Merkel, PA AF Tamura, Roy N. Krischer, Jeffrey P. Pagnoux, Christian Micheletti, Robert Grayson, Peter C. Chen, Yeh-Fong Merkel, Peter A. TI A small n sequential multiple assignment randomized trial design for use in rare disease research SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Re-randomization; Binary data; Weighted Z statistic ID CLINICAL-TRIALS; TREATMENT STRATEGIES AB Background: Clinical trials in rare diseases are difficult to conduct due to the limited number of patients available with each disorder. We developed a Phase 2 trial which is a small n sequential multiple assignment randomized trial (snSMART) design to test several treatments for a rare disease for which no standard therapy exists. Purpose: This paper illustrates the design, sample size estimation and operating characteristics of an snSMART. Methods: We investigate the performance of a class of weighted Z statistics via computer simulations. Results: We demonstrate the increase in power over traditional single stage designs, and indicate how the power changes as a function of the weight given to each stage. Conclusion: The snSMART design is promising in a rare disease setting where several alternative treatments are under consideration and small sample sizes are necessary. (C) 2015 Elsevier Inc. All rights reserved. C1 [Tamura, Roy N.; Krischer, Jeffrey P.] Univ S Florida, Hlth Informat Inst, Tampa, FL 33612 USA. [Pagnoux, Christian] Univ Toronto, Dept Rheumatol, Toronto, ON M5S 1A1, Canada. [Micheletti, Robert] Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. [Micheletti, Robert] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Grayson, Peter C.] Natl Inst Arthrit & Musculoskeletal Dis, Syst Autoimmun Branch, Bethesda, MD USA. [Chen, Yeh-Fong] US FDA, Div Biometr 3, Off Biostat, Silver Spring, MD USA. [Merkel, Peter A.] Univ Penn, Div Rheumatol, Philadelphia, PA 19104 USA. RP Tamura, RN (reprint author), Univ S Florida, Hlth Informat Inst, 3650 Spectrum Blvd, Tampa, FL 33612 USA. EM roy.tamura@epi.usf.edu; jeffrey.krischer@epi.usf.edu; Cpagnoux@mtsinia.on.ca; Robert.Micheletti@uphs.upenn.edu; peter.grayson@nih.gov; YehFong.Chen@fda.hhs.gov; Peter.Merkel@uphs.upenn.edu RI Pagnoux, Christian/C-4612-2015 FU Vasculitis Clinical Research Consortium (VCRC), Rare Diseases Clinical Research Network (RDCRN) [U54 AR057319, U01 AR51874 04]; Office of Rare Diseases Research (ORDR); NCATS; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Center for Research Resources [U54 RR019497]; Data Management and Coordinating Center, (DMCC) [U01 TR001263]; RDCRN; National Center for Advancing Translational Science (NCATS) FX The Vasculitis Clinical Research Consortium (VCRC) (U54 AR057319 and U01 AR51874 04) is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Science (NCATS). The VCRC is funded through collaboration between NCATS, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and has received funding from the National Center for Research Resources (U54 RR019497). The Data Management and Coordinating Center, (DMCC) (U01 TR001263) housed at the Health Informatics Institute, is part of the RDCRN and is funded through NCATS. NR 13 TC 3 Z9 3 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD JAN PY 2016 VL 46 BP 48 EP 51 DI 10.1016/j.cct.2015.11.010 PG 4 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA DB0NH UT WOS:000368204300008 PM 26586608 ER PT J AU Newman, AB Aviles-Santa, ML Anderson, G Heiss, G Howard, WJ Krucoff, M Kuller, LH Lewis, CE Robinson, JG Taylor, H Trevino, RP Weintraub, W AF Newman, Anne B. Aviles-Santa, M. Larissa Anderson, Garnet Heiss, Gerardo Howard, Wm. James Krucoff, Mitchell Kuller, Lewis H. Lewis, Cora E. Robinson, Jennifer G. Taylor, Herman Trevino, Roberto P. Weintraub, William TI Embedding clinical interventions into observational studies SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Epidemiology; Observational study; Cohort; Clinical trial; Hybrid design ID POSTMENOPAUSAL HORMONE-THERAPY; ESTROGEN PLUS PROGESTIN; CARDIOVASCULAR-DISEASE; GINKGO EVALUATION; RANDOMIZED-TRIAL; BLOOD-PRESSURE; BREAST-CANCER; LOWER TARGETS; RECRUITMENT; WOMEN AB Novel approaches to observational studies and clinical trials could improve the cost-effectiveness and speed of translation of research. Hybrid designs that combine elements of clinical trials with observational registries or cohort studies should be considered as part of a long-term strategy to transform clinical trials and epidemiology, adapting to the opportunities of big data and the challenges of constrained budgets. Important considerations include study aims, timing, breadth and depth of the existing infrastructure that can be leveraged, participant burden, likely participation rate and available sample size in the cohort, required sample size for the trial, and investigator expertise. Community engagement and stakeholder (including study participants) support are essential for these efforts to succeed. (C) 2015 Published by Elsevier Inc. C1 [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Aviles-Santa, M. Larissa] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Anderson, Garnet] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Heiss, Gerardo] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Howard, Wm. James] Medstar Washington Hosp Ctr, Medstar Hlth Res Inst, Dept Internal Med, Washington, DC 20010 USA. [Krucoff, Mitchell] Duke Univ, Dept Med, Med Ctr, Durham, NC 27705 USA. [Krucoff, Mitchell] Duke Univ, Dept Cardiol, Med Ctr, Durham, NC 27705 USA. [Kuller, Lewis H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Lewis, Cora E.] Univ Alabama Birmingham, Sch Med, Div Prevent Med, Birmingham, AL 35205 USA. [Robinson, Jennifer G.] Univ Iowa, Dept Epidemiol, Iowa City, IA 52242 USA. [Taylor, Herman] Univ Mississippi, Med Ctr, Jackson Heart Study, Jackson, MS 39216 USA. [Trevino, Roberto P.] Social & Hlth Res Ctr, San Antonio, TX 78210 USA. [Weintraub, William] Christiana Care Hlth Syst, Ctr Heart & Vasc Hlth, Newark, DE 19713 USA. RP Newman, AB (reprint author), Univ Pittsburgh, Dept Epidemiol, Ctr Aging & Populat Hlth Epidemiol Med & Clin & T, Grad Sch Publ Hlth, A527 Crabtree Hall,130 DeSoto St, Pittsburgh, PA 15261 USA. EM newmana@edc.pitt.edu; avilessantal@nhlbi.nih.gov; garnet@whi.org; gerardo_heiss@unc.edu; wm.james.howard@medstar.net; mitchell.krucoff@duke.edu; kullerl@edc.pitt.edu; bethlew@uab.edu; jennifer-g-robinson@uiowa.edu; htaylor@umc.edu; rtrevino@sahrc.org; wweintraub@christianacare.org RI Newman, Anne B./C-6408-2013 OI Anderson, Garnet/0000-0001-5087-7837; Newman, Anne B./0000-0002-0106-1150 FU National Heart, Lung and Blood Institute FX This paper is a result of the workshop "Embedding Clinical Interventions into Observational Studies" held on April 8-9,2013 and sponsored by the National Heart, Lung and Blood Institute [1]. NR 35 TC 1 Z9 1 U1 4 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD JAN PY 2016 VL 46 BP 100 EP 105 DI 10.1016/j.cct.2015.11.017 PG 6 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA DB0NH UT WOS:000368204300015 PM 26611435 ER PT J AU Sepeta, LN Berl, MM Wilke, M You, XZ Mehta, M Xu, B Inati, S Dustin, I Khan, O Austermuehle, A Theodore, WH Gaillard, WD AF Sepeta, Leigh N. Berl, Madison M. Wilke, Marko You, Xiaozhen Mehta, Meera Xu, Benjamin Inati, Sara Dustin, Irene Khan, Omar Austermuehle, Alison Theodore, William H. Gaillard, William D. TI Age-dependent mesial temporal lobe lateralization in language fMRI SO EPILEPSIA LA English DT Article DE Functional neuroimaging; Seizures; Neuropsychological assessment ID VERBAL MEMORY DECLINE; FUNCTIONAL MRI; SEIZURE FOCUS; INTRACTABLE EPILEPSY; ACTIVATION PATTERNS; ATYPICAL LANGUAGE; HIPPOCAMPAL; CHILDREN; REORGANIZATION; LOBECTOMY AB Objective: Functional magnetic resonance imaging (fMRI) activation of the mesial temporal lobe (MTL) may be important for epilepsy surgical planning. We examined MTL activation and lateralization during language fMRI in children and adults with focal epilepsy. Methods: One hundred forty-two controls and patients with left hemisphere focal epilepsy (pediatric: epilepsy, n = 17, mean age = 9.9 +/- 2.0; controls, n = 48; mean age = 9.1 +/- 2.6; adult: epilepsy, n = 20, mean age = 26.7 +/- 5.8; controls, n = 57, mean age = 26.2 +/- 7.5) underwent 3T fMRI using a language task (auditory description decision task). Image processing and analyses were conducted using Statistical Parametric Mapping (SPM8); regions of interest (ROIs) included MTL, Broca's area, and Wernicke's area. We assessed group and individual MTL activation, and examined degree of lateralization. Results: Patients and controls (pediatric and adult) demonstrated group and individual MTL activation during language fMRI. MTL activation was left lateralized for adults, but less so in children (p's < 0.005). Patients did not differ from controls in either age group. Stronger left-lateralized MTL activation was related to older age (p = 0.02). Language lateralization (Broca's and Wernicke's) predicted 19% of the variance in MTL lateralization for adults (p = 0.001), but for not children. Significance: Language fMRI may be used to elicit group and individual MTL activation. The developmental difference in MTL lateralization and its association with language lateralization suggests a developmental shift in lateralization of MTL function, with increased left lateralization across the age span. This shift may help explain why children have better memory outcomes following resection compared to adults. C1 [Sepeta, Leigh N.; Berl, Madison M.; You, Xiaozhen; Gaillard, William D.] Childrens Natl Hlth Syst, Washington, DC 20010 USA. [Sepeta, Leigh N.; Berl, Madison M.; You, Xiaozhen; Xu, Benjamin; Inati, Sara; Dustin, Irene; Khan, Omar; Austermuehle, Alison; Theodore, William H.; Gaillard, William D.] NINDS, NIH, Bethesda, MD 20892 USA. [Wilke, Marko] Univ Childrens Hosp, Tubingen, Germany. [Sepeta, Leigh N.; Berl, Madison M.; You, Xiaozhen; Mehta, Meera; Gaillard, William D.] George Washington Univ, Washington, DC USA. RP Sepeta, LN (reprint author), Childrens Natl Hlth Syst, Comprehens Pediat Epilepsy Program, 111 Michigan Ave NW, Washington, DC 20010 USA. EM lsepeta@childrensnational.org OI Inati, Sara/0000-0002-7587-5085 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) [5T32HD046388-08]; NINDS, NIH [5K23NS065121-01A2, R01NS44280]; National Center for Research Resources, NIH [M01RR020359]; Epilepsy Foundation of America; Intellectual and Developmental Disabilities Research Center, Children's National Health SystemGrant [HD040677-07]; Children's National Health System Clinical and Translational Science Award (CTSA) FX This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) [5T32HD046388-08 to L.N.S]; NINDS, NIH [5K23NS065121-01A2 to M.M.B., R01NS44280 to W.D.G.]; National Center for Research Resources, NIH [M01RR020359]; Epilepsy Foundation of America; Intellectual and Developmental Disabilities Research Center, Children's National Health SystemGrant [HD040677-07]; and Children's National Health System Clinical and Translational Science Award (CTSA). We thank the patients and controls who participated in the study and acknowledge the valuable contributions of L. Gilbert Vezina, M.D. and Nadia Biassou, M.D. NR 40 TC 1 Z9 1 U1 5 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 EI 1528-1167 J9 EPILEPSIA JI Epilepsia PD JAN PY 2016 VL 57 IS 1 BP 122 EP 130 DI 10.1111/epi.13258 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DA9MD UT WOS:000368132100019 PM 26696589 ER PT J AU Sim, MJW Stowell, J Sergeant, R Altmann, DM Long, EO Boyton, RJ AF Sim, Malcolm J. W. Stowell, Janet Sergeant, Ruhena Altmann, Daniel M. Long, Eric O. Boyton, Rosemary J. TI KIR2DL3 and KIR2DL1 show similar impact on licensing of human NK cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Human leukocyte antigen (HLA); Killer immunoglobulin-like receptor (KIR); Licensing; NK cell (NKC); Rheostat model ID NATURAL-KILLER-CELLS; MHC CLASS-I; IMMUNOGLOBULIN-LIKE RECEPTORS; INHIBITORY RECEPTORS; HLA-C; KIR GENES; RESPONSIVENESS; MOLECULES; EDUCATION; LIGANDS AB Killer cell immunoglobulin-like receptor/HLA class I (KIR/HLA-I) combinations are associated with disease risk, implicating functional roles for NK cells (NKCs) or KIR+ T cells. KIR/HLA-I interactions can act through inhibition of NKC activation by target cells and NKC licensing for greater intrinsic responsiveness. We compared licensing conferred by theweaker, HLA-C group 1/KIR2DL3, and the stronger, HLA-C group 2/KIR2DL1, inhibitory combinations. The "rheostat model" predicts weaker licensing by HLA-C1/KIR2DL3 interactions than HLA-C2/KIR2DL1. We analyzed degranulation in NKC subsets expressing single and multiple receptors for HLA-I. NKG2A had the strongest licensing impact, while KIR2DL3, KIR2DL1, and KIR3DL1 were weaker, and not significantly different to each other. Presence of one or two matched HLA-C allotypes did not alter licensing of KIR2DL3(+) and KIR2DL1(+) NKC. Coexpression of activating KIR2DS1 disarmed KIR2DL3(+) and KIR2DL1(+) NKC to a similar extent. KIR3DL1 and NKG2A combined for more enhanced licensing of double-positive NKC than the combination of KIR2DL3 and KIR2DL1. Thus, KIR2DL3 and KIR2DL1 have similar capacity to license NKC, suggesting that inhibitory signal strength and amount of available HLA-C ligands do not correlate with NKC licensing. Altogether, our results show that the basis for disease associations of HLA-C and KIR2DL likely encompasses factors other than licensing. C1 [Sim, Malcolm J. W.; Stowell, Janet; Altmann, Daniel M.; Boyton, Rosemary J.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Lung Immunol Grp, Dept Med,Infect Dis & Immun, London, England. [Sim, Malcolm J. W.; Long, Eric O.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Sergeant, Ruhena] Imperial Coll Healthcare NHS Trust, Hammersmith Hosp, London, England. RP Boyton, RJ (reprint author), Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Lung Immunol Grp, Dept Med,Infect Dis & Immun, London, England. EM r.boyton@imperial.ac.uk OI Sim, Malcolm/0000-0003-3407-9661; Altmann, Daniel/0000-0002-2436-6192 FU NIH; Wellcome Trust [WT095472MA]; Welton Foundation; National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London FX The authors thank Dr. Magdalena Opanowicz, Mr. Jiten Manji, Dr. Lucas Black, Mr. Jordie Roberts, and the Hammermsith Campus NIHR BRC Flow Cytometry and Confocal Imaging Facility. M J. W. S is supported by an NIH & Wellcome Trust PhD studentship (WT095472MA). The Welton Foundation (RJB) funded the project. Blood samples from healthy volunteers were collected through the Imperial College Healthcare NHS Trust Tissue Bank ethical approval (REC number 12/WA/0196). The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 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 JAN PY 2016 VL 46 IS 1 BP 185 EP 191 DI 10.1002/eji.201545757 PG 7 WC Immunology SC Immunology GA DB0YO UT WOS:000368234800021 PM 26467237 ER PT J AU Sasaki, CY Chen, G Munk, R Eitan, E Martindale, J Longo, DL Ghosh, P AF Sasaki, Carl Y. Chen, Gang Munk, Rachel Eitan, Erez Martindale, Jennifer Longo, Dan L. Ghosh, Paritosh TI p(70S6K1) in the TORC1 pathway is essential for the differentiation of Th17 Cells, but not Th1, Th2, or Treg cells in mice SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE IL-17; mTOR; p70S6K1; T-cell differentiation ID ROR-GAMMA; MAMMALIAN TARGET; T-CELLS; MTOR; METABOLISM; SPECIFICATION; COMMITMENT; ACTIVATION; EXPRESSION; EFFECTOR AB The TORC1 pathway is necessary for ribosomal biogenesis and initiation of protein translation. Furthermore, the differentiation of Th1 and Th17 cells requires TORC1 activity. To investigate the role of the TORC1 pathway in the differentiation of Th1 and/or Th17 cells in more detail, we compared the differentiation capacity of naive T cells from wild type and p70(S6K1) knockout mice. Expression of many of the genes associated with Th17-cell differentiation, such as IL17a, IL17f, and IL-23R, were reduced in p70(S6K1) knockout mice. In contrast, the development of Th1, Th2, and Treg cells was unaffected in the absence of p70S6K1. Furthermore, expression of the major transcription factor in Th17-cell differentiation, retinoic acid receptor-related orphan receptor gamma T, remained unchanged. However, the acetylation of histone 3 at the promoters of IL17a and IL17f was reduced in the absence of p70(S6K1). In accordance with the in vitro data, the kinetics, but not the development, of EAE was affected with the loss of p70(S6K1) expression. Collectively, our findings suggested that both in vitro and in vivo differentiation of Th17 cells were positively regulated by p70(S6K1). C1 [Sasaki, Carl Y.; Chen, Gang; Munk, Rachel; Martindale, Jennifer; Longo, Dan L.; Ghosh, Paritosh] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Eitan, Erez] NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Ghosh, P (reprint author), NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM ghoshp@grc.nia.nih.gov FU NIH, National Institute on Aging FX This research was supported (in part) by the Intramural Research Program of the NIH, National Institute on Aging. NR 37 TC 3 Z9 3 U1 0 U2 4 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 JAN PY 2016 VL 46 IS 1 BP 212 EP 222 DI 10.1002/eji.201445422 PG 11 WC Immunology SC Immunology GA DB0YO UT WOS:000368234800024 PM 26514620 ER PT J AU Tooley, JE Vudattu, N Choi, J Cotsapas, C Devine, L Raddassi, K Ehlers, MR McNamara, JG Harris, KM Kanaparthi, S Phippard, D Herold, KC AF Tooley, James E. Vudattu, Nalini Choi, Jinmyung Cotsapas, Chris Devine, Lesley Raddassi, Khadir Ehlers, Mario R. McNamara, James G. Harris, Kristina M. Kanaparthi, Sai Phippard, Deborah Herold, Kevan C. TI Changes in T-cell subsets identify responders to FcR-nonbinding anti-CD3 mAb (teplizumab) in patients with type 1 diabetes SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE AntiCD3 mAb; CD8(+) T cells; Immune therapy; Tolerance; Type 1 diabetes ID C-PEPTIDE RESPONSES; RANDOMIZED CONTROLLED-TRIAL; RECENT-ONSET; MONOCLONAL-ANTIBODY; REGULATORY FUNCTION; SELF-TOLERANCE; SINGLE COURSE; CD3; ACQUISITION; THERAPY AB The mechanisms whereby immune therapies affect progression of type 1 diabetes (T1D) are not well understood. Teplizumab, an FcR nonbinding anti-CD3 mAb, has shown efficacy in multiple randomized clinical trials. We previously reported an increase in the frequency of circulating CD8(+) central memory (CD8CM) T cells in clinical responders, but the generalizability of this finding and the molecular effects of teplizumab on these T cells have not been evaluated. We analyzed data from two randomized clinical studies of teplizumab in patients with new-and recent-onset T1D. At the conclusion of therapy, clinical responders showed a significant reduction in circulating CD4(+) effector memory T cells. Afterward, there was an increase in the frequency and absolute number of CD8CM T cells. In vitro, teplizumab expanded CD8CM T cells by proliferation and conversion of non-CM T cells. Nanostring analysis of gene expression of CD8CM T cells from responders and nonresponders versus placebo-treated control subjects identified decreases in expression of genes associated with immune activation and increases in expression of genes associated with T-cell differentiation and regulation. We conclude that CD8CM T cells with decreased activation and regulatory gene expression are associated with clinical responses to teplizumab in patients with T1D. C1 [Tooley, James E.; Vudattu, Nalini; Herold, Kevan C.] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06504 USA. [Tooley, James E.; Vudattu, Nalini; Herold, Kevan C.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Choi, Jinmyung; Cotsapas, Chris; Raddassi, Khadir] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA. [Devine, Lesley] Yale Univ, Sch Med, Dept Lab Med, New Haven, CT 06510 USA. [McNamara, James G.] NIAID, NIH, Bethesda, MD 20892 USA. [Ehlers, Mario R.; Harris, Kristina M.; Kanaparthi, Sai; Phippard, Deborah] Immune Tolerance Network, Bethesda, MD USA. RP Herold, KC (reprint author), Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06504 USA. EM kevan.herold@yale.edu FU National Institutes of Health [R01 DK057846, U01AI1U01-02011-01, 2UL1RR024139]; Immune Tolerance Network (NIH) [N01 AI15416]; National Institute of Allergy and Infectious Diseases; Juvenile Diabetes Research Foundation FX Supported by grants R01 DK057846, U01AI1U01-02011-01, 2UL1RR024139 from the National Institutes of Health, this research was performed as a project of the Immune Tolerance Network (NIH contract N01 AI15416), an international clinical research consortium headquartered at the Benaroya Research Institute and supported by the National Institute of Allergy and Infectious Diseases and the Juvenile Diabetes Research Foundation. NR 33 TC 6 Z9 6 U1 0 U2 2 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 JAN PY 2016 VL 46 IS 1 BP 230 EP 241 DI 10.1002/eji.201545708 PG 12 WC Immunology SC Immunology GA DB0YO UT WOS:000368234800026 PM 26518356 ER PT J AU Novakova, Z Cerny, J Choy, CJ Nedrow, JR Choi, JK Lubkowski, J Berkman, CE Barinka, C AF Novakova, Zora Cerny, Jiri Choy, Cindy J. Nedrow, Jessie R. Choi, Joeseph K. Lubkowski, Jacek Berkman, Clifford E. Barinka, Cyril TI Design of composite inhibitors targeting glutamate carboxypeptidase II: the importance of effector functionalities SO FEBS JOURNAL LA English DT Article DE molecular modeling; NAALADase; phosphoramidate; prostate-specific membrane antigen; X-ray crystallography ID UREA-BASED INHIBITORS; MEMBRANE ANTIGEN; PROSTATE-CANCER; STRUCTURAL-CHARACTERIZATION; BIOLOGICAL EVALUATION; LIGAND; GCPII; PSMA; SYSTEM; CRYSTALLOGRAPHY AB Inhibitors targeting human glutamate carboxypeptidase II (GCPII) typically consist of a P1 glutamate-derived binding module, which warrants the high affinity and specificity, linked to an effector function that is positioned within the entrance funnel of the enzyme. Here we present a comprehensive structural and computational study aimed at dissecting the importance of the effector function for GCPII binding and affinity. To this end we determined crystal structures of human GCPII in complex with a series of phosphoramidate-based inhibitors harboring effector functions of diverse physicochemical characteristics. Our data show that higher binding affinities of phosphoramidates, compared to matching phosphonates, are linked to the presence of additional hydrogen bonds between Glu424 and Gly518 of the enzyme and the amide group of the phosphoramidate. While the positioning of the P1 glutamate-derived module within the S1 pocket of GCPII is invariant, interaction interfaces between effector functions and residues lining the entrance funnel are highly varied, with the positively charged arginine patch defined by Arg463, Arg534 and Arg536 being the only hot-spot' common to several studied complexes. This variability stems in part from the fact that the effector/GCPII interfaces generally encompass isolated areas of nonpolar residues within the entrance funnel and resulting van der Waals contacts lack the directionality typical for hydrogen bonding interactions. The presented data unravel a complexity of binding modes of inhibitors within non-prime site(s) of GCPII and can be exploited for the design of novel GCPII-specific compounds. PDB ID codesAtomic coordinates of the present structures together with the experimental structure factor amplitudes were deposited at the RCSB Protein Data Bank under accession codes (complex with JRB-4-81), (complex with JRB-4-73), (complex with CTT54), (complex with MP1C), (complex with MP1D), (complex with NC-2-40), (complex with T33) and (complex with T33D). C1 [Novakova, Zora; Cerny, Jiri; Barinka, Cyril] Acad Sci Czech Republic, Inst Biotechnol, Prague, Czech Republic. [Choy, Cindy J.; Nedrow, Jessie R.; Choi, Joeseph K.; Berkman, Clifford E.] Washington State Univ, Dept Chem, Pullman, WA 99164 USA. [Lubkowski, Jacek] NCI, Ctr Canc Res, Macromol Crystallog Lab, Frederick, MD 21701 USA. RP Barinka, C (reprint author), Inst Biotechnol CAS, Vvi, Struct Biol Lab, Videnska 1083, Prague 14220 4, Czech Republic. EM cyril.barinka@ibt.cas.cz RI Cerny, Jiri/I-4733-2012 OI Cerny, Jiri/0000-0002-1969-9304 FU US Department of Energy [W-31-109-Eng38]; European Community [283570]; Czech Science Foundation [301/12/1513]; program 'Biotechnological Expert in Structural Biology and Gene Expression' [CZ.1.07/2.3.00/30.0045]; NIH [R01CA140617]; project BIOCEV from the ERDF [CZ.1.05/1.1.00/02.0109] FX We thank Petra Baranova (IBT, Czech Republic) for excellent technical assistance, Manfred Weiss (BES-SYII, Berlin) for help with data collection and Zsofia Kutil for help with figure preparation. The use of the Advanced Photon Source was supported by the US Department of Energy (contract no. W-31-109-Eng38). We thank Helmholtz-Zentrum Berlin for the allocation of synchrotron radiation beamtime that received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under BioStruct-X (grant agreement no. 283570). C. Barinka acknowledges support from the Czech Science Foundation (grant no. 301/12/1513). Z. Novakova acknowledges support from the program 'Biotechnological Expert in Structural Biology and Gene Expression', Reg. no. CZ.1.07/2.3.00/30.0045. C.E. Berkman acknowledges support from the NIH (R01CA140617). This publication is supported by the project BIOCEV (CZ.1.05/1.1.00/02.0109) from the ERDF. NR 46 TC 1 Z9 1 U1 3 U2 17 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 JAN PY 2016 VL 283 IS 1 BP 130 EP 143 DI 10.1111/febs.13557 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DA8DJ UT WOS:000368034600010 PM 26460595 ER PT J AU Wassif, CA Cross, JL Iben, J Sanchez-Pulido, L Cougnoux, A Platt, FM Ory, DS Ponting, CP Bailey-Wilson, JE Biesecker, LG Porter, FD AF Wassif, Christopher A. Cross, Joanna L. Iben, James Sanchez-Pulido, Luis Cougnoux, Antony Platt, Frances M. Ory, Daniel S. Ponting, Chris P. Bailey-Wilson, Joan E. Biesecker, Leslie G. Porter, Forbes D. TI High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets SO GENETICS IN MEDICINE LA English DT Article DE allele frequency; next-generation sequence study; Niemann-Pick disease; NPC; type C ID HISTONE DEACETYLASE INHIBITOR; EVOLUTIONARY CONSERVATION; CHOLESTEROL STORAGE; ADULT; NPC1; MUTATIONS; POLYMORPHISMS; ACCUMULATION; DISORDERS; BINDING AB Purpose: Niemann-Pick disease type C (NPC) is a recessive, neurodegenerative, lysosomal storage disease caused by mutations in either NPC1 or NPC2. The diagnosis is difficult and frequently delayed. Ascertainment is likely incomplete because of both these factors and because the full phenotypic spectrum may not have been fully delineated. Given the recent development of a blood-based diagnostic test and the development of potential therapies, understanding the incidence of NPC and defining at-risk patient populations are important. Method: We evaluated data from four large, massively parallel exome sequencing data sets. Variant sequences were identified and classified as pathogenic or nonpathogenic based on a combination of literature review and bioinformatic analysis. This methodology provided an unbiased approach to determining the allele frequency. Results: Our data suggest an incidence rate for NPC1 and NPC2 of 1/92,104 and 1/2,858,998, respectively. Evaluation of common NPC1 variants, however, suggests that there may be a late-onset NPC1 phenotype with a markedly higher incidence, on the order of 1/19,0001/ 36,000. Conclusion: We determined a combined incidence of classical NPC of 1/89,229, or 1.12 affected patients per 100,000 conceptions, but predict incomplete ascertainment of a late-onset phenotype of NPC1. This finding strongly supports the need for increased screening of potential patients. C1 [Wassif, Christopher A.; Cross, Joanna L.; Iben, James; Cougnoux, Antony; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Wassif, Christopher A.; Cross, Joanna L.; Platt, Frances M.] Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England. [Sanchez-Pulido, Luis; Ponting, Chris P.] Univ Oxford, Dept Physiol Anat & Genet, MRC, Funct Genom Unit, Oxford, England. [Ory, Daniel S.] Washington Univ, Sch Med, Diabet Cardiovasc Dis Ctr, St Louis, MO USA. [Bailey-Wilson, Joan E.] NHGRI, Stat Genet Sect, Computat & Stat Genom Branch, NIH,US Dept HHS, Bethesda, MD 20892 USA. [Biesecker, Leslie G.] NHGRI, Clin Genom Sect, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Wassif, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. EM wassifc@mail.nih.gov OI Bailey-Wilson, Joan/0000-0002-9153-2920; Sanchez Pulido, Luis/0000-0002-2300-8502; Ponting, Chris/0000-0003-0202-7816; Wassif, Christopher/0000-0002-2524-1420 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Human Genome Research Institute intramural research programs, Department of Health and Human Services; MRC FX J.L.C., J.I., C.L., A.T., S.S., J.E.B.-W., L.G.B., F.D.P., and C.A.W. are supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development or the National Human Genome Research Institute intramural research programs, Department of Health and Human Services. C.A.W. is an NIH/Oxford Scholar. J.L.C. is a Wellcome Trust/NIH Scholar. F.M.P. is a Royal Society Wolfson Research Merit Award holder. L.S.P. and C.P.P. are funded by the MRC. NR 39 TC 18 Z9 18 U1 3 U2 4 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 JAN PY 2016 VL 18 IS 1 BP 41 EP 48 DI 10.1038/gim.2015.25 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA DA9GG UT WOS:000368116400006 PM 25764212 ER PT J AU Pollett, S Leguia, M Nelson, MI Berry, IM Rutherford, G Bausch, DG Kasper, M Jarman, R Melendrez, M AF Pollett, S. Leguia, M. Nelson, M. I. Berry, I. Maljkovic Rutherford, G. Bausch, D. G. Kasper, M. Jarman, R. Melendrez, M. TI Feasibility and effectiveness of a brief, intensive phylogenetics workshop in a middle-income country SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Phylogenetics; Bioinformatics; Training; Low- and middle-income country; Viral pathogens ID PHYLOGEOGRAPHY; VIRUS AB There is an increasing role for bioinformatic and phylogenetic analysis in tropical medicine research. However, scientists working in low- and middle-income regions may lack access to training opportunities in these methods. To help address this gap, a 5-day intensive bioinformatics workshop was offered in Lima, Peru. The syllabus is presented here for others who want to develop similar programs. To assess knowledge gained, a 20-point knowledge questionnaire was administered to participants (21 participants) before and after the workshop, covering topics on sequence quality control, alignment/formatting, database retrieval, models of evolution, sequence statistics, tree building, and results interpretation. Evolution/tree-building methods represented the lowest scoring domain at baseline and after the workshop. There was a considerable median gain in total knowledge scores (increase of 30%, p < 0.001) with gains as high as 55%. A 5-day workshop model was effective in improving the pathogen-applied bioinformatics knowledge of scientists working in a middle-income country setting. (C) 2015 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. C1 [Pollett, S.; Leguia, M.; Bausch, D. G.] US Naval Med Res Unit 6, Lima, Peru. [Pollett, S.; Rutherford, G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Pollett, S.] Univ Sydney, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW 2006, Australia. [Nelson, M. I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Berry, I. Maljkovic; Jarman, R.; Melendrez, M.] Walter Reed Army Inst Res, Silver Spring, MD USA. [Kasper, M.] Armed Forces Hlth Surveillance Ctr, Global Emerging Infect Surveillance & Response Sy, Silver Spring, MD USA. RP Pollett, S (reprint author), US Naval Med Res Unit 6, Lima, Peru. EM spollett@med.usyd.edu.au OI Melendrez, Melanie/0000-0002-4811-4467 FU Global Emerging Infections Surveillance and Response System (GEIS), a division of the Armed Forces Health Surveillance Center (AFHSC) FX The authors thank Ana Sofia Rengifo and the Universidad Peruana Cayetano Heredia for their assistance. This work was supported by the Global Emerging Infections Surveillance and Response System (GEIS), a division of the Armed Forces Health Surveillance Center (AFHSC). NR 9 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1201-9712 EI 1878-3511 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD JAN PY 2016 VL 42 BP 24 EP 27 DI 10.1016/j.ijid.2015.11.001 PG 4 WC Infectious Diseases SC Infectious Diseases GA DA8FK UT WOS:000368040300006 PM 26571303 ER PT J AU Lebowitz, BK Weinstein, C Beiser, A Seshadri, S Wolf, PA Auerbach, S Au, R AF Lebowitz, Brian K. Weinstein, Cheryl Beiser, Alexa Seshadri, Sudha Wolf, Philip A. Auerbach, Sandford Au, Rhoda TI Lifelong Reading Disorder and Mild Cognitive Impairment: Implications for Diagnosis SO JOURNAL OF ALZHEIMERS DISEASE LA English DT Article DE Alzheimer's disease; cognition; dyslexia; learning disorders; memory disorders; mild cognitive impairment; neuropsychological tests ID ALZHEIMERS-DISEASE; TEST-PERFORMANCE; DISABILITY AB Although neuropsychological tests are commonly used in the evaluation of possible mild cognitive impairment (MCI), poor test scores may be indicative of factors other than neurological compromise. The current study assessed the role of lifelong reading disorder on MCI classification. Community dwelling older adults with a suspected developmental reading disorder were identified by inference based on reading test performance. Individuals with a suspected reading disorder were significantly more likely to perform at a level consistent with MCI on several commonly used neuropsychological tests. The findings suggest a relationship between a history of reading disorder and MCI classification. C1 [Lebowitz, Brian K.] SUNY Stony Brook, Dept Neurol, Med Ctr, Stony Brook, NY 11794 USA. [Lebowitz, Brian K.; Weinstein, Cheryl] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Beiser, Alexa; Seshadri, Sudha; Wolf, Philip A.; Auerbach, Sandford; Au, Rhoda] Boston Univ, Sch Med, Dept Neurol, Framingham Heart Study, Boston, MA 02118 USA. [Beiser, Alexa; Seshadri, Sudha; Wolf, Philip A.; Auerbach, Sandford; Au, Rhoda] NHLBI, Framingham Heart Study, Framingham, MA USA. [Beiser, Alexa; Seshadri, Sudha; Wolf, Philip A.; Auerbach, Sandford; Au, Rhoda] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Lebowitz, BK (reprint author), 14 Technol Dr,Suite 12B, East Setauket, NY 11733 USA. EM Brian.Lebowitz@stony-brookmedicine.edu OI Beiser, Alexa/0000-0001-8551-7778 FU National Heart, Lung, and Blood Institute [N01-HC-25195]; National Institute of Neurological Disorders and Stroke [R01 NS17950]; National Institute on Aging [R01 AG16495, AG08122] FX Grant Support: National Heart, Lung, and Blood Institute contract (N01-HC-25195) and by grants from the National Institute of Neurological Disorders and Stroke (R01 NS17950) and the National Institute on Aging (R01 AG16495; AG08122). NR 21 TC 1 Z9 1 U1 0 U2 3 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 1387-2877 EI 1875-8908 J9 J ALZHEIMERS DIS JI J. Alzheimers Dis. PY 2016 VL 50 IS 1 BP 41 EP 45 DI 10.3233/JAD-150543 PG 5 WC Neurosciences SC Neurosciences & Neurology GA DA8VS UT WOS:000368085200006 PM 26639959 ER PT J AU Roy, A Hua, DP Post, CB AF Roy, Amitava Hua, Duy P. Post, Carol Beth TI Analysis of Multidomain Protein Dynamics SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID MOLECULAR-DYNAMICS; MOTIONS; PHOSPHORYLATION; DOMAIN; SIMULATIONS; DEPENDENCE; SH2 AB Proteins with a modular architecture of multiple domains connected by linkers often exhibit diversity in the relative positions of domains, while the domain tertiary structure remains unchanged. The biological function of these modular proteins, or the regulation of their activity, depends on the variation in domain orientation and separation. Accordingly, careful characterization of interdomain motion and correlated fluctuations of multidomain systems is relevant for understanding the functional behavior of modular proteins. Molecular dynamics (MD) simulations provides a powerful approach to study these motions in atomic detail. Nevertheless, the common procedure for analyzing fluctuations from MD simulations after rigid-body alignment fails for multidomain proteins; it greatly overestimates correlated positional fluctuations in the presence of relative domain motion. We show here that expressing the atomic motions of a multidomain protein as a combination of displacement within the domain reference frame and motion of the relative domains correctly separates the internal motions to allow a useful description of correlated fluctuations. We illustrate the methodology of separating the domain fluctuations and local fluctuations by application to the tandem SH2 domains of human Syk protein ldnase and by characterizing an effect of phosphorylation on the dynamics. Correlated motions are assessed from a distance covariance rather than the more common vector-coordinate covariance. The approach makes it possible to calculate the proper correlations in fluctuations internal to a domain as well as between domains. C1 [Roy, Amitava] NIAID, Bioinformat & Computat Biosci Branch, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Hua, Duy P.; Post, Carol Beth] Purdue Univ, Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. [Hua, Duy P.; Post, Carol Beth] Purdue Univ, Markey Ctr Struct Biol, W Lafayette, IN 47907 USA. RP Roy, A (reprint author), NIAID, Bioinformat & Computat Biosci Branch, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM amitava.roy@nih.gov FU National Institutes of Health [R01 GM039478] FX We thank the Rosen Center for Advanced Computing at Purdue University for computational resources. We thank the Research Technologies Branch of National Institute of Allergy and Infectious Diseases, particularly Ryan Kissinger, for technical help with the graphics. This work was supported by National Institutes of Health Grant R01 GM039478. NR 22 TC 0 Z9 0 U1 2 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 EI 1549-9626 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD JAN PY 2016 VL 12 IS 1 BP 274 EP 280 DI 10.1021/acs.jctc.5b00796 PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA DB2FA UT WOS:000368322500025 PM 26675644 ER PT J AU Konig, G Mei, Y Pickard, FC Simmonett, AC Miller, BT Herbert, JM Woodcock, HL Brooks, BR Shao, YH AF Koenig, Gerhard Mei, Ye Pickard, Frank C. Simmonett, Andrew C. Miller, Benjamin T. Herbert, John M. Woodcock, H. Lee Brooks, Bernard R. Shao, Yihan TI Computation of Hydration Free Energies Using the Multiple Environment Single System Quantum Mechanical/Molecular Mechanical Method SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID SOLVATION FREE-ENERGIES; MOLECULAR-DYNAMICS SIMULATIONS; MOLLER-PLESSET CALCULATIONS; DUAL BASIS-SETS; BLIND PREDICTION; DENSITY FUNCTIONALS; PERTURBATION-THEORY; VIRIAL-COEFFICIENT; LIQUID WATER; CHALLENGE AB A recently developed MESS-E-QM/MM method (multiple-environment single-system quantum mechanical molecular/mechanical calculations with a Roothaan-step extrapolation) is applied to the computation of hydration free energies for the blind SAMPL4 test set and for 12 small molecules. First, free energy simulations are performed with a classical molecular mechanics force field using fixed-geometry solute molecules and explicit TIP3P solvent, and then the non-Boltzmann-Bennett method is employed to compute the QM/MM correction (QM/MM-NBB) to the molecular mechanical hydration free energies. For the SAMPL4 set, MESS-E-QM/MM-NBB corrections to the hydration free energy can be obtained 2 or 3 orders of magnitude faster than fully converged QM/MM-NBB corrections, and, on average, the hydration free energies predicted with MESS-E-QM/MM-NBB fall within 0.10-0.20 kcal/mol of full-converged QM/MM-NBB results. Out of five density functionals (BLYP, B3LYP, PBEO, M06-2X, and omega B97X-D), the BLYP functional is found to be most compatible with the TIP3P solvent model and yields the most accurate hydration free energies against experimental values for solute molecules included in this study. C1 [Koenig, Gerhard; Pickard, Frank C.; Simmonett, Andrew C.; Miller, Benjamin T.; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Rockville, MD 20852 USA. [Mei, Ye] E China Normal Univ, State Key Lab Precis Spect, Shanghai 200062, Peoples R China. [Mei, Ye] E China Normal Univ, Dept Phys, Shanghai 200062, Peoples R China. [Mei, Ye] E China Normal Univ, Inst Theoret & Computat Sci, Shanghai 200062, Peoples R China. [Mei, Ye] NYU Shanghai, NYU ECNU Ctr Computat Chem, Shanghai 200062, Peoples R China. [Herbert, John M.] Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA. [Woodcock, H. Lee] Univ S Florida, Dept Chem, Tampa, FL 33620 USA. [Shao, Yihan] Q Chem Inc, Pleasanton, CA 94588 USA. RP Shao, YH (reprint author), Q Chem Inc, 6601 Owens Dr,Suite 105, Pleasanton, CA 94588 USA. EM yihan@q-chem.com RI Herbert, John/A-9573-2008; MEI, Ye/C-5843-2009 OI Herbert, John/0000-0002-1663-2278; MEI, Ye/0000-0002-3953-8508 FU NIH [GM096678-02]; DOE [DE-SC0011297]; NIH, NHLBI; National Science Foundation [CHE-1464946] FX Y.S. is supported by NIH grant GM096678-02 and DOE grant No. DE-SC0011297. G.K., F.C.P., A.C.S, B.T.M., and B.R.B. are supported by the Intramural Research Program of the NIH, NHLBI. H.L.W. would like to acknowledge support from the National Science Foundation under CHE-1464946. G.K. and Y.S. thank Dr. Jing Huang for his help with optimizing CGenFF force field parameters for aniline. Computational resources and services used in this work were partially provided by the LoBoS cluster of the National Institutes of Health. Y.S. thanks Drs. Dieter Cremer, Robert DiStasio, Teresa Head-Gordon, Michael Jones, Ken Jordan, Elfi Kraka, Daniel Lambrecht, Richard Pastor, Edina Rosta, Alex Sodt, Peng Tao, and Richard Venable for helpful discussions. NR 66 TC 9 Z9 9 U1 4 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 EI 1549-9626 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD JAN PY 2016 VL 12 IS 1 BP 332 EP 344 DI 10.1021/acs.jctc.5b00874 PG 13 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA DB2FA UT WOS:000368322500031 PM 26613419 ER PT J AU Paquin, A Onabajo, OO Tang, W Prokunina-Olsson, L AF Paquin, Ashley Onabajo, Olusegun O. Tang, Wei Prokunina-Olsson, Ludmila TI Comparative Functional Analysis of 12 Mammalian IFN-lambda 4 Orthologs SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article ID HEPATITIS-C VIRUS; INTERFERON LAMBDA 4; INFECTIOUS-DISEASES; III INTERFERON; LOCALIZATION; RECEPTOR; CLEARANCE; SIGNALS AB IFN-4 is a novel type-III interferon with strong clinical significance in humans. Only a subset of individualsup to 10% of Asians, 50% of Europeans, and 90% of Africanscarry the G allele of a genetic variant rs368234815-TT/G and are genetically able to produce IFN-4 protein. Carriers of the G allele have impaired ability to clear infection with hepatitis C virus (HCV). IFN-4 is also predicted to exist and be functionally important in several nonhuman mammals. In this study, we present the first comparative analysis of 12 mammalian IFN-4 orthologs in a human hepatic cell line, HepG2, which supports signaling of the human IFN-4. We show that despite differences in protein sequences, functional properties of the recombinant human and nonhuman IFN-4 proteins are comparablethey are all expressed as predominantly cytoplasmic proteins that are biologically active for induction of interferon signaling. We show that several IFN-4 orthologs can be detected by Western blotting, flow cytometry, and confocal imaging using a monoclonal antibody developed for the human IFN-4. Studies of IFN-4 in animals should help improve our understanding of the biology of this novel clinically important interferon in normal and disease conditions. C1 [Paquin, Ashley; Onabajo, Olusegun O.; Tang, Wei; Prokunina-Olsson, Ludmila] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Prokunina-Olsson, L (reprint author), NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, 8717 Grovemont Circle, Bethesda, MD 20892 USA. EM prokuninal@mail.nih.gov FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US FX The work has been supported by the Intramural Research Program (IRP) of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US. NR 25 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1079-9907 EI 1557-7465 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD JAN 1 PY 2016 VL 36 IS 1 BP 30 EP 36 DI 10.1089/jir.2015.0096 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA DA7WD UT WOS:000368014900004 PM 26308395 ER PT J AU Tom, WL Playford, MP Admani, S Natarajan, B Joshi, AA Eichenfield, LF Mehta, NN AF Tom, Wynnis L. Playford, Martin P. Admani, Shehla Natarajan, Balaji Joshi, Aditya A. Eichenfield, Lawrence F. Mehta, Nehal N. TI Characterization of Lipoprotein Composition and Function in Pediatric Psoriasis Reveals a More Atherogenic Profile SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID CHOLESTEROL EFFLUX CAPACITY; CARDIOVASCULAR-DISEASE; INSULIN-RESISTANCE; METABOLIC SYNDROME; PARTICLE NUMBER; RISK; INFLAMMATION; CHILDREN; ASSOCIATION; INDEXES AB Psoriasis is associated with increased cardiovascular disease in adults, but the risk profile of children with psoriasis remains to be fully characterized. We measured lipoprotein composition and function in 44 patients with pediatric psoriasis and 44 age- and sex-matched healthy controls, using nuclear magnetic resonance spectroscopy and a validated ex vivo assay of high-density lipoprotein cholesterol efflux capacity. The mean age of the patients was 13 years and the population was ethnically diverse. Children with psoriasis had higher waist-to-hip ratios (0.85 vs. 0.80; P < 0.002) and insulin resistance measures (log-transformed homeostasis model assessment of insulin resistance 0.65 vs. 0.41; P = 0.07). Despite comparable traditional lipid values, having psoriasis was associated with higher apolipoprotein B concentrations (72.4 vs. 64.6; P = 0.02), decreased large high-density lipoprotein particles (5.3 vs. 6.7; P < 0.01), and reduced cholesterol efflux capacity after adjusting for age, sex, fasting glucose, homeostasis model assessment of insulin resistance, systolic blood pressure, body mass index, apolipoprotein A-1, and high-density lipoprotein cholesterol concentration (beta -0.22; P = 0.02). Patients with pediatric psoriasis have a more atherogenic cardiometabolic risk profile, with evidence of insulin resistance and lipoprotein dysfunction by particle size, number, and functional assessment. These findings may provide a basis for the observed link later in life between psoriasis and cardiovascular disease, and support the need to screen and educate young patients to minimize later complications. C1 [Tom, Wynnis L.; Admani, Shehla; Eichenfield, Lawrence F.] Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA. [Tom, Wynnis L.; Admani, Shehla; Eichenfield, Lawrence F.] Univ Calif San Diego, Dept Med Oncol, San Diego, CA 92103 USA. [Tom, Wynnis L.; Admani, Shehla; Eichenfield, Lawrence F.] Rady Childrens Hosp, San Diego, CA USA. [Playford, Martin P.; Natarajan, Balaji; Joshi, Aditya A.; Mehta, Nehal N.] Natl Inst Hlth, Cardiol Branch, Bethesda, MD USA. RP Tom, WL (reprint author), Univ Calif San Diego, Pediat & Adolescent Dermatol, 8010 Frost St,Suite 602, San Diego, CA 92123 USA. EM wtom@rchsd.org FU National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the National Institutes of Health [K23AR060274]; [NHLBIHL006193-01] FX WLT is supported by a Career Development Award (K23AR060274) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the National Institutes of Health. NNM is a Lasker Clinical Research Scholar in the Section of Inflammation and Cardiometabolic Diseases of the National Heart, Lung, and Blood Institute (supported by grant to the Intramural Research Program NHLBIHL006193-01). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 34 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JAN PY 2016 VL 136 IS 1 BP 67 EP 73 DI 10.1038/JID.2015.385 PG 7 WC Dermatology SC Dermatology GA DB0QH UT WOS:000368212100018 ER PT J AU Aas, S Wasserman, D AF Aas, Sean Wasserman, David TI Brain-computer interfaces and disability: extending embodiment, reducing stigma? SO JOURNAL OF MEDICAL ETHICS LA English DT Article DE Disability; Neuroethics AB Brain-Computer Interfaces (BCIs) now enable an individual without limb function to move a detached mechanical arm to perform simple actions, such as feeding herself. This technology may eventually offer almost everyone a way to move objects at a distance, by exercising cognitive control of a mechanical device. At that point, BCIs may be seen less as an assistive technology for disabled people, and more as a tool, like the internet, which can benefit all users. We will argue that BCIs will have a significant but uncertain impact on attitudes toward disabilities and on norms of bodily form and function. It may be liberating, oppressive, or both. Its impact, we argue, will depend - though not in any simple way - on whether BCIs come to be seen as parts of the body itself or as external tools. C1 [Aas, Sean; Wasserman, David] NIH, Dept Clin Bioeth, Bethesda, MD 20982 USA. RP Wasserman, D (reprint author), NIH, Dept Clin Bioeth, 10 Ctr Dr, Bethesda, MD 20982 USA. EM david.wasserman@nih.gov NR 19 TC 2 Z9 2 U1 3 U2 11 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 EI 1473-4257 J9 J MED ETHICS JI J. Med. Ethics PD JAN PY 2016 VL 42 IS 1 BP 37 EP 40 DI 10.1136/medethics-2015-102807 PG 4 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA DA5HJ UT WOS:000367833600010 PM 26336895 ER PT J AU Lih, CJ Sims, DJ Harrington, RD Polley, EC Zhao, YD Mehaffey, MG Forbes, TD Das, B Walsh, WD Datta, V Harper, KN Bouk, CH Rubinstein, LV Simon, RM Conley, BA Chen, AP Kummar, S Doroshow, JH Williams, PM AF Lih, Chih-Jian Sims, David J. Harrington, Robin D. Polley, Eric C. Zhao, Yingdong Mehaffey, Michele G. Forbes, Thomas D. Das, Biswajit Walsh, William D. Datta, Vivekananda Harper, Kneshay N. Bouk, Courtney H. Rubinstein, Lawrence V. Simon, Richard M. Conley, Barbara A. Chen, Alice P. Kummar, Shivaani Doroshow, James H. Williams, Paul M. TI Analytical Validation and Application of a Targeted Next-Generation Sequencing Mutation-Detection Assay for Use in Treatment Assignment in the NCI-MPACT Trial SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID CANCER-CELL-LINES; COMPREHENSIVE GENOMIC CHARACTERIZATION; WILD-TYPE P53; LUNG-CANCER; IN-VITRO; DNA MICROARRAYS; CLINICAL-TRIALS; MEK INHIBITION; BREAST-CANCER; RAS ONCOGENES AB Robust and analytically validated assays are essential for clinical studies. We outline an analytical validation study of a targeted next-generation sequencing mutation-detection assay used for patient selection in the National Cancer Institute Molecular Profiling Based Assignment of Cancer Therapy (NCI-MPACT) trial (NCT01827384). Using DNA samples from normal or tumor cell lines and xenografts with known variants, we assessed the sensitivity, specificity, and reproducibility of the NCI-MPACT assay in five variant types: single-nucleotide variants (SNVs), SNVs at homopolymeric (HP) regions (>= 3 identical bases), small insertions/deletions (indels), large indeLs (gap >= 4 bp), and indels at HP regions. The assay achieved sensitivities of 100% for 64 SNVs, nine SNVs at HP regions, and 11 large indels, 83.33% for six indels, and 93.33% for 15 indels at HP regions. Zero false positives (100% specificity) were found in 380 actionable mutation loci in 96 runs of hapLotype map cells. Reproducibility analysis showed 96.3% to 100% intraoperator and 98.1% to 100% interoperator mean concordance in detected variants and 100% reproducibility in treatment selection. To date, 38 tumors have been screened, 34 passed preanalytical quality control, and 18 had actionable mutations for treatment assignment. The NCI-MPACT assay is well suited for its intended investigational use and can serve as a template for developing next-generation sequencing assays for other cancer clinical trial applications. C1 [Lih, Chih-Jian; Sims, David J.; Harrington, Robin D.; Mehaffey, Michele G.; Forbes, Thomas D.; Das, Biswajit; Walsh, William D.; Datta, Vivekananda; Harper, Kneshay N.; Bouk, Courtney H.; Williams, Paul M.] Leidos Biomed Res Inc, Mol Characterizat & Clin Assay Dev Lab, Frederick, MD USA. [Lih, Chih-Jian] Frederick Natl Lab Canc Res, Ft Detrick, MD 21702 USA. [Rubinstein, Lawrence V.; Simon, Richard M.; Conley, Barbara A.; Chen, Alice P.; Kummar, Shivaani; Doroshow, James H.; Williams, Paul M.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Lih, CJ (reprint author), Frederick Natl Lab Canc Res, Bldg 320,Room 5,1050 Boyles St, Ft Detrick, MD 21702 USA. EM jason.lih@nih.gov FU National Cancer Institute, NIH [HHSN261200800001E, NO1-CO-2008-00001] FX Supported by federal funds from the National Cancer Institute, NIH, under contracts no. HHSN261200800001E and NO1-CO-2008-00001 (P.M.W.). NR 68 TC 9 Z9 9 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD JAN PY 2016 VL 18 IS 1 BP 51 EP 67 DI 10.1016/j.jmoldx.2015.07.006 PG 17 WC Pathology SC Pathology GA DB0PZ UT WOS:000368211300007 PM 26602013 ER PT J AU Romero, R Chaemsaithong, P Korzeniewski, SJ Tarca, AL Bhatti, G Xu, ZH Kusanovic, JP Dong, Z Docheva, N Martinez-Varea, A Yoon, BH Hassan, SS Chaiworapongsa, T Yeo, L AF Romero, Roberto Chaemsaithong, Piya Korzeniewski, Steven J. Tarca, Adi L. Bhatti, Gaurav Xu, Zhonghui Kusanovic, Juan P. Dong, Zhong Docheva, Nikolina Martinez-Varea, Alicia Yoon, Bo Hyun Hassan, Sonia S. Chaiworapongsa, Tinnakorn Yeo, Lami TI Clinical chorioamnionitis at term II: the intra-amniotic inflammatory response SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE Amniocentesis; chemokines; cytokines; funisitis; histologic chorioamnionitis; interleukin-6 (IL-6); intra-amniotic infection/inflammation; microbial invasion of the amniotic cavity (MIAC); polymerase chain reaction coupled with electrospray ionization mass spectrometry (PCR/ESI-MS); sterile inflammation ID TUMOR-NECROSIS-FACTOR; AMNIOTIC-FLUID INTERLEUKIN-6; SMOOTH-MUSCLE-CELLS; NF-KAPPA-B; ACTIVATING PEPTIDE-1 INTERLEUKIN-8; DEFENSIN ANTIMICROBIAL PEPTIDES; IMMEDIATE POSTPARTUM TREATMENT; PROSTAGLANDIN E-2 PRODUCTION; NEONATAL SEPSIS EVALUATION; SPONTANEOUS PRETERM BIRTH AB Objective: Recent studies indicate that clinical chorioamnionitis is a heterogeneous condition and only approximately one-half of the patients have bacteria in the amniotic cavity, which is often associated with intra-amniotic inflammation. The objective of this study is to characterize the nature of the inflammatory response within the amniotic cavity in patients with clinical chorioamnionitis at term according to the presence or absence of 1) bacteria in the amniotic cavity and 2) intra-amniotic inflammation. Materials and methods: A retrospective cross-sectional case-control study was conducted to examine cytokine and chemokine concentrations in the amniotic fluid (AF). Cases consisted of women with clinical chorioamnionitis at term (n = 45). Controls were women with uncomplicated pregnancies at term who did not have intra-amniotic inflammation and were in labor (n = 24). Women with clinical chorioamnionitis were classified according to the results of AF cultures, broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry, and AF concentration of interleukin-6 (IL-6) into those: 1) without intra-amniotic inflammation, 2) with microbial-associated intra-amniotic inflammation, and 3) with intra-amniotic inflammation without detectable bacteria. The AF concentrations of 29 cytokines/chemokines were determined using sensitive and specific V-PLEX immunoassays. Results: 1) The AF concentrations of pro-and anti-inflammatory cytokines/chemokines such as interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), interleukin-4 (IL-4), macrophage inflammatory protein-1 beta (MIP-1 beta), and interleukin-8 (IL-8) (except Eotaxin-3) were significantly higher in women with clinical chorioamnionitis at term than in controls (term labor without intra-amniotic inflammation); 2) patients with microbial-associated intra-amniotic inflammation, and those with intra-amniotic inflammation without detectable bacteria, had a dramatic differential expression of cytokines and chemokines in AF compared to patients with spontaneous labor without intra-amniotic inflammation. However, no difference could be detected in the pattern of the intra-amniotic inflammatory response between patients with intra-amniotic inflammation with and without detectable bacteria; and 3) in patients with clinical chorioamnionitis at term but without intra-amniotic inflammation, the behavior of cytokines and chemokines in the AF was similar to those in spontaneous labor at term. Conclusions: Patients with clinical chorioamnionitis who had microbial-associated intra-amniotic inflammation or intra-amniotic inflammation without detectable bacteria had a dramatic upregulation of the intra-amniotic inflammatory response assessed by amniotic fluid concentrations of cytokines. A subset of patients with term clinical chorioamnionitis does not have intra-amniotic infection/inflammation, as demonstrated by elevated AF concentrations of inflammation-related proteins, when compared to women in term labor with uncomplicated pregnancies, suggesting over-diagnosis. These observations constitute the first characterization of the cytokine/chemokine network in the amniotic cavity of patients with clinical chorioamnionitis at term. C1 [Romero, Roberto] Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, Detroit, MI 48201 USA. [Romero, Roberto; Chaemsaithong, Piya; Korzeniewski, Steven J.; Tarca, Adi L.; Bhatti, Gaurav; Xu, Zhonghui; Kusanovic, Juan P.; Dong, Zhong; Docheva, Nikolina; Martinez-Varea, Alicia; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Yeo, Lami] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Romero, Roberto; Chaemsaithong, Piya; Korzeniewski, Steven J.; Tarca, Adi L.; Bhatti, Gaurav; Xu, Zhonghui; Kusanovic, Juan P.; Dong, Zhong; Docheva, Nikolina; Martinez-Varea, Alicia; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Yeo, Lami] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto; Korzeniewski, Steven J.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Dept Mol Obstet & Genet, Detroit, MI 48201 USA. [Chaemsaithong, Piya; Korzeniewski, Steven J.; Tarca, Adi L.; Bhatti, Gaurav; Xu, Zhonghui; Kusanovic, Juan P.; Dong, Zhong; Docheva, Nikolina; Martinez-Varea, Alicia; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Yeo, Lami] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Kusanovic, Juan P.] Hosp Dr Sotero del Rio, Ctr Res & Innovat Maternal Fetal Med CIMAF, Santiago, Chile. [Kusanovic, Juan P.] Pontificia Univ Catolica Chile, Dept Obstet & Gynecol, Santiago, Chile. [Yoon, Bo Hyun] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM romeror@mail.nih.gov RI Gomez-Lopez, Nardhy/R-7664-2016 OI Gomez-Lopez, Nardhy/0000-0002-3406-5262 FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); Federal funds from NICHD, NIH [HSN275201300006C] FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); and, in part, with Federal funds from NICHD, NIH under Contract No. HSN275201300006C. NR 186 TC 12 Z9 12 U1 2 U2 7 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 EI 1619-3997 J9 J PERINAT MED JI J. Perinat. Med. PD JAN PY 2016 VL 44 IS 1 BP 5 EP 22 DI 10.1515/jpm-2015-0045 PG 18 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA DA9RF UT WOS:000368146600002 PM 25938217 ER PT J AU Romero, R Chaemsaithong, P Korzeniewski, SJ Kusanovic, JP Docheva, N Martinez-Varea, A Ahmed, AI Yoon, BH Hassan, SS Chaiworapongsa, T Yeo, L AF Romero, Roberto Chaemsaithong, Piya Korzeniewski, Steven J. Kusanovic, Juan P. Docheva, Nikolina Martinez-Varea, Alicia Ahmed, Ahmed I. Yoon, Bo Hyun Hassan, Sonia S. Chaiworapongsa, Tinnakorn Yeo, Lami TI Clinical chorioamnionitis at term III: how well do clinical criteria perform in the identification of proven intra-amniotic infection? SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE Amniocentesis; fever; foul-smelling amniotic fluid; funisitis; histological chorioamnionitis; intra-amniotic inflammation; maternal leukocytosis; preterm birth; sterile inflammation; tachycardia; uterine tenderness ID INFLAMMATORY RESPONSE SYNDROME; INTRA-AMNIOTIC INFECTION; NEONATAL SEPSIS EVALUATION; PRETERM PREMATURE RUPTURE; EPIDURAL LABOR ANALGESIA; MICROBIAL INVASION; INTACT MEMBRANES; RANDOMIZED-TRIAL; HISTOLOGIC CHORIOAMNIONITIS; INTESTINAL MICROBIOTA AB Objective: The diagnosis of clinical chorioamnionitis is based on a combination of signs [fever, maternal or fetal tachycardia, foul-smelling amniotic fluid (AF), uterine tenderness and maternal leukocytosis]. Bacterial infections within the amniotic cavity are considered the most frequent cause of clinical chorioamnionitis and an indication for antibiotic administration to reduce maternal and neonatal morbidity. Recent studies show that only 54% of patients with the diagnosis of clinical chorioamnionitis at term have bacteria in the AF and evidence of intra-amniotic inflammation. The objective of this study was to examine the performance of the clinical criteria for the diagnosis of chorioamnionitis to identify patients with microbial-associated intra-amniotic inflammation (also termed intra-amniotic infection). Materials and methods: This retrospective cross-sectional study included 45 patients with the diagnosis of clinical chorioamnionitis at term, whose AF underwent analysis for: 1) the presence of microorganisms using both cultivation and molecular biologic techniques [polymerase chain reaction (PCR) with broad primers], and 2) interleukin (IL)-6 concentrations by enzyme-linked immunosorbent assay. The diagnostic performance (sensitivity, specificity, accuracy, and likelihood ratios) of each clinical sign and their combination to identify clinical chorioamnionitis were determined using microbial-associated intra-amniotic inflammation [presence of microorganisms in the AF using cultivation or molecular techniques and elevated AF IL-6 concentrations (>= 2.6 ng/mL)] as the gold standard. Results: The accuracy of each clinical sign for the identification of microbial-associated intra-amniotic inflammation (intra-amniotic infection) ranged between 46.7% and 57.8%. The combination of fever with three or more clinical criteria did not substantially improve diagnostic accuracy. Conclusion: In the presence of a fever during labor at term, signs used to diagnose clinical chorioamnionitis do not accurately identify the patient with proven intra-amniotic infection (i.e., those with microorganisms detected by culture or molecular microbiologic techniques and an associated intra-amniotic inflammatory response). C1 [Romero, Roberto] Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, Detroit, MI 48201 USA. [Romero, Roberto; Chaemsaithong, Piya; Korzeniewski, Steven J.; Kusanovic, Juan P.; Docheva, Nikolina; Martinez-Varea, Alicia; Ahmed, Ahmed I.; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Yeo, Lami] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Romero, Roberto; Chaemsaithong, Piya; Korzeniewski, Steven J.; Kusanovic, Juan P.; Docheva, Nikolina; Martinez-Varea, Alicia; Ahmed, Ahmed I.; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Yeo, Lami] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto; Chaemsaithong, Piya; Korzeniewski, Steven J.; Docheva, Nikolina; Martinez-Varea, Alicia; Ahmed, Ahmed I.; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Yeo, Lami] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Dept Mol Obstet & Genet, Detroit, MI 48201 USA. [Chaemsaithong, Piya; Korzeniewski, Steven J.; Kusanovic, Juan P.; Docheva, Nikolina; Martinez-Varea, Alicia; Ahmed, Ahmed I.; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Yeo, Lami] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Kusanovic, Juan P.] Hosp Dr Sotero del Rio, Ctr Res & Innovat Maternal Fetal Med CIMAF, Santiago, Chile. [Kusanovic, Juan P.] Pontificia Univ Catolica Chile, Dept Obstet & Gynecol, Santiago, Chile. [Yoon, Bo Hyun] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM romeror@mail.nih.gov NR 135 TC 10 Z9 10 U1 3 U2 10 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 EI 1619-3997 J9 J PERINAT MED JI J. Perinat. Med. PD JAN PY 2016 VL 44 IS 1 BP 23 EP 32 DI 10.1515/jpm-2015-0044 PG 10 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA DA9RF UT WOS:000368146600003 PM 25918914 ER PT J AU Romero, R Chaemsaithong, P Docheva, N Korzeniewski, SJ Kusanovic, JP Yoon, BH Kim, JS Chaiyasit, N Ahmed, AI Qureshi, F Jacques, SM Kim, CJ Hassan, SS Chaiworapongsa, T Yeo, L Kim, YM AF Romero, Roberto Chaemsaithong, Piya Docheva, Nikolina Korzeniewski, Steven J. Kusanovic, Juan P. Yoon, Bo Hyun Kim, Jung-Sun Chaiyasit, Noppadol Ahmed, Ahmed I. Qureshi, Faisal Jacques, Suzanne M. Kim, Chong Jai Hassan, Sonia S. Chaiworapongsa, Tinnakorn Yeo, Lami Kim, Yeon Mee TI Clinical chorioamnionitis at term VI: acute chorioamnionitis and funisitis according to the presence or absence of microorganisms and inflammation in the amniotic cavity SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE Acute histologic chorioamnionitis; fetal inflammatory response syndrome (FIRS); interleukin-6 (IL-6); microbial-associated intra-amniotic inflammation; neonatal sepsis ID ONSET NEONATAL SEPSIS; C-REACTIVE PROTEIN; TUMOR-NECROSIS-FACTOR; BLOOD-CELL COUNT; PRETERM PREMATURE RUPTURE; UMBILICAL-CORD BLOOD; BIRTH-WEIGHT INFANTS; ACTIVATING PEPTIDE-1 INTERLEUKIN-8; COLONY-STIMULATING FACTOR; B STREPTOCOCCAL SEPSIS AB Objective: Neonates born to mothers with clinical chorioamnionitis at term are at an increased risk of infection. Acute subchorionitis, chorioamnionitis, and funisitis are considered placental histologic features consistent with acute inflammation according to the Society for Pediatric Pathology. The objectives of this study were to examine the performance of placental histologic features in the identification of: 1) microbial-associated intra-amniotic inflammation (intra-amniotic infection); and 2) fetal inflammatory response syndrome (FIRS). Methods: This retrospective cohort study included women with the diagnosis of clinical chorioamnionitis at term (n = 45), who underwent an amniocentesis to determine: 1) the presence of microorganisms using both cultivation and molecular biologic techniques [polymerase chain reaction (PCR) with broad range primers]; and 2) interleukin (IL)-6 concentrations by enzyme-linked immunosorbent assay (ELISA). The diagnostic performance (sensitivity, specificity, accuracy, and likelihood ratios) of placental histologic features consistent with acute inflammation was determined for the identification of microbial-associated intra-amniotic inflammation and FIRS. Results: 1) The presence of acute histologic chorioamnionitis and funisitis was associated with the presence of proven intra-amniotic infection assessed by amniotic fluid analysis; 2) funisitis was also associated with the presence of FIRS; 3) the negative predictive value of acute funisitis >= stage 2 for the identification of neonates born to mothers with intra-amniotic infection was <50%, and therefore, suboptimal to exclude fetal exposure to bacteria in the amniotic cavity; and 4) acute funisitis >= stage 2 had a negative predictive value of 86.8% for the identification of FIRS in a population with a prevalence of 20%. Conclusion: Acute histologic chorioamnionitis and funisitis are associated with intra-amniotic infection and the presence of FIRS. However, current pathologic methods have limitations in the identification of the fetus exposed to microorganisms present in the amniotic cavity. Further studies are thus required to determine whether molecular markers can enhance the performance of placental pathology in the identification of neonates at risk for neonatal sepsis. C1 [Romero, Roberto] Wayne State Univ, Hutzel Womens Hosp, NICHD NIH DHHS, Perinatol Res Branch,Dept Med Sci, Detroit, MI 48201 USA. [Kim, Yeon Mee] Inje Univ, Coll Med, Haeundae Paik Hosp, Dept Pathol, Busan 612896, South Korea. [Romero, Roberto; Chaemsaithong, Piya; Docheva, Nikolina; Korzeniewski, Steven J.; Kusanovic, Juan P.; Yoon, Bo Hyun; Kim, Jung-Sun; Chaiyasit, Noppadol; Ahmed, Ahmed I.; Qureshi, Faisal; Jacques, Suzanne M.; Kim, Chong Jai; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Yeo, Lami; Kim, Yeon Mee] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH DHHS, Bethesda, MD USA. [Romero, Roberto; Chaemsaithong, Piya; Docheva, Nikolina; Korzeniewski, Steven J.; Kusanovic, Juan P.; Yoon, Bo Hyun; Kim, Jung-Sun; Chaiyasit, Noppadol; Ahmed, Ahmed I.; Qureshi, Faisal; Jacques, Suzanne M.; Kim, Chong Jai; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Yeo, Lami; Kim, Yeon Mee] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH DHHS, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Wayne State Univ, Dept Mol Obstet & Genet, Detroit, MI 48201 USA. [Romero, Roberto; Korzeniewski, Steven J.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Chaemsaithong, Piya; Docheva, Nikolina; Korzeniewski, Steven J.; Chaiyasit, Noppadol; Ahmed, Ahmed I.; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Yeo, Lami] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Kusanovic, Juan P.] Hosp Dr Sotero del Rio, Dept Obstet & Gynecol, Ctr Res & Innovat Maternal Fetal Med CIMAF, Santiago, Chile. [Kusanovic, Juan P.] Pontificia Univ Catolica Chile, Dept Obstet & Gynecol, Santiago, Chile. [Yoon, Bo Hyun] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. [Kim, Jung-Sun] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Pathol, Seoul, South Korea. [Qureshi, Faisal; Jacques, Suzanne M.] Wayne State Univ, Harper Univ Hosp, Dept Pathol, Detroit, MI 48201 USA. [Qureshi, Faisal; Jacques, Suzanne M.] Wayne State Univ, Dept Pathol, Detroit, MI 48201 USA. [Kim, Chong Jai] Univ Ulsan, Coll Med, Dept Pathol, Seoul, South Korea. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, NICHD NIH DHHS, Perinatol Res Branch,Dept Med Sci, 3990 John R,Box 4, Detroit, MI 48201 USA. EM romeror@mail.nih.gov; ykim.haeundae@gmail.com FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); NICHD, NIH [HSN275201300006C] FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); and, in part, with Federal funds from NICHD, NIH under Contract No. HSN275201300006C. NR 269 TC 6 Z9 6 U1 2 U2 5 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 EI 1619-3997 J9 J PERINAT MED JI J. Perinat. Med. PD JAN PY 2016 VL 44 IS 1 BP 33 EP 51 DI 10.1515/jpm-2015-0119 PG 19 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA DA9RF UT WOS:000368146600004 PM 26352071 ER PT J AU Romero, R Chaemsaithong, P Docheva, N Korzeniewski, SJ Tarca, AL Bhatti, G Xu, ZH Kusanovic, JP Chaiyasit, N Dong, Z Yoon, BH Hassan, SS Chaiworapongsa, T Yeo, L Kim, YM AF Romero, Roberto Chaemsaithong, Piya Docheva, Nikolina Korzeniewski, Steven J. Tarca, Adi L. Bhatti, Gaurav Xu, Zhonghui Kusanovic, Juan P. Chaiyasit, Noppadol Dong, Zhong Yoon, Bo Hyun Hassan, Sonia S. Chaiworapongsa, Tinnakorn Yeo, Lami Kim, Yeon Mee TI Clinical chorioamnionitis at term V: umbilical cord plasma cytokine profile in the context of a systemic maternal inflammatory response SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE Biomarker; chemokine; fetal inflammatory response syndrome (FIRS); funisitis; interleukin-6; interleukin-8; intra-amniotic infection/inflammation; monocyte chemoattractant protein (MCP)-1; neonatal sepsis; umbilical cord plasma ID TUMOR-NECROSIS-FACTOR; PRETERM PREMATURE RUPTURE; CELL STIMULATORY FACTOR; STAINED AMNIOTIC-FLUID; BIRTH-WEIGHT INFANTS; INTERFERON-GAMMA PRODUCTION; PRENATAL IMMUNE CHALLENGE; ONSET NEONATAL SEPSIS; INTERLEUKIN-1 RECEPTOR ANTAGONIST; NEURODEVELOPMENTAL ANIMAL-MODEL AB Objective: Microbial invasion of the fetus due to intra-amniotic infection can lead to a systemic inflammatory response characterized by elevated concentrations of cytokines in the umbilical cord plasma/serum. Clinical chorioamnionitis represents the maternal syndrome often associated with intra-amniotic infection, although other causes of this syndrome have been recently described. The objective of this study was to characterize the umbilical cord plasma cytokine profile in neonates born to mothers with clinical chorioamnionitis at term, according to the presence or absence of bacteria and/or intra-amniotic inflammation. Materials and methods: A cross-sectional study was conducted, including patients with clinical chorioamnionitis at term (n = 38; cases) and those with spontaneous term labor without clinical chorioamnionitis (n = 77; controls). Women with clinical chorioamnionitis were classified according to the results of amniotic fluid culture, broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry (PCR/ESI-MS) and amniotic fluid interleukin (IL)-6 concentration into three groups: 1) no intra-amniotic inflammation; 2) intra-amniotic inflammation without detectable microorganisms; or 3) microbial-associated intra-amniotic inflammation. A fetal inflammatory response syndrome (FIRS) was defined as an umbilical cord plasma IL-6 concentration > 11 pg/mL. The umbilical cord plasma concentrations of 29 cytokines were determined with sensitive and specific V-PLEX immunoassays. Nonparametric statistical methods were used for analysis, adjusting for a false discovery rate of 5%. Results: 1) Neonates born to mothers with clinical chorioamnionitis at term (considered in toto) had significantly higher median umbilical cord plasma concentrations of IL-6, IL-12p70, IL-16, IL-13, IL-4, IL-10 and IL-8, but significantly lower interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF)-alpha concentrations than neonates born to mothers with spontaneous term labor without clinical chorioamnionitis; 2) neonates born to mothers with clinical chorioamnionitis at term but without intra-amniotic inflammation had higher concentrations of IL-6, IL-12p70, IL-13, IL-4, IL-5, and IL-8, but lower IFN-gamma, than neonates not exposed to clinical chorioamnionitis, suggesting that maternal fever in the absence of intra-amniotic inflammation leads to a change in the fetal cytokine network; 3) there were significant, positive correlations between maternal and umbilical cord plasma IL-6 and IL-8 concentrations (IL-6: Spearman correlation = 0.53; P < 0.001; IL-8: Spearman correlation = 0.42; P < 0.001), consistent with placental transfer of cytokines; 4) an elevated fetal plasma IL-6 (> 11 pg/mL), the diagnostic criterion for FIRS, was present in 21% of cases (8/38), and all these neonates were born to mothers with proven intra-amniotic infection; and 5) FIRS was associated with a high concentration of umbilical cord plasma IL-8, IL-10 and monocyte chemoattractant protein (MCP)-1. Conclusions: Neonates born to mothers with clinical chorioamnionitis at term had higher concentrations of umbilical cord plasma cytokines than those born to mothers without clinical chorioamnionitis. Even neonates exposed to clinical chorioamnionitis but not to intra-amniotic inflammation had elevated concentrations of multiple cytokines, suggesting that intrapartum fever alters the fetal immune response. C1 [Romero, Roberto] Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, Detroit, MI 48201 USA. [Romero, Roberto; Chaemsaithong, Piya; Docheva, Nikolina; Korzeniewski, Steven J.; Tarca, Adi L.; Bhatti, Gaurav; Xu, Zhonghui; Kusanovic, Juan P.; Chaiyasit, Noppadol; Dong, Zhong; Yoon, Bo Hyun; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Yeo, Lami] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Romero, Roberto; Chaemsaithong, Piya; Docheva, Nikolina; Korzeniewski, Steven J.; Tarca, Adi L.; Bhatti, Gaurav; Kusanovic, Juan P.; Chaiyasit, Noppadol; Dong, Zhong; Yoon, Bo Hyun; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Yeo, Lami] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto; Korzeniewski, Steven J.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Kim, Yeon Mee] Inje Univ, Coll Med, Haeundae Paik Hosp, Dept Pathol, Busan 612896, South Korea. [Kim, Yeon Mee] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Kim, Yeon Mee] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI USA. [Chaemsaithong, Piya; Docheva, Nikolina; Korzeniewski, Steven J.; Tarca, Adi L.; Bhatti, Gaurav; Xu, Zhonghui; Chaiyasit, Noppadol; Dong, Zhong; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Yeo, Lami] Wayne State Univ, Dept Obstet & Gynecol, Sch Med, Detroit, MI 48201 USA. [Kusanovic, Juan P.] Hosp Dr Sotero del Rio, Dept Obstet & Gynecol, Ctr Res & Innovat Maternal Fetal Med CIMAF, Santiago, Chile. [Kusanovic, Juan P.] Pontificia Univ Catolica Chile, Dept Obstet & Gynecol, Santiago, Chile. [Yoon, Bo Hyun] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM romeror@mail.nih.gov; ykim.haeundae@gmail.com FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); Federal funds from NICHD, NIH [HSN275201300006C] FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); and, in part, with Federal funds from NICHD, NIH under Contract No. HSN275201300006C. NR 363 TC 5 Z9 5 U1 3 U2 9 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 EI 1619-3997 J9 J PERINAT MED JI J. Perinat. Med. PD JAN PY 2016 VL 44 IS 1 BP 53 EP 76 DI 10.1515/jpm-2015-0121 PG 24 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA DA9RF UT WOS:000368146600005 PM 26360486 ER PT J AU Romero, R Chaemsaithong, P Docheva, N Korzeniewski, SJ Tarca, AL Bhatti, G Xu, ZH Kusanovic, JP Dong, Z Chaiyasit, N Ahmed, AI Yoon, BH Hassan, SS Chaiworapongsa, T Yeo, L AF Romero, Roberto Chaemsaithong, Piya Docheva, Nikolina Korzeniewski, Steven J. Tarca, Adi L. Bhatti, Gaurav Xu, Zhonghui Kusanovic, Juan P. Dong, Zhong Chaiyasit, Noppadol Ahmed, Ahmed I. Yoon, Bo Hyun Hassan, Sonia S. Chaiworapongsa, Tinnakorn Yeo, Lami TI Clinical chorioamnionitis at term IV: the maternal plasma cytokine profile SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE Acute histologic chorioamnionitis; amniotic fluid; biomarkers; chemokines; fever; funisitis; interferon-gamma (IFN-gamma); interleukin-1 beta (IL-1 beta); interleukin-2 (IL-2); interleukin-6 (IL-6); microbial-associated intra-amniotic inflammation; pyrogens; tumor necrosis factor-alpha (TNF-alpha); V-PLEX immunoassays ID TUMOR-NECROSIS-FACTOR; PRETERM PREMATURE RUPTURE; AMNIOTIC-FLUID INTERLEUKIN-6; FETAL INFLAMMATORY RESPONSE; TOLL-LIKE RECEPTORS; LABOR EPIDURAL ANALGESIA; ACTIVATING PEPTIDE-1 INTERLEUKIN-8; MONOCYTE CHEMOTACTIC PROTEIN-1; PROSTAGLANDIN E-2 PRODUCTION; NEONATAL SEPSIS EVALUATION AB Introduction: Fever is a major criterion for clinical chorioamnionitis; yet, many patients with intrapartum fever do not have demonstrable intra-amniotic infection. Some cytokines, such as interleukin (IL)-1, IL-6, interferon-gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha), can induce a fever. The objective of this study was to determine whether maternal plasma concentrations of cytokines could be of value in the identification of patients with the diagnosis of clinical chorioamnionitis at term who have microbial-associated intra-amniotic inflammation. Methods: A retrospective cross-sectional study was conducted, including patients with clinical chorioamnionitis at term (n = 41; cases) and women in spontaneous labor at term without clinical chorioamnionitis (n = 77; controls). Women with clinical chorioamnionitis were classified into three groups according to the results of amniotic fluid culture, broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry (PCR/ESI-MS), and amniotic fluid IL-6 concentration: 1) no intra-amniotic inflammation; 2) intra-amniotic inflammation without detectable microorganisms; or 3) microbial-associated intra-amniotic inflammation. The maternal plasma concentrations of 29 cytokines were determined with sensitive and specific V-PLEX immunoassays. Nonparametric statistical methods were used for analysis, adjusting for a false discovery rate of 5%. Results: 1) The maternal plasma concentrations of pyrogenic cytokines (IL-1 beta, IL-2, IL-6, IFN-gamma, and TNF-alpha) were significantly higher in patients with clinical chorioamnionitis at term than in those with spontaneous term labor without clinical chorioamnionitis; 2) the maternal plasma concentrations of cytokines were not significantly different among the three subgroups of patients with clinical chorioamnionitis (intra-amniotic inflammation with and without detectable bacteria and those without intra-amniotic inflammation); and 3) among women with the diagnosis of clinical chorioamnionitis, but without evidence of intra-amniotic inflammation, the maternal plasma concentrations of pyrogenic cytokines were significantly higher than in patients with spontaneous labor at term. These observations suggest that a fever can be mediated by increased circulating concentrations of these cytokines, despite the absence of a local intra-amniotic inflammatory response. Conclusions: 1) The maternal plasma concentrations of pyrogenic cytokines (e.g. IL-1 beta, IL-2, IL-6, IFN-gamma, and TNF-alpha) are higher in patients with intra-partum fever and the diagnosis of clinical chorioamnionitis at term than in those in spontaneous labor at term without a fever; and 2) maternal plasma cytokine concentrations have limited value in the identification of patients with bacteria in the amniotic cavity. Accurate assessment of the presence of intra-amniotic infection requires amniotic fluid analysis. C1 [Romero, Roberto] Wayne State Univ, Hutzel Womens Hosp, NICHD NIH DHHS, Perinatol Res Branch,Dept Med Sci, Detroit, MI 48201 USA. [Romero, Roberto; Chaemsaithong, Piya; Docheva, Nikolina; Korzeniewski, Steven J.; Tarca, Adi L.; Bhatti, Gaurav; Xu, Zhonghui; Kusanovic, Juan P.; Dong, Zhong; Chaiyasit, Noppadol; Ahmed, Ahmed I.; Yoon, Bo Hyun; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Yeo, Lami] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Romero, Roberto; Chaemsaithong, Piya; Docheva, Nikolina; Korzeniewski, Steven J.; Tarca, Adi L.; Bhatti, Gaurav; Xu, Zhonghui; Kusanovic, Juan P.; Dong, Zhong; Chaiyasit, Noppadol; Ahmed, Ahmed I.; Yoon, Bo Hyun; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Yeo, Lami] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto; Korzeniewski, Steven J.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Dept Mol Obstet & Genet, Detroit, MI 48201 USA. [Chaemsaithong, Piya; Docheva, Nikolina; Korzeniewski, Steven J.; Tarca, Adi L.; Bhatti, Gaurav; Xu, Zhonghui; Dong, Zhong; Chaiyasit, Noppadol; Ahmed, Ahmed I.; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Yeo, Lami] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Kusanovic, Juan P.] Hosp Dr Sotero del Rio, Dept Obstet & Gynecol, Ctr Res & Innovat Maternal Fetal Med CIMAF, Santiago, Chile. [Kusanovic, Juan P.] Pontificia Univ Catolica Chile, Dept Obstet & Gynecol, Santiago, Chile. [Yoon, Bo Hyun] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, NICHD NIH DHHS, Perinatol Res Branch,Dept Med Sci, 3990 John R,Box 4, Detroit, MI 48201 USA. EM romeror@mail.nih.gov NR 356 TC 6 Z9 6 U1 4 U2 6 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 EI 1619-3997 J9 J PERINAT MED JI J. Perinat. Med. PD JAN PY 2016 VL 44 IS 1 BP 77 EP 98 DI 10.1515/jpm-2015-0103 PG 22 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA DA9RF UT WOS:000368146600006 PM 26352068 ER PT J AU Vaca, FE Li, KG Hingson, R Simons-Morton, BG AF Vaca, Federico E. Li, Kaigang Hingson, Ralph Simons-Morton, Bruce G. TI Transitions in Riding With an Alcohol/Drug-Impaired Driver From Adolescence to Emerging Adulthood in the United States SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID DRIVING BEHAVIORS; PEER INFLUENCES; RISK BEHAVIORS; SUBSTANCE USE; DRINKING; ASSOCIATION; PREDICTORS; PARENTS; FRIENDS; NORMS AB Objective: The purpose of this study was to examine changes and predictors of changes in riding with an alcohol/drug-impaired driver (RWI) from 10th grade through the first post high school year. Method: Transition models were used to estimate the association of four waves (W1-W4) of RWI with W4 environmental-status variables and time-varying covariates in the NEXT Generation Health Study, a nationally representative cohort of U.S. 10th graders (N = 2,785). Results: Overall, 33% (weighted) of adolescents reported RWI in the past 12 months in W1, and slightly declined in W2 (24%), W3 (27%), and W4 (26%). Across time, transition models with generalized estimating equations showed that RWI was more likely among those who previously reported RWI (ORs from 3.62 to 3.66, p < .001), substance use (ORs from 1.81 to 1.82, p < .001), and heavy episodic drinking (ORs from 1.85 to 1.86, p < .001). Those living on college campuses were somewhat more likely to engage in RWI (OR = 1.38, .05 < p < .10) than those living at home. The effects of parental monitoring knowledge and peer alcohol/substance use on RWI were suppressed when individual substance use and heavy episodic drinking were taken into consideration. Conclusions: Substance use and heavy episodic drinking in previous waves and the history of RWI were persistent factors of RWI in a dynamic pattern. The setting in which emerging adults live during their first post high school year could affect their engagement in RWI. The findings suggest that harm-reduction strategies should focus on the identification of early RWI coupled with reduction of substance use and heavy episodic drinking. C1 [Vaca, Federico E.] Yale Univ, Sch Med, Dept Emergency Med, New Haven, CT USA. [Li, Kaigang] Colorado State Univ, Dept Hlth & Exercise Sci, Ft Collins, CO 80523 USA. [Hingson, Ralph] NIAAA, Div Epidemiol & Prevent Res, Bethesda, MD USA. [Simons-Morton, Bruce G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, Bethesda, MD USA. RP Li, KG (reprint author), Colorado State Univ, Dept Hlth & Exercise Sci, B 215E Moby Complex, Ft Collins, CO 80523 USA. EM kaigang.li@colostate.edu OI Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural Research Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN275201200001I]; National Heart, Lung and Blood Institute (NHLBI); National Institute on Alcohol Abuse and Alcoholism (NIAAA); Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA) FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contract # HHSN275201200001I), the National Heart, Lung and Blood Institute (NHLBI), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and the Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA), with supplemental support from the National Institute on Drug Abuse (NIDA). NR 35 TC 1 Z9 1 U1 0 U2 3 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 EI 1938-4114 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD JAN PY 2016 VL 77 IS 1 BP 77 EP 85 PG 9 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA DB0QC UT WOS:000368211600009 PM 26751357 ER PT J AU Simons-Morton, B Haynie, D Liu, DP Chaurasia, A Li, KG Hingson, R AF Simons-Morton, Bruce Haynie, Denise Liu, Danping Chaurasia, Ashok Li, Kaigang Hingson, Ralph TI The Effect of Residence, School Status, Work Status, and Social Influence on the Prevalence of Alcohol Use Among Emerging Adults SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID COLLEGE BINGE DRINKING; LATENT CLASS ANALYSIS; SUBSTANCE USE; DEPRESSIVE SYMPTOMS; PARENTING PRACTICES; STUDENTS; ADOLESCENCE; RISK; CONSEQUENCES; BEHAVIOR AB Objective: The first year after high school is a transitional year, with increased independence from parental supervision, contact with other independent youth, and exposure to new environments, all of which may influence substance use. This article reports longitudinal predictors of change in the prevalence of alcohol use and heavy episodic drinking among adolescents and environmental correlates (i.e., residence, college attendance, and work status) with drinking the year after high school. Method: A national sample of study participants (N = 2,659; 55% female) in the NEXT Generation Health Study were followed annually from 10th grade (Wave 1) to the year after high school (Wave 4). Longitudinal binary outcomes, including recent (30-day) drinking and two measures of heavy episodic drinking, were examined. Transition models with generalized estimating equations estimated the effect of previous drinking behaviors, social influences, and current residential status and activity (school and/or work) on drinking prevalence. Results: Drinking increased from 40.5% among high school seniors (Wave 3) to 53.5% in Wave 4 for 30-day use, and from 29.0% to 41.2% for heavy episodic drinking. Significant predictors of 30-day drinking included previous drinking status (odds ratio [OR] = 5.48), peer drinking often (OR = 3.25), parental expectations (OR = 0.91), and current year living on campus (OR = 2.10). The same significant predictors with similar magnitudes were found for both measures of heavy episodic drinking. Peer use did not interact with college attendance or residence. Conclusions: Predictors of drinking and heavy episodic drinking during the first year after high school included being White, living on campus, previous drinking, lower parental expectations, and having peers who drink. C1 [Simons-Morton, Bruce; Haynie, Denise; Liu, Danping; Chaurasia, Ashok; Li, Kaigang] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. [Hingson, Ralph] NIDA, Div Epidemiol Serv & Prevent Res, NIH, Bethesda, MD 20892 USA. RP Simons-Morton, B (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B13Q,MSC 7510, Bethesda, MD 20892 USA. EM mortonb@mail.nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617; Haynie, Denise/0000-0002-8270-6079 FU intramural research program of Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HHSN275201200001I]; National Heart, Lung and Blood Institute (NHLBI); National Institute on Alcohol Abuse and Alcoholism (NIAAA); Maternal and Child Health Bureau (MCHB) of Health Resources and Services Administration (HRSA); National Institute on Drug Abuse (NIDA) FX This research (contract number HHSN275201200001I) was supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); the National Heart, Lung and Blood Institute (NHLBI); the National Institute on Alcohol Abuse and Alcoholism (NIAAA); the Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA); and the National Institute on Drug Abuse (NIDA). NR 57 TC 2 Z9 2 U1 5 U2 10 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 EI 1938-4114 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD JAN PY 2016 VL 77 IS 1 BP 121 EP 132 PG 12 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA DB0QC UT WOS:000368211600014 PM 26751362 ER PT J AU Johnson, CG Tang, YQ Beck, A Dreher, MR Woods, DL Negussie, AH Donahue, D Levy, EB Willis, SL Lewis, AL Wood, BJ Sharma, KV AF Johnson, Carmen Gacchina Tang, Yiqing Beck, Avi Dreher, Matthew R. Woods, David L. Negussie, Ayele H. Donahue, Danielle Levy, Elliot B. Willis, Sean L. Lewis, Andrew L. Wood, Bradford J. Sharma, Karun V. TI Preparation of Radiopaque Drug-Eluting Beads for Transcatheter Chemoembolization SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID VX2 LIVER-TUMORS; HEPATOCELLULAR-CARCINOMA; ARTERIAL EMBOLIZATION; MICROSPHERES; DOXORUBICIN; DELIVERY; MODEL; PHARMACOKINETICS; PARTICLES; CONTRAST AB Purpose: To develop a simple method to produce radiopaque drug-eluting microspheres (drug-eluting beads [DEBs]) that could be incorporated into the current clinical transcatheter arterial chemoembolization workflow and evaluate their performance in vitro and in vivo. Materials and Methods: An ethiodized oil (Lipiodol; Guerbet, Villepinte, France) and ethanol solution was added to a lyophilized 100-300 mu m bead before loading with doxorubicin. These radiopaque drug-eluting beads (DEBs; Biocompatibles UK Ltd, Farnham, United Kingdom) were evaluated in vitro for x-ray attenuation, composition, size, drug loading and elution, and correlation between attenuation and doxorubicin concentration. In vivo conspicuity was evaluated in a VX2 tumor model. Results: Lipiodol was loaded into lyophilized beads using two glass syringes and a three-way stopcock. Maximum bead attenuation was achieved within 30 minutes. X-ray attenuation of radiopaque beads increased linearly (21-867 HU)with the amount of beads (0.4-12.5 vol%; R-2 = 0.9989). Doxorubicin loading efficiency and total amount eluted were similar to DC Bead (Biocompatibles UK Ltd); however, the elution rate was slower for radiopaque DEBs (P < 05). Doxorubicin concentration linearly correlated with x-ray attenuation of radiopaque DEBs: (R-2 = 0.99). Radiopaque DEBs were seen in tumor feeding arteries after administration by fluoroscopy, computed tomography, and micro-computed tomography, and their location was confirmed by histology. Conclusions: A simple, rapid method to produce radiopaque DEBs was developed. These radiopaque DEBs provided sufficient conspicuity to be visualized with x-ray imaging techniques. C1 [Johnson, Carmen Gacchina; Beck, Avi; Dreher, Matthew R.; Woods, David L.; Negussie, Ayele H.; Levy, Elliot B.; Wood, Bradford J.; Sharma, Karun V.] NIH, Ctr Clin, Ctr Intervent Oncol Radiol & Imaging Sci, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. [Tang, Yiqing; Dreher, Matthew R.; Willis, Sean L.; Lewis, Andrew L.] Biocompatibles UK Ltd, Farnham, Surrey, England. [Donahue, Danielle] NINDS, Mouse Imaging Facil, NIH, Bethesda, MD 20892 USA. [Sharma, Karun V.] Georgetown Univ Hosp, Dept Radiol, Washington, DC 20007 USA. [Sharma, Karun V.] Childrens Natl Med Ctr, Dept Radiol, Washington, DC 20010 USA. [Sharma, Karun V.] Childrens Natl Med Ctr, Sheikh Zayed Inst Pediat Surg Innovat, Washington, DC 20010 USA. RP Sharma, KV (reprint author), NIH, Ctr Clin, Ctr Intervent Oncol Radiol & Imaging Sci, Bethesda, MD 20892 USA. EM kvsharma@cnmc.org OI Lewis, Andrew/0000-0001-5779-5631 FU Intramural Research Program of the National Institutes, of Health; Society of Interventional Radiology Foundation; Imaging Sciences Training Program of the National Institutes of Health FX We thank Dr. Bacher and his team in the Division of Veterinary Resources, Office of Research Services. We also thank Pavel Yarmolenko for his assistance and useful discussions. This study was conducted in the Center for Interventional Oncology and is supported in part by the Intramural Research Program of the National Institutes, of Health and the Society of Interventional Radiology Foundation Ring Grant. C.G.J. was supported by the Imaging Sciences Training Program of the National Institutes of Health. The National Institutes of Health and Biocompatibles UK Ltd are parties to a Cooperative Research and Development Agreement. The mention of commercial products, their source, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the National Institutes of Health. NR 27 TC 3 Z9 3 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD JAN PY 2016 VL 27 IS 1 BP 117 EP 126 DI 10.1016/j.jvir.2015.09.011 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA DA7DA UT WOS:000367963600016 PM 26549370 ER PT J AU Johnson, CG Sharma, KV Levy, EB Woods, DL Morris, AH Bacher, JD Lewis, AL Wood, BJ Dreher, MR AF Johnson, Carmen Gacchina Sharma, Karun V. Levy, Elliot B. Woods, David L. Morris, Aaron H. Bacher, John D. Lewis, Andrew L. Wood, Bradford J. Dreher, Matthew R. TI Microvascular Perfusion Changes following Transarterial Hepatic Tumor Embolization SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID TRANSCATHETER INTRAARTERIAL PERFUSION; CHEMOEMBOLIZATION END-POINTS; INTERMITTENT BLOOD-FLOW; HEPATOCELLULAR-CARCINOMA; MONITORING CHEMOEMBOLIZATION; ARTERIAL EMBOLIZATION; TRANSIENT PERFUSION; FLUCTUATIONS; LIVER; SHEEP AB Purpose: To quantify changes in tumor microvascular (<1 mm) perfusion relative to commonly used angiographic endpoints. Materials and Methods: Rabbit Vx2 liver tumors were embolized with 100300-mu m LC Bead particles to endpoints of substasis or complete stasis (controls were not embolized). Microvascular perfusion wars evaluated by delivering two,different fluorophore-conjugated perfusion markers (ie, lectins) through the catheter before embolization and 5 min after reaching the desired angiographic endpoint. Tumor microvasculature was labeled with an anti-CD31 antibody and analyzed with fluorescence microscopy for perfusion marker overlap/mismatch. Data were analyzed by analysis of variance and post hoc test (n = 3-5 per group; 18 total). Results: Mean microvascular density was 70 vessels/mm(2) +/- 17 (standard error of the mean), and 81% 1 of microvasculature (ie, CD31(+) structures) was functionally perfused within viable Vx2 tumor regions. Embolization to the extent of substasis eliminated perfusion in 37% +/- 9 of perfused microvessels P > .05 vs baseline), whereas embolization to the extent of angiographic stasis eliminated perfusion in 56% +/- 8 of perfused microvessels. Persistent microvascular perfusion following embolization was predominantly found in the tumor periphery, adjacent to normal tissue. Newly perfused microvasculatute was evident following embolization to substasis but not when embolization was performed to complete angiographic stasis. Conclusions: Nearly half of tumor microvasculature remained patent despite embolization to complete angiographic stasis. The observed preservation of tumor microvasculature perfusion with angiographic endpoints of substasis and stasis may have implications for tumor response to embolothetapy. C1 [Johnson, Carmen Gacchina; Sharma, Karun V.; Levy, Elliot B.; Woods, David L.; Morris, Aaron H.; Wood, Bradford J.; Dreher, Matthew R.] Ctr Clin, Ctr Intervent Oncol Radiol & Imaging Sci, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. [Bacher, John D.] NIH, Div Vet Resources, Bethesda, MD 20892 USA. [Sharma, Karun V.] Childrens Natl Med Ctr, Dept Radiol, Washington, DC 20010 USA. [Lewis, Andrew L.; Dreher, Matthew R.] Biocompatibles BTG UK, Farnham, Surrey, England. RP Wood, BJ (reprint author), Ctr Clin, Ctr Intervent Oncol Radiol & Imaging Sci, Bethesda, MD 20892 USA. EM bwood@cc.nih.gov OI Lewis, Andrew/0000-0001-5779-5631 FU Intramural Research Program of the NIH; NIH Center for Interventional Oncology; NIH Imaging Sciences Training Program FX The authors thank the Division of Veterinary Resources staff of the National Institutes of Health (NIH) for their expertise and assistance with the animal studies. This study was supported by the Intramural Research Program of the NIH, the NIH Center for Interventional Oncology, and the NIH Imaging Sciences Training Program. The NIH and Biocompatibles BTG UK are parties to a Cooperative Research and Development Agreement. The mention of commercial products, their source, or their use in connection with material reported herein is not to be construed as an actual or implied endorsement of such products by the United States Food and Drug Administration, the National Institutes of Health, the Department of Health and Human Services, or the Public Health Service. NR 22 TC 3 Z9 3 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD JAN PY 2016 VL 27 IS 1 BP 133 EP 141 DI 10.1016/j.jvir.2015.06.036 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA DA7DA UT WOS:000367963600018 PM 26321051 ER PT J AU Wallace, ME Mendola, P Chen, Z Hwang, BS Grantz, KL AF Wallace, Maeve E. Mendola, Pauline Chen, Zhen Hwang, Beom Seuk Grantz, Katherine L. TI Preterm Birth in the Context of Increasing Income Inequality SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Preterm birth; Income inequality; Gini coefficient ID UNITED-STATES; SOCIOECONOMIC-STATUS; POPULATION HEALTH; OUTCOMES; MORTALITY; COUNTRIES; DISPARITIES; HOMICIDE AB Objective Preterm birth is a leading cause of infant morbidity and mortality. Little is known about the contextual effect of US income inequality on preterm birth, an issue of increasing concern given that the current economic divide is the largest since 1928. Methods We examined changes in inequality over time in relation to preterm birth among singleton deliveries from an electronic medical record-based cohort (n = 223,512) conducted in 11 US states and the District of Columbia from 2002 to 2008. Increasing income inequality was defined as a positive change in state-level Gini coefficient from the year prior to birth. Multi-level models estimated the independent effect of increasing inequality on preterm birth (>22 and <37 weeks) controlling for maternal demographics, health behaviors, insurance status, chronic medical conditions, and state-level poverty and unemployment during the year of birth. Results The preterm birth rate was 12.3 % where inequality increased and 10.9 % where it did not. After adjustment, increasing inequality remained significantly associated with preterm birth (adjusted odds ratio 1.07, 95 % confidence interval 1.04, 1.11). We observed no significant interaction by insurance status or race, suggesting that increasing inequality had a broad effect across the population. Conclusions The contextual effect of increasing income inequality on preterm birth risk merits further study. C1 [Wallace, Maeve E.; Mendola, Pauline; Grantz, Katherine L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Populat Hlth Res, Epidemiol Branch, Rockville, MD 20852 USA. [Chen, Zhen; Hwang, Beom Seuk] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Populat Hlth Res, Biostat & Bioinformat Branch, Rockville, MD 20852 USA. RP Mendola, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Populat Hlth Res, Epidemiol Branch, 6100 Execut Blvd, Rockville, MD 20852 USA. EM Pauline.mendola@nih.gov OI Mendola, Pauline/0000-0001-5330-2844; Grantz, Katherine/0000-0003-0276-8534 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Intramural Research Program of the NICHD [HHSN267200603425C] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The Consortium on Safe Labor was funded by the Intramural Research Program of the NICHD, through Contract No. HHSN267200603425C. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The study sponsor has no direct role in the study design; collection, analysis and interpretation of data; or in the writing of the report. All manuscripts undergo Institute clearance before submission. The corresponding author has full access to the data and the final responsibility of the decision to submit the work for publication. NR 33 TC 0 Z9 0 U1 5 U2 12 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD JAN PY 2016 VL 20 IS 1 BP 164 EP 171 DI 10.1007/s10995-015-1816-9 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DB0LM UT WOS:000368199600019 PM 26450504 ER PT J AU Maudsley, S Martin, B Janssens, J Etienne, H Jushaj, A van Gastel, J Willemsen, A Chen, HY Gesty-Palmer, D Luttrell, LM AF Maudsley, Stuart Martin, Bronwen Janssens, Jonathan Etienne, Harmonie Jushaj, Areta van Gastel, Jaana Willemsen, Ann Chen, Hongyu Gesty-Palmer, Diane Luttrell, Louis M. TI Informatic deconvolution of biased GPCR signaling mechanisms from in vivo pharmacological experimentation SO METHODS LA English DT Article DE G protein-coupled receptor; Signaling bias; Arrestin; Informatic; Transcriptome; In vivo ID FUNCTIONAL SELECTIVITY; HUNTINGTON DISEASE; RECEPTOR; PATHWAYS; EFFICACY; CANCER; PHOSPHORYLATION; BETA-ARRESTIN2; ACTIVATION; AGONISM AB Ligands possessing different physico-chemical structures productively interact with G protein-coupled receptors generating distinct downstream signaling events due to their abilities to activate/select idiosyncratic receptor entities ('receptorsomes') from the full spectrum of potential receptor partners. We have employed multiple novel informatic approaches to identify and characterize the in vivo transcriptomic signature of an arrestin-signaling biased ligand, [D-Trp(12),Tyr(34)]-bPTH(7-34), acting at the parathyroid hormone type I receptor (PTH1R), across six different murine tissues after chronic drug exposure. We are able to demonstrate that [D-Trp(12),Tyr(34)]-bPTH(7-34) elicits a distinctive arrestin-signaling focused transcriptomic response that is more coherently regulated, in an arrestin signaling-dependent manner, across more tissues than that of the pluripotent endogenous PTIIIR ligand, hPTH(1-34). This arrestin-focused response signature is strongly linked with the transcriptional regulation of cell growth and development. Our informatic deconvolution of a conserved arrestin-dependent transcriptomic signature from wild type mice demonstrates a conceptual framework within which the in vivo outcomes of biased receptor signaling may be further investigated or predicted. Published by Elsevier Inc. C1 [Maudsley, Stuart; Janssens, Jonathan; Etienne, Harmonie; Jushaj, Areta; van Gastel, Jaana; Willemsen, Ann] Univ Antwerp, Translat Neurobiol Grp, VIB Dept Mol Genet, B-2020 Antwerp, Belgium. [Maudsley, Stuart; Janssens, Jonathan; Etienne, Harmonie; Jushaj, Areta] Univ Antwerp, Inst Born Bunge, Neurogenet Lab, B-2020 Antwerp, Belgium. [Martin, Bronwen] NIA, Metab Unit, NIH, Baltimore, MD 21224 USA. [Chen, Hongyu] Dartmouth Coll, Hanover, NH 03755 USA. [Gesty-Palmer, Diane] Duke Univ, Med Ctr, Durham, NC 27705 USA. [Luttrell, Louis M.] Med Univ S Carolina, Charleston, SC 29425 USA. RP Maudsley, S (reprint author), Univ Antwerp, Inst Born Bunge, VIB Dept Mol Genet, B-2020 Antwerp, Belgium. EM stuart.maudsley@molgen.vib-ua.be FU National Institutes of Health [AG000916-01]; National Institutes of Health National Institute of General Medical Sciences [R01-GM095497]; National Institutes of Health National Institute of Diabetes, Digestive and Kidney Diseases [R01-DK055524]; National Institutes of Health National Institute of Child Health and Human Development [T32-HD043446] FX The study was in-part funded by the National Institutes of Health Grants AG000916-01 (S.M.) and the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM095497]; the National Institutes of Health National Institute of Diabetes, Digestive and Kidney Diseases [Grant R01-DK055524]; the National Institutes of Health National Institute of Child Health and Human Development [Grant T32-HD043446] (L.M.L.). NR 43 TC 3 Z9 3 U1 2 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD JAN 1 PY 2016 VL 92 BP 51 EP 63 DI 10.1016/j.ymeth.2015.05.013 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DB0QL UT WOS:000368212500006 PM 25986936 ER PT J AU Ellinsworth, DC Sandow, SL Shukla, N Liu, YP Jeremy, JY Gutterman, DD AF Ellinsworth, David C. Sandow, Shaun L. Shukla, Nilima Liu, Yanping Jeremy, Jamie Y. Gutterman, David D. TI Endothelium-Derived Hyperpolarization and Coronary Vasodilation: Diverse and Integrated Roles of Epoxyeicosatrienoic Acids, Hydrogen Peroxide, and Gap Junctions SO MICROCIRCULATION LA English DT Review DE human coronary microcirculation; coronary blood flow; endothelium-derived hyperpolarization; endothelium-derived hyperpolarizing factor; Ca2+-activated K+ channels; epoxyeicosatrienoic acids; hydrogen peroxide; gap junctions; myoendothelial signaling microdomains; transient receptor potential channels; connexins; cytochrome P450 epoxygenases; NADPH oxidase; mitochondrial electron transport chain; nitric oxide; coronary artery disease ID CA2+-ACTIVATED K+ CHANNELS; FLOW-INDUCED DILATION; BRADYKININ-INDUCED RELAXATION; ACTIVATED POTASSIUM CHANNELS; INTERNAL ELASTIC LAMINA; NITRIC-OXIDE; REACTIVE OXYGEN; SMOOTH-MUSCLE; IN-VIVO; NADPH OXIDASE AB Myocardial perfusion and coronary vascular resistance are regulated by signaling metabolites released from the local myocardium that act either directly on the VSMC or indirectly via stimulation of the endothelium. A prominent mechanism of vasodilation is EDH of the arteriolar smooth muscle, with EETs and H2O2 playing important roles in EDH in the coronary microcirculation. In some cases, EETs and H2O2 are released as transferable hyperpolarizing factors (EDHFs) that act directly on the VSMCs. By contrast, EETs and H2O2 can also promote endothelial K-Ca activity secondary to the amplification of extracellular Ca2+ influx and Ca2+ mobilization from intracellular stores, respectively. The resulting endothelial hyperpolarization may subsequently conduct to the media via myoendothelial gap junctions or potentially lead to the release of a chemically distinct factor(s). Furthermore, in human isolated coronary arterioles dilator signaling involving EETs and H2O2 may be integrated, being either complimentary or inhibitory depending on the stimulus. With an emphasis on the human coronary microcirculation, this review addresses the diverse and integrated mechanisms by which EETs and H2O2 regulate vessel tone and also examines the hypothesis that myoendothelial microdomain signaling facilitates EDH activity in the human heart. C1 [Ellinsworth, David C.; Shukla, Nilima; Jeremy, Jamie Y.] Univ Bristol, Bristol Heart Inst, Bristol BS2 8HW, Avon, England. [Sandow, Shaun L.] Univ Sunshine Coast, Fac Sci Hlth Educ & Engn, Maroochydore, Qld, Australia. [Liu, Yanping] NIH, Div Res Infrastruct, Natl Ctr Res Resources, Bethesda, MD 20892 USA. [Gutterman, David D.] Med Coll Wisconsin, Dept Med Physiol & Pharmacol, Div Cardiovasc Med, Milwaukee, WI 53226 USA. RP Ellinsworth, DC (reprint author), Univ Bristol, Bristol Heart Inst, Bristol BS2 8HW, Avon, England. EM davidellinsworth@gmail.com RI Sandow, Shaun/N-4256-2016 OI Sandow, Shaun/0000-0002-0753-2742 FU Brain Foundation; Diabetes Australia Research Trust; National Health and Medical Research Council of Australia (NHMRC) [APP1048885]; National Heart, Lung and Blood Institute (NHLBI) [HL113612] FX This work was supported by the Brain Foundation, the Diabetes Australia Research Trust, the National Health and Medical Research Council of Australia (NHMRC) (Project Grant APP1048885, to Shaun L. Sandow), and the National Heart, Lung and Blood Institute (NHLBI) (Project Grant HL113612, to David D. Gutterman). NR 156 TC 2 Z9 2 U1 3 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1073-9688 EI 1549-8719 J9 MICROCIRCULATION JI Microcirculation PD JAN PY 2016 VL 23 IS 1 BP 15 EP 32 DI 10.1111/micc.12255 PG 18 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DA8XA UT WOS:000368089000002 PM 26541094 ER PT J AU Cadet, JL AF Cadet, Jean Lud TI Epigenetics of Stress, Addiction, and Resilience: Therapeutic Implications SO MOLECULAR NEUROBIOLOGY LA English DT Article DE Alcohol; Cocaine; DNA methylation; Heroin; Histone acetylation; Methamphetamine; Nicotine ID SUBSTANCE USE DISORDERS; HISTONE DEACETYLASE INHIBITORS; COCAINE-INDUCED PLASTICITY; VENTRAL TEGMENTAL AREA; NOVELTY-SEEKING BEHAVIOR; RECEPTOR GENE NR3C1; NUCLEUS-ACCUMBENS; DNA METHYLATION; MATERNAL-BEHAVIOR; INDIVIDUAL-DIFFERENCES AB Substance use disorders (SUDs) are highly prevalent. SUDs involve vicious cycles of binges followed by occasional periods of abstinence with recurrent relapses despite treatment and adverse medical and psychosocial consequences. There is convincing evidence that early and adult stressful life events are risks factors for the development of addiction and serve as cues that trigger relapses. Nevertheless, the fact that not all individuals who face traumatic events develop addiction to licit or illicit drugs suggests the existence of individual and/or familial resilient factors that protect these mentally healthy individuals. Here, I give a brief overview of the epigenetic bases of responses to stressful events and of epigenetic changes associated with the administration of drugs of abuse. I also discuss the psychobiology of resilience and alterations in epigenetic markers that have been observed in models of resilience. Finally, I suggest the possibility that treatment of addiction should involve cognitive and pharmacological approaches that enhance resilience in at risk individuals. Similar approaches should also be used with patients who have already succumbed to the nefarious effects of addictive substances. C1 [Cadet, Jean Lud] NIDA, Mol Neuropsychiat Res Branch, DHHS, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Cadet, JL (reprint author), NIDA, Mol Neuropsychiat Res Branch, DHHS, Intramural Res Program,NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM jcadet@intra.nida.nih.gov FU Intramural Research Program of the DHHS/NIH/NIDA FX This work was supported by funds of the Intramural Research Program of the DHHS/NIH/NIDA. The author thanks Maryann Carrigan, Christie Brannock, and Dr. Subramaniam Jayanthi for editorial help. The author also thanks two anonymous reviewers whose comments helped to improve this paper. NR 226 TC 6 Z9 6 U1 9 U2 33 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 EI 1559-1182 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD JAN PY 2016 VL 53 IS 1 BP 545 EP 560 DI 10.1007/s12035-014-9040-y PG 16 WC Neurosciences SC Neurosciences & Neurology GA DB0CN UT WOS:000368176300047 PM 25502297 ER PT J AU Smith, DJ Brat, GA Medina, SH Tong, DD Huang, Y Grahammer, J Furtmuller, GJ Oh, BC Nagy-Smith, KJ Walczak, P Brandacher, G Schneider, JP AF Smith, Daniel J. Brat, Gabriel A. Medina, Scott H. Tong, Dedi Huang, Yong Grahammer, Johanna Furtmueller, Georg J. Oh, Byoung Chol Nagy-Smith, Katelyn J. Walczak, Piotr Brandacher, Gerald Schneider, Joel P. TI A multiphase transitioning peptide hydrogel for suturing ultrasmall vessels SO NATURE NANOTECHNOLOGY LA English DT Article ID ANTIPARALLEL BETA-SHEETS; MICROVASCULAR ANASTOMOSIS; DESIGNED PEPTIDE AB Many surgeries are complicated by the need to anastomose, or reconnect, micrometre-scale vessels. Although suturing remains the gold standard for anastomosing vessels, it is difficult to place sutures correctly through collapsed lumen, making the procedure prone to failure. Here, we report a multiphase transitioning peptide hydrogel that can be injected into the lumen of vessels to facilitate suturing. The peptide, which contains a photocaged glutamic acid, forms a solid-like gel in a syringe and can be shear-thin delivered to the lumen of collapsed vessels (where it distends the vessel) and the space between two vessels (where it is used to approximate the vessel ends). Suturing is performed directly through the gel. Light is used to initiate the final gel-sol phase transition that disrupts the hydrogel network, allowing the gel to be removed and blood flow to resume. This gel adds a new tool to the armamentarium for micro-and supermicrosurgical procedures. C1 [Smith, Daniel J.; Medina, Scott H.; Nagy-Smith, Katelyn J.; Schneider, Joel P.] NCI, Chem Biol Lab, Frederick, MD 21702 USA. [Smith, Daniel J.; Nagy-Smith, Katelyn J.] Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA. [Brat, Gabriel A.; Tong, Dedi; Grahammer, Johanna; Furtmueller, Georg J.; Oh, Byoung Chol; Brandacher, Gerald] Johns Hopkins Univ, Sch Med, Dept Plast & Reconstruct Surg, Vascularized Composite Allotransplantat VCA Lab, Baltimore, MD 21287 USA. [Huang, Yong] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. [Walczak, Piotr] Johns Hopkins Univ, Sch Med, Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. RP Smith, DJ (reprint author), NCI, Chem Biol Lab, Frederick, MD 21702 USA. EM schneiderjp@mail.nih.gov RI Brandacher, Gerald/L-7540-2016 FU Intramural Research Program of National Institutes of Health; National Cancer Institute; Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, and the Center for Cancer Research. The authors thank B. Bush for performing the atomic force microscopy analysis. NR 26 TC 9 Z9 9 U1 9 U2 42 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1748-3387 EI 1748-3395 J9 NAT NANOTECHNOL JI Nat. Nanotechnol. PD JAN PY 2016 VL 11 IS 1 BP 95 EP + DI 10.1038/NNANO.2015.238 PG 9 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA DA5JO UT WOS:000367839600018 PM 26524396 ER PT J AU Ramos-Alvarez, I Nakamura, T Mantey, SA Moreno, P Nuche-Berenguer, B Jensen, RT AF Ramos-Alvarez, Irene Nakamura, Taichi Mantey, Samuel A. Moreno, Paola Nuche-Berenguer, Bernardo Jensen, Robert T. TI Novel chiral-diazepines function as specific, selective receptor agonists with variable coupling and species variability in human, mouse and rat BRS-3 receptor cells SO PEPTIDES LA English DT Article DE BRS-3; Chiral diazepine; Bombesin receptor; Obesity; Diabetes; Nonpeptide agonist ID HUMAN BOMBESIN RECEPTORS; HUMAN ORPHAN RECEPTOR; LUNG-CANCER CELLS; BRONCHIAL EPITHELIAL-CELLS; SUBTYPE-3 BRS-3; PANCREATIC ACINI; PEPTIDE AGONIST; DISEASE STATES; CCK1 RECEPTOR; SMOOTH-MUSCLE AB Bombesin receptor subtype-3 (BRS-3) is an orphan G-protein coupled receptor which is classified in the bombesin receptor (BnR) family with which it shares high homology. It is present widely in the central nervous system and peripheral tissues and primarily receptor-knockout studies suggest it is involved in metabolic-glucose-insulin homeostasis, feeding and other CNS behaviors, gastrointestinal motility and cancer growth. However, the role of BRS-3 physiologically or in pathologic disorders has been not well defined because the natural ligand is unknown. Until recently, no selective agonists/antagonists were available; however, recently synthetic high-affinity agonists, chiral-diazepines nonpeptide-analogs (3F, 9D, 9F, 9G) with low CNS penetrance, were described, but are not well-categorized pharmacologically or in different labarotory species. The present study characterizes the affinities, potencies, selectivities of the chiral-diazepine BRS-3 agonists in human and rodents (mice,rat). In human BRS-3 receptors, the relative affinities of the chiral-diazepines was 9G > 9D > 9F > 3F; each was selective for BRS-3. For stimulating PLC activity, in h-BRS-3 each of the four chiral diazepine analogs was fully efficacious and their relative potencies were: 9G (EC50: 9 nM) > 9D (EC50: 9.4 nM) > 9F (EC50: 39 nM) > 3F (EC50: 48 nM). None of the four chiral diazepine analogs activated r,m,h-GRPR/NMBR. The nonpeptide agonists showed marked differences from each other and a peptide agonist in receptor-coupling-stiochiometry and in affinities/potencies in different species. These results demonstrate that chiral diazepine analogs (9G, 9D, 9F, 3F) have high/affinity/potency for the BRS-3 receptor in human and rodent cells, but different coupling-relationships and species differences from a peptide agonist. Published by Elsevier Inc. C1 [Ramos-Alvarez, Irene; Nakamura, Taichi; Mantey, Samuel A.; Moreno, Paola; Nuche-Berenguer, Bernardo; Jensen, Robert T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Jensen, RT (reprint author), NIDDK, Digest Dis Branch, NIH, Bldg 10,Roo 9C 103,10 Ctr Dr MSC 1804, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov FU NIDDK, NIH FX This work was partially supported by intramural funds of the NIDDK, NIH. NR 69 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 EI 1873-5169 J9 PEPTIDES JI Peptides PD JAN PY 2016 VL 75 BP 8 EP 17 DI 10.1016/j.peptides.2015.10.007 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA DA8CW UT WOS:000368033000002 PM 26524625 ER PT J AU Rong, PF Wu, JZ Liu, ZG Ma, XQ Yu, L Zhou, KC Zeng, WB Wang, W AF Rong, Pengfei Wu, Jianzhen Liu, Zhiguo Ma, Xiaoqian Yu, Lun Zhou, Kechao Zeng, Wenbin Wang, Wei TI Fluorescence dye loaded nano-graphene for multimodal imaging guided photothermal therapy SO RSC ADVANCES LA English DT Article ID NANOSHEETS; DELIVERY AB Photoacoustic imaging (PA) has emerged as a novel and noninvasive imaging modality owing to its high spatial resolution and high soft tissue contrast. Herein, we loaded a near-infrared (NIR) fluorescence dye (CySCOOH) onto the surface of PEGylated graphene oxide (GO) via pi-pi stacking to increase the NIR absorbance of GO. The PA imaging proved that PEGylated GO-CysCOOH (GO-PEG-CysCOOH) significantly enhances the PA signal in the tumor site compared with free GO-PEG. We then utilized the strong optical absorbance of GO-PEG-CySCOOH in the NIR region for in vivo photothermal therapy, achieving efficient tumor ablation after intravenous injection of GO-PEG-CySCOOH and low-power laser irradiation on the tumor. Our results indicate that this graphene-based nanocomposite can be developed as a promising contrast agent for PA imaging and a thermal agent for imaging guided photothermal therapy. C1 [Rong, Pengfei; Wu, Jianzhen; Ma, Xiaoqian; Wang, Wei] Cent S Univ, Xiangya Hosp 3, Dept Radiol, Changsha 410013, Hunan, Peoples R China. [Rong, Pengfei] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Rong, Pengfei; Zhou, Kechao] Cent S Univ, State Key Lab Powder Met, Changsha 410083, Hunan, Peoples R China. [Liu, Zhiguo; Yu, Lun; Zeng, Wenbin] Cent S Univ, Sch Pharmaceut Sci, Changsha 410013, Hunan, Peoples R China. RP Wu, JZ (reprint author), Cent S Univ, Xiangya Hosp 3, Dept Radiol, Changsha 410013, Hunan, Peoples R China. EM wujianzhen66@163.com; cjr.wangwei@vip.163.com FU Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH); National Natural Science Foundation of China [81471715, 81201171, 30900359]; Hunan healthcare research funds [B2013-06] FX This work was supported by the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), and grants from National Natural Science Foundation of China (81471715, 81201171, 30900359), Hunan healthcare research funds (B2013-06). NR 17 TC 2 Z9 2 U1 9 U2 26 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2046-2069 J9 RSC ADV JI RSC Adv. PY 2016 VL 6 IS 3 BP 1894 EP 1901 DI 10.1039/c5ra24752g PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA DB0IF UT WOS:000368191100024 PM 27547385 ER PT S AU Vacchio, MS Ciucci, T Bosselut, R AF Vacchio, Melanie S. Ciucci, Thomas Bosselut, Remy BE Bosselut, R Vacchio, MS TI 200 Million Thymocytes and I: A Beginner's Survival Guide to T Cell Development SO T-CELL DEVELOPMENT: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE T cells; T cell development; T cell receptor; TCR gene rearrangement; Positive selection; Negative selection ID DELTA-LIKE 4; NEGATIVE SELECTION; LINEAGE COMMITMENT; ALPHA-BETA; FATE SPECIFICATION; POSITIVE SELECTION; CLONAL DELETION; THYMUS; RECEPTOR; DIFFERENTIATION AB T lymphocytes (T cells) are essential for proper adaptive immune responses. They perform a variety of functions in defenses against pathogens, and notably control, positively or negatively, other cells involved in immune responses. T cells develop in the thymus from bone marrow-derived precursors. These precursors (thymocytes) proliferate, rearrange the genes encoding subunits of the T cell antigen receptor, which endow them with their unique antigen specificity, and undergo various degrees of pre-programming for their functions in immune responses. Thus, analyzing T cell development in the thymus is essential for understanding their functions in immune responses. In addition, the thymus constitutes an attractive experimental model to analyze mechanisms of cell proliferation, differentiation and survival, all of which are involved in thymocyte development. This chapter presents a quick overview of the key events characterizing intrathymic T cell development, as an introduction for readers entering this field of study. C1 [Vacchio, Melanie S.; Ciucci, Thomas; Bosselut, Remy] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Vacchio, MS (reprint author), NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 75 TC 1 Z9 1 U1 3 U2 15 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-2809-5; 978-1-4939-2808-8 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1323 BP 3 EP 21 DI 10.1007/978-1-4939-2809-5_1 D2 10.1007/978-1-4939-2809-5 PG 19 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA BE1KZ UT WOS:000368096000002 PM 26294394 ER PT S AU Bosselut, R Vacchio, MS AF Bosselut, Remy Vacchio, Melanie S. BE Bosselut, R Vacchio, MS TI T-Cell Development Methods and Protocols Preface SO T-CELL DEVELOPMENT: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Editorial Material; Book Chapter C1 [Bosselut, Remy; Vacchio, Melanie S.] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bosselut, R (reprint author), NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-2809-5; 978-1-4939-2808-8 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1323 BP V EP VI D2 10.1007/978-1-4939-2809-5 PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA BE1KZ UT WOS:000368096000001 PM 26512377 ER PT S AU Ciucci, T Vacchio, MS Bosselut, R AF Ciucci, Thomas Vacchio, Melanie S. Bosselut, Remy BE Bosselut, R Vacchio, MS TI Genetic Tools to Study T Cell Development SO T-CELL DEVELOPMENT: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Cre recombinase; Genetic strategies; Lineage-specific gene disruption; TCR transgenic mice; Deletion reporter genes ID RECEPTOR TRANSGENIC MICE; TCR-ALPHA EXPRESSION; NEGATIVE SELECTION; ANTIGEN RECEPTOR; IN-VIVO; POSITIVE SELECTION; CYTOTOXIC-LINEAGE; THYMIC SELECTION; MHC; LYMPHOCYTES AB Genetics tools, and especially the ability to enforce, by transgenesis, or disrupt, by homologous recombination, gene expression in a cell-specific manner, have revolutionized the study of immunology and propelled the laboratory mouse as the main model to study immune responses. Perhaps more than any other aspect of immunology, the study of T cell development has benefited from these technologies. This brief chapter summarizes genetic tools specific to T cell development studies, focusing on mouse strains with lineage- and stage-specific expression of the Cre recombinase, or expressing unique antigen receptor specificities. It ends with a broader discussion of strategies to enforce ectopic lineage and stage-specific gene expression. C1 [Ciucci, Thomas; Vacchio, Melanie S.; Bosselut, Remy] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ciucci, T (reprint author), NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 60 TC 1 Z9 1 U1 1 U2 23 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-2809-5; 978-1-4939-2808-8 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1323 BP 35 EP 45 DI 10.1007/978-1-4939-2809-5_3 D2 10.1007/978-1-4939-2809-5 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA BE1KZ UT WOS:000368096000004 PM 26294396 ER PT S AU Lee, JYM Love, PE AF Lee, Jan Y. M. Love, Paul E. BE Bosselut, R Vacchio, MS TI Assessment of T Cell Development by Flow Cytometry SO T-CELL DEVELOPMENT: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE T cell development; Thymocytes; T lymphocytes; Flow cytometry; Antibody staining; Intracellular staining; alpha beta T cells; gamma delta T cells; NKT cells; Regulatory T cells ID SELECTION; THYMOCYTES AB T cell development is a complex multistep process that requires the coordinated activation of distinct signaling responses and the regulated progression of developing cells (thymocytes) through key stages of maturation. Although sophisticated techniques such as fetal thymus organ culture, in vitro thymocyte culture, and multi-parameter flow cytometric analysis are now widely employed to evaluate thymocyte maturation by experienced laboratories, defects in T cell development can usually be identified with more simplified screening methods. Here, we provide a basic protocol for assessment of T cell development that will enable laboratories with access to a four parameter flow cytometer to screen mouse strains, including those generated from embryonic stem cells with targeted gene mutations, for thymocyte maturation defects. C1 [Lee, Jan Y. M.; Love, Paul E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular & Dev Biol, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Lee, JYM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular & Dev Biol, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. NR 13 TC 1 Z9 1 U1 1 U2 32 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-2809-5; 978-1-4939-2808-8 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1323 BP 47 EP 64 DI 10.1007/978-1-4939-2809-5_4 D2 10.1007/978-1-4939-2809-5 PG 18 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA BE1KZ UT WOS:000368096000005 PM 26294397 ER PT S AU Carpenter, AC Kim, JK Bosselut, R AF Carpenter, Andrea C. Kim, Jong Kyong Bosselut, Remy BE Bosselut, R Vacchio, MS TI Purification of Thymocyte and T Cell Subsets SO T-CELL DEVELOPMENT: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Single-cell suspension; T cell purification; Magnetic bead depletion; Flow cytometric sorting AB Many analytical or cell culture procedures require homogeneous starting cell populations that cannot be obtained directly from organ dissection. Here, we describe two enrichment procedures to achieve this goal and discuss their respective advantages in specific experimental contexts. Notes in this chapter include some tips on how to determine the appropriate level of purity (see Note 1). C1 [Carpenter, Andrea C.; Bosselut, Remy] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kim, Jong Kyong] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou 510275, Guangdong, Peoples R China. RP Carpenter, AC (reprint author), NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-2809-5; 978-1-4939-2808-8 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1323 BP 87 EP 97 DI 10.1007/978-1-4939-2809-5_7 D2 10.1007/978-1-4939-2809-5 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA BE1KZ UT WOS:000368096000008 PM 26294400 ER PT S AU Flomerfelt, FA Gress, RE AF Flomerfelt, Francis A. Gress, Ronald E. BE Bosselut, R Vacchio, MS TI Bone Marrow and Fetal Liver Radiation Chimeras SO T-CELL DEVELOPMENT: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Bone marrow; Transplantation; Hematopoietic stem cells; Immune reconstitution; T cell AB Radiation chimeras are prepared by subjecting recipient mice to sublethal or lethal dose of irradiation and injecting them with hematopoietic stem cells (HSC) from untreated donor mice. HSC can be obtained from bone marrow or fetal liver. This technique is a powerful tool when coupled with gene targeting strategies to investigate function of HSCs, thymocyte development, and T cell function. This protocol describes how to produce bone marrow or fetal liver chimeras. C1 [Flomerfelt, Francis A.; Gress, Ronald E.] NCI, Expt Immunol & Transplantat Branch, Bethesda, MD 20892 USA. RP Flomerfelt, FA (reprint author), NCI, Expt Immunol & Transplantat Branch, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 4 TC 0 Z9 0 U1 1 U2 14 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-2809-5; 978-1-4939-2808-8 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1323 BP 109 EP 115 DI 10.1007/978-1-4939-2809-5_9 D2 10.1007/978-1-4939-2809-5 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA BE1KZ UT WOS:000368096000010 PM 26294402 ER PT S AU Wohlfert, EA Carpenter, AC Belkaid, Y Bosselut, R AF Wohlfert, Elizabeth A. Carpenter, Andrea C. Belkaid, Yasmine Bosselut, Remy BE Bosselut, R Vacchio, MS TI In Vitro Analyses of T Cell Effector Differentiation SO T-CELL DEVELOPMENT: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE T cell differentiation; Tc; Th0; ThN; Th1; Th2; Th17; iTreg ID RETINOIC-ACID; INTERLEUKIN-2 AB In vitro culture is an important complement, or substitute, to in vivo approaches in order to study T cell effector differentiation. Here, we describe culture conditions that generate specific effector cell types by exposing naive T cells to appropriate cytokine signals. C1 [Wohlfert, Elizabeth A.] SUNY Buffalo, Dept Microbiol & Immunol, Sch Med & Biomed Sci, Buffalo, NY 14260 USA. [Carpenter, Andrea C.; Bosselut, Remy] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Belkaid, Yasmine] NIAID, Program Barrier Immun & Repair, Mucosal Immunol Sect, Lab Parasit Dis,NIH, Bethesda, MD 20892 USA. RP Wohlfert, EA (reprint author), SUNY Buffalo, Dept Microbiol & Immunol, Sch Med & Biomed Sci, Buffalo, NY 14260 USA. NR 9 TC 0 Z9 0 U1 3 U2 6 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-2809-5; 978-1-4939-2808-8 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1323 BP 117 EP 128 DI 10.1007/978-1-4939-2809-5_10 D2 10.1007/978-1-4939-2809-5 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA BE1KZ UT WOS:000368096000011 PM 26294403 ER PT S AU Manna, S Bhandoola, A AF Manna, Sugata Bhandoola, Avinash BE Bosselut, R Vacchio, MS TI Intrathymic Injection SO T-CELL DEVELOPMENT: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Thymus; Mouse; Intrathymic injection; Thoracotomy; Surgical incision ID ACQUIRED THYMIC TOLERANCE; IN-VIVO; GENE-TRANSFER; THYMOCYTE PRECURSORS; MICE; MECHANISMS AB Intrathymic injection is used in several T cell-associated immunological studies to deliver cells or other substances directly into the thymus. Here, we describe the intrathymic injection procedure involving surgical incision of the mouse with or without a thoracotomy. Though this procedure can result in poor recovery, postsurgical complications, and distress to the animal, it is actually a simple procedure that can be carried out relatively easily and quickly with experience. C1 [Manna, Sugata] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Bhandoola, Avinash] NCI, T Cell Biol & Dev Sect, Lab Genome Integr,Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Manna, S (reprint author), NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 21 TC 1 Z9 1 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-2809-5; 978-1-4939-2808-8 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1323 BP 203 EP 209 DI 10.1007/978-1-4939-2809-5_17 D2 10.1007/978-1-4939-2809-5 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA BE1KZ UT WOS:000368096000018 PM 26294410 ER PT S AU Flomerfelt, FA Gress, RE AF Flomerfelt, Francis A. Gress, Ronald E. BE Bosselut, R Vacchio, MS TI Analysis of Cell Proliferation and Homeostasis Using EdU Labeling SO T-CELL DEVELOPMENT: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE EdU (5-ethynyl-2 '-deoxyuridine); Click it chemistry; Proliferation; S-phase; DNA replication ID CLICK CHEMISTRY; DNA-SYNTHESIS; T-CELLS; IN-VIVO; BROMODEOXYURIDINE; CYTOMETRY; TURNOVER; MEMORY AB Determination of cellular proliferation and population turnover is an important tool for research on lymphoid cell function. Historically this has been done using radiolabeled nucleotides or nucleoside analogs, such as BrdU (5-bromo-2-deoxyuridine), that are incorporated into nascent DNA during S-phase. Recently, a new procedure was developed to label nascent DNA using EdU (5-Ethynyl-2-deoxyuridine). This new method overcomes limitations imposed by the procedure used to detect BrdU because EdU detection is based on an easily performed chemical reaction that does not require DNA denaturation, is quick and reproducible, and has a superior signal-to-noise ratio. This technique offers a wide range of opportunities to analyze cellular proliferation, population homeostasis, and cell marking procedures. C1 [Flomerfelt, Francis A.; Gress, Ronald E.] NCI, Expt Immunol & Transplantat Branch, Bethesda, MD 20892 USA. RP Flomerfelt, FA (reprint author), NCI, Expt Immunol & Transplantat Branch, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 12 TC 2 Z9 2 U1 1 U2 17 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-2809-5; 978-1-4939-2808-8 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1323 BP 211 EP 220 DI 10.1007/978-1-4939-2809-5_18 D2 10.1007/978-1-4939-2809-5 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA BE1KZ UT WOS:000368096000019 PM 26294411 ER PT J AU Choi, JK Kim, SW Kim, DS Lee, JY Lee, S Oh, HM Ha, YS Yoo, J Park, PH Shin, TY Kwon, TK Rho, MC Kim, SH AF Choi, Jin Kyeong Kim, Sung-Wan Kim, Duk-Sil Lee, Jong Yeong Lee, Soyoung Oh, Hyun-Mee Ha, Yeong Su Yoo, Jeongsoo Park, Pil-Hoon Shin, Tae-Yong Kwon, Taeg Kyu Rho, Mun-Chual Kim, Sang-Hyun TI Oleanolic acid acetate inhibits rheumatoid arthritis by modulating T cell immune responses and matrix-degrading enzymes SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Collagen-induced arthritis; Synovial fibroblasts; Oleanolic acid acetate; Matrix metalloproteinase; Lymph nodes; Inflammatory cytokine ID COLLAGEN-INDUCED ARTHRITIS; FIBROBLAST-LIKE SYNOVIOCYTES; SYNOVIAL FIBROBLASTS; ANIMAL-MODELS; MURINE MODEL; URSOLIC ACID; SUPPRESSION; INFLAMMATION; PATHWAY; DIFFERENTIATION AB Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with a combination of synovium joint inflammation, synovium hyperplasia, and destruction of cartilage and bone. Oleanolic acid acetate (OAA), a compound isolated from Vigna angularis, has been known to possess pharmacological activities, including antiinflammation and anti-bone destruction. In this study, we investigated the effects of OAA on RA and the underlying mechanisms of action by using a type-II collagen-induced arthritis (CIA) mouse model and tumor necrosis factor (TNF)-alpha-stimulated RA synovial fibroblasts. Oral administration of OAA decreased the clinical arthritis symptoms, paw thickness, histologic and radiologic changes, and serum total and anti-type II collagen IgG, IgGl, and IgG2a levels. OAA administration reduced Thl/Th17 phenotype CD4+ T lymphocyte expansions and inflammatory cytokine productions in T cell activated draining lymph nodes and spleen. OM reduced the expression and production of inflammatory mediators, such as cytokines and matrix metalloproteinase (MMP)-1/3, in the ankle joint tissue and RA synovial fibroblasts by down-regulating Akt, mitogen-activated protein kinases, and nuclear factor-kappa B. Our results clearly support that OAA plays a therapeutic role in RA pathogenesis by modulating helper T cell immune responses and matrix-degrading enzymes. The immunosuppressive effects of OAA were comparable to dexamethasone and ketoprofen. We provide evidences that OAA could be a potential therapeutic candidate for RA. (C) 2015 Elsevier Inc. All rights reserved. C1 [Choi, Jin Kyeong; Lee, Jong Yeong; Lee, Soyoung; Kim, Sang-Hyun] Kyungpook Natl Univ, Sch Med, Dept Pharmacol, Daegu 700422, South Korea. [Choi, Jin Kyeong] NEI, Mol Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Kim, Sung-Wan; Kim, Duk-Sil] CHA Univ, CHA Gumi Med Ctr, Dept Thorac & Cardiovasc Surg, Gumi 730040, South Korea. [Lee, Soyoung; Oh, Hyun-Mee; Rho, Mun-Chual] Korea Res Inst Biosci & Biotechnol, Biomat Res Inst, Jeongeup 580185, South Korea. [Ha, Yeong Su; Yoo, Jeongsoo] Kyungpook Natl Univ, Sch Med, Dept Mol Med, Daegu 700422, South Korea. [Park, Pil-Hoon] Yeungnam Univ, Coll Pharm, Gyeongbuk 712749, South Korea. [Shin, Tae-Yong] Woosuk Univ, Coll Pharm, Jeonju 565701, South Korea. [Kwon, Taeg Kyu] Keimyung Univ, Sch Med, Dept Immunol, Daegu 704701, South Korea. RP Rho, MC (reprint author), KRIBB, Biomat Res Inst, Bioind Proc Res Ctr, 1404 Sinjeong Dong, Jeongeup 580185, Jeonbuk, South Korea. EM rho-m@kribb.re.kr; shkim72@knu.ac.kr FU National Research Foundation of Korea Grant - Korean Government [2014R1A5A2009242, 2012M3A9B6055416]; KRIBB Research Initiative Program; High Value-added Food Technology Development Program; Ministry of Agriculture, Food and Rural Affairs FX This work was supported by the National Research Foundation of Korea Grant funded by the Korean Government (2014R1A5A2009242 and 2012M3A9B6055416), KRIBB Research Initiative Program, and by High Value-added Food Technology Development Program, Ministry of Agriculture, Food and Rural Affairs. NR 42 TC 3 Z9 3 U1 1 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JAN 1 PY 2016 VL 290 BP 1 EP 9 DI 10.1016/j.taap.2015.11.005 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA DB2FM UT WOS:000368323700001 PM 26570984 ER PT J AU Finley, D Chen, X Walters, KJ AF Finley, Daniel Chen, Xiang Walters, Kylie J. TI Gates, Channels, and Switches: Elements of the Proteasome Machine SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID REG-GAMMA-PROTEASOME; NF-KAPPA-B; UCH37 DEUBIQUITINATING ENZYME; UBIQUITIN LIGASE HUL5; PROTEIN HALF-LIFE; 26 S PROTEASOME; REGULATORY PARTICLE; SUBSTRATE DEGRADATION; TRANSCRIPTION FACTOR; 20S PROTEASOME AB The proteasome has emerged as an intricate machine that has dynamic mechanisms to regulate the timing of its activity, its selection of substrates, and its processivity. The 19-subunit regulatory particle (RP) recognizes ubiquitinated proteins, removes ubiquitin, and injects the target protein into the proteolytic chamber of the core particle (CP) via a narrow channel. Translocation into the CP requires substrate unfolding, which is achieved through mechanical force applied by a hexameric ATPase ring of the RP. Recent cryoelectron microscopy (cryoEM) studies have defined distinct conformational states of the RP, providing illustrative snapshots of what appear to be progressive steps of substrate engagement. Here, we bring together this new information with molecular analyses to describe the principles of proteasome activity and regulation. C1 [Finley, Daniel] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Chen, Xiang; Walters, Kylie J.] NCI, Prot Proc Sect, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Finley, D (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, 240 Longwood Ave, Boston, MA 02115 USA. EM daniel_finley@hms.harvard.edu; kylie.walters@nih.gov FU National Institutes of Heath [R37-GM043601, R01-GM65592]; Intramural Research Program of the NIH, NCI, CCR FX Proteasome studies in the authors' laboratories are supported by grants from the National Institutes of Heath (R37-GM043601 and R01-GM65592 to D.F.) and by the Intramural Research Program of the NIH, NCI, CCR to K.J.W. We thank A. Matouschek for valuable comments on the manuscript. NR 158 TC 26 Z9 26 U1 4 U2 24 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD JAN PY 2016 VL 41 IS 1 SI SI BP 77 EP 93 DI 10.1016/j.tibs.2015.10.009 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DB0NW UT WOS:000368205800009 PM 26643069 ER PT J AU Ostrander, EA Davis, BW Ostrander, GK AF Ostrander, Elaine A. Davis, Brian W. Ostrander, Gary K. TI Transmissible Tumors: Breaking the Cancer Paradigm SO TRENDS IN GENETICS LA English DT Review ID DEVIL SARCOPHILUS-HARRISII; RETICULUM CELL SARCOMA; SOFT-SHELL CLAMS; VENEREAL TUMOR; TASMANIAN DEVIL; MYA-ARENARIA; SYRIAN-HAMSTER; IMMUNOHISTOCHEMICAL CHARACTERIZATION; POPULATION-STRUCTURE; MOLECULAR ANALYSIS AB Transmissible tumors are those that have transcended the bounds of their incipient hosts by evolving the ability to infect another individual through direct transfer of cancer cells, thus becoming parasitic cancer clones. Coitus, biting, and scratching are transfer mechanisms for the two primary species studied, the domestic dog (Canis lupus familiaris) and the Tasmanian devil (Sarcophilus harrisii). Canine transmissible venereal tumors (CTVT) are likely thousands of years old, and have successfully travelled from host to host around the world, while the Tasmanian devil facial tumor disease (DFTD) is much younger and geographically localized. The dog tumor is not necessarily lethal, while the devil tumor has driven the population to near extinction. Transmissible tumors are uniform in that they have complex immunologic profiles, which allow them to escape immune detection by their hosts, sometimes for long periods of time. In this review, we explore how transmissible tumors in CTVT, DFTD, and as well as the soft-shell clam and Syrian hamster, can advance studies of tumor biology. C1 [Ostrander, Elaine A.; Davis, Brian W.] NHGRI, NIH, Bethesda, MD 20892 USA. [Ostrander, Gary K.] Florida State Univ, Coll Med, Dept Biomed Sci, Tallahassee, FL 32306 USA. RP Ostrander, EA (reprint author), NHGRI, NIH, 50 South Dr,Bldg 50 Room 5351, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov OI Ostrander, Elaine/0000-0001-6075-9738 FU National Human Genome Research Institute FX We thank Brennan Decker, Danielle Karyadi, and Heidi Parker for helpful comments on this manuscript. E.A.O. and B.W.D. are supported by the Intramural Program of the National Human Genome Research Institute. NR 79 TC 4 Z9 5 U1 10 U2 61 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD JAN PY 2016 VL 32 IS 1 BP 1 EP 15 DI 10.1016/j.tig.2015.10.001 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA DB0RI UT WOS:000368214800001 PM 26686413 ER PT J AU Grossman, CI Ross, AL Auerbach, JD Ananworanich, J Dube, K Tucker, JD Noseda, V Possas, C Rausch, DM AF Grossman, Cynthia I. Ross, Anna Laura Auerbach, Judith D. Ananworanich, Jintanat Dube, Karine Tucker, Joseph D. Noseda, Veronica Possas, Cristina Rausch, Dianne M. CA Int AIDS Soc IAS HIV Cure' initiat TI Towards Multidisciplinary HIV-Cure Research: Integrating Social Science with Biomedical Research SO TRENDS IN MICROBIOLOGY LA English DT Review ID RESERVOIR; EXPECTATIONS; REPLICATION; ETHICS; CELLS; SIZE AB The quest for a cure for HIV remains a timely and key challenge for the HIV research community. Despite significant scientific advances, current HIV therapy regimens do not completely eliminate the negative impact of HIV on the immune system; and the economic impact of treating all people infected with HIV globally, for the duration of their lifetimes, presents significant challenges. This article discusses, from a multidisciplinary approach, critical social, behavioral, ethical, and economic issues permeating the HIV-cure research agenda. As part of a search for an HIV cure, both the perspective of patients/participants and clinical researchers should be taken into account. In addition, continued efforts should be made to involve and educate the broader community. C1 [Grossman, Cynthia I.; Rausch, Dianne M.] NIMH, NIH, Bethesda, MD 20892 USA. [Ross, Anna Laura] ANRS, F-75013 Paris, France. [Auerbach, Judith D.] Univ Calif San Francisco, Sch Med, Dept Med, Ctr AIDS Prevent Studies, San Francisco, CA 94158 USA. [Ananworanich, Jintanat] Henry M Jackson Fdn Adv Mil Med Inc, Bethesda, MD USA. [Dube, Karine] CARE, IGHID, Chapel Hill, NC 27516 USA. [Tucker, Joseph D.] UNC Project China, Guangzhou 510095, Guangdong, Peoples R China. [Tucker, Joseph D.] Univ N Carolina, Chapel Hill, NC USA. [Noseda, Veronica] Sidaction, F-75010 Paris, France. [Possas, Cristina] Fundacao Oswaldo Cruz, Evandro Chagas Natl Inst Infect Dis & Biomanguinh, BR-21040360 Rio De Janeiro, Brazil. RP Grossman, CI (reprint author), NIMH, NIH, 5601 Fishers Lane Room 9G19,MSC 9831, Bethesda, MD 20892 USA. EM grossmanc@mail.nih.gov FU NIAID [U19 A1096113, P30-A150410, R01A108366-01] FX The contributions of the International AIDS Society (IAS) 'Towards an HIV Cure' Working Groups, especially the Psychosocial, Cost-Effectiveness and Ethics Working Groups, are acknowledged as critical in the development of the content found in this manuscript. The authors are grateful to Frangoise Barre-Sinoussi for her important contribution to this research collaboration. The IAS 'Towards an HIV Cure' team and Rosanne Lamp lough are acknowledged for their facilitation of the meetings and discussions that led to this manuscript. K.D. is supported by NIAID U19 A1096113 (Collaboratory of AIDS Researchers for Eradication; PI: David M. Margolis). J.T. is supported by NIAID P30-A150410, NIAID R01A108366-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the U.S. Army or the U.S. Department of Defense, All authors do not have any related conflicts of interest. NR 34 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0966-842X EI 1878-4380 J9 TRENDS MICROBIOL JI Trends Microbiol. PD JAN PY 2016 VL 24 IS 1 BP 5 EP 11 DI 10.1016/j.tim.2016.10.011 PG 7 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA DB0NZ UT WOS:000368206100003 PM 26642901 ER PT J AU Salton, M Misteli, T AF Salton, Maayan Misteli, Tom TI Small Molecule Modulators of Pre-mRNA Splicing in Cancer Therapy SO TRENDS IN MOLECULAR MEDICINE LA English DT Review ID HUMAN HEPATOCELLULAR CARCINOMAS; PHYSICOCHEMICAL PROPERTIES; ANTITUMOR SUBSTANCES; IN-VITRO; BIOLOGICAL-ACTIVITIES; GENE-EXPRESSION; STREPTOMYCES SP; GEX1 COMPOUNDS; SOLID TUMORS; CELL-DEATH AB Pre-mRNA splicing is a fundamental process in mammalian gene expression and alternative RNA splicing plays a considerable role in generating protein diversity. RNA splicing events are also key to the pathology of numerous diseases, particularly cancers. Some tumors are molecularly addicted to specific RNA splicing isoforms making interference with pre-mRNA processing a viable therapeutic strategy. Several RNA splicing modulators have recently been characterized, some showing promise in preclinical studies. While the targets of most splicing modulators are constitutive RNA processing components, possibly leading to undesirable side effects, selectivity for individual splicing events has been observed. Given the high prevalence of splicing defects in cancer, small molecule modulators of RNA processing represent a potentially promising novel therapeutic strategy in cancer treatment. Here, we review their reported effects, mechanisms, and limitations. C1 [Salton, Maayan; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. [Salton, Maayan] Hebrew Univ Jerusalem, Hadassah Med Sch, Inst Med Res Israel Canada, Dept Biochem & Mol Biol, IL-91120 Jerusalem, Israel. RP Salton, M (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM maayansa@ekmd.huji.ac.il; mistelit@mail.nih.gov FU Intramural NIH HHS [ZIA BC010309-16] NR 87 TC 8 Z9 8 U1 2 U2 15 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4914 EI 1471-499X J9 TRENDS MOL MED JI Trends Mol. Med PD JAN PY 2016 VL 22 IS 1 BP 28 EP 37 DI 10.1016/j.molmed.2015.11.005 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DB0TP UT WOS:000368220700006 PM 26700537 ER PT J AU Kraemer, MUG Hay, SI Pigott, DM Smith, DL Wint, GRW Golding, N AF Kraemer, Moritz U. G. Hay, Simon I. Pigott, David M. Smith, David L. Wint, G. R. William Golding, Nick TI Progress and Challenges in Infectious Disease Cartography SO TRENDS IN PARASITOLOGY LA English DT Review ID PLASMODIUM-FALCIPARUM; DEVELOPING-COUNTRIES; SYSTEMATIC ANALYSIS; AEDES-ALBOPICTUS; AVIAN INFLUENZA; SOUTHEAST-ASIA; GLOBAL BURDEN; POPULATION; DENGUE; GLOBALIZATION AB Quantitatively mapping the spatial distributions of infectious diseases is key to both investigating their epidemiology and identifying populations at risk of infection. Important advances in data quality and methodologies have allowed for better investigation of disease risk and its association with environmental factors. However, incorporating dynamic human behavioural processes in disease mapping remains challenging. For example, connectivity among human populations, a key driver of pathogen dispersal, has increased sharply over the past century, along with the availability of data derived from mobile phones and other dynamic data sources. Future work must be targeted towards the rapid updating and dissemination of appropriately designed disease maps to guide the public health community in reducing the global burden of infectious disease. C1 [Kraemer, Moritz U. G.; Pigott, David M.; Smith, David L.; Wint, G. R. William] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England. [Hay, Simon I.; Pigott, David M.; Golding, Nick] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Hay, Simon I.] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. [Hay, Simon I.; Smith, David L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Smith, David L.] Sanaria Inst Global Hlth & Trop Med, Rockville, MD 20850 USA. [Wint, G. R. William] Univ Oxford, Dept Zool, ERGO, Oxford OX1 3PS, England. RP Kraemer, MUG (reprint author), Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England. EM moritz.kraemer@zoo.ox.ac.uk RI Hay, Simon/F-8967-2015; OI Hay, Simon/0000-0002-0611-7272; Pigott, David/0000-0002-6731-4034; Golding, Nick/0000-0001-8916-5570 FU German Academic Exchange Service (DAAD); Senior Research Fellowship from the Wellcome Trust [095066]; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center (FIC), National Institutes of Health (NIH); International Research Consortium on Dengue Risk Assessment Management and Surveillance [IDAMS, European Commission 7th Framework Programme] [21803]; Bill and Melinda Gates Foundation [OPP1093011] FX M.U.G.K. is funded by the German Academic Exchange Service (DAAD) through a graduate scholarship. S.I.H. is funded by a Senior Research Fellowship from the Wellcome Trust (#095066). S.I.H. and D.L.S. also acknowledge funding support from the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center (FIC), National Institutes of Health (NIH). S.I.H. and G.R.W.W. acknowledge funding from the International Research Consortium on Dengue Risk Assessment Management and Surveillance [IDAMS, European Commission 7th Framework Programme (#21803) http://www.idams.eu]. N.G. and D.M.P. are funded by a grant from the Bill and Melinda Gates Foundation (OPP1093011). NR 80 TC 11 Z9 11 U1 4 U2 23 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4922 EI 1471-5007 J9 TRENDS PARASITOL JI Trends Parasitol. PD JAN PY 2016 VL 32 IS 1 BP 19 EP 29 DI 10.1016/j.pt.2015.09.006 PG 11 WC Parasitology SC Parasitology GA DB0OH UT WOS:000368206900007 PM 26604163 ER PT J AU Vaidehi, N Grisshammer, R Tate, CG AF Vaidehi, Nagarajan Grisshammer, Reinhard Tate, Christopher G. TI How Can Mutations Thermostabilize G-Protein-Coupled Receptors? SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID ADENOSINE A(2A) RECEPTOR; NEUROTENSIN RECEPTOR; BETA(1)-ADRENERGIC RECEPTOR; CONFORMATIONAL STATES; STRUCTURAL INSIGHTS; CRYSTAL-STRUCTURE; GPCR ACTIVATION; DRUG DESIGN; AGONIST; RHODOPSIN AB Structures of over 30 different G-protein-coupled receptors (GPCRs) have advanced our understanding of cell signaling and have provided a foundation for structure-guided drug design. This exciting progress has required the development of three complementary methods to facilitate GPCR crystallization, one of which is the thermostabilization of receptors by systematic mutagenesis. However, the reason why a particular mutation, or combination of mutations, stabilizes the receptor is not always evident from a static crystal structure. Molecular dynamics (MD) simulations have been used to identify and estimate the energetic factors that affect thermostability through comparing the dynamics of the thermostabilized receptors with structure-based models of the wild-type receptor. The data indicate that receptors are stabilized through a combination of factors, including an increase in receptor rigidity, a decrease in collective motion, reduced stress at specific residues, and the presence of ordered water molecules. Predicting thermostabilizing mutations computationally represents a major challenge for the field. C1 [Vaidehi, Nagarajan] Beckman Res Inst City Hope, Div Immunol, Duarte, CA 91010 USA. [Grisshammer, Reinhard] NINDS, NIH, Dept Hlth & Human Serv, Membrane Prot Struct Funct Unit, Rockville, MD 20852 USA. [Tate, Christopher G.] Mol Biol Lab, MRC, Cambridge CB2 0QH, England. RP Vaidehi, N (reprint author), Beckman Res Inst City Hope, Div Immunol, 1500 East Duarte Rd, Duarte, CA 91010 USA. EM NVaidehi@coh.org FU MRC [U105197215]; Intramural Research Program of National Institute of Neurological Disorders and Stroke, NIH; [NIH-RO1GM097261] FX N.V. thanks Dr Sangbae Lee, Dr Supriyo Bhattachatya, and Mr Benjamin Levy for their help with the preparation of some of the figures and references. Funding for this work was provided by NIH-RO1GM097261. C.G.T. is funded by the MRC (U105197215). The research of R.G. is supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, NIH. NR 53 TC 6 Z9 6 U1 2 U2 10 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD JAN PY 2016 VL 37 IS 1 BP 37 EP 46 DI 10.1016/j.tips.2015.09.005 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB0NA UT WOS:000368203600004 PM 26547284 ER PT J AU Grobman, W AF Grobman, William TI When has an induction failed? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Grobman, William] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 348 BP S196 EP S196 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800344 ER PT J AU Welsh, WN Knudsen, HK Knight, K Ducharme, L Pankow, J Urbine, T Lindsey, A Abdel-Salam, S Wood, J Monico, L Link, N Albizu-Garcia, C Friedmann, PD AF Welsh, Wayne N. Knudsen, Hannah K. Knight, Kevin Ducharme, Lori Pankow, Jennifer Urbine, Terry Lindsey, Adrienne Abdel-Salam, Sami Wood, Jennifer Monico, Laura Link, Nathan Albizu-Garcia, Carmen Friedmann, Peter D. TI Effects of an Organizational Linkage Intervention on Inter-Organizational Service Coordination Between Probation/Parole Agencies and Community Treatment Providers SO ADMINISTRATION AND POLICY IN MENTAL HEALTH AND MENTAL HEALTH SERVICES RESEARCH LA English DT Article DE Treatment; Implementation; Substance-related disorders; Interagency relationships; Inter-organizational relationships ID CRIMINAL-JUSTICE SYSTEM; DRUG-ABUSE TREATMENT; ACCESS PROGRAM; IMPLEMENTATION RESEARCH; MENTAL-HEALTH; ADDICTION TREATMENT; HOMELESS PERSONS; RANDOMIZED TRIALS; ROLE-CONFLICT; INTEGRATION AB Weak coordination between community correctional agencies and community-based treatment providers is a major barrier to diffusion of medication-assisted treatment (MAT)-the inclusion of medications (e.g., methadone and buprenorphine) in combination with traditional counseling and behavioral therapies to treat substance use disorders. In a multisite cluster randomized trial, experimental sites (j = 10) received a 3-h MAT training plus a 12-month linkage intervention; control sites (j = 10) received the 3-h training alone. Hierarchical linear models showed that the intervention resulted in significant improvements in perceptions of interagency coordination among treatment providers, but not probation/parole agents. Implications for policy and practice are discussed. C1 [Welsh, Wayne N.; Wood, Jennifer; Link, Nathan] Temple Univ, Philadelphia, PA 19122 USA. [Knudsen, Hannah K.] Univ Kentucky, Lexington, KY 40506 USA. [Knight, Kevin; Pankow, Jennifer] Texas Christian Univ, Ft Worth, TX 76129 USA. [Ducharme, Lori] NIAAA, Rockville, MD 20852 USA. [Urbine, Terry; Lindsey, Adrienne] Arizona State Univ, Phoenix, AZ USA. [Abdel-Salam, Sami; Monico, Laura] Univ Delaware, Newark, DE 19716 USA. [Albizu-Garcia, Carmen] Univ Puerto Rico, San Juan, PR 00936 USA. [Friedmann, Peter D.] Providence Vet Affairs Med Ctr, Providence, RI USA. [Friedmann, Peter D.] Brown Univ, Providence, RI 02912 USA. [Friedmann, Peter D.] Rhode Isl Hosp, Providence, RI USA. RP Welsh, WN (reprint author), Temple Univ, Philadelphia, PA 19122 USA. EM wwelsh@temple.edu FU U.S. Department of Health and Human Services; Substance Abuse and Mental Health Services Administration (SAMHSA); Bureau of Justice Assistance; National Institutes of Health; National Institute on Drug Abuse (NIH/NIDA); US Department of Justice; U.S. government FX This study was funded under a cooperative agreement from the U.S. Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse (NIH/NIDA), with support from the Substance Abuse and Mental Health Services Administration (SAMHSA) and the Bureau of Justice Assistance, US Department of Justice. The authors gratefully acknowledge the collaborative contributions by NIDA; the Coordinating Center, AMAR International, Inc.; and the Research Centers participating in CJ-DATS. The Research Centers include: Arizona State University and Maricopa County Adult Probation (U01DA025307); University of Connecticut and the Connecticut Department of Correction (U01DA016194); University of Delaware and the Delaware Department of Correction (U01DA016230); Friends Research Institute and the Maryland Department of Public Safety Correctional Services' Division of Parole and Probation (U01DA025233); University of Kentucky and the Kentucky Department of Corrections (U01DA016205); University of Rhode Island, Rhode Island Hospital and the Rhode Island Department of Corrections (U01DA016191); Texas Christian University and the Illinois Department of Corrections (U01DA016190); Temple University and the Pennsylvania Department of Corrections (U01DA025284); and the University of California at Los Angeles and the Washington State Department of Corrections (U01DA016211). The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of NIDA nor any of the sponsoring organizations, agencies, CJ-DATS partner sites, or the U.S. government. NR 76 TC 3 Z9 3 U1 6 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0894-587X EI 1573-3289 J9 ADM POLICY MENT HLTH JI Adm. Policy. Ment. Health PD JAN PY 2016 VL 43 IS 1 BP 105 EP 121 DI 10.1007/s10488-014-0623-8 PG 17 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DA4CH UT WOS:000367747200010 PM 25559124 ER PT J AU Ghany, MG AF Ghany, Marc G. TI Should Family Physicians Routinely Screen Patients for Hepatitis C? SO AMERICAN FAMILY PHYSICIAN LA English DT Editorial Material ID SUSTAINED VIROLOGICAL RESPONSE; ALL-CAUSE MORTALITY; UNITED-STATES; VIRUS-INFECTION; BURDEN C1 [Ghany, Marc G.] NIH, Bethesda, MD 20892 USA. RP Ghany, MG (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM marcg@intra.niddk.nih.gov NR 15 TC 0 Z9 0 U1 0 U2 0 PU AMER ACAD FAMILY PHYSICIANS PI KANSAS CITY PA 8880 WARD PARKWAY, KANSAS CITY, MO 64114-2797 USA SN 0002-838X EI 1532-0650 J9 AM FAM PHYSICIAN JI Am. Fam. Physician PD JAN 1 PY 2016 VL 93 IS 1 BP 15 EP 16 PG 2 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA DA5SU UT WOS:000367863600001 PM 26760834 ER PT J AU Kmush, BL Labrique, A Li, W Klein, SL Schulze, K Shaikh, S Ali, H Engle, RE Wu, L Purcell, RH Mehra, S Christian, P West, K Nelson, K AF Kmush, Brittany L. Labrique, Alain Li, Wei Klein, Sabra L. Schulze, Kerry Shaikh, Saijuddin Ali, Hasmot Engle, Ronald E. Wu, Lee Purcell, Robert H. Mehra, Sucheta Christian, Parul West, Keith, Jr. Nelson, Kenrad TI The Association of Cytokines and Micronutrients with Hepatitis E Virus Infection during Pregnancy and the Postpartum Period in Rural Bangladesh SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID ENZYME-IMMUNOASSAY; ZINC-DEFICIENCY; IMMUNE FUNCTION; TRACE-ELEMENTS; WOMEN; OUTCOMES; DISEASE; SUPPLEMENTATION; EPIDEMIOLOGY; INFLAMMATION AB Hepatitis E virus (HEV) infection is severe during pregnancy, with a pregnant case fatality rate around 30%. In Bangladesh, plasma samples from 1,100 women during the first trimester (TM) and third TM of pregnancy and 3 months postpartum (PP) were tested for anti-HEY IgG. During this time, 40 women developed antibody responses to HEV. These seroconverters are classified as the cases (incidence = 46 infections per 1,000 person-years). All except one seroconversion occurred between the third TM and 3 months PP. The cases and 40 matched non-seroconverters (controls) underwent analysis of a panel of 10 cytokines, 12 vitamins and minerals, and two markers of inflammation. Throughout pregnancy, seroconverting cases displayed higher concentrations of both pro- and anti-inflammatory cytokines compared with the non-seroconverting controls, even prior to infection. In the first TM, seroconverters had lower circulating zinc concentrations (P = 0.03), an increased prevalence of vitamin D deficiency (25-hydroxy vitamin D [25(OH)2D] < 50 nmol/L, P = 0.08), and anemia (hemoglobin < 110 g/L, P = 0.05) compared with controls. There were no differences in C-reactive protein or alpha-1-acid glycoprotein. Antecedent micronutrient deficiencies may lead to dysregulated cytokine expression and immunologic compromise, increasing the risk of HEV infection, especially during pregnancy. This exploratory analysis reveals potential novel associations that deserve further study. C1 [Kmush, Brittany L.; Labrique, Alain; Schulze, Kerry; Wu, Lee; Mehra, Sucheta; Christian, Parul; West, Keith, Jr.; Nelson, Kenrad] Johns Hopkins Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21205 USA. [Labrique, Alain; Nelson, Kenrad] Johns Hopkins Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Klein, Sabra L.] Johns Hopkins Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [Klein, Sabra L.] Johns Hopkins Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA. [Shaikh, Saijuddin] JiVitA Maternal & Child Hlth Res Project, Gaibandha, Bangladesh. [Engle, Ronald E.; Purcell, Robert H.] NIAID, Hepatitis Viruses Sect, NIH, US Dept HHS, Rockville, MD USA. RP Labrique, A (reprint author), Johns Hopkins Sch Publ Hlth, W5501,615 N Wolfe St, Baltimore, MD 21205 USA. EM bkmush1@jhu.edu; alabriqu@gmail.com; wli@anr.msu.edu; sklein2@jhu.edu; kschulz1@jhu.edu; saiju.jivita@gmail.com; hasmot.jivita@gmail.com; rengle@niaid.nih.gov; leewu@jhmi.edu; roberthpurcell@gmail.com; smehra5@jhu.edu; pchrist1@jhu.edu; kwest1@jhu.edu; knelson3@jhu.edu FU NIH [AI068813-01A2]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH; Bill & Melinda Gates Foundation, Seattle, WA [614]; Sight and Life Global Nutrition Research Institute, Baltimore, MD FX This work was funded by NIH R56 award number AI068813-01A2. Support was also provided by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. The field trial was supported through grant 614 (Global Control of Micronutrient Deficiency) from the Bill & Melinda Gates Foundation, Seattle, WA (Ellen Piwoz, Senior Program Officer) and through additional support from the Sight and Life Global Nutrition Research Institute, Baltimore, MD; DSM N.V., Kaiseraugst (Switzerland), Bombay (India), and Singapore formulated, prepared, and delivered in-country micronutrient premixes for supplement production and Beximco Pharmaceuticals, Ltd., Dhaka produced, bottled, labeled, and delivered tablets during the trial, both gratis; and the Ministry of Health and Family Welfare, Government of Bangladesh, Dhaka. NR 47 TC 2 Z9 2 U1 1 U2 2 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JAN PY 2016 VL 94 IS 1 BP 203 EP 211 DI 10.4269/ajtmh.15-0238 PG 9 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA DA3NX UT WOS:000367705500037 PM 26621563 ER PT J AU Krupovic, M Kuhn, JH Fischer, MG AF Krupovic, Mart Kuhn, Jens H. Fischer, Matthias G. TI A classification system for virophages and satellite viruses SO ARCHIVES OF VIROLOGY LA English DT Article ID TOBACCO NECROSIS VIRUS; PANICUM MOSAIC-VIRUS; EXTRA SMALL VIRUS; MACROBRACHIUM-ROSENBERGII NODAVIRUS; BEE-PARALYSIS VIRUS; FRESH-WATER PRAWN; WHITE-TAIL DISEASE; NUCLEOTIDE-SEQUENCE; GIANT VIRUSES; HELPER VIRUS AB Satellite viruses encode structural proteins required for the formation of infectious particles but depend on helper viruses for completing their replication cycles. Because of this unique property, satellite viruses that infect plants, arthropods, or mammals, as well as the more recently discovered satellite-like viruses that infect protists (virophages), have been grouped with other, so-called "sub-viral agents." For the most part, satellite viruses are therefore not classified. We argue that possession of a coat-protein-encoding gene and the ability to form virions are the defining features of a bona fide virus. Accordingly, all satellite viruses and virophages should be consistently classified within appropriate taxa. We propose to create four new genera - Albetovirus, Aumaivirus, Papanivirus, and Virtovirus - for positive-sense single-stranded (+) RNA satellite viruses that infect plants and the family Sarthroviridae, including the genus Macronovirus, for (+)RNA satellite viruses that infect arthopods. For double-stranded DNA virophages, we propose to establish the family Lavidaviridae, including two genera, Sputnikvirus and Mavirus. C1 [Krupovic, Mart] Inst Pasteur, Unite Biol Mol Gene Chez Extremophiles, Dept Microbiol, Paris, France. [Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD USA. [Fischer, Matthias G.] Max Planck Inst Med Res, D-69120 Heidelberg 1, Germany. RP Krupovic, M (reprint author), Inst Pasteur, Unite Biol Mol Gene Chez Extremophiles, Dept Microbiol, Paris, France. EM krupovic@pasteur.fr; matthias.fischer@mpimf-heidelberg.mpg.de RI Krupovic, Mart/I-4209-2012; OI Krupovic, Mart/0000-0001-5486-0098; Fischer, Matthias/0000-0002-4014-3626; Kuhn, Jens H./0000-0002-7800-6045 FU Battelle Memorial Institute; US National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200700016I] FX This work was funded in part through Battelle Memorial Institute's prime contract with the US National Institute of Allergy and Infectious Diseases (NIAID) under Contract No. HHSN272200700016I. NR 111 TC 7 Z9 7 U1 1 U2 11 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0304-8608 EI 1432-8798 J9 ARCH VIROL JI Arch. Virol. PD JAN PY 2016 VL 161 IS 1 BP 233 EP 247 DI 10.1007/s00705-015-2622-9 PG 15 WC Virology SC Virology GA DA2DM UT WOS:000367605500030 PM 26446887 ER PT J AU Lloyd, TE Christopher-Stine, L Pinal-Fernandez, I Tiniakou, E Petri, M Baer, A Danoff, SK Pak, K Casciola-Rosen, LA Mammen, AL AF Lloyd, Thomas E. Christopher-Stine, Lisa Pinal-Fernandez, Iago Tiniakou, Eleni Petri, Michelle Baer, Alan Danoff, Sonye K. Pak, Katherine Casciola-Rosen, Livia A. Mammen, Andrew L. TI Cytosolic 5'-Nucleotidase 1A As a Target of Circulating Autoantibodies in Autoimmune Diseases SO ARTHRITIS CARE & RESEARCH LA English DT Article ID INCLUSION-BODY MYOSITIS; 5'-NUCLEOTIDASE 1A; PULMONARY FIBROSIS; POLYMYOSITIS; DERMATOMYOSITIS; PATHOGENESIS; METABOLISM; ENZYMES AB Objective. Prior investigations demonstrated that autoantibodies recognizing cytosolic 5'-nucleotidase 1A (NT5C1A) are found in 33-76% of patients with inclusion body myositis (IBM) but are observed only rarely in patients with polymyositis (PM). Thus, anti-NT5C1A may help distinguish IBM from PM. Although 4-21% of patients with dermatomyositis (DM) were shown to be anti-NT5C1A antibody positive, the clinical features of anti-NT5C1A-positive patients with DM have not been described. Furthermore, the prevalence of anti-NT5C1A antibodies in other rheumatic conditions has not been reported. This study was undertaken to define the prevalence and clinical features of anti-NT5C1A-positive patients with DM, PM, IBM, or other systemic autoimmune diseases. Methods. We screened for anti-NT5C1A autoantibodies in patients with IBM, DM, PM, Sjogren's syndrome (SS), or systemic lupus erythematosus (SLE) and in healthy volunteers. Clinical characteristics were compared between patients who were anti-NT5C1A positive and those who were anti-NT5C1A negative. Results. Anti-NT5C1A autoantibodies were detected in 71 (61%) of 117 patients with IBM, 2 (5%) of 42 patients with PM, 2 (5%) of 42 healthy volunteers, 24 (15%) of 159 patients with DM, 10 (23%) of 44 patients with SS, and 13 (14%) of 96 patients with SLE. No anti-NT5C1A antibody-positive patients with SS or SLE had muscle involvement. AntiNT5C1A-positive patients with IBM had a lower prevalence of rimmed vacuoles (62% versus 83% of antibody negative patients; P = 50.02). No differences in the clinical characteristics of antibody-positive and antibody-negative patients with DM, SS, or SLE were observed. Conclusion. Anti-NT5C1A is a common target of circulating autoantibodies, especially in IBM but also in several different autoimmune diseases. In SLE and SS, anti-NT5C1A autoreactivity is not associated with muscle disease. C1 [Lloyd, Thomas E.; Christopher-Stine, Lisa; Tiniakou, Eleni; Petri, Michelle; Baer, Alan; Danoff, Sonye K.; Casciola-Rosen, Livia A.; Mammen, Andrew L.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Pinal-Fernandez, Iago] Vall Hebron Univ Hosp, Barcelona, Spain. [Pak, Katherine; Mammen, Andrew L.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Mammen, AL (reprint author), NIAMSD, Muscle Dis Unit, Lab Muscle Stem Cells & Gene Express, NIH, 50 South Dr,Room 1146,Bldg 50,MSC 8024, Bethesda, MD 20892 USA. EM andrew.mammen@nih.gov FU Intramural Research program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH; Johns Hopkins Rheumatic Disease Research Core Center; NIH [P30-AR-053503, RO-1-AR-43727, R01-NS-082563, R56-AR-062615-01A1]; Huayi and Siuling Zhang Discovery Fund; ALS Association; Donald and Dorothy Stabler Foundation FX Supported by the Intramural Research program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH, by The Johns Hopkins Rheumatic Disease Research Core Center and by the NIH (grant P30-AR-053503). The Hopkins Lupus Cohort is supported by the NIH (grant RO-1-AR-43727). The Myositis Research Database is supported by the The Huayi and Siuling Zhang Discovery Fund. Dr. Lloyd's work was supported by the NIH (grant R01-NS-082563) and ALS Association. Drs. Christopher-Stine and Danoff's work was supported by the The Huayi and Siuling Zhang Discovery Fund. Dr. Casciola-Rosen's work was supported by the NIH (grant R56-AR-062615-01A1) and The Donald and Dorothy Stabler Foundation. NR 16 TC 9 Z9 9 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD JAN PY 2016 VL 68 IS 1 BP 66 EP 71 DI 10.1002/acr.22600 PG 6 WC Rheumatology SC Rheumatology GA DA3FQ UT WOS:000367682800006 PM 25892010 ER PT J AU Lukkahatai, N Walitt, B Espina, A Gelio, A Saligan, LN AF Lukkahatai, Nada Walitt, Brian Espina, Alexandra Gelio, Alves Saligan, Leorey N. TI Understanding the Association of Fatigue With Other Symptoms of Fibromyalgia: Development of a Cluster Model SO ARTHRITIS CARE & RESEARCH LA English DT Article ID PAIN CATASTROPHIZING SCALE; SELF-REPORT QUESTIONNAIRE; EPWORTH SLEEPINESS SCALE; RHEUMATOID-ARTHRITIS; MULTIDIMENSIONAL FATIGUE; CANCER-PATIENTS; DEPRESSION; RELIABILITY; ANXIETY; INVENTORY AB Objective. To develop a symptoms cluster model that can describe factors of fibromyalgia syndrome (FMS) associated with fatigue severity as reported by the sample and to explore FMS clinical symptom subclusters based on varying symptom intensities. Methods. FMS individuals (n = 120, 82% ages 31-60 years, 90% women, 59% white) diagnosed with the 1990 or 2010 American College of Rheumatology diagnostic criteria were enrolled. Participants completed multiple validated self-report questionnaires to measure fatigue, pain, depression, anxiety, pain catastrophizing, daytime sleepiness, cognitive function, and FMS-related polysymptomatic distress. Cluster analysis using SPSS 19.0 and structural equation modeling using AMOS 17.0 were used. Results. Final structural equation modeling the symptoms cluster model showed good fit and revealed that FMS fatigue was associated with widespread pain, symptoms severity, pain intensity, pain interference, cognitive dysfunction, catastrophizing, anxiety, and depression (x(2) = 121.72 (98df), P > 0.05, x(2)/df = 1.242, comparative fit index = 0.982, root mean square error of approximation = 0.045). Two distinct clinical symptom subclusters emerged: subcluster 1 (78% of total subjects), defined by widespread pain, unrefreshed waking, and somatic symptoms, and subcluster 2 (22% of total subjects), defined by fatigue and cognitive dysfunction with pain being a less severe and less widespread occurrence. Conclusion. Overall, subcluster 1 had more intense symptoms than subcluster 2. FMS symptoms may be categorized into 2 clinical subclusters. These findings have implications for an illness whose diagnosis and management are symptom dependent. A longitudinal study capturing the variability in the symptom experience of FMS subjects is warranted. C1 [Lukkahatai, Nada] Univ Nevada, Sch Nursing, Las Vegas, NV 89154 USA. [Lukkahatai, Nada; Walitt, Brian; Espina, Alexandra; Saligan, Leorey N.] NINR, NIH, Bethesda, MD 20892 USA. [Walitt, Brian] Washington Hosp Ctr, Medstar Res Inst, Washington, DC 20010 USA. [Gelio, Alves] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Lukkahatai, N (reprint author), Univ Nevada, Sch Nursing, 4505 South Maryland Pkwy,Box 453018, Las Vegas, NV 89154 USA. EM nada.lukkahatai@unlv.edu FU Medstar Research Institute [NCT00888563]; Division of Intramural Research of the National Institute of Nursing Research FX Supported by Medstar Research Institute (grant NCT00888563) and the Division of Intramural Research of the National Institute of Nursing Research. NR 51 TC 1 Z9 1 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD JAN PY 2016 VL 68 IS 1 BP 99 EP 107 DI 10.1002/acr.22626 PG 9 WC Rheumatology SC Rheumatology GA DA3FQ UT WOS:000367682800011 PM 26017904 ER PT J AU Nussinov, R Tsai, CJ Chakrabarti, M Jang, H AF Nussinov, Ruth Tsai, Chung-Jung Chakrabarti, Mayukh Jang, Hyunbum TI A New View of Ras Isoforms in Cancers SO CANCER RESEARCH LA English DT Review ID H-RAS; K-RAS; CAAX MOTIF; N-RAS; LOCALIZATION; CALMODULIN; BINDING; KRAS; IDENTIFICATION; TRAFFICKING AB Does small GTPase K-Ras4A have a single state or two states, one resembling K-Ras4B and the other N-Ras? A recent study of K-Ras4A made the remarkable observation that even in the absence of the palmitoyl, K-Ras4A can be active at the plasma membrane. Importantly, this suggests that K-Ras4A may exist in two distinct signaling states. In state 1, K-Ras4A is only farnesylated, like K-Ras4B; in state 2, farnesylated and palmitoylated, like N-Ras. The K-Ras4A hypervariable region sequence is positively charged, in between K-Ras4B and N-Ras. Taken together, this raises the possibility that the farnesylated but nonpalmitoylated state 1, like K-Ras4B, binds calmodulin and is associated with colorectal and other adenocarcinomas like lung cancer and pancreatic ductal adenocarcinoma. On the other hand, state 2 may be associated with melanoma and other cancers where N-Ras is a major contributor, such as acute myeloid leukemia. Importantly, H-Ras has two, singly and doubly, palmitoylated states that may also serve distinct functional roles. The multiple signaling states of palmitoylated Ras isoforms question the completeness of small GTPase Ras isoform statistics in different cancer types and call for reevaluation of concepts and protocols. They may also call for reconsideration of oncogenic Ras therapeutics. (C)2015 AACR. C1 [Nussinov, Ruth; Tsai, Chung-Jung; Chakrabarti, Mayukh; Jang, Hyunbum] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Fac Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. [Chakrabarti, Mayukh] Johns Hopkins Univ, Dept Biotechnol, Baltimore, MD USA. RP Nussinov, R (reprint author), Tel Aviv Univ, NCI Frederick, Sackler Sch Med, Build 542, Frederick, MD 21702 USA. EM NussinoR@helix.nih.gov FU Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E]; Intramural Research Program of NIH, Frederick National Laboratory, Center for Cancer Research FX This project has been funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, NIH, under contract HHSN261200800001E. This research was supported (in part) by the Intramural Research Program of NIH, Frederick National Laboratory, Center for Cancer Research. NR 33 TC 16 Z9 16 U1 9 U2 23 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JAN 1 PY 2016 VL 76 IS 1 BP 18 EP 23 DI 10.1158/0008-5472.CAN-15-1536 PG 6 WC Oncology SC Oncology GA DA1KE UT WOS:000367553900005 PM 26659836 ER PT J AU Alper, K Bai, R Liu, NA Fowler, SJ Huang, XP Priori, SG Ruan, YF AF Alper, Kenneth Bai, Rong Liu, Nian Fowler, Steven J. Huang, Xi-Ping Priori, Silvia G. Ruan, Yanfei TI hERG Blockade by Iboga Alkaloids SO CARDIOVASCULAR TOXICOLOGY LA English DT Article DE Toxicology; hERG; Iboga alkaloid; Ibogaine; Noribogaine; 18-Methoxycoronaridine (18-MC) ID LONG-QT SYNDROME; TORSADES-DE-POINTES; VENTRICULAR-TACHYCARDIA; TABERNANTHE-IBOGA; DRUG IBOGAINE; CHANNEL BLOCK; ADDICTION; INGESTION; IDENTIFICATION; PROLONGATION AB The iboga alkaloids are a class of naturally occurring and synthetic compounds, some of which modify drug self-administration and withdrawal in humans and preclinical models. Ibogaine, the prototypic iboga alkaloid that is utilized clinically to treat addictions, has been associated with QT prolongation, torsades de pointes and fatalities. hERG blockade as IKr was measured using the whole-cell patch clamp technique in HEK 293 cells. This yielded the following IC50 values: ibogaine manufactured by semisynthesis via voacangine (4.09 +/- A 0.69 A mu M) or by extraction from T. iboga (3.53 +/- A 0.16 A mu M); ibogaine's principal metabolite noribogaine (2.86 +/- A 0.68 A mu M); and voacangine (2.25 +/- A 0.34 A mu M). In contrast, the IC50 of 18-methoxycoronaridine, a product of rational synthesis and current focus of drug development was > 50 A mu M. hERG blockade was voltage dependent for all of the compounds, consistent with low-affinity blockade. hERG channel binding affinities (K (i)) for the entire set of compounds, including 18-MC, ranged from 0.71 to 3.89 A mu M, suggesting that 18-MC binds to the hERG channel with affinity similar to the other compounds, but the interaction produces substantially less hERG blockade. In view of the extended half-life of noribogaine, these results may relate to observations of persistent QT prolongation and cardiac arrhythmia at delayed intervals of days following ibogaine ingestion. The apparent structure-activity relationships regarding positions of substitutions on the ibogamine skeleton suggest that the iboga alkaloids might provide an informative paradigm for investigation of the structural biology of the hERG channel. C1 [Alper, Kenneth] NYU, Sch Med, Dept Psychiat & Neurol, New York, NY 10016 USA. [Bai, Rong; Liu, Nian; Ruan, Yanfei] Capital Med Univ, Natl Clin Res Ctr Cardiovasc Dis, Beijing 100029, Peoples R China. [Bai, Rong; Liu, Nian; Ruan, Yanfei] Capital Med Univ, Beijing An Zhen Hosp, Dept Cardiol, Beijing 100029, Peoples R China. [Fowler, Steven J.; Priori, Silvia G.; Ruan, Yanfei] NYU, Sch Med, Dept Med, Div Cardiol, New York, NY 10016 USA. [Huang, Xi-Ping] Univ N Carolina, Dept Pharmacol, NIMH PDSP, Chapel Hill, NC 27599 USA. RP Ruan, YF (reprint author), Capital Med Univ, Natl Clin Res Ctr Cardiovasc Dis, Beijing 100029, Peoples R China. EM ruanyanfei@hotmail.com OI fowler, steven/0000-0003-1361-0476 FU National Natural Science Foundation of China [NSFC-81370290, NSFC-81370292] FX Drs. Rong Bai and Nian Liu were supported by the National Natural Science Foundation of China (NSFC-81370290 and NSFC-81370292). We thank Stevenson Flemer and Bruce O'Rourke from the University of Vermont for HPLC/MS analyses. We thank Dr. Maarten E. A. Reith and Dr. Dave Nichols for helpful discussion and Reith Lab for logistical support regarding the research compounds. NR 48 TC 3 Z9 3 U1 4 U2 14 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1530-7905 EI 1559-0259 J9 CARDIOVASC TOXICOL JI Cardiovasc. Toxicol. PD JAN PY 2016 VL 16 IS 1 BP 14 EP 22 DI 10.1007/s12012-015-9311-5 PG 9 WC Cardiac & Cardiovascular Systems; Toxicology SC Cardiovascular System & Cardiology; Toxicology GA DA1ED UT WOS:000367538200003 PM 25636206 ER PT J AU Rahnasto-Rilla, M Kokkola, T Jarho, E Lahtela-Kakkonen, M Moaddel, R AF Rahnasto-Rilla, Minna Kokkola, Tarja Jarho, Elina Lahtela-Kakkonen, Maija Moaddel, Ruin TI N-Acylethanolamines Bind to SIRT6 SO CHEMBIOCHEM LA English DT Article DE enzymes; ethanolamides; natural products; quercetin; sirtuins ID PROLIFERATOR-ACTIVATED RECEPTORS; DEACETYLASE SIRT6; MAMMALIAN SIRTUINS; PPAR-GAMMA; PROTEIN; ANANDAMIDE; MICE; DIFFERENTIATION; ADIPOCYTES AB Sirtuin6 (SIRT6) is an NAD+-dependent histone deacetylase enzyme that is involved in multiple molecular pathways related to aging. Initially, it was reported that SIRT6 selectively deacetylated H3K9Ac and H3K56Ac; however, it has more recently been shown to preferentially hydrolyze long-chain fatty acyl groups over acetyl groups in vitro. Subsequently, fatty acids were demonstrated to increase the catalytic activity of SIRT6. In this study, we investigated whether a series of N-acylethanolamines (NAEs), quercetin, and luteolin could regulate SIRT6 activity. NAEs increased SIRT6 activity, with oleoylethanolamide having the strongest activity (EC50 value of 3.1m). Quercetin and luteolin were demonstrated to have dual functionality with respect to SIRT6 activity; namely, they inhibited SIRT6 activity with IC50 values of 24 and 2m, respectively, and stimulated SIRT6 activity more than sixfold (EC50 values of 990 and 270m, respectively). C1 [Rahnasto-Rilla, Minna; Moaddel, Ruin] NIA, Bioanalyt Chem & Drug Screening Ctr, Lab Clin Invest, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. [Rahnasto-Rilla, Minna; Kokkola, Tarja; Jarho, Elina; Lahtela-Kakkonen, Maija] Univ Eastern Finland, Sch Pharm, Kuopio 70210, Finland. RP Moaddel, R (reprint author), NIA, Bioanalyt Chem & Drug Screening Ctr, Lab Clin Invest, NIH,Biomed Res Ctr, Suite 100,251 Bayview Blvd, Baltimore, MD 21224 USA. EM moaddelru@grc.nia.nih.gov RI Kokkola, Tarja/E-4526-2011 OI Kokkola, Tarja/0000-0002-3303-3912 FU National Institute on Aging (NIA) Intramural Research Program; Academy of Finland [137788, 269341]; Orion-Farmos Research Foundation; Saastamoinen Foundation FX This work was supported in part by funds from the National Institute on Aging (NIA) Intramural Research Program (R.M.), the Academy of Finland (grants.137788 and 269341), the Orion-Farmos Research Foundation (2014, 2015), and the Saastamoinen Foundation. We thank Sari Ukkonen for her skillful assistance. NR 27 TC 2 Z9 2 U1 1 U2 4 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1439-4227 EI 1439-7633 J9 CHEMBIOCHEM JI ChemBioChem PD JAN 1 PY 2016 VL 17 IS 1 BP 77 EP 81 DI 10.1002/cbic.201500482 PG 5 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA DA3TB UT WOS:000367720700013 PM 26607666 ER PT J AU Hoofnagle, AN Whiteaker, JR Carr, SA Kuhn, E Liu, T Massoni, SA Thomas, SN Townsend, RR Zimmerman, LJ Boja, E Chen, J Crimmins, DL Davies, SR Gao, YG Hiltke, TR Ketchum, KA Kinsinger, CR Mesri, M Meyer, MR Qian, WJ Schoenherr, RM Scott, MG Shi, TJ Whiteley, GR Wrobel, JA Wu, CC Ackermann, BL Aebersold, R Barnidge, DR Bunk, DM Clarke, N Fishman, JB Grant, RP Kusebauch, U Kushnir, MM Lowenthal, MS Moritz, RL Neubert, H Patterson, SD Rockwood, AL Rogers, J Singh, RJ Van Eyk, JE Wong, SH Zhang, SC Chan, DW Chen, X Ellis, MJ Liebler, DC Rodland, KD Rodriguez, H Smith, RD Zhang, Z Zhang, H Paulovich, AG AF Hoofnagle, Andrew N. Whiteaker, Jeffrey R. Carr, Steven A. Kuhn, Eric Liu, Tao Massoni, Sam A. Thomas, Stefani N. Townsend, R. Reid Zimmerman, Lisa J. Boja, Emily Chen, Jing Crimmins, Daniel L. Davies, Sherri R. Gao, Yugian Hiltke, Tara R. Ketchum, Karen A. Kinsinger, Christopher R. Mesri, Mehdi Meyer, Matthew R. Qian, Wei-Jun Schoenherr, Regine M. Scott, Mitchell G. Shi, Tujin Whiteley, Gordon R. Wrobel, John A. Wu, Chaochao Ackermann, Brad L. Aebersold, Ruedi Barnidge, David R. Bunk, David M. Clarke, Nigel Fishman, Jordan B. Grant, Russ P. Kusebauch, Ulrike Kushnir, Mark M. Lowenthal, Mark S. Moritz, Robert L. Neubert, Hendrik Patterson, Scott D. Rockwood, Alan L. Rogers, John Singh, Ravinder J. Van Eyk, Jennifer E. Wong, Steven H. Zhang, Shucha Chan, Daniel W. Chen, Xian Ellis, Matthew J. Liebler, Daniel C. Rodland, Karin D. Rodriguez, Henry Smith, Richard D. Zhang, Zhen Zhang, Hui Paulovich, Amanda G. TI Recommendations for the Generation, Quantification, Storage, and Handling of Peptides Used for Mass Spectrometry-Based Assays SO CLINICAL CHEMISTRY LA English DT Article ID AMINO-ACID-ANALYSIS; PERFORMANCE LIQUID-CHROMATOGRAPHY; PROTEIN QUANTIFICATION; ISOTOPE-DILUTION; QUANTITATIVE BIOANALYSIS; PROTEOTYPIC PEPTIDES; INTERNAL STANDARD; LC-MS/MS; PROTEOMICS; PREDICTION AB BACKGROUND: For many years, basic and clinical researchers have taken advantage of the analytical sensitivity and specificity afforded by mass spectrometry in the measurement of proteins. Clinical laboratories are now beginning to deploy these work flows as well. For assays that use proteolysis to generate peptides for protein quantification and characterization, synthetic stable isotope labeled internal standard peptides are of central importance. No general recommendations are currently available surrounding the use of peptides in protein mass spectrometric assays. CONTENT: The Clinical Proteomic Tumor Analysis Consortium of the National Cancer Institute has collaborated with clinical laboratorians, peptide manufacturers, metrologists, representatives of the pharmaceutical industry, and other professionals to develop a consensus set of recommendations for peptide procurement, characterization, storage, and handling, as well as approaches to the interpretation of the data generated by mass spectrometric protein assays. Additionally, the importance of carefully characterized reference materials in particular, peptide standards for the improved concordance of amino acid analysis methods across the industry is highlighted. The alignment of practices around the use of peptides and the transparency of sample preparation protocols should allow for the harmonization of peptide and protein quantification in research and clinical care. (C) 2015 American Association for Clinical Chemistry C1 [Hoofnagle, Andrew N.] Univ Washington, Seattle, WA 98115 USA. [Whiteaker, Jeffrey R.; Schoenherr, Regine M.; Paulovich, Amanda G.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Carr, Steven A.; Kuhn, Eric] Broad Inst, Cambridge, MA USA. [Liu, Tao; Gao, Yugian; Qian, Wei-Jun; Shi, Tujin; Wu, Chaochao; Rodland, Karin D.; Smith, Richard D.] Pacific NW Natl Lab, Richland, WA 99352 USA. [Massoni, Sam A.] New England Peptide Inc, Gardner, MA USA. [Thomas, Stefani N.; Zhang, Zhen; Zhang, Hui] Johns Hopkins Univ, Baltimore, MD USA. [Townsend, R. Reid; Crimmins, Daniel L.; Davies, Sherri R.; Meyer, Matthew R.; Scott, Mitchell G.] Washington Univ, St Louis, MO USA. [Zimmerman, Lisa J.; Liebler, Daniel C.] Vanderbilt Univ, Nashville, TN 37235 USA. [Boja, Emily; Hiltke, Tara R.; Mesri, Mehdi; Rodriguez, Henry] NCI, Bethesda, MD 20892 USA. [Ketchum, Karen A.] ESAC Inc, Rockville, MD USA. [Whiteley, Gordon R.] Frederick Natl Lab Canc Res, Frederick, MD USA. [Wrobel, John A.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Ackermann, Brad L.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Aebersold, Ruedi] Swiss Fed Inst Technol, Inst Mol Syst Biol, Zurich, Switzerland. [Barnidge, David R.] Mayo Clin, Coll Med, Rochester, MN USA. [Bunk, David M.; Lowenthal, Mark S.] NIST, Gaithersburg, MD 20899 USA. [Clarke, Nigel] Quest Diagnost, San Juan Capistrano, CA USA. [Fishman, Jordan B.] 21st Century Biochem Inc, Marlborough, MA USA. [Grant, Russ P.] Lab Corp Amer Holdings Inc, Burlington, NC USA. [Moritz, Robert L.] Inst Syst Biol, Seattle, WA USA. [Kushnir, Mark M.; Rockwood, Alan L.] Univ Utah, Salt Lake City, UT USA. [Kushnir, Mark M.; Rockwood, Alan L.] ARUP Labs, Salt Lake City, UT USA. [Neubert, Hendrik] Pfizer Inc, Andover, MA USA. [Patterson, Scott D.] Gilead Sci Inc, Foster City, CA USA. [Rogers, John] Thermo Fisher Sci, Rockford, IL USA. [Van Eyk, Jennifer E.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Wong, Steven H.] Wake Forest Sch Med, Winston Salem, NC USA. [Zhang, Shucha] Enanta Pharmaceut, Watertown, MA USA. [Ellis, Matthew J.] Baylor Coll Med, Houston, TX 77030 USA. RP Hoofnagle, AN (reprint author), Univ Washington, Box 357110, Seattle, WA 98115 USA. EM ahoof@u.washington.edu; apaulovi@fhcrc.org RI Smith, Richard/J-3664-2012 OI Smith, Richard/0000-0002-2381-2349 FU Waters Inc.; Thermo Inc.; NIDDK [U01DK085689]; NCI [U24CA115102]; NIGMS [P50GM076547, R01GM087221]; NCI CPTAC [U24CA160034, U24CA160019, U24CA160036, U24CA160035, U24CA159988] FX A.N. Hoofnagle, Waters Inc. and Thermo Inc.; J.E. Van Eyk, NIDDK (U01DK085689); D.W. Chan, NCI (U24CA115102); R.L. Moritz, NIGMS (P50GM076547 and R01GM087221); S.A. Carr (PI), A.N. Hoofnagle, E. Kuhn, A.G. Paulovich (PI), and R.M. Schoenherr, NCI CPTAC (U24CA160034); Y. Gao, T. Liu, W-J. Qian, K.D. Rodland (PI), T. Shi, R.D. Smith (PI), and C. Wu, NCI CPTAC (U24CA160019); D.W. Chan (PI), J. Chen, S.N. Thomas, H. Zhang (PI), and Z. Zhang (PI), NCI CPTAC (U24CA160036); X. Chen (PI), D.L. Crimmins, S.R. Davies, M.J. Ellis (PI), M.R. Meyer, KG. Scott, and R.R. Townsend (PI), NCI CPTAC (U24CA160035); D.C. Liebler (PI) and L.J. Zimmerman, NCI CPTAC (U24CA159988). NR 76 TC 16 Z9 16 U1 10 U2 30 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 JAN PY 2016 VL 62 IS 1 BP 48 EP 69 DI 10.1373/clinchem.2015.250563 PG 22 WC Medical Laboratory Technology SC Medical Laboratory Technology GA DA3NC UT WOS:000367703400013 PM 26719571 ER PT J AU Diao, XX Wohlfarth, A Pang, SK Scheidweiler, KB Huestis, MA AF Diao, Xingxing Wohlfarth, Ariane Pang, Shaokun Scheidweiler, Karl B. Huestis, Marilyn A. TI High-Resolution Mass Spectrometry for Characterizing the Metabolism of Synthetic Cannabinoid THJ-018 and Its 5-Fluoro Analog THJ-2201 after Incubation in Human Hepatocytes SO CLINICAL CHEMISTRY LA English DT Article ID URINARY METABOLITES; ILLEGAL PRODUCTS; FREQUENT SMOKERS; DRUG CANDIDATES; PHASE-I; IDENTIFICATION; DISPOSITION; DERIVATIVES; MIXTURES; AM-2201 AB BACKGROUND: Despite increasing prevalence of novel psychoactive substances, no human metabolism data are currently available, complicating laboratory documentation of intake in urine samples and assessment of the drugs' pharmacodynamic, pharmacokinetic, and toxicological properties. In 2014, THJ-018 and THJ-2201, synthetic cannabinoid indazole analogs of JWH-018 and AM-2201, were identified, with the National Forensic Laboratory Information System containing 220 THJ-2201 reports. Because of numerous adverse events, the Drug Enforcement Administration listed THJ-2201 as Schedule I in January 2015. METHODS: We used high-resolution mass spectrometry (HR-MS) (TripleTOF 5600(+)) to identify optimal metabolite markers after incubating 10 mu mol/L THJ-018 and THJ-2201 in human hepatocytes for 3 h. Data were acquired via full scan and information-dependent acquisition triggered product ion scans with mass defect filter. In silico metabolite predictions were performed with Meta Site and compared with metabolites identified in human hepatocytes. RESULTS: Thirteen THJ-018 metabolites were detected, with the major metabolic pathways being hydroxylation on the N-pentyl chain and further oxidation or glucuronidation. For THJ-2201, 27 metabolites were observed, predominantly oxidative defluorination plus subsequent carboxylation or glucuronidation, and glucuronidation of hydroxylated metabolites. Dihydrodiol formation on the naphthalene moiety was observed for both compounds. Meta Site prediction matched well with THJ-018 hepatocyte metabolites but underestimated THJ-2201 oxidative defluorination. CONCLUSIONS: With HR-MS for data acquisition and processing, we characterized THJ-018 and THJ-2201 metabolism in human hepatocytes and suggest appropriate markers for laboratories to identify THJ-018 and THJ-2201 intake and link observed adverse events to these new synthetic cannabinoids. (C) 2015 American Association for Clinical Chemistry C1 [Diao, Xingxing; Wohlfarth, Ariane; Scheidweiler, Karl B.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, IRP, NIH, Baltimore, MD 21224 USA. [Pang, Shaokun] SCIEX Ltd, Redwood City, CA USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab, IRP, NIH, 251 Bayview Blvd,Suite 200 Room 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program (IRP) of the National Institute on Drug Abuse, NIH FX The Intramural Research Program (IRP) of the National Institute on Drug Abuse, NIH. The Molecular Discovery Company provided the MetaSite software. NR 39 TC 15 Z9 15 U1 7 U2 20 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 JAN PY 2016 VL 62 IS 1 BP 157 EP 169 DI 10.1373/clinchem.2015.243535 PG 13 WC Medical Laboratory Technology SC Medical Laboratory Technology GA DA3NC UT WOS:000367703400024 PM 26430074 ER PT J AU Callahan, A Anderson, WF Patel, S Barnholtz-Sloan, JS Bordeaux, JS Tucker, MA Gerstenblith, MR AF Callahan, Adrienne Anderson, William F. Patel, Sital Barnholtz-Sloan, Jill S. Bordeaux, Jeremy S. Tucker, Margaret A. Gerstenblith, Meg R. TI Epidemiology of Anorectal Melanoma in the United States: 1992 to 2011 SO DERMATOLOGIC SURGERY LA English DT Article ID CUTANEOUS MELANOMA; MUCOSAL MELANOMAS; ANAL MELANOMA; SURVIVAL; OUTCOMES; SKIN; HISPANICS; PATTERNS; SURGERY; US AB BACKGROUNDAnorectal melanoma is a rare type of malignant melanoma and thus the epidemiology of patients with this tumor has been poorly defined.OBJECTIVETo describe the epidemiology of anorectal melanoma in the United States.METHODS AND MATERIALSWe obtained case and population data from the Surveillance, Epidemiology, and End Results 13 Registries Database (SEER 13) between 1992 and 2011 using rectal diagnostic codes C20.9 to 21.8 and ICD-O-3 melanoma codes 8720 to 8721 and 8742 to 8746.RESULTSThere were 260 primary anorectal melanomas in SEER 13 from 1992 to 2011, occurring mostly in the rectum. The incidence of anorectal melanoma was higher among women than men with the highest rates occurring among white Hispanics ages 65 to 74 years. During this time period, the age-adjusted incidence rates rose significantly (p < .05) for both women and men with estimated annual percentage changes of 3.02% and 5.08%, respectively. Overall and melanoma-specific survival was poor irrespective of gender or ethnicity.CONCLUSIONAnorectal melanoma in the United States is increasing in both men and women, with the highest rates in elderly Hispanic white women. Hispanic whites were more likely to develop anorectal melanoma than non-Hispanic whites, suggesting that this population may be targeted for screening interventions. These results warrant further investigation to better understand the gender, racial, ethnic, and geographic variations for anorectal melanomas. C1 [Callahan, Adrienne; Patel, Sital; Bordeaux, Jeremy S.; Gerstenblith, Meg R.] Univ Hosp Cleveland, Case Med Ctr, Dept Dermatol, Cleveland, OH 44106 USA. [Anderson, William F.; Tucker, Margaret A.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Barnholtz-Sloan, Jill S.; Bordeaux, Jeremy S.; Gerstenblith, Meg R.] Case Comprehens Canc Ctr, Cleveland, OH USA. RP Gerstenblith, MR (reprint author), Dept Dermatol, 11100 Euclid Ave,Lakeside 3500, Cleveland, OH 44106 USA. EM meg.gerstenblith@uhhospitals.org FU Char and Chuck Fowler Family Foundation; Dermatology Foundation; National Cancer Institute from the Case Comprehensive Cancer Center [P30 CA043703] FX This study was supported by the Char and Chuck Fowler Family Foundation and the Dermatology Foundation Career Development Award in Medical Dermatology (M. R. Gerstenblith) and in part by National Cancer Institute grant P30 CA043703 from the Case Comprehensive Cancer Center (J. S. Barnholtz-Sloan). The authors have indicated no significant interest with commercial supporters. NR 26 TC 2 Z9 2 U1 4 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1076-0512 EI 1524-4725 J9 DERMATOL SURG JI Dermatol. Surg. PD JAN PY 2016 VL 42 IS 1 BP 94 EP 99 DI 10.1097/DSS.0000000000000579 PG 6 WC Dermatology; Surgery SC Dermatology; Surgery GA DA5GX UT WOS:000367832300014 PM 26655698 ER PT J AU Ulrich, F Carretero-Ortega, J Menendez, J Narvaez, C Sun, B Lancaster, E Pershad, V Trzaska, S Veliz, E Kamei, M Prendergast, A Kidd, KR Shaw, KM Castranova, DA Pham, VN Lo, BD Martin, BL Raible, DW Weinstein, BM Torres-Vazquez, J AF Ulrich, Florian Carretero-Ortega, Jorge Menendez, Javier Narvaez, Carlos Sun, Belinda Lancaster, Eva Pershad, Valerie Trzaska, Sean Veliz, Evelyn Kamei, Makoto Prendergast, Andrew Kidd, Kameha R. Shaw, Kenna M. Castranova, Daniel A. Pham, Van N. Lo, Brigid D. Martin, Benjamin L. Raible, David W. Weinstein, Brant M. Torres-Vazquez, Jesus TI Reck enables cerebrovascular development by promoting canonical Wnt signaling SO DEVELOPMENT LA English DT Article DE Angiogenesis; Blood-brain barrier; Brain vasculature; Reck; VEGF; Wnt ID ENDOTHELIAL-GROWTH-FACTOR; BLOOD-BRAIN-BARRIER; CENTRAL-NERVOUS-SYSTEM; SYNTHASE KINASE 3; VASCULAR DEVELOPMENT; BETA-CATENIN; IN-VIVO; ZEBRAFISH EMBRYOS; GENE-EXPRESSION; PATHOLOGICAL ANGIOGENESIS AB The cerebral vasculature provides the massive blood supply that the brain needs to grow and survive. By acquiring distinctive cellular and molecular characteristics it becomes the blood-brain barrier (BBB), a selectively permeable and protective interface between the brain and the peripheral circulation that maintains the extracellular milieu permissive for neuronal activity. Accordingly, there is great interest in uncovering the mechanisms that modulate the formation and differentiation of the brain vasculature. By performing a forward genetic screen in zebrafish we isolated no food for thought (nft(y72)), a recessive late-lethal mutant that lacks most of the intracerebral central arteries (CtAs), but not other brain blood vessels. We found that the cerebral vascularization deficit of nft(y72) mutants is caused by an inactivating lesion in reversion-inducing cysteine-rich protein with Kazal motifs [reck; also known as suppressor of tumorigenicity 15 protein (ST15)], which encodes a membrane-anchored tumor suppressor glycoprotein. Our findings highlight Reck as a novel and pivotal modulator of the canonical Wnt signaling pathway that acts in endothelial cells to enable intracerebral vascularization and proper expression of molecular markers associated with BBB formation. Additional studies with cultured endothelial cells suggest that, in other contexts, Reck impacts vascular biology via the vascular endothelial growth factor (VEGF) cascade. Together, our findings have broad implications for both vascular and cancer biology. C1 [Ulrich, Florian; Carretero-Ortega, Jorge; Menendez, Javier; Narvaez, Carlos; Sun, Belinda; Lancaster, Eva; Pershad, Valerie; Trzaska, Sean; Veliz, Evelyn; Torres-Vazquez, Jesus] NYU, Langone Med Ctr, Dept Cell Biol, Skirball Inst Biomol Med, New York, NY 10016 USA. [Kamei, Makoto; Kidd, Kameha R.; Shaw, Kenna M.; Castranova, Daniel A.; Pham, Van N.; Lo, Brigid D.; Weinstein, Brant M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Prendergast, Andrew; Raible, David W.] Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. [Martin, Benjamin L.] SUNY Stony Brook, Stony Brook, NY 11794 USA. RP Torres-Vazquez, J (reprint author), NYU, Langone Med Ctr, Dept Cell Biol, Skirball Inst Biomol Med, 540 First Ave, New York, NY 10016 USA. EM torres@saturn.med.nyu.edu OI Kamei, Makoto/0000-0002-1438-0783 FU Consejo Nacional de Ciencia y Tecnologia [187031, 203862]; American Heart Association [0735352N]; American Chemical Society [RSG-14045-01-DDC]; National Institutes of Health [3R01HL092263-05S1-01A1, 1R56HL118055-01A1] FX Research was supported by a Consejo Nacional de Ciencia y Tecnologia postdoctoral fellowship [187031 and 203862 to J.C.-O.], the American Heart Association [0735352N], the American Chemical Society [RSG-14045-01-DDC] and the National Institutes of Health [3R01HL092263-05S1-01A1 and 1R56HL118055-01A1] to J.T.-V. Deposited in PMC for release after 12 months. NR 136 TC 4 Z9 4 U1 1 U2 9 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD JAN 1 PY 2016 VL 143 IS 1 BP 147 EP 159 DI 10.1242/dev.123059 PG 13 WC Developmental Biology SC Developmental Biology GA DA2IJ UT WOS:000367618200015 PM 26657775 ER PT J AU Mordukhovich, I Beyea, J Herring, AH Hatch, M Stellman, SD Teitelbaum, SL Richardson, DB Millikan, RC Engel, LS Shantakumar, S Steck, SE Neugut, AI Rossner, P Santella, RM Gammon, MD AF Mordukhovich, Irina Beyea, Jan Herring, Amy H. Hatch, Maureen Stellman, Steven D. Teitelbaum, Susan L. Richardson, David B. Millikan, Robert C. Engel, Lawrence S. Shantakumar, Sumitra Steck, Susan E. Neugut, Alfred I. Rossner, Pavel, Jr. Santella, Regina M. Gammon, Marilie D. TI Vehicular Traffic-Related Polycyclic Aromatic Hydrocarbon Exposure and Breast Cancer Incidence: The Long Island Breast Cancer Study Project (LIBCSP) SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID HORMONE-RECEPTOR STATUS; TIME-ACTIVITY PATTERNS; RISK-FACTORS; DNA-ADDUCTS; NEW-YORK; TOBACCO-SMOKE; AIR-POLLUTION; WOMEN; DIET; EPIDEMIOLOGY AB BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental-pollutants, known human lung carcinogens, and potent mammary carcinogens in laboratory animals. However, the association between PAHs and breast cancer in women is unclear. Vehicular traffic is a major ambient source of PAH exposure. OBJECTIVES: Our study aim was to evaluate the association between residential exposure to-vehicular traffic and breast cancer incidence. METHODS: Residential histories of 1,508 participants with breast cancer (case participants) and 1,556 particpants with no breast cancer (control participants) were assessed in a population-based investigation conducted in 1996-1997. Traffic exposure estimates of benzo[a]pyrene (B[a]P), as a proxy for traffic-related PAHs, for the years 1960-1995 were reconstructed using a model previously shown to generate estimates consistent with measured soil PAHs, PAH-DNA adducts, and CO readings. Associations between vehicular traffic exposure estimates and breast cancer incidence were evaluated using unconditional logistic regression. RESULTS: The odds ratio (95% CI) was modestly elevated by 1.44 (0.78, 2.68) for the association between breast cancer and long-term 1960-1990 vehicular traffic estimates in the top 5%, compared with below the median. The association with recent 1995 traffic exposure was elevated by 1.14 (0.80, 1.64) for the top 5%, compared with below the median, which was stronger among women with low fruit/vegetable intake [1.46 (0.89, 2.40)], but not among those with high fruit/vegetable intake [0.92 (0.53, 1.60)]. Among the subset of women with information regarding traffic exposure and tumor hormone receptor subtype, the traffic-breast cancer association was higher for those with estrogen/progesterone-negative tumors [1.67 (0.91, 3.05) relative to control participants], but lower among all other tumor subtypes [0.80 (0.50, 1.27) compared with control participants]. CONCLUSIONS: In our population-based study, we observed positive associations between vehicular traffic-related B[a]P exposure and breast cancer incidence among women with comparatively high long-term traffic B[a]P exposures, although effect estimates were imprecise. C1 [Mordukhovich, Irina; Richardson, David B.; Millikan, Robert C.; Engel, Lawrence S.; Gammon, Marilie D.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Beyea, Jan] Consulting Publ Interest, Lambertville, NJ USA. [Herring, Amy H.] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Herring, Amy H.] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. [Hatch, Maureen] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Stellman, Steven D.; Neugut, Alfred I.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Teitelbaum, Susan L.] Mt Sinai Sch Med, Dept Prevent Med, New York, NY USA. [Shantakumar, Sumitra] GlaxoSmithKline Inc, Singapore, Singapore. [Steck, Susan E.] Univ S Carolina, Dept Epidemiol & Biostat, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. [Neugut, Alfred I.] Columbia Univ, Dept Med, New York, NY USA. [Rossner, Pavel, Jr.; Santella, Regina M.] Columbia Univ, Dept Environm Hlth Sci, New York, NY USA. [Rossner, Pavel, Jr.] Inst Expt Med AS CR, Lab Genet Ecotoxicol, Prague, Czech Republic. RP Mordukhovich, I (reprint author), Harvard Univ, Dept Environm Hlth, Exposure Epidemiol & Risk Program, TH Chan Sch Publ Hlth,Landmark Ctr, 401 Pk Dr, Boston, MA 02215 USA. EM imordukh@hsph.harvard.edu RI Rossner, Pavel/H-2569-2014; OI Beyea, Jan/0000-0002-0547-880X; Engel, Lawrence/0000-0001-9268-4830 FU U.S. Department of Defense [BC100414, BC972772]; National Cancer Institute; National Institute of Environmental Health Sciences, National Institutes of Health [CA/ES66572, P30ES009089, P30ES10126, T32CA09330, T32ES007018]; Breast Cancer Research Foundation; Columbia University Women at Risk Program; GlaxoSmithKline FX This work was supported in part by awards from the U.S. Department of Defense (BC100414, BC972772), the National Cancer Institute and the National Institute of Environmental Health Sciences, National Institutes of Health (CA/ES66572, P30ES009089, P30ES10126, T32CA09330, and T32ES007018), the Breast Cancer Research Foundation, Columbia University Women at Risk Program, and gifts from private citizens.; J.B. is employed by Consulting in the Public Interest Inc. S.S. participated in this research during her time as a doctoral student at UNC Chapel Hill and is currently an employee and shareholder of GlaxoSmithKline, Singapore. Neither GlaxoSmithKline nor anyone connected to litigation provided any funding for this analysis. The other authors declare they have no actual or potential competing financial interests. NR 56 TC 5 Z9 5 U1 8 U2 31 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 JAN PY 2016 VL 124 IS 1 BP 30 EP 38 DI 10.1289/ehp.1307736 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DA1XQ UT WOS:000367589600012 PM 26008800 ER PT J AU Liao, LM Friesen, MC Xiang, YB Cai, H Koh, DH Ji, BT Yang, G Li, HL Locke, SJ Rothman, N Zheng, W Gao, YT Shu, XO Purdue, MP AF Liao, Linda M. Friesen, Melissa C. Xiang, Yong-Bing Cai, Hui Koh, Dong-Hee Ji, Bu-Tian Yang, Gong Li, Hong-Lan Locke, Sarah J. Rothman, Nathaniel Zheng, Wei Gao, Yu-Tang Shu, Xiao-Ou Purdue, Mark P. TI Occupational Lead Exposure and Associations with Selected Cancers: The Shanghai Men's and Women's Health Study Cohorts SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID RENAL-CELL CARCINOMA; ADULT BRAIN-TUMORS; NERVOUS-SYSTEM; INORGANIC LEAD; LUNG-CANCER; RISK; MORTALITY; CADMIUM; GENES; CHINA AB BACKGROUND: Epidemiologic studies of occupational lead exposure have suggested increased risks of cancers of the stomach, lung, kidney, brain, and meninges; however, the totality of the evidence is inconsistent. OBJECTIVE: We investigated the relationship between occupational lead exposure and cancer incidence at the five abovementioned sites in two prospective cohorts in Shanghai, China. METHODS: Annual job/industry-specific estimates of lead fume and lead dust exposure, derived from a statistical model combining expert lead intensity ratings with inspection measurements, were applied to the lifetime work histories of participants from the Shanghai Women's Health Study (SWHS; n = 73,363) and the Shanghai Men's Health Study (SMHS; n = 61,379) to estimate cumulative exposure to lead fume and lead dust. These metrics were then combined into an overall occupational lead exposure variable. Cohort-specific relative hazard rate ratios (RRs) and 95% confidence intervals (CIs) comparing exposed and unexposed participants were estimated using Cox proportional hazards regression and combined by meta-analysis. RESULTS: The proportions of SWHS and SMHS participants with estimated occupational lead exposure were 8.9% and 6.9%, respectively. Lead exposure was positively associated with meningioma risk in women only (n = 38 unexposed and 9 exposed cases; RR = 2.4; 95% CI: 1.1, 5.0), particularly with above-median cumulative exposure (RR = 3.1; 95% CI: 1.3, 7.4). However, all 12 meningioma cases among men were classified as unexposed to lead. We also observed nonsignificant associations with lead exposure for cancers of the kidney (n = 157 unexposed and 17 ever exposed cases; RR = 1.4; 95% CI: 0.9, 2.3) and brain (n = 67 unexposed and 10 ever exposed cases; RR = 1.8; 95% CI: 0.7, 4.8) overall. CONCLUSIONS: Our findings, though limited by small numbers of cases, suggest that lead is associated with the risk of several cancers in women and men. C1 [Liao, Linda M.; Friesen, Melissa C.; Ji, Bu-Tian; Locke, Sarah J.; Rothman, Nathaniel; Purdue, Mark P.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Xiang, Yong-Bing; Li, Hong-Lan; Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Cai, Hui; Yang, Gong; Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med, Nashville, TN 37212 USA. [Koh, Dong-Hee] Natl Canc Ctr, Natl Canc Control Inst, Goyang, South Korea. RP Liao, LM (reprint author), NCI, Occupat & Environm Epidemiol Branch, 9609 Med Ctr Dr,Room 6-E632,MSC 9771, Bethesda, MD 20892 USA. EM Linda.Liao@nih.gov RI Purdue, Mark/C-9228-2016; Friesen, Melissa/A-5362-2009; Zheng, Wei/O-3351-2013; OI Purdue, Mark/0000-0003-1177-3108; Zheng, Wei/0000-0003-1226-070X; Liao, Linda/0000-0002-1923-5294 FU U.S. National Institutes of Health [R37 CA070867, R01 CA082729, UM1 CA173640]; Intramural Research Program [N02 CP1101066] FX This project was supported by grants from the U.S. National Institutes of Health (R37 CA070867 to W.Z., and R01 CA082729 and UM1 CA173640 to X.-O.S.) and by the Intramural Research Program (contract N02 CP1101066). NR 34 TC 1 Z9 2 U1 1 U2 19 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 JAN PY 2016 VL 124 IS 1 BP 97 EP 103 DI 10.1289/ehp.1408171 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DA1XQ UT WOS:000367589600021 PM 26091556 ER PT J AU Darney, SP Dimes, MM AF Darney, Sally Perreault Dimes, Martha M. TI Perspectives on the Children's Health Collection 2015 SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 [Darney, Sally Perreault; Dimes, Martha M.] NIEHS, Environm Hlth Perspect, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Darney, SP (reprint author), NIEHS, Environm Hlth Perspect, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM sally.darney@nih.gov NR 5 TC 0 Z9 0 U1 0 U2 2 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 JAN PY 2016 VL 124 IS 1 BP A1 EP A2 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DA1XQ UT WOS:000367589600001 PM 26720198 ER PT J AU Kane, AE Mitchell, SJ Mach, J Huizer-Pajkos, A McKenzie, C Jones, B Cogger, V Le Couteur, DG de Cabo, R Hilmer, SN AF Kane, Alice E. Mitchell, Sarah J. Mach, John Huizer-Pajkos, Aniko McKenzie, Catriona Jones, Brett Cogger, Victoria Le Couteur, David G. de Cabo, Rafael Hilmer, Sarah N. TI Acetaminophen hepatotoxicity in mice: Effect of age, frailty and exposure type SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE Acetaminophen; Hepatotoxicity; Ageing; Frailty; Mice; Liver; Paracetamol ID INDUCED LIVER-INJURY; INDUCED LETHALITY; FISCHER-344 RATS; OXIDANT STRESS; SERUM-ALBUMIN; GLUTATHIONE; TOXICITY; OLDER; RESTRICTION; INCREASES AB Acetaminophen is a commonly used analgesic that can cause severe hepatotoxicity in overdose. Despite old age and frailty being associated with extensive and long-termutilization of acetaminophen and a high prevalence of adverse drug reactions, there is limited information on the risks of toxicity from acetaminophen in old age and frailty. This study aimed to assess changes in the risk and mechanisms of hepatotoxicity from acute, chronic and sub-acute acetaminophen exposure with old age and frailty in mice. Young and old male C57BL/6 mice were exposed to either acute (300 mg/kg via oral gavage), chronic (100 mg/kg/day in diet for six weeks) or sub-acute (250 mg/kg, t.i.d., for three days) acetaminophen, or saline control. Pre-dosing mice were scored for the mouse clinical frailty index, and after dosing serum and liver tissue were collected for assessment of toxicity and mechanisms. There were no differences with old age or frailty in the degree of hepatotoxicity induced by acute, chronic or subacute acetaminophen exposure as assessed by serum liver enzymes and histology. Age-related changes in the acetaminophen toxicity pathways included increased liver GSH concentrations, increased NQO1 activity and an increased pro-and anti-inflammatory response to acetaminophen in old age. Frailty-related changes included a negative correlation between frailty index and serum protein, albumin and ALP concentrations for some mouse groups. In conclusion, although there were changes in some pathways that would be expected to influence susceptibility to acetaminophen toxicity, there was no overall increase in acetaminophen hepatotoxicity with old age or frailty in mice. (C) 2015 Elsevier Inc. All rights reserved. C1 [Kane, Alice E.; Mach, John; Huizer-Pajkos, Aniko; Jones, Brett; Hilmer, Sarah N.] Kolling Inst Med Res, Sydney, NSW, Australia. [Kane, Alice E.; Mach, John; Huizer-Pajkos, Aniko; Jones, Brett; Hilmer, Sarah N.] Royal N Shore Hosp, Sydney, NSW, Australia. [Kane, Alice E.; Mach, John; Jones, Brett; Cogger, Victoria; Le Couteur, David G.; Hilmer, Sarah N.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Mitchell, Sarah J.] NIA, Baltimore, MD 21224 USA. [McKenzie, Catriona] Royal Prince Alfred Hosp, Sydney, NSW, Australia. [Cogger, Victoria; Le Couteur, David G.] ANZAC Res Inst, Ctr Educ & Res Ageing, Sydney, NSW, Australia. RP Kane, AE (reprint author), Lab Ageing & Pharmacol, Level 12,Kolling Bldg, St Leonards, NSW 2065, Australia. EM alice.kane@sydney.edu.au; sarah.mitchell@nih.gov; jmach@uni.sydney.edu.au; aniko.huizerpajkos@health.nsw.gov.au; catriona.mckenzie@sswahs.nsw.gov.au; bjones@med.usyd.edu.au; victoria.cogger@sydney.edu.au; david.lecouteur@sydney.edu.au; decabora@grc.nia.nih.gov; sarah.hilmer@sydney.edu.au RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; Kane, Alice/0000-0002-4303-0491; , rafael/0000-0003-2830-5693 FU Intramural Research Program of the National Institute on Ageing, National Institutes of Health; National Health and Medical Research Council (NHMRC) biomedical postgraduate scholarship; Australian Association of Gerontology RM Gibson Scientific Research Grant; Penney Ageing Research Unit, Royal North Shore Hospital FX SJM and RdC are supported by the Intramural Research Program of the National Institute on Ageing, National Institutes of Health.; AEK is supported by a National Health and Medical Research Council (NHMRC) biomedical postgraduate scholarship.; This project was partly funded by an Australian Association of Gerontology RM Gibson Scientific Research Grant and by the Penney Ageing Research Unit, Royal North Shore Hospital. NR 48 TC 2 Z9 2 U1 3 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 EI 1873-6815 J9 EXP GERONTOL JI Exp. Gerontol. PD JAN PY 2016 VL 73 BP 95 EP 106 DI 10.1016/j.exger.2015.11.013 PG 12 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA DA3CR UT WOS:000367674000014 PM 26615879 ER PT J AU Harland, M Petljak, M Robles-Espinoza, CD Ding, ZH Gruis, NA van Doorn, R Pooley, KA Dunning, AM Aoude, LG Wadt, KAW Gerdes, AM Brown, KM Hayward, NK Newton-Bishop, JA Adams, DJ Bishop, DT AF Harland, Mark Petljak, Mia Robles-Espinoza, Carla Daniela Ding, Zhihao Gruis, Nelleke A. van Doorn, Remco Pooley, Karen A. Dunning, Alison M. Aoude, Lauren G. Wadt, Karin A. W. Gerdes, Anne-Marie Brown, Kevin M. Hayward, Nicholas K. Newton-Bishop, Julia A. Adams, David J. Bishop, D. Timothy TI Germline TERT promoter mutations are rare in familial melanoma SO FAMILIAL CANCER LA English DT Article DE Melanoma; Familial; Genetic; TERT; Mutation ID CUTANEOUS MELANOMA; TELOMERE LENGTH; RISK-FACTORS; CANCER; VARIANTS; METAANALYSIS; PREDISPOSE; UVEAL; LUNG; BAP1 AB Germline CDKN2A mutations occur in 40 % of 3-or-more case melanoma families while mutations of CDK4, BAP1, and genes involved in telomere function (ACD, TERF2IP, POT1), have also been implicated in melanomagenesis. Mutation of the promoter of the telomerase reverse transcriptase (TERT) gene (c.-57 T > G variant) has been reported in one family. We tested for the TERT promoter variant in 675 multicase families wild-type for the known high penetrance familial melanoma genes, 1863 UK population-based melanoma cases and 529 controls. Germline lymphocyte telomere length was estimated in carriers. The c.-57 T > G TERT promoter variant was identified in one 7-case family with multiple primaries and early age of onset (earliest, 15 years) but not among population cases or controls. One family member had multiple primary melanomas, basal cell carcinomas and a bladder tumour. The blood leukocyte telomere length of a carrier was similar to wild-type cases. We provide evidence confirming that a rare promoter variant of TERT (c.-57 T > G) is associated with high penetrance, early onset melanoma and potentially other cancers, and explains < 1 % of UK melanoma multicase families. The identification of POT1 and TERT germline mutations highlights the importance of telomere integrity in melanoma biology. C1 [Harland, Mark; Newton-Bishop, Julia A.; Bishop, D. Timothy] Univ Leeds, Leeds Inst Canc & Pathol, Sect Epidemiol & Biostat, Leeds LS9 7TF, W Yorkshire, England. [Petljak, Mia; Robles-Espinoza, Carla Daniela; Ding, Zhihao; Adams, David J.] Wellcome Trust Sanger Inst, Expt Canc Genet, Cambridge CB10 1SA, England. [Gruis, Nelleke A.; van Doorn, Remco] Leiden Univ, Med Ctr, Dept Dermatol, Leiden, Netherlands. [Pooley, Karen A.] Univ Cambridge, Ctr Canc Genet Epidemiol, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Dunning, Alison M.] Univ Cambridge, Ctr Canc Genet Epidemiol, Strangeways Res Lab, Dept Oncol, Cambridge CB1 8RN, England. [Aoude, Lauren G.; Hayward, Nicholas K.] QIMR Berghofer Med Res Inst, Oncogen Lab, Brisbane, Qld, Australia. [Wadt, Karin A. W.; Gerdes, Anne-Marie] Univ Copenhagen Hosp, Dept Clin Genet, DK-2100 Copenhagen, Denmark. [Brown, Kevin M.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Bishop, DT (reprint author), Univ Leeds, Leeds Inst Canc & Pathol, Sect Epidemiol & Biostat, Leeds LS9 7TF, W Yorkshire, England. EM m.harland@leeds.ac.uk; D.T.Bishop@leeds.ac.uk OI Robles Espinoza, Carla Daniela/0000-0003-3277-7466; Dunning, Alison Margaret/0000-0001-6651-7166; Bishop, Tim/0000-0002-8752-8785; Newton Bishop, Julia/0000-0001-9147-6802 FU Cancer Research UK [C588/A19167, C8216/A6129]; NIH [CA83115]; Dutch Cancer Society [UL 2012-5489]; ERC Combat Cancer; Wellcome Trust; National Health and Medical Research Council of Australia; CRUK grant [C8197/A16565]; Isaac Newton Trust; Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institutes of Health FX The authors would like to thank the families for their willingness to participate; and Rajiv Kumar for the provision of mutation positive samples. The collection of samples in the UK population-ascertained sample set was funded by Cancer Research UK (awards C588/A19167 and C8216/A6129) and by the NIH (CA83115). The work of N.A.G. and R.v.D was supported by the Dutch Cancer Society (UL 2012-5489). D.J.A and C.D.R.E are supported by Cancer Research UK, ERC Combat Cancer and the Wellcome Trust. N.K.H is supported by a fellowship from the National Health and Medical Research Council of Australia. A.M.D. and K.A.P. were supported by CRUK grant (C8197/A16565) and The Isaac Newton Trust. K.M.B. is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institutes of Health. NR 22 TC 6 Z9 6 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9600 EI 1573-7292 J9 FAM CANCER JI Fam. Cancer PD JAN PY 2016 VL 15 IS 1 BP 139 EP 144 DI 10.1007/s10689-015-9841-9 PG 6 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA DA1ZK UT WOS:000367594700017 PM 26433962 ER PT J AU Cheng, J Dackor, RT Bradbury, JA Li, H DeGraff, LM Hong, LK King, D Lih, FB Gruzdev, A Edin, ML Travlos, GS Flake, GP Tomer, KB Zeldin, DC AF Cheng, Jennifer Dackor, Ryan T. Bradbury, J. Alyce Li, Hong DeGraff, Laura M. Hong, Lee K. King, Debra Lih, Fred B. Gruzdev, Artiom Edin, Matthew L. Travlos, Gregory S. Flake, Gordon P. Tomer, Kenneth B. Zeldin, Darryl C. TI Contribution of alveolar type II cell-derived cyclooxygenase-2 to basal airway function, lung inflammation, and lung fibrosis SO FASEB JOURNAL LA English DT Article DE prostaglandins; airway hyperresponsiveness; lipopolysaccharide; bleomycin ID INDUCED PULMONARY-FIBROSIS; PROSTAGLANDIN E-2 PRODUCTION; EPITHELIAL-CELLS; DEFICIENT MICE; MOUSE LUNG; LIPOPOLYSACCHARIDE; EXPRESSION; PROTECTS; SYNTHASE; INJURY AB Cyclooxygenase (COX)-2 has been shown to be involved in regulating basal airway function, bacterial LPS-induced airway hyperresponsiveness (AHR) and lung inflammation, and bleomycin-induced lung fibrosis; however, the cellular source of COX-2 that underlies these effects is unknown. We generated mice with alveolar type II (ATII) cell-specific knockdown of COX-2 (AT2CC(-/-)), to examine the role of ATII cell-derived prostaglandins (PGs) in these processes. Specific knockdown of COX-2 was confirmed by real-time RT-PCR and Western blot analyses. LC/MS/MS analysis showed that ATII cells produced PGs. Basal airway responsiveness of AT2CC(-/-) mice was decreased compared to that of wild-type (WT) mice. LPS-induced hypothermic response, infiltration of inflammatory cells into the airway, and lung inflammation were enhanced in AT2CC(-/-) mice relative to WT controls; however, LPS-induced AHR and proinflammatory cytokine and chemokine expression were similar between the genotypes. After 21 d of bleomycin administration, AT2CC(-/-) mice behaved in a manner similar to WT mice. Thus, ATII cell-derived COX-2 plays an important role in regulating basal airway function and LPS-induced lung inflammation, but does not play a role in bleomycin-induced fibrosis. These findings provide insight into the cellular source of COX-2 related to these lung phenotypes.-Cheng, J., Dackor, R. T., Bradbury, J. A., Li, H., DeGraff, L. M., Hong, L. K., King, D., Lih, F. B., Gruzdev, A., Edin, M. L., Travlos, G. S., Flake, G. P., Tomer, K. B., Zeldin, D. C. Contribution of alveolar type II cell-derived cyclooxygenase-2 to basal airway function, lung inflammation, and lung fibrosis. FASEB J. 30, 160-173 (2016). www.fasebj.org C1 [Cheng, Jennifer; Dackor, Ryan T.; Bradbury, J. Alyce; Li, Hong; DeGraff, Laura M.; Hong, Lee K.; King, Debra; Lih, Fred B.; Gruzdev, Artiom; Edin, Matthew L.; Travlos, Gregory S.; Flake, Gordon P.; Tomer, Kenneth B.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Zeldin, DC (reprint author), NIEHS, NIH, 111 TW Alexander Dr,Bldg 101,Rm A214, Res Triangle Pk, NC 27709 USA. EM zeldin@niehs.nih.gov FU U.S. National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES050167, Z01 ES025034] FX This work was supported by U.S. National Institutes of Health, National Institute of Environmental Health Sciences, Intramural Research Program Grants Z01 ES050167 (to K.B.T.) and Z01 ES025034 (to D.C.Z.). The authors declare no conflicts of interest. NR 36 TC 2 Z9 2 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD JAN PY 2016 VL 30 IS 1 BP 160 EP 173 DI 10.1096/fj.14-268458 PG 14 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA DA2JL UT WOS:000367621000018 PM 26396235 ER PT J AU Sharma, BK Kolhe, R Black, SM Keller, JR Mivechi, NF Satyanarayana, A AF Sharma, Bal Krishan Kolhe, Ravindra Black, Stephen M. Keller, Jonathan R. Mivechi, Nahid F. Satyanarayana, Ande TI Inhibitor of differentiation 1 transcription factor promotes metabolic reprogramming in hepatocellular carcinoma cells SO FASEB JOURNAL LA English DT Article DE glucose metabolism; glutamine metabolism; liver cancer; c-Myc; Hif1 alpha ID LOOP-HELIX PROTEINS; C-MYC; ID PROTEINS; CANCER; EXPRESSION; HYPOXIA; GROWTH; PROLIFERATION; HIF; TRANSACTIVATION AB Reprograming of metabolism is one of the central hallmarks of cancer. The majority of cancer cells depend on high rates of glycolysis and glutaminolysis for their growth and survival. A number of oncogenes and tumor suppressors have been connected to the regulation of altered glucose and glutamine metabolism in cancer cells. For example, the oncogene c-Myc plays vital roles in cancer cell metabolic adaptation by directly regulating various genes that participate in aerobic glycolysis and glutaminolysis. Inhibitor of differentiation 1 (Id1) is a helix-loop-helix transcription factor that plays important roles in cell proliferation, differentiation, and cell fate determination. Overexpression of Id1 causes intestinal adenomas and thymic lymphomas in mice, suggesting that Id1 could function as an oncogene. Despite it being an oncogene, whether Id1 plays any prominent role in cancer cell metabolic reprograming is unknown. Here, we demonstrate that Id1 is strongly expressed in human and mouse liver tumors and in hepatocellular carcinoma (HCC) cell lines, whereas its expression is very low or undetectable in normal liver tissues. In HCC cells, Id1 expression is regulated by the MAPK/ERK pathway at the transcriptional level. Knockdown of Id1 suppressed aerobic glycolysis and glutaminolysis, suggesting that Id1 promotes a metabolic shift toward aerobic glycolysis. At the molecular level, Id1 mediates its metabolic effects by regulating the expression levels of c-Myc. Knockdown of Id1 resulted in down-regulation (similar to 75%) of c-Myc, whereas overexpression of Id1 strongly induced (3-fold) c-Myc levels. Interestingly, knockdown of c-Myc resulted in down-regulation (similar to 60%) of Id1, suggesting a positive feedback-loop regulatory mechanism between Id1 and c-Myc. Under anaerobic conditions, both Id1 and c-Myc are down-regulated (50-70%), and overexpression of oxygen-insensitive hypoxia-inducible factor 1 alpha (Hif1 alpha) or its downstream target Mxi1 resulted in a significant reduction of c-Myc and Id1 (similar to 70%), suggesting that Hif1 alpha suppresses Id1 and c-Myc under anaerobic conditions via Mxi1. Together, our findings indicate a prominent novel role for Id1 in liver cancer cell metabolic adaptation. C1 [Sharma, Bal Krishan; Satyanarayana, Ande] Georgia Regents Univ, Mol Oncol & Biomarkers Program, Dept Biochem & Mol Biol, Augusta, GA 30912 USA. [Mivechi, Nahid F.] Georgia Regents Univ, Ctr Canc, Augusta, GA 30912 USA. [Kolhe, Ravindra] Georgia Regents Univ, Dept Pathol, Augusta, GA 30912 USA. [Black, Stephen M.] Georgia Regents Univ, Vasc Biol Ctr, Program Pulm Vasc Dis, Augusta, GA 30912 USA. [Keller, Jonathan R.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Mouse Canc & Genet Program, Basic Sci Program, Frederick, MD USA. RP Satyanarayana, A (reprint author), Georgia Regents Univ, Ctr Canc, Dept Biochem & Mol Biol, Mol Oncol & Biomarkers Program, 1410 Laney Walker Blvd,Room CN3150, Augusta, GA 30912 USA. EM sande@gru.edu FU U.S. National Institutes of Health (NIH) National Cancer Institute [K22CA168828]; NIH National Heart, Lung, and Blood Institute [HL060190] FX The authors thank Jingling Yuan, Ashis Mondal, and Kimya Jones for technical help and Dr. Rhea-Beth Markowitz for reviewing and editing the manuscript. This research is supported by a grant from the U.S. National Institutes of Health (NIH) National Cancer Institute Grant K22CA168828 to A.S. and NIH National Heart, Lung, and Blood Institute Grant HL060190 to S.M.B. The authors declare no conflicts of interest. NR 40 TC 2 Z9 2 U1 1 U2 8 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD JAN PY 2016 VL 30 IS 1 BP 262 EP 275 DI 10.1096/fj.15-277749 PG 14 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA DA2JL UT WOS:000367621000026 PM 26330493 ER PT J AU Su, WP Hsu, SH Chia, LC Lin, JY Chang, SB Jiang, ZD Lin, YJ Shih, MY Chen, YC Chang, MS Yang, WB Hung, JJ Hung, PC Wu, WS Myung, K Liaw, H AF Su, Wen-Pin Hsu, Sen-Huei Chia, Li-Chiao Lin, Jui-Yang Chang, Song-Bin Jiang, Zong-da Lin, Yi-Ju Shih, Min-Yu Chen, Yi-Cheng Chang, Mau-Sun Yang, Wen-Bin Hung, Jan-Jong Hung, Po-Cheng Wu, Wei-Sheng Myung, Kyungjae Liaw, Hungjiun TI Combined Interactions of Plant Homeodomain and Chromodomain Regulate NuA4 Activity at DNA Double-Strand Breaks SO GENETICS LA English DT Article DE Saccharomyces cerevisiae; DSB repair; NuA4; histone modification; multivalent interaction ID HISTONE ACETYLTRANSFERASE COMPLEX; SACCHAROMYCES-CEREVISIAE; YEATS DOMAIN; PHD FINGER; CHROMATIN MODIFICATION; COMBINATORIAL READOUT; YEAST; ACETYLATION; REPAIR; METHYLATION AB DNA double-strand breaks (DSBs) represent one of the most threatening lesions to the integrity of genomes. In yeast Saccharomyces cerevisiae, NuA4, a histone acetylation complex, is recruited to DSBs, wherein it acetylates histones H2A and H4, presumably relaxing the chromatin and allowing access to repair proteins. Two subunits of NuA4, Yng2 and Eaf3, can interact in vitro with methylated H3K4 and H3K36 via their plant homeodomain (PHD) and chromodomain. However, the roles of the two domains and how they interact in a combinatorial fashion are still poorly characterized. In this study, we generated mutations in the PHD and chromodomain that disrupt their interaction with methylated H3K4 and H3K36. We demonstrate that the combined mutations in both the PHD and chromodomain impair the NuA4 recruitment, reduce H4K12 acetylation at the DSB site, and confer sensitivity to bleomycin that induces DSBs. In addition, the double mutant cells are defective in DSB repair as judged by Southern blot and exhibit prolonged activation of phospho-S129 of H2A. Cells harboring the H3K4R, H3K4R, K36R, or set1 set2 mutant that disrupts H3K4 and H3K36 methylation also show very similar phenotypes to the PHD and chromodomain double mutant. Our results suggest that multivalent interactions between the PHD, chromodomain, and methylated H3K4 and H3K36 act in a combinatorial manner to recruit NuA4 and regulate the NuA4 activity at the DSB site. C1 [Su, Wen-Pin] Natl Cheng Kung Univ, Inst Clin Med, Coll Med, Tainan 701, Taiwan. [Su, Wen-Pin] Natl Cheng Kung Univ, Dept Internal Med, Natl Cheng Kung Univ Hosp, Coll Med, Tainan 701, Taiwan. [Hsu, Sen-Huei; Chia, Li-Chiao; Lin, Jui-Yang; Chang, Song-Bin; Jiang, Zong-da; Lin, Yi-Ju; Shih, Min-Yu; Chen, Yi-Cheng; Liaw, Hungjiun] Natl Cheng Kung Univ, Dept Life Sci, Tainan 701, Taiwan. [Yang, Wen-Bin; Hung, Jan-Jong] Natl Cheng Kung Univ, Inst Bioinformat & Biosignal Transduct, Tainan 701, Taiwan. [Hung, Po-Cheng; Wu, Wei-Sheng] Natl Cheng Kung Univ, Dept Elect Engn, Tainan 701, Taiwan. [Chang, Mau-Sun] Natl Taiwan Univ, Inst Biochem Sci, Coll Life Sci, Taipei 10617, Taiwan. [Myung, Kyungjae] NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Liaw, H (reprint author), Natl Cheng Kung Univ, Dept Life Sci, 1 Univ Rd, Tainan 701, Taiwan. EM liawh@mail.ncku.edu.tw OI Liaw, Hungjiun/0000-0002-3481-709X; CHANG, MAU-SUN/0000-0002-3703-2386 FU Taiwan Ministry of Science and Technology [NSC100-2311-B-006-001, NSC100-2320-B-006-016, NSC-102-2628-B-006-013-MY3]; National Cheng Kung University Hospital [10408001]; Taiwan Ministry of Education; Aim for the Top University Project [D100-38B10]; Ministry of Science and Technology FX We thank James Haber, Mary Ann Osley, Chuang-Rung Chang, Cheng-Fu Kao, Jun-Yi Leu, Fang-Jen Lee, Shu-Chun Teng (Taiwan Yeast Resources Center), and Huang-Mo Sung for providing strains and technical support; Wu-Chou Su and Ming-Daw Tsai for their generous support; and Shu-Chun Teng and Paul Steed for critical reading of the manuscript. This work was supported by the Taiwan Ministry of Science and Technology (NSC100-2311-B-006-001 and NSC100-2320-B-006-016 to H.L. and NSC-102-2628-B-006-013-MY3 to W.-P.S.); National Cheng Kung University Hospital grant (10408001); and the Taiwan Ministry of Education and the Aim for the Top University Project to the National Cheng Kung University (D100-38B10 to H.L.). Funding for the open access fee was provided by the Ministry of Science and Technology. NR 60 TC 1 Z9 1 U1 0 U2 3 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 EI 1943-2631 J9 GENETICS JI Genetics PD JAN PY 2016 VL 202 IS 1 BP 77 EP + DI 10.1534/genetics.115.184432 PG 20 WC Genetics & Heredity SC Genetics & Heredity GA DA3SE UT WOS:000367718100010 PM 26564157 ER PT J AU Diao, FC Mena, W Shi, J Park, D Diao, FQ Taghert, P Ewer, J White, BH AF Diao, Feici Mena, Wilson Shi, Jonathan Park, Dongkook Diao, Fengqiu Taghert, Paul Ewer, John White, Benjamin H. TI The Splice Isoforms of the Drosophila Ecdysis Triggering Hormone Receptor Have Developmentally Distinct Roles SO GENETICS LA English DT Article DE behavior; ecdysis; hormones; neural circuit; transgene targeting ID GENE-EXPRESSION; PEPTIDERGIC ENSEMBLES; NEURONAL NETWORK; INNATE BEHAVIOR; IMAGE-ANALYSIS; MELANOGASTER; RELEASE; SYSTEM; BRAIN; CELLS AB To grow, insects must periodically shed their exoskeletons. This process, called ecdysis, is initiated by the endocrine release of Ecdysis Trigger Hormone (ETH) and has been extensively studied as a model for understanding the hormonal control of behavior. Understanding how ETH regulates ecdysis behavior, however, has been impeded by limited knowledge of the hormone's neuronal targets. An alternatively spliced gene encoding a G-protein-coupled receptor (ETHR) that is activated by ETH has been identified, and several lines of evidence support a role in ecdysis for its A-isoform. The function of a second ETHR isoform (ETHRB) remains unknown. Here we use the recently introduced Trojan exon technique to simultaneously mutate the ETHR gene and gain genetic access to the neurons that express its two isoforms. We show that ETHRA and ETHRB are expressed in largely distinct subsets of neurons and that ETHRA- but not ETHRB-expressing neurons are required for ecdysis at all developmental stages. However, both genetic and neuronal manipulations indicate an essential role for ETHRB at pupal and adult, but not larval, ecdysis. We also identify several functionally important subsets of ETHR-expressing neurons including one that coexpresses the peptide Leucokinin and regulates fluid balance to facilitate ecdysis at the pupal stage. The general strategy presented here of using a receptor gene as an entry point for genetic and neuronal manipulations should be useful in establishing patterns of functional connectivity in other hormonally regulated networks. C1 [Diao, Feici; Diao, Fengqiu; White, Benjamin H.] NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Mena, Wilson; Ewer, John] Univ Valparaiso, Ctr Interdisciplinario Neurociencia, Valparaiso, Chile. [Shi, Jonathan; Park, Dongkook; Taghert, Paul] Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. RP White, BH (reprint author), NIMH, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM benjaminwhite@mail.nih.gov OI Ewer, John/0000-0002-6806-3628 FU Intramural Research Program of the National Institute of Mental Health; FONDECYT [1141278]; Centro Interdisciplinario de Neurociencia de Valparaiso [P09-022-F]; Millennium Scientific Initiative of the Ministerio de Economia, Fomento y Turismo; National Institutes of Health (NIH) grants from the National Institute of Neurological Disease and Stroke [R01NS021749]; National Institute of Mental Health [R01MH067122] FX We thank Michael Adams for the eth25a mutant and anti-ETH antibody, Haojiang Luan, Amicia Elliott, and Rodrigo Mancilla for technical assistance, and Haojiang Luan and Amicia Elliott for critical reading of the manuscript. This work was supported by the Intramural Research Program of the National Institute of Mental Health (B.H.W.) and by grants from FONDECYT (no. 1141278) and Centro Interdisciplinario de Neurociencia de Valparaiso (P09-022-F), which is supported by the Millennium Scientific Initiative of the Ministerio de Economia, Fomento y Turismo (J.E.), and by National Institutes of Health (NIH) grants from the National Institute of Neurological Disease and Stroke (R01NS021749) and the National Institute of Mental Health (R01MH067122) (P.T.). In addition, we thank the Bloomington Stock Center and the Drosophila Gene Disruption Project which generated the MiMIC lines used here. The authors declare no conflicts of interest. NR 32 TC 2 Z9 2 U1 3 U2 15 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 EI 1943-2631 J9 GENETICS JI Genetics PD JAN PY 2016 VL 202 IS 1 BP 175 EP + DI 10.1534/genetics.115.182121 PG 25 WC Genetics & Heredity SC Genetics & Heredity GA DA3SE UT WOS:000367718100016 PM 26534952 ER PT J AU Lei, JP Rudolph, A Moysich, KB Behrens, S Goode, EL Bolla, MK Dennis, J Dunning, AM Easton, DF Wang, Q Benitez, J Hopper, JL Southey, MC Schmidt, MK Broeks, A Fasching, PA Haeberle, L Peto, J dos-Santos-Silva, I Sawyer, EJ Tomlinson, I Burwinkel, B Marme, F Guenel, P Truong, T Bojesen, SE Flyger, H Nielsen, SF Nordestgaard, BG Gonzalez-Neira, A Menendez, P Anton-Culver, H Neuhausen, SL Brenner, H Arndt, V Meindl, A Schmutzler, RK Brauch, H Hamann, U Nevanlinna, H Fagerholm, R Dork, T Bogdanova, NV Mannermaa, A Hartikainen, JM Van Dijck, L Smeets, A Flesch-Janys, D Eilber, U Radice, P Peterlongo, P Couch, FJ Hallberg, E Giles, GG Milne, RL Haiman, CA Schumacher, F Simard, J Goldberg, MS Kristensen, V Borresen-Dale, AL Zheng, W Beeghly-Fadiel, A Winqvist, R Grip, M Andrulis, IL Glendon, G Garcia-Closas, M Figueroa, J Czene, K Brand, JS Darabi, H Eriksson, M Hall, P Li, JM Cox, A Cross, SS Pharoah, PDP Shah, M Kabisch, M Torres, D Jakubowska, A Lubinski, J Ademuyiwa, F Ambrosone, CB Swerdlow, A Jones, M Chang-Claude, J AF Lei, Jieping Rudolph, Anja Moysich, Kirsten B. Behrens, Sabine Goode, Ellen L. Bolla, Manjeet K. Dennis, Joe Dunning, Alison M. Easton, Douglas F. Wang, Qin Benitez, Javier Hopper, John L. Southey, Melissa C. Schmidt, Marjanka K. Broeks, Annegien Fasching, Peter A. Haeberle, Lothar Peto, Julian dos-Santos-Silva, Isabel Sawyer, Elinor J. Tomlinson, Ian Burwinkel, Barbara Marme, Frederik Guenel, Pascal Truong, Therese Bojesen, Stig E. Flyger, Henrik Nielsen, Sune F. Nordestgaard, Borge G. Gonzalez-Neira, Anna Menendez, Primitiva Anton-Culver, Hoda Neuhausen, Susan L. Brenner, Hermann Arndt, Volker Meindl, Alfons Schmutzler, Rita K. Brauch, Hiltrud Hamann, Ute Nevanlinna, Heli Fagerholm, Rainer Doerk, Thilo Bogdanova, Natalia V. Mannermaa, Arto Hartikainen, Jaana M. Van Dijck, Laurien Smeets, Ann Flesch-Janys, Dieter Eilber, Ursula Radice, Paolo Peterlongo, Paolo Couch, Fergus J. Hallberg, Emily Giles, Graham G. Milne, Roger L. Haiman, Christopher A. Schumacher, Fredrick Simard, Jacques Goldberg, Mark S. Kristensen, Vessela Borresen-Dale, Anne-Lise Zheng, Wei Beeghly-Fadiel, Alicia Winqvist, Robert Grip, Mervi Andrulis, Irene L. Glendon, Gord Garcia-Closas, Montserrat Figueroa, Jonine Czene, Kamila Brand, Judith S. Darabi, Hatef Eriksson, Mikael Hall, Per Li, Jingmei Cox, Angela Cross, Simon S. Pharoah, Paul D. P. Shah, Mitul Kabisch, Maria Torres, Diana Jakubowska, Anna Lubinski, Jan Ademuyiwa, Foluso Ambrosone, Christine B. Swerdlow, Anthony Jones, Michael Chang-Claude, Jenny CA Australian Ovarian Study Grp kConFab Investigators TI Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium SO HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; REGULATORY T-CELLS; SUPPRESSOR-CELLS; TUMOR MICROENVIRONMENT; MULTIPLE-SCLEROSIS; ANTITUMOR IMMUNITY; CROHNS-DISEASE; JAPANESE POPULATION; LOCI; STAT3 AB Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A > G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03-1.08; p value = 1.4 x 10(-6)). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 x 10(-3) and 7.0 x 10(-3), respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 x 10(-3), 4.5 x 10(-4) and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3, IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry. C1 [Lei, Jieping; Rudolph, Anja; Behrens, Sabine; Eilber, Ursula; Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. [Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Goode, Ellen L.; Hallberg, Emily] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Bolla, Manjeet K.; Dennis, Joe; Easton, Douglas F.; Wang, Qin; Pharoah, Paul D. P.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Dunning, Alison M.; Easton, Douglas F.; Pharoah, Paul D. P.; Shah, Mitul] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Benitez, Javier; Gonzalez-Neira, Anna] Spanish Natl Canc Res Ctr, Human Canc Genet Program, Madrid, Spain. [Benitez, Javier] Ctr Invest Red Enfermedades Raras, Valencia, Spain. [Hopper, John L.; Giles, Graham G.; Milne, Roger L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Schmidt, Marjanka K.; Broeks, Annegien] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Fasching, Peter A.; Haeberle, Lothar] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Obstet & Gynaecol, D-91054 Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, Dept Med, Div Hematol & Oncol, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Peto, Julian; dos-Santos-Silva, Isabel] London Sch Hyg & Trop Med, Dept Non Communicable Dis Epidemiol, London WC1, England. [Sawyer, Elinor J.] Kings Coll London, Guys Hosp, Res Oncol, London WC2R 2LS, England. [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Tomlinson, Ian] Univ Oxford, Oxford NIHR Biomed Res Ctr, Oxford, England. [Burwinkel, Barbara; Marme, Frederik] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, D-69120 Heidelberg, Germany. [Marme, Frederik] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Guenel, Pascal; Truong, Therese] INSERM, Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc, Villejuif, France. [Guenel, Pascal; Truong, Therese] Univ Paris Sud, Villejuif, France. [Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark. [Bojesen, Stig E.; Nielsen, Sune F.; Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Herlev, Denmark. [Menendez, Primitiva] Hosp Monte Naranco, Serv Anat Patol, Oviedo, Spain. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Neuhausen, Susan L.] Beckman Res Inst City Hope, Duarte, CA USA. [Brenner, Hermann; Arndt, Volker] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany. [Brenner, Hermann] Natl Ctr Tumor Dis NCT, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Brenner, Hermann; Brauch, Hiltrud] German Canc Res Ctr, German Canc Consortium DKTK, D-69120 Heidelberg, Germany. [Meindl, Alfons] Tech Univ Munich, Div Gynaecol & Obstet, D-80290 Munich, Germany. [Schmutzler, Rita K.] Univ Hosp, Ctr Hereditary Breast & Ovarian Canc, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp, CIO, Cologne, Germany. [Schmutzler, Rita K.] Univ Cologne, CMMC, D-50931 Cologne, Germany. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Tubingen, Germany. [Hamann, Ute; Kabisch, Maria; Torres, Diana] German Canc Res Ctr, Mol Genet Breast Canc, D-69120 Heidelberg, Germany. [Nevanlinna, Heli; Fagerholm, Rainer] Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland. [Doerk, Thilo] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Bogdanova, Natalia V.] Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany. [Mannermaa, Arto; Hartikainen, Jaana M.] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland. [Mannermaa, Arto; Hartikainen, Jaana M.] Univ Eastern Finland, Inst Clin Med, Pathol & Forens Med, Kuopio, Finland. [Mannermaa, Arto; Hartikainen, Jaana M.] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland. [Australian Ovarian Study Grp] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld, Australia. [kConFab Investigators] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Van Dijck, Laurien] Univ Leuven, Dept Oncol, VIB Vesalius Res Ctr, Leuven, Belgium. [Smeets, Ann] Univ Leuven, Univ Hosp Leuven, Multidisciplinary Breast Ctr, Leuven, Belgium. [Flesch-Janys, Dieter] Univ Med Ctr Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany. [Flesch-Janys, Dieter] Univ Med Ctr Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, Hamburg, Germany. [Radice, Paolo] Fdn IRCCS, Ist Ricovero & Cura A Carattere Sci, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing,INT, Milan, Italy. [Peterlongo, Paolo] Fdn Ist FIRC, Italian Fdn Canc Res Oncol Mol, IFOM, Milan, Italy. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Giles, Graham G.; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Haiman, Christopher A.; Schumacher, Fredrick] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Simard, Jacques] Univ Laval, CHU Quebec, Res Ctr, Genom Ctr, Quebec City, PQ, Canada. [Goldberg, Mark S.] McGill Univ, Dept Med, Montreal, PQ H3A 1A1, Canada. [Goldberg, Mark S.] McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ H3A 1A1, Canada. [Kristensen, Vessela; Borresen-Dale, Anne-Lise] Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Genet, Oslo, Norway. [Kristensen, Vessela; Borresen-Dale, Anne-Lise] Univ Oslo, Fac Med, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, Oslo, Norway. [Kristensen, Vessela] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway. [Zheng, Wei; Beeghly-Fadiel, Alicia] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37235 USA. [Winqvist, Robert] Univ Oulu, Dept Clin Chem, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Winqvist, Robert] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Winqvist, Robert] Jyvaskyla Cent Hosp, Cent Finland Hosp Dist, Jyvaskyla, Finland. [Grip, Mervi] Univ Oulu, Oulu Univ Hosp, Dept Surg, Oulu, Finland. [Andrulis, Irene L.; Glendon, Gord] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Garcia-Closas, Montserrat; Figueroa, Jonine] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Czene, Kamila; Brand, Judith S.; Darabi, Hatef; Eriksson, Mikael; Hall, Per; Li, Jingmei] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Cox, Angela] Univ Sheffield, Dept Oncol, Sheffield Canc Res Ctr, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England. [Torres, Diana] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia. [Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Ademuyiwa, Foluso; Ambrosone, Christine B.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Swerdlow, Anthony; Jones, Michael] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England. [Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, UCCH, Hamburg, Germany. RP Chang-Claude, J (reprint author), German Canc Res Ctr, Div Canc Epidemiol, Neuenheimer Feld 581, D-69120 Heidelberg, Germany. EM j.chang-claude@dkfz-heidelberg.de RI Li, Jingmei/I-2904-2012; Andrulis, Irene/E-7267-2013; Van Dyck, Laurien/I-4018-2016; Hartikainen, Jaana/E-6256-2015; Dork, Thilo/J-8620-2012; Zheng, Wei/O-3351-2013; Brenner, Hermann/B-4627-2017; OI Giles, Graham/0000-0003-4946-9099; Arndt, Volker/0000-0001-9320-8684; Dunning, Alison Margaret/0000-0001-6651-7166; ADEMUYIWA, FOLUSO/0000-0002-6766-2258; Li, Jingmei/0000-0001-8587-7511; Van Dyck, Laurien/0000-0002-1373-7656; Zheng, Wei/0000-0003-1226-070X; Brenner, Hermann/0000-0002-6129-1572; Cross, Simon/0000-0003-2044-1754; Cox, Angela/0000-0002-5138-1099 FU European Community [223175 (HEALTH-F2-2009-223175), 223175 HEALTH-F2-2009-223175]; Cancer Research UK [C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565, C1287/A12014, C490/A10124]; National Institutes of Health (NIH) [CA128978, CA122443]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112-the GAME-ON initiative]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR); Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; National Cancer Institute (USA) [UM1 CA164920]; National Health and Medical Research Council of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Victorian Breast Cancer Research Consortium; Dutch Cancer Society [NKI 2007-3839, 2009 4363]; Biobanking and BioMolecular resources Research Infrastructure-Netherlands (BBMRI-NL); Dutch government [NWO 184.021.007]; ELAN-Fond of the University Hospital of Erlangen; Cancer Research UK; Breakthrough Breast Cancer; National Health Service (NHS); National Cancer Research Network (NCRN); NIHR Comprehensive Biomedical Research Centre; Guy's & St. Thomas' NHS Foundation Trust; King's College London, United Kingdom; Oxford Biomedical Research Centre; Dietmar-Hopp Foundation; Helmholtz Society; Deutsches Krebsforschungszentrum (DKFZ); Fondation de France; Institut National du Cancer (INCa); Ligue Nationale contre le Cancer; Ligue contre le Cancer Grand Ouest; Agence Nationale de Securite' Sanitaire (ANSES); Agence Nationale de la Recherche (ANR); Lise Boserup Fund; Danish Medical Research Council; Herlev Hospital; Instituto de Salud Carlos III; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra el Cancer; Fondo de Investigacion Sanitario [PI11/00923, PI12/00070]; California Breast Cancer Act; California Breast Cancer Research Fund [97-10500]; NIH [CA128978, R01 CA77398, CA116167, CA176785, CA116201, CA63464, CA54281, CA098758, CA132839, R01CA100374]; California Department of Public Health as part of the statewide cancer reporting program; Lon V Smith Foundation [LVS39420]; Baden Wurttemberg Ministry of Science, Research and Arts; German Cancer Aid (Deutsche Krebshilfe); German Cancer Aid [110837]; Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114, 01KH0402]; Robert Bosch Foundation, Stuttgart; DKFZ, Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance; Institute of the Ruhr University Bochum (IPA), Bochum; Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany; Helsinki University Central Hospital Research Fund, Academy of Finland [266528]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; Friends of Hannover Medical School; Rudolf Bartling Foundation; special Government Funding (EVO) of Kuopio University Hospital; Cancer Fund of North Savo Organization; Finnish Cancer Organization; University of Eastern Finland; 'Stichting tegen Kanker' [232-2008, 196-2010]; Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419]; Hamburg Cancer Society; DKFZ; Italian Association for Cancer Research (AIRC); Fondazione IRCCS Istituto Nazionale Tumori; VicHealth; Australian NHMRC [209057, 251553, 504711]; Quebec Breast Cancer Foundation; Canadian Institutes of Health Research (CIHR) [CRN-87521]; Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]; K.G. Jebsen Centre for Breast Cancer Research; Research Council of Norway [193387/V50, 193387/H10]; South Eastern Norway Health Authority [39346]; Norwegian Cancer Society; Finnish Cancer Foundation; Academy of Finland [250083, 122715]; Academy of Finland Center of Excellence [251314]; University of Oulu; University of Oulu Support Foundation; special Governmental EVO funds; National Cancer Institute, Department of Health and Human Services, USA; Agency for Science, Technology and Research of Singapore (A*STAR); US National Institute of Health; Susan G. Komen Breast Cancer Foundation; Yorkshire Cancer Research [S295, S299, S305PA]; Sheffield Experimental Cancer Medicine Centre; UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; Polish State Committee for Scientific Research Grant [PBZ_KBN_122/P05/2004]; Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; Stefanie Spielman Breast Cancer fund; Hellenic Cooperative Oncology Group research grant [HR R_BG/04]; Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II; European Union (European Social Fund-ESF); Greek national funds through the Operational Program "Education and Lifelong Learning'' of the National Strategic Reference Framework (NSRF)-ARISTEIA; Breast Cancer Now; Institute of Cancer Research (ICR), London; NHS; National Breast Cancer Foundation; Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria; Cancer Councils of New South Wales, Tasmania; Cancer Councils of New South Wales, South Australia; Cancer Foundation of Western Australia; United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]; Cancer Council Victoria; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; National Health and Medical Research Council of Australia (NHMRC) [400413, 400281, 199600]; Marit and Hans Rausings Initiative Against Breast Cancer; [P30 CA68485] FX Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement number 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (NIH, CA128978, CA122443) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112-the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community's Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). The ABCFS study was supported by grant UM1 CA164920 from the National Cancer Institute (USA). This study was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. The ABCS study was supported by the Dutch Cancer Society (grants NKI 2007-3839; 2009 4363), and Biobanking and BioMolecular resources Research Infrastructure-Netherlands (BBMRI-NL), which is a Research Infrastructure financed by the Dutch government (NWO 184.021.007). The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS study was funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges National Health Service (NHS) funding to the National Institute for Health Research (NIHR) Biomedical Research Centre, and the National Cancer Research Network (NCRN). The BIGGS study was supported by NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, United Kingdom. IT was supported by the Oxford Biomedical Research Centre. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the Deutsches Krebsforschungszentrum (DKFZ). The CECILE study was funded by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Ligue contre le Cancer Grand Ouest, Agence Nationale de Securite' Sanitaire (ANSES), Agence Nationale de la Recherche (ANR). The CGPS study was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The CNIO-BCS study was supported by the Instituto de Salud Carlos III, the Red Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario (PI11/00923 and PI12/00070). The CTS study was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the NIH (R01 CA77398). Collection of cancer incidence data (GLOBOCAN 2012) was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Sect. 103885. HAC received support from the Lon V Smith Foundation (LVS39420). The ESTHER study was supported by a grant from the Baden Wurttemberg Ministry of Science, Research and Arts.; Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The GC-HBOC study was supported by the German Cancer Aid (grant no 110837, coordinator: Rita K. Schmutzler). The GENICA study was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, DKFZ, Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The HEBCS study was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, the Nordic Cancer Union and the Sigrid Juselius Foundation. The HMBCS study was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. The KBCP study was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland. The LMBC study was supported by the 'Stichting tegen Kanker' (232-2008 and 196-2010). The MARIE study was supported by the Deutsche Krebshilfe e.V. (70-2892-BR I, 106332, 108253, 108419), the Hamburg Cancer Society, DKFZ and the Federal Ministry of Education and Research (BMBF) Germany (01KH0402). The MBCSG study was supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "5 x 1000"). The MCBCS study was supported by the NIH grants CA128978, CA116167, CA176785 and NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. The MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. This study was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index. The MEC study was support by NIH grants CA63464, CA54281, CA098758 and CA132839. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research (CIHR) for the "CIHR Team in Familial Risks of Breast Cancer'' program-grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade-grant # PSR-SIIRI-701. The NBCS study has received funding from the K.G. Jebsen Centre for Breast Cancer Research, the Research Council of Norway grant 193387/V50 (to A-L Borresen-Dale and V.N. Kristensen) and grant 193387/H10 (to A-L Borresen-Dale and V.N. Kristensen), South Eastern Norway Health Authority (grant 39346 to A-L Borresen-Dale) and the Norwegian Cancer Society (to A-L Borresen-Dale and V.N. Kristensen). The NBHS study was supported by NIH grant R01CA100374.; Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The OBCS study was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation and the special Governmental EVO funds for Oulu University Hospital-based research activities. The OFBCR study was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The PBCS study was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health and the Susan G. Komen Breast Cancer Foundation. The SBCS study was supported by Yorkshire Cancer Research S295, S299, S305PA and Sheffield Experimental Cancer Medicine Centre. The SEARCH study was funded by a programme grant from Cancer Research UK (C490/A10124) and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The SKKDKFZS study was supported by the DKFZ. The SZBCS study was supported by Polish State Committee for Scientific Research Grant PBZ_KBN_122/P05/2004. The TNBCC study was supported by: a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation, the Stefanie Spielman Breast Cancer fund and the OSU Comprehensive Cancer Center, the Hellenic Cooperative Oncology Group research grant (HR R_BG/04) and the Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II, the European Union (European Social Fund-ESF), and Greek national funds through the Operational Program "Education and Lifelong Learning'' of the National Strategic Reference Framework (NSRF)-ARISTEIA. The UKBGS study was funded by Breast Cancer Now and the Institute of Cancer Research (ICR), London. ICR acknowledged NHS funding to the NIHR Biomedical Research Centre. The kConFab study was supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command (DAMD17-01-1-0729), Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, the Cancer Foundation of Western Australia, Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; 400413, 400281, 199600). The pKARMA study was supported by Marit and Hans Rausings Initiative Against Breast Cancer. NR 62 TC 2 Z9 2 U1 5 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD JAN PY 2016 VL 135 IS 1 BP 137 EP 154 DI 10.1007/s00439-015-1616-8 PG 18 WC Genetics & Heredity SC Genetics & Heredity GA DA2FY UT WOS:000367611900012 PM 26621531 ER PT J AU Low, JT Hughes, P Lin, A Siebenlist, U Jain, R Yaprianto, K Gray, DHD Gerondakis, S Strasser, A O'Reilly, LA AF Low, J. T. Hughes, P. Lin, A. Siebenlist, U. Jain, R. Yaprianto, K. Gray, D. H. D. Gerondakis, S. Strasser, A. O'Reilly, L. A. TI Impact of loss of NF-kappa B1, NF-kappa B2 or c-REL on SLE-like autoimmune disease and lymphadenopathy in Fas(lpr)/(lpr) mutant mice SO IMMUNOLOGY AND CELL BIOLOGY LA English DT Article ID NF-KAPPA-B; SYSTEMIC-LUPUS-ERYTHEMATOSUS; FAMILY-MEMBER BIM; ATOPIC-DERMATITIS; IMMUNE-RESPONSES; T-CELLS; SPLENIC MICROARCHITECTURE; DEFICIENCY; APOPTOSIS; FAS AB Defects in apoptosis can cause autoimmune disease. Loss-of-function mutations in the 'death receptor' FAS impair the deletion ofautoreactive lymphocytes in the periphery, leading to progressive lymphadenopathy and systemic lupus erythematosus-like autoimmune disease in mice (Fas(lpr)/(lpr) (mice homozygous for the lymphoproliferation inducing spontaneous mutation)) and humans. The REL/nuclear factor-kappa B (NF-kappa B) transcription factors regulate a broad range of immune effector functions and are also implicated in various autoimmune diseases. We generated compound mutant mice to investigate the individual functions of the NF-kappa B family members NF-kappa B1, NF-kappa B2 and c-REL in the various autoimmune pathologies of Fas(lpr)/(lpr) mutant mice. We show that loss of each of these transcription factors resulted in amelioration of many classical features of autoimmune disease, including hypergammaglobulinaemia, anti-nuclear autoantibodies and autoantibodies against tissue-specific antigens. Remarkably, only c-REL deficiency substantially reduced immune complex-mediated glomerulonephritis and extended the lifespan of Fas(lpr)/(lpr) mice. Interestingly, compared with the Fas(lpr)/(lpr) animals, Fas(lpr)/(lpr) nfkb2(-/-) mice presented with a dramatic acceleration and augmentation of lymphadenopathy that was accompanied by severe lung pathology due to extensive lymphocytic infiltration. The Fas(lpr)/(lpr) nfkb1(-/-) mice exhibited the combined pathologies caused by defects in FAS-mediated apoptosis and premature ageing due to loss of NF-kappa B1. These findings demonstrate that different NF-kappa B family members exert distinct roles in the development of the diverse autoimmune and lymphoproliferative pathologies that arise in Fas(lpr)/(lpr) mice, and suggest that pharmacological targeting of c-REL should be considered as a strategy for therapeutic intervention in autoimmune diseases. C1 [Low, J. T.; Lin, A.; Jain, R.; Yaprianto, K.; Gray, D. H. D.; Strasser, A.; O'Reilly, L. A.] Walter & Eliza Hall Inst Med Res, Mol Genet Canc Div, Parkville, Vic 3052, Australia. [Low, J. T.; Jain, R.; Yaprianto, K.; Gray, D. H. D.; Strasser, A.; O'Reilly, L. A.] Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, Australia. [Hughes, P.] Royal Melbourne Hosp, Dept Nephrol, Parkville, Vic 3050, Australia. [Siebenlist, U.] NIAID, Immune Activat Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Gerondakis, S.] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic, Australia. RP O'Reilly, LA (reprint author), Walter & Eliza Hall Inst Med Res, 1G Royal Parade, Parkville, Vic 3052, Australia. EM oreilly@wehi.edu.au RI Strasser, Andreas/C-7581-2013; Gray, Daniel/A-3293-2013; OI Gray, Daniel/0000-0002-8457-8242; Strasser, Andreas/0000-0002-5020-4891 FU NHMRC, Canberra [1016701, 637353, 1090236, 1020363, 1046010, 1009145, 1049724]; Australian Postgraduate Award; NHMRC; Independent Research Institutes Infrastructure Support Scheme Grant [361646]; Victorian State Government (OIS grant); Leukemia and Lymphoma Society (SCOR grant) [7413, 7001-13]; JDRF/NHMRC [466658]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (US) FX We thank G Siciliano and K Hughes for animal care; J Corbin for automated blood analysis; B Helbert, C Young and Karen Mackwell for genotyping; and E Tsui, V Babo, K Weston and all histology staff for preparation of histological sections. This work was supported by fellowships and grants from the NHMRC, Canberra, programme 1016701, fellowships; 637353 (DHDG), 1090236 (DHDG), 1020363 (AS) and project grants; 1046010 (AS), 1009145 (LAO'R), 1049724 (DHDG), Australian Postgraduate Award (JTL) and an NHMRC infrastructure grant; Independent Research Institutes Infrastructure Support Scheme Grant 361646, the Victorian State Government (OIS grant), the Leukemia and Lymphoma Society (SCOR grant 7413 and 7001-13) and the JDRF/NHMRC 466658 (AS). This research was also supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (US). NR 52 TC 2 Z9 3 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0818-9641 EI 1440-1711 J9 IMMUNOL CELL BIOL JI Immunol. Cell Biol. PD JAN PY 2016 VL 94 IS 1 BP 66 EP 78 DI 10.1038/icb.2015.66 PG 13 WC Cell Biology; Immunology SC Cell Biology; Immunology GA DA2MJ UT WOS:000367628600007 PM 26084385 ER PT J AU Gomez-Lopez, N Olson, DM Robertson, SA AF Gomez-Lopez, Nardhy Olson, David M. Robertson, Sarah A. TI Interleukin-6 controls uterine Th9 cells and CD8(+) T regulatory cells to accelerate parturition in mice SO IMMUNOLOGY AND CELL BIOLOGY LA English DT Article ID AMNIOTIC-FLUID INTERLEUKIN-6; HUMAN FETAL MEMBRANES; PRETERM LABOR; TGF-BETA; IN-VIVO; TERM; PREGNANCY; ACTIVATION; IL-6; LEUKOCYTES AB Interleukin-6 (IL6) is a determinant of the timing of parturition and birth in mice. We previously demonstrated that genetic IL6 deficiency delays parturition by similar to 24 h, and this is restored by administration of exogenous IL6. In this study, we have investigated whether IL6 influences the number or phenotypes of T cells or other leukocytes in uterine decidual tissue at the maternal-fetal interface. In late gestation, decidual leukocytes in Il6 null mutant (Il6(-/-)) mice exhibit an altered profile, characterized by reduced numbers of cells expressing the monocyte/macrophage marker F4/80 or the T-cell marker CD4, increased cells expressing the natural killer (NK) cell marker CD49b or the dendritic cell marker CD11c, but no change in cells expressing the neutrophil marker Ly6G. These changes are specific to late pregnancy, as similar differences in decidual leukocytes were not evident in mid-gestation Il6(-/-) mice. The IL6-regulated changes in decidual NK and dendritic cells appear secondary to local recruitment, as no comparable changes occurred in peripheral blood of Il6(-/-) mice. When exogenous IL6 was administered to restore normal timing of parturition, a partial reversal of the altered leukocyte profile was observed, with a 10% increase in the proportion of decidual CD4(+) T cells, a notable 60% increase in CD8(+) T cells including CD8(+)CD25(+)Foxp3(+) regulatory T cells and a 60% reduction in CD4(+)IL9(+) Th9 cells. Together these findings suggest that IL6-controlled accumulation of decidual CD4+ T cells and CD8+ regulatory T cells, with an associated decline in decidual Th9 cells, is instrumental for progressing parturition in mice. C1 [Gomez-Lopez, Nardhy; Robertson, Sarah A.] Univ Adelaide, Robinson Res Inst, Adelaide, SA 5005, Australia. [Gomez-Lopez, Nardhy; Robertson, Sarah A.] Univ Adelaide, Sch Med, Adelaide, SA 5005, Australia. [Gomez-Lopez, Nardhy] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Gomez-Lopez, Nardhy] NICHD, Perinatol Res Branch, NIH, Detroit, MI USA. [Gomez-Lopez, Nardhy] Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Detroit, MI 48201 USA. [Olson, David M.] Univ Alberta, Dept Obstet & Gynecol Pediat & Physiol, Edmonton, AB, Canada. RP Robertson, SA (reprint author), Univ Adelaide, Robinson Res Inst, Adelaide, SA 5005, Australia. EM sarah.robertson@adelaide.edu.au RI Gomez-Lopez, Nardhy/R-7664-2016 OI Gomez-Lopez, Nardhy/0000-0002-3406-5262 FU National Health and Medical Research Council (Australia); Canadian Institutes of Health Research; Molly Towell Perinatal Research Foundation (Canada); Wayne State University Research Initiative in Maternal, Perinatal and Child Health FX This study was supported by project and fellowship grants from the National Health and Medical Research Council (Australia), the Canadian Institutes of Health Research and the Molly Towell Perinatal Research Foundation (Canada). NG-L is currently supported by the Wayne State University Research Initiative in Maternal, Perinatal and Child Health. NR 66 TC 5 Z9 5 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0818-9641 EI 1440-1711 J9 IMMUNOL CELL BIOL JI Immunol. Cell Biol. PD JAN PY 2016 VL 94 IS 1 BP 79 EP 89 DI 10.1038/icb.2015.63 PG 11 WC Cell Biology; Immunology SC Cell Biology; Immunology GA DA2MJ UT WOS:000367628600008 PM 26073576 ER PT J AU Singh, N Moody, AR Roifman, I Bluemke, DA Zavodni, AEH AF Singh, Navneet Moody, Alan R. Roifman, Idan Bluemke, David A. Zavodni, Anna E. H. TI Advanced MRI for carotid plaque imaging SO INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING LA English DT Article DE Atherosclerosis; Imaging; Carotid; MRI; Cardiovascular risk ID DEPICTED INTRAPLAQUE HEMORRHAGE; MAGNETIC-FIELD STRENGTHS; BLACK-BLOOD MRI; ATHEROSCLEROTIC PLAQUE; ASYMPTOMATIC INDIVIDUALS; CARDIOVASCULAR EVENTS; SYMPTOMATIC PATIENTS; ARTERY-DISEASE; HEART-DISEASE; RISK-SCORE AB Atherosclerosis is the ubiquitous underling pathological process that manifests in heart attack and stroke, cumulating in the death of one in three North American adults. High-resolution magnetic resonance imaging (MRI) is able to delineate atherosclerotic plaque components and total plaque burden within the carotid arteries. Using dedicated hardware, high resolution images can be obtained. Combining pre- and post-contrast T1, T2, proton-density, and magnetization-prepared rapid acquisition gradient echo weighted fat-saturation imaging, plaque components can be defined. Post-processing software allows for semi- and fully automated quantitative analysis. Imaging correlation with surgical specimens suggests that this technique accurately differentiates plaque features. Total plaque burden and specific plaque components such as a thin fibrous cap, large fatty or necrotic core and intraplaque hemorrhage are accepted markers of neuroischemic events. Given the systemic nature of atherosclerosis, emerging science suggests that the presence of carotid plaque is also an indicator of coronary artery plaque burden, although the preliminary data primarily involves patients with stable coronary disease. While the availability and cost-effectiveness of MRI will ultimately be important determinants of whether carotid MRI is adopted clinically in cardiovascular risk assessment, the high accuracy and reliability of this technique suggests that it has potential as an imaging biomarker of future risk. C1 [Singh, Navneet; Moody, Alan R.; Zavodni, Anna E. H.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Med Imaging, Toronto, ON M4N 3M5, Canada. [Roifman, Idan] Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Internal Med, Div Cardiol, Toronto, ON M4N 3M5, Canada. [Bluemke, David A.] NIH, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. RP Zavodni, AEH (reprint author), Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Med Imaging, 2075 Bayview Ave,Room AG56b, Toronto, ON M4N 3M5, Canada. EM anna.zavodni@sunnybrook.ca OI Bluemke, David/0000-0002-8323-8086 FU Canadian Institute of Health Research (CIHR) [FRN 120988]; Radiology Society of North America (RSNA) RE Foundation [RR1561]; Schulich Heart Program, Sunnybrook Health Sciences Centre, University of Toronto; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research; Radiology Society of North America (RSNA) R&E Foundation RSNA Scholar Grant FX NS/ARM are supported by the Canadian Institute of Health Research (CIHR FRN 120988) and the Radiology Society of North America (RSNA) R&E Foundation (#RR1561). IR/AZ are supported by the Schulich Heart Program, Sunnybrook Health Sciences Centre, University of Toronto. IR is supported by the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research. AZ is supported by the Radiology Society of North America (RSNA) R&E Foundation RSNA Scholar Grant. NR 67 TC 4 Z9 4 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1569-5794 EI 1573-0743 J9 INT J CARDIOVAS IMAG JI Int. J. Cardiovasc. Imaging PD JAN PY 2016 VL 32 IS 1 SI SI BP 83 EP 89 DI 10.1007/s10554-015-0743-6 PG 7 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DA5QD UT WOS:000367856700009 PM 26293362 ER PT J AU Sagae, S Monk, BJ Pujade-Lauraine, E Gaffney, DK Narayan, K Ryu, SY McCormack, M Plante, M Casado, A Reuss, A Chavez-Blanco, A Kitchener, H Nam, BH Jhingran, A Temkin, S Mileshkin, L Berns, E Scholl, S Doll, C Abu-Rustum, NR Lecuru, F Small, W AF Sagae, Satoru Monk, Bradley J. Pujade-Lauraine, Eric Gaffney, David K. Narayan, Kailash Ryu, Sang Young McCormack, Mary Plante, Marie Casado, Antonio Reuss, Alexander Chavez-Blanco, Adriana Kitchener, Henry Nam, Byung-Ho Jhingran, Anuja Temkin, Sarah Mileshkin, Linda Berns, Els Scholl, Suzy Doll, Corinne Abu-Rustum, Nadeem R. Lecuru, Fabrice Small, William, Jr. CA Participants Gynecol Canc InterGrp TI Advances and Concepts in Cervical Cancer Trials A Road Map for the Future SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Article DE Cervical cancer; Clinical trials; Gynecologic Cancer InterGroup; GCIG ID POSITIVE LUNG-CANCER; CLINICAL-RESEARCH; OPEN-LABEL; CHEMOTHERAPY; CRIZOTINIB; MUTATIONS; THERAPY; FERTILITY; SURVIVAL; OUTCOMES AB Objective Cervical cancer is responsible for more than a quarter of a million deaths globally each year, mostly in developing countries, making therapeutic advances in all health care settings a top priority. The Gynecologic Cancer InterGroup (GCIG) is a worldwide collaboration of leading national research groups that develops and promotes multinational trials in gynecologic cancer. In recognition of the pressing need for action, the GCIG convened an international meeting with expert representation from the GCIG groups and selected large sites in low- and middle-income countries. Methods The focus was to develop a consensus on several concepts for future clinical trials, which would be developed and promoted by the GCIG and launched with major international participation. The first half of the meeting was devoted to a resume of the current state of the knowledge and identifying the gaps in need of new evidence, validating control arms for present and future clinical trials and identifying national and international barriers for studies of cervix cancers. The second half of the meeting was concerned with achieving consensus on a path forward. Results and Conclusions There were 5 principal outcomes as follows: first, a proposal to expand fertility-preserving options with neoadjuvant chemotherapy; second, validation of the assessment of sentinel lymph nodes using minimally invasive surgery with an emphasis on identification and management of low-volume metastasis, such as isolated tumor cells and micrometastasis; third, evaluation of hypofractionation for palliative and curative radiation under the umbrella of the GCIG Cervix Cancer Research Network; fourth, adding to the advances in antiangiogenesis therapy in the setting of metastatic disease; and fifth, developing a maintenance study among women at high risk of relapse. The latter 2 systemic interventions could study PI3K (phosphatidylinositol-3-kinase) inhibitors, immunotherapy, anti-human papillomavirus approaches, or novel antiangiogenic agents/combinations. C1 [Sagae, Satoru] Sapporo West Kojinkai Clin, Dept Gynecol Oncol, Sapporo, Hokkaido 0630051, Japan. [Monk, Bradley J.] Creighton Univ, Sch Med, St Josephs Hosp & Med Ctr, Univ Arizona Canc Ctr Phoenix, Phoenix, AZ USA. [Pujade-Lauraine, Eric] Univ Paris 05, Hotel Dieu, AP HP, Paris, France. [Gaffney, David K.] Univ Utah Hlth Care, Dept Radiat Oncol, Huntsman Canc Hosp, Salt Lake City, UT USA. [Narayan, Kailash; Mileshkin, Linda] Univ Melbourne, PeterMacCallum Canc Ctr, Div Radiat Oncol, Melbourne, Vic, Australia. [Ryu, Sang Young] Chonnam Natl Univ, Dept Surg, Sch Med, Gwangju, South Korea. [McCormack, Mary] Univ Coll London Hosp, Dept Oncol, London, England. [Plante, Marie] Ctr Hosp Univ Quebec, Div Gynecol Oncol, Quebec City, PQ, Canada. [Casado, Antonio] Hosp Clin San Carlos, Dept Med Oncol, Madrid, Spain. [Reuss, Alexander] Univ Marburg, Coordinating Ctr Clin Trials, Marburg, Germany. [Chavez-Blanco, Adriana] GICOM Grp Mexicano Invest Canc Ovario & Tumores G, Mexico City, DF, Mexico. [Kitchener, Henry] Univ Manchester, St Marys Hosp, Inst Canc Sci, Manchester M13 0JH, Lancs, England. [Nam, Byung-Ho] Natl Fisheries Res & Dev Inst, Biotechnol Res Div, Busan, South Korea. [Jhingran, Anuja] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Temkin, Sarah] NCI, Community Oncol & Prevent Trials Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Berns, Els] Erasmus MC Canc Inst, Dept Med Oncol, Rotterdam, Netherlands. [Scholl, Suzy] Inst Curie, Med Specialiste Oncol, Paris, France. [Doll, Corinne] Univ Calgary, Div Radiat Oncol, Dept Oncol, Calgary, AB, Canada. [Abu-Rustum, Nadeem R.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10021 USA. [Lecuru, Fabrice] Univ Paris 05, Sorbonne Paris Cite, Chirurg Cancerol Gynecol & Sein, Paris, France. [Small, William, Jr.] Loyola Univ, Stritch Sch Med, Dept Radiat Oncol, Chicago, IL 60611 USA. RP Sagae, S (reprint author), Sapporo West Kojinkai Clin, Dept Gynecol Oncol, Nishi Ku, Miyanosawa 1-1-1-30, Sapporo, Hokkaido 0630051, Japan. EM s_sagae@kojinkai.or.jp FU NCI NIH HHS [U10 CA180818, P30 CA008748, U10 CA180802] NR 29 TC 2 Z9 2 U1 4 U2 4 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 JAN PY 2016 VL 26 IS 1 BP 199 EP 207 DI 10.1097/IGC.0000000000000587 PG 9 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DA1DU UT WOS:000367537300027 PM 26569057 ER PT J AU Liu, AY Cohen, SE Vittinghoff, E Anderson, PL Doblecki-Lewis, S Bacon, O Chege, W Postle, BS Matheson, T Amico, KR Liegler, T Rawlings, MK Trainor, N Blue, RW Estrada, Y Coleman, ME Cardenas, G Feaster, DJ Grant, R Philip, SS Elion, R Buchbinder, S Kolber, MA AF Liu, Albert Y. Cohen, Stephanie E. Vittinghoff, Eric Anderson, Peter L. Doblecki-Lewis, Susanne Bacon, Oliver Chege, Wairimu Postle, Brian S. Matheson, Tim Amico, K. Rivet Liegler, Teri Rawlings, M. Keith Trainor, Nikole Blue, Robert Wilder Estrada, Yannine Coleman, Megan E. Cardenas, Gabriel Feaster, Daniel J. Grant, Robert Philip, Susan S. Elion, Richard Buchbinder, Susan Kolber, Michael A. TI Preexposure Prophylaxis for HIV Infection Integrated With Municipal- and Community-Based Sexual Health Services SO JAMA INTERNAL MEDICINE LA English DT Article ID MEDICATION ADHERENCE; TRANSGENDER WOMEN; UNITED-STATES; MEN; PREVENTION; RISK; DISPARITIES; RESISTANCE; IPREX; COST AB IMPORTANCE Several randomized clinical trials have demonstrated the efficacy of preexposure prophylaxis (PrEP) in preventing human immunodeficiency virus (HIV) acquisition. Little is known about adherence to the regimen, sexual practices, and overall effectiveness when PrEP is implemented in clinics that treat sexually transmitted infections (STIs) and community-based clinics serving men who have sex with men (MSM). OBJECTIVE To assess PrEP adherence, sexual behaviors, and the incidence of STIs and HIV infection in a cohort of MSM and transgender women initiating PrEP in the United States. DESIGN, SETTING, AND PARTICIPANTS Demonstration project conducted from October 1, 2012, through February 10, 2015 (last date of follow-up), among 557 MSM and transgender women in 2 STI clinics in San Francisco, California, and Miami, Florida, and a community health center in Washington, DC. Data were analyzed from December 18, 2014, through August 8, 2015. INTERVENTIONS A combination of daily, oral tenofovir disoproxil fumarate and emtricitabine was provided free of charge for 48 weeks. All participants received HIV testing, brief client-centered counseling, and clinical monitoring. MAIN OUTCOMES AND MEASURES Concentrations of tenofovir diphosphate in dried blood spot samples, self-reported numbers of anal sex partners and episodes of condomless receptive anal sex, and incidence of STI and HIV acquisition. RESULTS Overall, 557 participants initiated PrEP, and 437 of these (78.5%) were retained through 48 weeks. Based on the findings from the 294 participants who underwent measurement of tenofovir diphosphate levels, 80.0% to 85.6% had protective levels (consistent with >= 4 doses/wk) at follow-up visits. African American participants (56.8% of visits; P =.003) and those from the Miami site (65.1% of visits; P <.001) were less likely to have protective levels, whereas those with stable housing (86.8%; P =.02) and those reporting at least 2 condomless anal sex partners in the past 3 months (88.6%; P =.01) were more likely to have protective levels. The mean number of anal sex partners declined during follow-up from 10.9 to 9.3, whereas the proportion engaging in condomless receptive anal sex remained stable at 65.5% to 65.6%. Overall STI incidence was high (90 per 100 person-years) but did not increase over time. Two individuals became HIV infected during follow-up (HIV incidence, 0.43 [95% CI, 0.05-1.54] infections per 100 person-years); both had tenofovir diphosphate levels consistent with fewer than 2 doses/wk at seroconversion. CONCLUSIONS AND RELEVANCE The incidence of HIV acquisition was extremely low despite a high incidence of STIs in a large US PrEP demonstration project. Adherence was higher among those participants who reported more risk behaviors. Interventions that address racial and geographic disparities and housing instability may increase the impact of PrEP. C1 [Liu, Albert Y.; Cohen, Stephanie E.; Bacon, Oliver; Matheson, Tim; Trainor, Nikole; Blue, Robert Wilder; Philip, Susan S.; Buchbinder, Susan] San Francisco Dept Publ Hlth, San Francisco, CA 94102 USA. [Liu, Albert Y.; Cohen, Stephanie E.; Bacon, Oliver; Liegler, Teri; Philip, Susan S.; Buchbinder, Susan] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Vittinghoff, Eric; Buchbinder, Susan] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Anderson, Peter L.] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Aurora, CO USA. [Doblecki-Lewis, Susanne] Univ Miami, Miller Sch Med, Dept Med, Miami, FL 33136 USA. [Chege, Wairimu] Natl Inst Hlth, Div AIDS, Bethesda, MD USA. [Postle, Brian S.] DF Net Res Inc, Seattle, WA USA. [Amico, K. Rivet] Univ Michigan, Sch Publ Hlth, Dept Hlth Behav & Hlth Educ, Ann Arbor, MI 48109 USA. [Rawlings, M. Keith] Gilead Sci, Foster City, CA USA. [Estrada, Yannine; Cardenas, Gabriel] Univ Miami, Miller Sch Med, Dept Publ Hlth Sci, Miami, FL 33136 USA. [Coleman, Megan E.; Elion, Richard] Whitman Walker Hlth, Washington, DC USA. [Feaster, Daniel J.] Univ Miami, Miller Sch Med, Dept Publ Hlth Sci, Div Biostat, Miami, FL 33136 USA. [Grant, Robert] Gladstone Inst, San Francisco, CA USA. [Grant, Robert] San Francisco AIDS Fdn, San Francisco, CA USA. [Elion, Richard] George Washington Univ, Sch Med, Dept Med, Washington, DC USA. RP Liu, AY (reprint author), San Francisco Dept Publ Hlth, 25 Van Ness Ave,Ste 100, San Francisco, CA 94102 USA. EM albert.liu@sfdph.org FU National Institute for Allergies and Infectious Diseases (NIAID) [UM1AI069496]; National Institute for Mental Health [R01MH095628]; National Institutes of Health (NIH) (Miami Center for AIDS Research) [P30AI073961]; NIH (Gladstone Institute of Virology and Immunology-University of California, San Francisco, Center for AIDS Research) [P30AI027763]; Gilead Sciences FX This study was supported by grant UM1AI069496 from the National Institute for Allergies and Infectious Diseases (NIAID); by grant R01MH095628 from the National Institute for Mental Health; by grant P30AI073961 from the National Institutes of Health (NIH) (Miami Center for AIDS Research); and by grant P30AI027763 from the NIH (Gladstone Institute of Virology and Immunology-University of California, San Francisco, Center for AIDS Research). The study drug and support for pharmacokinetic and resistance testing were provided by Gilead Sciences. NR 50 TC 43 Z9 43 U1 6 U2 15 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JAN PY 2016 VL 176 IS 1 BP 75 EP 84 DI 10.1001/jamainternmed.2015.4683 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DA1II UT WOS:000367549100019 PM 26571482 ER PT J AU Shah, RV Murthy, VL Colangelo, LA Reis, J Venkatesh, BA Sharma, R Abbasi, SA Goff, DC Carr, JJ Rana, JS Terry, JG Bouchard, C Sarzynski, MA Eisman, A Neilan, T Das, S Jerosch-Herold, M Lewis, CE Carnethon, M Lewis, GD Lima, JAC AF Shah, Ravi V. Murthy, Venkatesh L. Colangelo, Laura A. Reis, Jared Venkatesh, Bharath Ambale Sharma, Ravi Abbasi, Siddique A. Goff, David C., Jr. Carr, J. Jeffrey Rana, Jamal S. Terry, James G. Bouchard, Claude Sarzynski, Mark A. Eisman, Aaron Neilan, Tomas Das, Saumya Jerosch-Herold, Michael Lewis, Cora E. Carnethon, Mercedes Lewis, Gregory D. Lima, Joao A. C. TI Association of Fitness in Young Adulthood With Survival and Cardiovascular Risk The Coronary Artery Risk Development in Young Adults (CARDIA) Study SO JAMA INTERNAL MEDICINE LA English DT Article ID SOCIETY-OF-CARDIOLOGY; LEFT-VENTRICULAR MASS; HEALTHY LIFE-STYLE; CARDIORESPIRATORY FITNESS; HEART-FAILURE; ATHEROSCLEROSIS MESA; PHYSICAL-ACTIVITY; MIDDLE-AGE; DISEASE; CALCIFICATION AB IMPORTANCE Although cardiorespiratory fitness (CRF) is prognostic in older adults, the effect of CRF during early adulthood on long-term cardiovascular structure, function, and prognosis is less clear. OBJECTIVE To examine whether CRF in young adults is associated with long-term clinical outcome and subclinical cardiovascular disease (CVD). DESIGN, SETTING, AND PARTICIPANTS Prospective study of 4872 US adults aged 18 to 30 years who underwent treadmill exercise testing at a baseline study visit from March 25, 1985, to June 7, 1986, and 2472 individuals who underwent a second treadmill test 7 years later. Median follow-up was 26.9 years, with assessment of obesity, left ventricular mass and strain, coronary artery calcification (CAC), and vital status and incident CVD. Follow-up was complete on August 31, 2011, and data were analyzed from recruitment through the end of follow-up. MAIN OUTCOMES AND MEASURES The presence of CAC was assessed by computed tomography at years 15 (2000-2001), 20 (2005-2006), and 25 (2010-2011), and left ventricular mass was assessed at years 5 (1990-1991) and 25 (with global longitudinal strain). Incident CVD and all-cause mortality were adjudicated. RESULTS Of the 4872 individuals, 273 (5.6%) died and 193 (4.0%) experienced CVD events during follow-up. After comprehensive adjustment, each additional minute of baseline exercise test duration was associated with a 15% lower hazard of death (hazard ratio [HR], 0.85; 95% CI, 0.80-0.91; P <.001) and a 12% lower hazard of CVD (HR, 0.88; 95% CI, 0.81-0.96; P =.002). Higher levels of baseline CRF were associated with significantly lower left ventricular mass index (beta = -0.24; 95% CI, -0.45 to -0.03; P =.02) and significantly better lobal longitudinal strain (beta = -0.09; 95% CI, -0.14 to -0.05; P <.001) at year 25. Fitness was not associated with CAC. A 1-minute reduction in fitness by year 7 was associated with 21% and 20% increased hazards of death (HR, 1.21; 95% CI, 1.07-1.37; P =.002) and CVD (HR, 1.20; 95% CI, 1.06-1.37; P =.006), respectively, along with a more impaired strain (beta = 0.15; 95% CI, 0.08-0.23; P <.001). No association between change in fitness and CAC was found. CONCLUSIONS AND RELEVANCE Higher levels of fitness at baseline and improvement in fitness early in adulthood are favorably associated with lower risks for CVD and mortality. Fitness and changes in fitness are associated withmyocardial hypertrophy and dysfunction but not CAC. Regular efforts to ascertain and improve CRF in young adulthood may play a critical role in promoting cardiovascular health and interrupting early CVD pathogenesis. C1 [Shah, Ravi V.; Das, Saumya] Beth Israel Deaconess Med Ctr, Cardiovasc Div, Dept Med, Boston, MA 02215 USA. [Murthy, Venkatesh L.] Univ Michigan, Dept Med, Cardiovasc Med Div, Ann Arbor, MI 48109 USA. [Murthy, Venkatesh L.] Univ Michigan, Dept Radiol, Div Nucl Med, Ann Arbor, MI 48109 USA. [Colangelo, Laura A.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Reis, Jared] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Venkatesh, Bharath Ambale; Sharma, Ravi; Lima, Joao A. C.] Johns Hopkins Univ, Johns Hopkins Med Inst, Inst Heart & Vasc, Dept Med & Cardiol, Baltimore, MD 21287 USA. [Abbasi, Siddique A.] Brown Univ, Rhode Isl Hosp, Dept Internal Med, Div Cardiol, Providence, RI 02912 USA. [Goff, David C., Jr.] Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA. [Carr, J. Jeffrey; Terry, James G.] Vanderbilt Univ, Dept Epidemiol, Nashville, TN 37235 USA. [Rana, Jamal S.] Kaiser Permanente No Calif, Dept Cardiol, Oakland, CA USA. [Rana, Jamal S.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Bouchard, Claude; Sarzynski, Mark A.; Lewis, Gregory D.] Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA 70808 USA. [Eisman, Aaron; Neilan, Tomas] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Jerosch-Herold, Michael] Brigham & Womens Hosp, Dept Med, Cardiovasc Div, Noninvas Cardiovasc Imaging Sect, Boston, MA 02115 USA. [Jerosch-Herold, Michael] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Lewis, Cora E.] Univ Alabama Birmingham, Dept Med, Div Preventat Med, Birmingham, AL USA. [Carnethon, Mercedes] Northwestern Univ, Feinberg Sch Med, Dept Preventat Med, Chicago, IL 60611 USA. RP Lima, JAC (reprint author), Johns Hopkins Univ, Inst Heart & Vasc, Johns Hopkins Med Inst, 600 N Wolfe St,Blalock 524, Baltimore, MD 21287 USA. EM jlima@jhmi.edu RI Sarzynski, Mark/A-9798-2014; Ambale Venkatesh, Bharath/F-4941-2016; Bouchard, Claude/A-7637-2009; OI Ambale Venkatesh, Bharath/0000-0002-2330-2373; Murthy, Venkatesh/0000-0002-7901-1321 FU National Heart, Lung, and Blood Institute (NHLBI) [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-95168, N01-HC-95169, HL098445-05, AG0005]; National Center for Research Resources [UL1-TR-000040, UL1-RR-025005]; Fellow-to-Faculty Award from the American Heart Association; Centers of Biomedical Research Excellence from the National Institute of General Medical Sciences, National Institutes of Health [8P20 GM-1033528]; NHLBI, the Intramural Research Program of the National Institute on Aging (NIA) [HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268200900041C]; NIA [AG0005]; NHLBI [AG0005] FX This study was supported by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95168, N01-HC-95169, and HL098445-05 from the National Heart, Lung, and Blood Institute (NHLBI) (Dr Carr); by grants UL1-TR-000040 and UL1-RR-025005 from the National Center for Research Resources; by a Fellow-to-Faculty Award from the American Heart Association (Dr Shah); by Centers of Biomedical Research Excellence grant 8P20 GM-1033528 from the National Institute of General Medical Sciences, National Institutes of Health (Dr Sarzynski); and by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C from the NHLBI, the Intramural Research Program of the National Institute on Aging (NIA), and intra-agency agreement AG0005 between the NIA and NHLBI (Coronary Artery Risk Development in Young Adults [CARDIA] study). NR 41 TC 15 Z9 15 U1 2 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JAN PY 2016 VL 176 IS 1 BP 87 EP 95 DI 10.1001/jamainternmed.2015.6309 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DA1II UT WOS:000367549100021 PM 26618471 ER PT J AU Grant, BF Saha, TD Ruan, WJ Goldstein, RB Chou, SP Jung, JS Zhang, HT Smith, SM Pickering, RP Huang, BJ Hasin, DS AF Grant, Bridget F. Saha, Tulshi D. Ruan, W. June Goldstein, Rise B. Chou, S. Patricia Jung, Jeesun Zhang, Haitao Smith, Sharon M. Pickering, Roger P. Huang, Boji Hasin, Deborah S. TI Epidemiology of DSM-5 Drug Use Disorder Results From the National Epidemiologic Survey on Alcohol and Related Conditions-III SO JAMA PSYCHIATRY LA English DT Article ID SUBSTANCE USE DISORDERS; GENERAL-POPULATION SAMPLE; UNITED-STATES; PSYCHIATRIC-DISORDERS; PROCEDURAL VALIDITY; COMORBIDITY-SURVEY; MARIJUANA USE; RISK-FACTORS; IV; PREVALENCE AB IMPORTANCE Current information on the prevalence and sociodemographic and clinical profiles of individuals in the general population with DSM-5 drug use disorder (DUD) is limited. Given the present societal and economic context in the United States and the new diagnostic system, up-to-date national information is needed from a single uniform data source. OBJECTIVE To present nationally representative findings on the prevalence, correlates, psychiatric comorbidity, disability, and treatment of DSM-5 DUD diagnoses overall and by severity level. DESIGN, SETTING, AND PARTICIPANTS In-person interviews were conducted with 36 309 adults in the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III, a cross-sectional representative survey of the United States. The household response rate was 72%; person-level response rate, 84%; and overall response rate, 60.1%. Data were collected April 2012 through June 2013 and analyzed from February through March 2015. MAIN OUTCOMES AND MEASURES Twelve-month and lifetime DUD, based on amphetamine, cannabis, club drug, cocaine, hallucinogen, heroin, nonheroin opioid, sedative/tranquilizer, and/or solvent/inhalant use disorders. RESULTS Prevalences of 12-month and lifetime DUD were 3.9% and 9.9%, respectively. Drug use disorder was generally greater among men, white and Native American individuals, younger and previously or never married adults, those with lower education and income, and those residing in the West. Significant associations were found between 12-month and lifetime DUD and other substance use disorders. Significant associations were also found between any 12-month DUD and major depressive disorder (odds ratio [OR], 1.3; 95% CI, 1.09-1.64), dysthymia (OR, 1.5; 95% CI, 1.09-2.02), bipolar I (OR, 1.5; 95% CI, 1.06-2.05), posttraumatic stress disorder (OR, 1.6; 95% CI, 1.27-2.10), and antisocial (OR, 1.4; 95% CI, 1.11-1.75), borderline (OR, 1.8; 95% CI, 1.41-2.24), and schizotypal (OR, 1.5; 95% CI, 1.18-1.87) personality disorders. Similar associations were found for any lifetime DUD with the exception that lifetime DUD was also associated with generalized anxiety disorder (OR, 1.3; 95% CI, 1.06-1.49), panic disorder (OR, 1.3; 95% CI, 1.06-1.59), and social phobia (OR, 1.3; 95% CI, 1.09-1.64). Twelve-month DUD was associated with significant disability, increasing with DUD severity. Among respondents with 12-month and lifetime DUD, only 13.5% and 24.6% received treatment, respectively. CONCLUSIONS AND RELEVANCE DSM-5 DUD is a common, highly comorbid, and disabling disorder that largely goes untreated in the United States. These findings indicate the need for additional studies to understand the broad relationships in more detail; estimate present-day economic costs of DUDs; investigate hypotheses regarding etiology, chronicity, and treatment use; and provide information to policy makers about allocation of resources for service delivery and research. Findings also indicate an urgent need to destigmatize DUD and educate the public, clinicians, and policy makers about its treatment to encourage affected individuals to obtain help. C1 [Grant, Bridget F.; Saha, Tulshi D.; Ruan, W. June; Goldstein, Rise B.; Chou, S. Patricia; Jung, Jeesun; Zhang, Haitao; Smith, Sharon M.; Pickering, Roger P.; Huang, Boji] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Rockville, MD 20852 USA. [Hasin, Deborah S.] Columbia Univ, Dept Psychiat, Coll Phys & Surg, New York, NY USA. [Hasin, Deborah S.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Hasin, Deborah S.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. RP Grant, BF (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, 5635 Fishers Ln,Room 3077, Rockville, MD 20852 USA. EM bgrant@mail.nih.gov OI Goldstein, Rise/0000-0002-9603-9473 FU National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institutes of Health (NIH) [R01DA018652-06A1]; NIAAA, NIH FX The National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III) was sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), with supplemental support from the National Institute on Drug Abuse. Support is acknowledged from National Institutes of Health (NIH) grant R01DA018652-06A1 (Dr Hasin) and from the Intramural Program, NIAAA, NIH. NR 62 TC 22 Z9 22 U1 4 U2 21 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD JAN PY 2016 VL 73 IS 1 BP 39 EP 47 DI 10.1001/jamapsychiatry.2015.2132 PG 9 WC Psychiatry SC Psychiatry GA DA5CP UT WOS:000367820000008 PM 26580136 ER PT J AU Hoang, TD Reis, J Zhu, N Jacobs, DR Launer, LJ Whitmer, RA Sidney, S Yaffe, K AF Hoang, Tina D. Reis, Jared Zhu, Na Jacobs, David R., Jr. Launer, Lenore J. Whitmer, Rachel A. Sidney, Stephen Yaffe, Kristine TI Effect of Early Adult Patterns of Physical Activity and Television Viewing on Midlife Cognitive Function SO JAMA PSYCHIATRY LA English DT Article ID YOUNG-ADULTS; SEDENTARY BEHAVIOR; ALZHEIMERS-DISEASE; OLDER-ADULTS; EXECUTIVE FUNCTION; RISK DEVELOPMENT; TEMPORAL TRENDS; LIFE-COURSE; MIDDLE-AGE; TIME USE AB IMPORTANCE Sedentary behaviors and physical inactivity are not only increasing worldwide but also are critical risk factors for adverse health outcomes. Yet, few studies have examined the effects of sedentary behavior on cognition or the long-term role of either behavior in early to middle adulthood. OBJECTIVE To investigate the association between 25-year patterns of television viewing and physical activity and midlife cognition. DESIGN, SETTING, AND PARTICIPANTS Prospective study of 3247 adults (black and white races; aged 18-30 years) enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study (March 25, 1985, to August 31, 2011). Data analysis was performed June 1, 2014, through April 15, 2015. MAIN OUTCOMES AND MEASURES We assessed television viewing and physical activity at repeated visits (>= 3 assessments) over 25 years using a validated questionnaire. A 25-year pattern of high television viewing was defined as watching TV above the upper baseline quartile (>3 hours/d) for more than two-thirds of the visits, and a 25-year pattern of low physical activity was defined as activity levels below the lower, sex-specific baseline quartile for more than two-thirds of the of the visits. We evaluated cognitive function at year 25 using the Digit Symbol Substitution Test (DSST), Stroop test, and Rey Auditory Verbal Learning Test. RESULTS At baseline, the mean (SD) age of the 3247 study participants was 25.1 (3.6) years, 1836 (56.5%) were female, 1771 (54.5%) were white, and 3015 (92.9%) had completed at least high school. Compared with participants with low television viewing, those with high television viewing during 25 years (353 of 3247 [10.9%]) were more likely to have poor cognitive performance (<1 SD below the race-specific mean) on the DSST and Stroop test, with findings reported as adjusted odds ratio (95% CI): DSST, 1.64 (1.21-2.23) and Stroop test, 1.56 (1.13-2.14), but not the Rey Auditory Verbal Learning Test, adjusted for age, race, sex, educational level, smoking, alcohol use, body mass index, and hypertension. Low physical activity during 25 years in 528 of 3247 participants (16.3%) was significantly associated with poor performance on the DSST, 1.47 (1.14-1.90). Compared with participants with low television viewing and high physical activity, the odds of poor performance were almost 2 times higher for adults with both high television viewing and low physical activity in 107 of 3247 (3.3%) (DSST, 1.95 [1.19-3.22], and Stroop test, 2.20 [1.36-3.56]). CONCLUSIONS AND RELEVANCE High television viewing and low physical activity in early adulthood were associated with worse midlife executive function and processing speed. This is one of the first studies to demonstrate that these risk behaviors may be critical targets for prevention of cognitive aging even before middle age. C1 [Hoang, Tina D.] Northern Calif Inst Res & Educ, San Francisco, CA 94121 USA. [Reis, Jared] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Zhu, Na; Jacobs, David R., Jr.] Univ Minnesota, Div Epidemiol, Sch Publ Hlth, Minneapolis, MN 55455 USA. [Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Whitmer, Rachel A.; Sidney, Stephen] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94143 USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. RP Hoang, TD (reprint author), Northern Calif Inst Res & Educ, Vet Affairs Med Ctr, 4150 Clement St,116-H, San Francisco, CA 94121 USA. EM tina.hoang@va.gov RI Dey, Kamalesh/E-6568-2017 FU National Heart, Lung, and Blood Institute (NHLBI); University of Alabama at Birmingham [HHSN268201300025C, HHSN268201300026C]; Northwestern University [HHSN268201300027C]; University of Minnesota [HHSN268201300028C]; Kaiser Foundation Research Institute [HHSN268201300029C]; Johns Hopkins University School of Medicine [HHSN268200900041C]; Intramural Research Program of the National Institute on Aging (NIA); NIA [AG0005, K24 AG031155]; NHLBI [AG0005, HL122658] FX The Coronary Artery Risk Development in Young Adults (CARDIA) Study is conducted and supported by grants from the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (HHSN268201300025C and HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and the Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between the NIA and NHLBI (AG0005). The CARDIA Cognitive Function Ancillary Study is supported by grant HL122658 from the NHLBI. Dr Yaffe is also supported by grant K24 AG031155 from the NIA. NR 66 TC 2 Z9 2 U1 4 U2 12 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD JAN PY 2016 VL 73 IS 1 BP 73 EP 79 DI 10.1001/jamapsychiatry.2015.2468 PG 7 WC Psychiatry SC Psychiatry GA DA5CP UT WOS:000367820000012 PM 26629780 ER PT J AU Hartmann, K Escribano, L Grattan, C Brockow, K Carter, MC Alvarez-Twose, I Matito, A Broesby-Olsen, S Siebenhaar, F Lange, M Niedoszytko, M Castells, M Oude Elberink, JNG Bonadonna, P Zanotti, R Hornick, JL Torrelo, A Grabbe, J Rabenhorst, A Nedoszytko, B Butterfield, JH Gotlib, J Reiter, A Radia, D Hermine, O Sotlar, K George, TI Kristensen, TK Kluin-Nelemans, HC Yavuz, S Hagglund, H Sperr, WR Schwartz, LB Triggiani, M Maurer, M Nilsson, G Horny, HP Arock, M Orfao, A Metcalfe, DD Akin, C Valent, P AF Hartmann, Karin Escribano, Luis Grattan, Clive Brockow, Knut Carter, Melody C. Alvarez-Twose, Ivan Matito, Almudena Broesby-Olsen, Sigurd Siebenhaar, Frank Lange, Magdalena Niedoszytko, Marek Castells, Mariana Oude Elberink, Joanna N. G. Bonadonna, Patrizia Zanotti, Roberta Hornick, Jason L. Torrelo, Antonio Grabbe, Juergen Rabenhorst, Anja Nedoszytko, Boguslaw Butterfield, Joseph H. Gotlib, Jason Reiter, Andreas Radia, Deepti Hermine, Olivier Sotlar, Karl George, Tracy I. Kristensen, Thomas K. Kluin-Nelemans, Hanneke C. Yavuz, Selim Hagglund, Hans Sperr, Wolfgang R. Schwartz, Lawrence B. Triggiani, Massimo Maurer, Marcus Nilsson, Gunnar Horny, Hans-Peter Arock, Michel Orfao, Alberto Metcalfe, Dean D. Akin, Cem Valent, Peter TI Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Classification; cutaneous mastocytosis; diagnostic criteria; mast cell; mastocytosis; standardization; urticaria pigmentosa ID MAST-CELL DISORDERS; C-KIT MUTATIONS; PEDIATRIC MASTOCYTOSIS; SYSTEMIC MASTOCYTOSIS; URTICARIA PIGMENTOSA; ONSET MASTOCYTOSIS; DIAGNOSTIC-CRITERIA; GERMLINE MUTATION; TRYPTASE LEVELS; ADULT PATIENTS AB Cutaneous lesions in patients with mastocytosis are highly heterogeneous and encompass localized and disseminated forms. Although a classification and criteria for cutaneous mastocytosis (CM) have been proposed, there remains a need to better define subforms of cutaneous manifestations in patients with mastocytosis. To address this unmet need, an international task force involving experts from different organizations (including the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology) met several times between 2010 and 2014 to discuss the classification and criteria for diagnosis of cutaneous manifestations in patients with mastocytosis. This article provides the major outcomes of these meetings and a proposal for a revised definition and criteria. In particular, we recommend that the typical maculopapular cutaneous lesions (urticaria pigmentosa) should be subdivided into 2 variants, namely a monomorphic variant with small maculopapular lesions, which is typically seen in adult patients, and a polymorphic variant with larger lesions of variable size and shape, which is typically seen in pediatric patients. Clinical observations suggest that the monomorphic variant, if it develops in children, often persists into adulthood, whereas the polymorphic variant may resolve around puberty. This delineationmight have important prognostic implications, and its implementation in diagnostic algorithms and future mastocytosis classifications is recommended. Refinements are also suggested for the diagnostic criteria of CM, removal of telangiectasia macularis eruptiva perstans from the current classification of CM, and removal of the adjunct solitary from the term solitary mastocytoma. C1 [Hartmann, Karin; Rabenhorst, Anja] Univ Cologne, Dept Dermatol, Cologne, Germany. [Hartmann, Karin] Med Univ Lubeck, Dept Dermatol, D-23538 Lubeck, Germany. [Escribano, Luis; Orfao, Alberto] Univ Salamanca, Serv Cent Citometria NUCLEUS, Ctr Invest Canc IBMCC, CSIC USAL, E-37008 Salamanca, Spain. [Escribano, Luis; Orfao, Alberto] Univ Salamanca, Dept Med, E-37008 Salamanca, Spain. [Escribano, Luis; Orfao, Alberto] Univ Salamanca, IBSAL, E-37008 Salamanca, Spain. [Grattan, Clive] Norfolk & Norwich Univ Hosp, Norwich, Norfolk, England. [Brockow, Knut] Tech Univ Munich, Dept Dermatol & Allergy Biederstein, D-80290 Munich, Germany. [Carter, Melody C.; Metcalfe, Dean D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Alvarez-Twose, Ivan; Matito, Almudena] Hosp Virgen del Valle, Inst Estudios Mastocitosis Castilla La Mancha CLM, Toledo, Spain. [Broesby-Olsen, Sigurd] Odense Univ Hosp, Dept Dermatol, Odense, Denmark. [Broesby-Olsen, Sigurd] Odense Univ Hosp, Allergy Ctr, Odense, Denmark. [Kristensen, Thomas K.] Odense Univ Hosp, Dept Pathol, Odense, Denmark. [Siebenhaar, Frank; Maurer, Marcus] Charite Univ Med Berlin, Dept Dermatol & Allergy, Interdisciplinary Mastocytosis Ctr Charite, Berlin, Germany. [Lange, Magdalena; Nedoszytko, Boguslaw] Med Univ Gdansk, Dept Dermatol Venereol & Allergol, Gdansk, Poland. [Niedoszytko, Marek] Med Univ Gdansk, Dept Allergol, Gdansk, Poland. [Castells, Mariana; Akin, Cem] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Oude Elberink, Joanna N. G.] Univ Groningen, Univ Med Ctr Groningen, Groningen Res Inst Asthma & COPD, Dept Allergol, NL-9700 AB Groningen, Netherlands. [Bonadonna, Patrizia] Verona Univ Hosp, Allergy Unit, Verona, Italy. [Zanotti, Roberta] Verona Univ Hosp, Dept Med, Sect Hematol, Verona, Italy. [Hornick, Jason L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [Torrelo, Antonio] Hosp Nino Jesus, Dept Dermatol, Madrid, Spain. [Grabbe, Juergen] Cantonal Hosp Aarau, Dept Dermatol, Aarau, Switzerland. [Butterfield, Joseph H.] Mayo Clin, Div Allerg Dis, Rochester, MN USA. [Gotlib, Jason] Stanford Univ, Sch Med, Div Hematol, Dept Med, Stanford, CA 94305 USA. [Reiter, Andreas] Heidelberg Univ, Med Klin 3, Univ Med Mannheim, Mannheim, Germany. [Radia, Deepti] Guys & St Thomas NHS Fdn Trust, Guys Hosp, Dept Haematol, London, England. [Hermine, Olivier] Univ Paris 05, Sorbonne Paris Cite, Natl Reference Ctr Mastocytosis,Imaging Inst, Dept Hematol,INSERM U1163,CNRS ERL8564, Paris, France. [Sotlar, Karl; Horny, Hans-Peter] Univ Munich, Inst Pathol, D-80539 Munich, Germany. [George, Tracy I.] Univ New Mexico, Dept Pathol, Albuquerque, NM 87131 USA. [Kluin-Nelemans, Hanneke C.] Univ Groningen, Univ Med Ctr Groningen, Dept Hematol, NL-9700 AB Groningen, Netherlands. [Yavuz, Selim] Istanbul Univ, Dept Internal Med, Div Hematol, Istanbul, Turkey. [Hagglund, Hans] Karolinska Univ Hosp, Hematol Ctr Karolinska, Stockholm, Sweden. [Sperr, Wolfgang R.; Valent, Peter] Med Univ Vienna, Dept Internal Med 1, Div Hematol & Hemostaseol, Vienna, Austria. [Schwartz, Lawrence B.] Virginia Commonwealth Univ, Med Coll Virginia, Dept Internal Med, Div Rheumatol Allergy & Immunol, Richmond, VA 23298 USA. [Triggiani, Massimo] Univ Salerno, Div Clin Immunol & Allergy, Salerno, Italy. [Nilsson, Gunnar] Karolinska Inst, Dept Med, Clin Immunol & Allergy, Stockholm, Sweden. [Arock, Michel] Ecole Normale Super, Mol Oncol & Pharmacol, LBPA CNRS UMR8113, Cachan, France. RP Hartmann, K (reprint author), Med Univ Lubeck, Dept Dermatol, Ratzeburger Allee 160, D-23538 Lubeck, Germany. EM karin.hartmann@uksh.de RI Hartmann, Karin/N-4865-2015; Rabenhorst, Anja/J-3217-2016; OI Hartmann, Karin/0000-0002-4595-8226; Akin, Cem/0000-0001-6301-4520; Lange, Magdalena/0000-0002-6967-1393 FU German Research Council (DFG) [HA 2393/6-1, CRC/SFB832]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases; Austrian Science Funds (FWF) [SFB F4611, SFB F4707-B20]; American Academy of Allergy, Asthma Immunology; European Academy of Allergy and Clinical Immunology FX Supported by research grants from the German Research Council (DFG; HA 2393/6-1; CRC/SFB832, project A14; to K.H.); from the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (to D.D.M.); and from the Austrian Science Funds (FWF; projects SFB F4611 and SFB F4707-B20; to P.V.). The Consensus Conference on Mastocytosis in Boston, Massachusetts (October 2012), was supported by the American Academy of Allergy, Asthma & Immunology. A task force/consensus panel on mastocytosis between 2010 and 2012 was supported by the European Academy of Allergy and Clinical Immunology. NR 80 TC 17 Z9 17 U1 6 U2 16 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JAN PY 2016 VL 137 IS 1 BP 35 EP 45 DI 10.1016/j.jaci.2015.08.034 PG 11 WC Allergy; Immunology SC Allergy; Immunology GA DA3UK UT WOS:000367724300041 PM 26476479 ER PT J AU Munoz-Cano, R Pascal, M Bartra, J Picado, C Valero, A Kim, DK Brooks, S Ombrello, M Metcalfe, DD Rivera, J Olivera, A AF Munoz-Cano, Rosa Pascal, Mariona Bartra, Joan Picado, Cesar Valero, Antonio Kim, Do-Kyun Brooks, Stephen Ombrello, Michael Metcalfe, Dean D. Rivera, Juan Olivera, Ana TI Distinct transcriptome profiles differentiate nonsteroidal anti-inflammatory drug-dependent from nonsteroidal anti-inflammatory drug-independent food-induced anaphylaxis SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Anaphylaxis; food allergy; lipid transfer protein syndrome; nonsteroidal anti-inflammatory drugs; transcriptome analysis ID FC-GAMMA-RI; LIPID TRANSFER PROTEINS; EXERCISE-INDUCED ANAPHYLAXIS; AFFINITY IGG RECEPTOR; MAST-CELLS; ADENOSINE RECEPTORS; AUTOIMMUNE-DISEASES; BARRIER FUNCTION; MOUSE MODEL; ALLERGY AB Background: Lipid transfer protein (LTP), an abundant protein in fruits, vegetables, and nuts, is a common food allergen in Mediterranean areas causing diverse allergic reactions. Approximately 40% of food-related anaphylaxis induced by LTPs requires nonsteroidal anti-inflammatory drugs (NSAIDs) as a triggering cofactor. Objective: We sought to better understand the determinants of NSAID-dependent and NSAID-independent LTP-induced anaphylaxis (LTP-A). Methods: Selection of patients was based on a proved clinical history of NSAID-dependent or NSAID-independent anaphylaxis to LTPs, positive skin prick test response to LTPs, and serum LTP IgE. Whole-transcriptome (RNA sequencing) analysis of blood cells from 14 patients with NSAID-related LTP-A (NSAID-LTP-A), 7 patients with LTP-A, and 13 healthy control subjects was performed to identify distinct gene expression signatures. Results: Expression of genes regulating gastrointestinal epithelial renewal was altered in both patient sets, particularly in those with LTP-A, who also presented with gene expression profiles characteristic of an inflammatory syndrome. These included altered B-cell pathways, increased neutrophil activation markers, and increased reactive oxygen species levels. Increased expression of the IgG receptor (CD64) in patients with LTP-A was mirrored by the presence of LTP-specific IgG(1) and IgG(3). Conversely, patients with NSAID-LTP-A were characterized by reduced expression of IFN-gamma-regulated genes and IFN-gamma levels, as well as upregulated expression of adenosine receptor 3 (ADORA3) and genes related to adenosine metabolism. Conclusions: Gene ontology analysis suggests disturbances in gut epithelial homeostasis in both groups with LTP-A, with potential integrity breaches in patients with LTP-A that might explain their distinct inflammatory signatures. Differential regulation in patients with LTP-A and those with NSAID-LTP-A of the IFN-g pathway, IgG receptors, and ADORA3 might provide the pathogenic basis of their distinct responses. C1 [Munoz-Cano, Rosa; Kim, Do-Kyun; Metcalfe, Dean D.; Rivera, Juan] NIAID, Mast Cell Biol Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Munoz-Cano, Rosa; Bartra, Joan; Picado, Cesar; Valero, Antonio] Univ Barcelona, Unitat Al Lergia, Serv Neumol & Al Lergia Resp, Hosp Clin, Barcelona, Spain. [Munoz-Cano, Rosa; Pascal, Mariona; Bartra, Joan; Picado, Cesar; Valero, Antonio] Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain. [Pascal, Mariona] Univ Barcelona, Hosp Clin, CDB, Serv Immunol, Barcelona, Spain. [Pascal, Mariona; Bartra, Joan] Carlos III Hlth Inst, Spanish Res Network Adverse React Allergens & Dru, Madrid, Spain. [Rivera, Juan] NIAMSD, Immunogenet Mol Lab, Bethesda, MD 20892 USA. [Brooks, Stephen; Ombrello, Michael] NIAMSD, Off Sci & Technol, Bethesda, MD 20892 USA. [Brooks, Stephen; Ombrello, Michael] NIAMSD, Translat Genet & Genom Unit, Bethesda, MD 20892 USA. RP Munoz-Cano, R (reprint author), NIAID, Mast Cell Biol Sect, Lab Allerg Dis, NIH, Bldg 10,Rm 11C205,10 Ctr Dr, Bethesda, MD 20892 USA. EM rmunoz@clinic.ub.es RI Munoz Cano, Rosa/K-9413-2014 OI Munoz Cano, Rosa/0000-0001-8566-8285 FU Division of Intramural Research Program within the National Institute of Allergy and Infectious Diseases; Ministerio de Economia y Competitividad-Instituto de Salud Carlos III, Spain [FIS-PI11/01326]; "Rio Hortega'' Fellowship, Ministerio de Economia y Competitividad, Instituto de Salud Carlos III, Spain; Division of Intramural Research Program within National Institute of Arthritis and Musculoskeletal and Skin Diseased, National Institutes of Health FX Supported by the Division of Intramural Research Programs within the National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseased, National Institutes of Health and by Ministerio de Economia y Competitividad-Instituto de Salud Carlos III (FIS-PI11/01326), Spain. R.M. C. was the recipient of the "Rio Hortega'' Fellowship, Ministerio de Economia y Competitividad, Instituto de Salud Carlos III, Spain. NR 52 TC 5 Z9 5 U1 1 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JAN PY 2016 VL 137 IS 1 BP 137 EP 146 DI 10.1016/j.jaci.2015.05.042 PG 10 WC Allergy; Immunology SC Allergy; Immunology GA DA3UK UT WOS:000367724300004 PM 26194548 ER PT J AU de Bildt, A Sytema, S Meffert, H Bastiaansen, JACJ AF de Bildt, Annelies Sytema, Sjoerd Meffert, Harma Bastiaansen, Jojanneke A. C. J. TI The Autism Diagnostic Observation Schedule, Module 4: Application of the Revised Algorithms in an Independent, Well-Defined, Dutch Sample (n=93) SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Autism Spectrum Disorder; Schizophrenia; Psychopathy; Assessment; Classification; Adults ID SCHIZOPHRENIA AB This study examined the discriminative ability of the revised Autism Diagnostic Observation Schedule module 4 algorithm (Hus and Lord in J Autism Dev Disord 44(8):1996-2012, 2014) in 93 Dutch males with Autism Spectrum Disorder (ASD), schizophrenia, psychopathy or controls. Discriminative ability of the revised algorithm ASD cut-off resembled the original algorithm ASD cut-off: highly specific for psychopathy and controls, lower sensitivity than Hus and Lord (2014; i.e. ASD .61, AD .53). The revised algorithm AD cut-off improved sensitivity over the original algorithm. Discriminating ASD from schizophrenia was still challenging, but the better-balanced sensitivity (.53) and specificity (.78) of the revised algorithm AD cut-off may aide clinicians' differential diagnosis. Findings support using the revised algorithm, being conceptually conform the other modules, thus improving comparability across the lifespan. C1 [de Bildt, Annelies] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [de Bildt, Annelies] Accare Univ, Ctr Child & Adolescent Psychiat, NL-9700 AR Groningen, Netherlands. [Meffert, Harma] NIH, Sect Affect & Cognit Neurosci, Bethesda, MD 20892 USA. [Sytema, Sjoerd; Bastiaansen, Jojanneke A. C. J.] Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Dept Psychiat, Groningen, Netherlands. [Meffert, Harma] Univ Groningen, Univ Med Ctr Groningen, Dept Neurosci, Social Brain Lab, NL-9713 AV Groningen, Netherlands. [Meffert, Harma; Bastiaansen, Jojanneke A. C. J.] Forens Psychiat Clin Dr S Van Mesdag, Groningen, Netherlands. [Bastiaansen, Jojanneke A. C. J.] Lentis, Autism Team North Netherlands, Groningen, Netherlands. RP de Bildt, A (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. EM a.de.bildt@accare.nl OI Meffert, Harma/0000-0002-7298-7276 FU National Institute of Mental Health, National Institutes of Health [1-ZIA-MH002860-08] FX HM was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (1-ZIA-MH002860-08). The authors wish to thank all participants for their time and effort. Additionally, we thank Lentis, Groningen (Autism Team North Netherlands and WWA); FPC Dr. S. van Mesdag, Groningen; FPC Veldzicht, Balkbrug; and GGZ Drenthe, Assen (Psychosencircuit) for the support in recruitment and assessment of the participants. NR 16 TC 2 Z9 2 U1 2 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 EI 1573-3432 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD JAN PY 2016 VL 46 IS 1 BP 21 EP 30 DI 10.1007/s10803-015-2532-4 PG 10 WC Psychology, Developmental SC Psychology GA DA6AG UT WOS:000367883500003 PM 26319249 ER PT J AU Pradhan, MA Blackford, JA Devaiah, BN Thompson, PS Chow, CC Singer, DS Simons, SS AF Pradhan, Madhumita A. Blackford, John A., Jr. Devaiah, Ballachanda N. Thompson, Petria S. Chow, Carson C. Singer, Dinah S. Simons, S. Stoney, Jr. TI Kinetically Defined Mechanisms and Positions of Action of Two New Modulators of Glucocorticoid Receptor-regulated Gene Induction SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE cyclin-dependent kinase (CDK); gene expression; glucocorticoid receptor; steroid hormone; transcription factor; EC50; accelerator; decelerator; kinetically defined activity; transactivation competition assay ID RNA-POLYMERASE-II; NEGATIVE ELONGATION-FACTOR; P-TEFB; PRODUCTIVE ELONGATION; NUCLEAR RECEPTORS; TERMINAL DOMAIN; IN-VIVO; PROTEIN; BRD4; TRANSACTIVATION AB Most of the steps in, and many of the factors contributing to, glucocorticoid receptor (GR)-regulated gene induction are currently unknown. A competition assay, based on a validated chemical kinetic model of steroid hormone action, is now used to identify two new factors (BRD4 and negative elongation factor (NELF)-E) and to define their sites and mechanisms of action. BRD4 is a kinase involved in numerous initial steps of gene induction. Consistent with its complicated biochemistry, BRD4 is shown to alter both the maximal activity (A(max)) and the steroid concentration required for half-maximal induction (EC50) of GR-mediated gene expression by acting at a minimum of three different kinetically defined steps. The action at two of these steps is dependent on BRD4 concentration, whereas the third step requires the association of BRD4 with P-TEFb. BRD4 is also found to bind to NELF-E, a component of the NELF complex. Unexpectedly, NELF-E modifies GR induction in a manner that is independent of the NELF complex. Several of the kinetically defined steps of BRD4 in this study are proposed to be related to its known biochemical actions. However, novel actions of BRD4 and of NELF-E in GR-controlled gene induction have been uncovered. The model-based competition assay is also unique in being able to order, for the first time, the sites of action of the various reaction components: GR < Cdk9 < BRD4 induced gene < NELF-E. This ability to order factor actions will assist efforts to reduce the side effects of steroid treatments. C1 [Pradhan, Madhumita A.; Blackford, John A., Jr.; Simons, S. Stoney, Jr.] NIDDK, Steroid Hormones Sect, Lab Endocrinol & Receptor Biol, Bethesda, MD 20892 USA. [Devaiah, Ballachanda N.; Thompson, Petria S.; Singer, Dinah S.] NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. [Chow, Carson C.] NIDDK, Math Biol Sect, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Simons, SS (reprint author), NIDDK, LERB, NIH, Bldg 10,Rm 8N-307B, Bethesda, MD 20892 USA. EM stoneys@helix.nih.gov FU Intramural Research Program of NIDDK; NCI, National Institutes of Health FX This work was supported by the Intramural Research Program of NIDDK and NCI, National Institutes of Health. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 39 TC 1 Z9 1 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 1 PY 2016 VL 291 IS 1 BP 342 EP 354 DI 10.1074/jbc.M115.683722 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DA1XP UT WOS:000367589500027 PM 26504077 ER PT J AU Lowy, DR AF Lowy, Douglas R. TI HPV vaccination to prevent cervical cancer and other HPV-associated disease: from basic science to effective interventions SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID HUMAN-PAPILLOMAVIRUS VACCINE; VIRUS-LIKE PARTICLES; COSTA-RICA VACCINE; AS04-ADJUVANTED VACCINE; YOUNG-WOMEN; BOVINE PAPILLOMAVIRUS; TRANSFORMING GENE; CONTROLLED-TRIAL; UNITED-STATES; INFECTION AB Identification of HPV infection as the etiologic agent of virtually all cases of cervical cancer, as well as a proportion of other epithelial cancers, has led to development of three FDA-approved multivalent prophylactic HPV vaccines composed of virus-like particles (VLPs). This essay describes the research and development that led to the VLP vaccines; discusses their safety, efficacy, and short-term effect on HPV-associated disease; and speculates that even a single dose of these vaccines, when given to adolescents, might be able to confer long-term protection. The HPV field exemplifies how long-term funding for basic research has lead to clinical interventions with the long-term potential to eradicate most cancers attributable to HPV infection. Although this essay is the result of my receiving the 2015 Harrington Prize for Innovation in Medicine from the Harrington Discovery Institute and the American Society for Clinical Investigation, this clinical advance has depended on the research of many investigators, development of commercial vaccines by the pharmaceutical companies, and participation of many patient volunteers in the clinical trials. C1 [Lowy, Douglas R.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Lowy, DR (reprint author), NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. EM lowyd@mail.nih.gov FU Intramural Research Program; Center for Cancer Research; NIH; NCI FX I thank John Schiller for his critical reading of the manuscript. This research is supported by the Intramural Research Program, NIH, NCI, and Center for Cancer Research. NR 50 TC 6 Z9 7 U1 4 U2 12 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JAN PY 2016 VL 126 IS 1 BP 5 EP 11 DI 10.1172/JCI85446 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DA4JG UT WOS:000367765600003 PM 26727228 ER PT J AU Li, YQ Shrestha, Y Pandey, M Chen, M Kablan, A Gavrilova, O Offermanns, S Weinstein, LS AF Li, Yong-Qi Shrestha, Yogendra Pandey, Mritunjay Chen, Min Kablan, Ahmed Gavrilova, Oksana Offermanns, Stefan Weinstein, Lee S. TI G(q/11)alpha and G(s)alpha mediate distinct physiological responses to central melanocortins SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID CORTICOTROPIN-RELEASING HORMONE; CENTRAL-NERVOUS-SYSTEM; FOOD-INTAKE; G-PROTEIN; PARAVENTRICULAR HYPOTHALAMUS; ENERGY-EXPENDITURE; BLOOD-PRESSURE; RECEPTOR GENE; SIM1 GENE; OBESITY AB Activation of brain melanocortin 4 receptors (MC4Rs) leads to reduced food intake, increased energy expenditure, increased insulin sensitivity, and reduced linear growth. MC4R effects on energy expenditure and glucose metabolism are primarily mediated by the G protein G(s)alpha in brain regions outside of the paraventricular nucleus of the hypothalamus (PVN). However, the G protein(s) that is involved in MC4R-mediated suppression of food intake and linear growth, which are believed to be regulated primarily though action in the PVN, is unknown. Here, we show that PVN-specific loss of G(q)alpha and G(11)alpha, which stimulate PLC, leads to severe hyperphagic obesity, increased linear growth, and inactivation,of the hypothalamic-pituitary-adrenal axis, without affecting energy expenditure or glucose metabolism. Moreover, we demonstrate that the ability of an MC4R agonist delivered to PVN to inhibit food intake is lost in mice lacking G(q/11)alpha in the PVN but not in animals deficient for Gsa. The blood pressure response to the same MC4R agonist was only lost in animals lacking G(s)alpha specifically in the PVN. Together, our results exemplify how different physiological effects of GPCRs may be mediated by different G proteins and identify a pathway for appetite regulation that could be selectively targeted by G(q/11)alpha-biased MC4R agonists as a potential treatment for obesity. C1 [Li, Yong-Qi; Shrestha, Yogendra; Pandey, Mritunjay; Chen, Min; Kablan, Ahmed; Weinstein, Lee S.] NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. [Gavrilova, Oksana] NIDDK, Mouse Metab Core Lab, NIH, Bethesda, MD 20892 USA. [Offermanns, Stefan] Max Planck Inst Heart & Lung Res, Bad Nauheim, Germany. RP Weinstein, LS (reprint author), NIDDK, Metab Dis Branch, NIH, Bldg 10 Rm 8C101, Bethesda, MD 20892 USA. EM lee@mail.nih.gov FU Intramural Research Program of the NIDDK, NIH, Bethesda, Maryland, USA FX We would like to thank T. Chanturiya for technical assistance. This work was supported by the Intramural Research Program of the NIDDK, NIH, Bethesda, Maryland, USA. NR 39 TC 6 Z9 6 U1 0 U2 4 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JAN PY 2016 VL 126 IS 1 BP 40 EP 49 DI 10.1172/JCI76348 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DA4JG UT WOS:000367765600009 PM 26595811 ER PT J AU Klebanoff, CA Scott, CD Leonardi, AJ Yamamoto, TN Cruz, AC Ouyang, C Ramaswamy, M Roychoudhuri, R Ji, Y Eil, RL Sukumar, M Crompton, JG Palmer, DC Borman, ZA Clever, D Thomas, SK Patel, S Yu, ZY Muranski, P Liu, H Wang, E Marincola, FM Gros, A Gattinoni, L Rosenberg, SA Siegel, RM Restifo, NP AF Klebanoff, Christopher A. Scott, Christopher D. Leonardi, Anthony J. Yamamoto, Tori N. Cruz, Anthony C. Ouyang, Claudia Ramaswamy, Madhu Roychoudhuri, Rahul Ji, Yun Eil, Robert L. Sukumar, Madhusudhanan Crompton, Joseph G. Palmer, Douglas C. Borman, Zachary A. Clever, David Thomas, Stacy K. Patel, Shashankkumar Yu, Zhiya Muranski, Pawel Liu, Hui Wang, Ena Marincola, Francesco M. Gros, Alena Gattinoni, Luca Rosenberg, Steven A. Siegel, Richard M. Restifo, Nicholas P. TI Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID CHIMERIC ANTIGEN RECEPTOR; SUPERIOR ANTITUMOR IMMUNITY; IN-VIVO; TRANSCRIPTION FACTOR; STEM-CELLS; GLUCOSE-METABOLISM; EFFECTOR FUNCTIONS; RECALL RESPONSES; LYMPH-NODES; L-SELECTIN AB Adoptive cell transfer (ACT) of purified naive, stem cell memory, and central memory T cell subsets results in superior persistence and antitumor immunity compared with ACT of populations containing more-differentiated effector memory and effector T cells. Despite a clear advantage of the less-differentiated populations, the majority of ACT trials utilize unfractionated T cell subsets. Here, we have challenged the notion that the mere presence of less-differentiated T cells in starting populations used to generate therapeutic T cells is sufficient to convey their desirable attributes. Using both mouse and human cells, We identified a T cell-T cell interaction whereby antigen-experienced subsets directly promote the phenotypic, functional, and metabolic differentiation of naive T cells. This process led to the loss of less-differentiated T cell subsets and resulted in impaired cellular persistence and tumor regression in mouse models following ACT. The T memory-induced conversion of naive T cells was mediated by a nonapoptotic Fas signal, resulting in Akt-driven cellular differentiation. Thus, induction of Fas signaling enhanced T cell differentiation and impaired antitumor immunity, while Fas signaling blockade preserved the antitumor efficacy of naive cells within mixed populations. These findings reveal that T cell subsets can synchronize their differentiation state in a process similar to quorum sensing in unicellular organisms and suggest that disruption of this quorum-like behavior among T cells has potential to enhance T cell-based immunotherapies. C1 [Klebanoff, Christopher A.] NCI, Clin Investigator Dev Program, NIH, Bethesda, MD 20892 USA. [Klebanoff, Christopher A.; Scott, Christopher D.; Leonardi, Anthony J.; Yamamoto, Tori N.; Roychoudhuri, Rahul; Ji, Yun; Eil, Robert L.; Sukumar, Madhusudhanan; Crompton, Joseph G.; Palmer, Douglas C.; Borman, Zachary A.; Clever, David; Patel, Shashankkumar; Yu, Zhiya; Muranski, Pawel; Gros, Alena; Gattinoni, Luca; Rosenberg, Steven A.; Restifo, Nicholas P.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yamamoto, Tori N.] Univ Penn, Immunol Grad Grp, Philadelphia, PA 19104 USA. [Cruz, Anthony C.; Ouyang, Claudia; Ramaswamy, Madhu; Thomas, Stacy K.; Siegel, Richard M.] NIAMSD, Autoimmun Branch, NIH, Bethesda, MD USA. [Ramaswamy, Madhu] MedImmune, Gaithersburg, MD USA. [Ji, Yun; Gattinoni, Luca] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Clever, David] Ohio State Univ, Coll Med, Med Scientist Training Program, Columbus, OH 43210 USA. [Patel, Shashankkumar] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Muranski, Pawel] NHLBI, Bethesda, MD 20892 USA. [Liu, Hui; Wang, Ena; Marincola, Francesco M.] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Ena; Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. RP Klebanoff, CA (reprint author), 10 Ctr Dr,Bldg 10-CRC,Room 3W-5816, Bethesda, MD 20892 USA. EM klebanoc@mail.nih.gov RI Gattinoni, Luca/A-2281-2008; Ji, Yun/B-7245-2009; Roychoudhuri, Rahul/A-7442-2010; OI Gattinoni, Luca/0000-0003-2239-3282; Ji, Yun/0000-0001-6340-7009; Roychoudhuri, Rahul/0000-0002-5392-1853; Gros, Alena/0000-0002-1207-1880 FU Intramural Research Program of NCI; Intramural Research Program of NIAMS; Center for Cancer Research of NIH [ZIA BC011586, ZIA BC010763]; NIH Center for Regenerative Medicine FX We thank A. Mixon and S. Farid of the NCI Surgery Branch Flow Cytometry Unit for help with flow cytometry sorting. This work was supported by the Intramural Research Programs of the NCI and NIAMS, the Center for Cancer Research of the NIH (ZIA BC011586 and ZIA BC010763), and the NIH Center for Regenerative Medicine. Additional support was provided by gifts from Li Jinyuan and the Tiens Charitable Foundation and the Milstein Family Foundation. NR 78 TC 18 Z9 18 U1 3 U2 12 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JAN PY 2016 VL 126 IS 1 BP 318 EP 334 DI 10.1172/JCI81217 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DA4JG UT WOS:000367765600029 PM 26657860 ER PT J AU Youn, JH Drake, SK Weingarten, RA Frank, KM Dekker, JP Lau, AF AF Youn, Jung-Ho Drake, Steven K. Weingarten, Rebecca A. Frank, Karen M. Dekker, John P. Lau, Anna F. TI Clinical Performance of a Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry Method for Detection of Certain bla(KPC)-Containing Plasmids SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID TN4401 CARRYING BLA(KPC); KLEBSIELLA-PNEUMONIAE; IDENTIFICATION; BACTERIA; ENTEROBACTERIACEAE; REPRODUCIBILITY; INSERTION; PKPQIL; MEDIA; MS AB Rapid detection of bla(KPC)-containing organisms can significantly impact infection control and clinical practices, as well as therapeutic choices. Current molecular and phenotypic methods to detect these organisms, however, require additional testing beyond routine organism identification. In this study, we evaluated the clinical performance of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) to detect pKpQIL_p019 (p019)-an similar to 11,109-Da protein associated with certain bla(KPC)-containing plasmids that was previously shown to successfully track a clonal outbreak of bla(KPC)-pKpQIL-Klebsiella pneumoniae in a proof-of-principle study (A. F. Lau, H. Wang, R. A. Weingarten, S. K. Drake, A. F. Suffredini, M. K. Garfield, Y. Chen, M. Gucek, J. H. Youn, F. Stock, H. Tso, J. DeLeo, J. J. Cimino, K. M. Frank, and J. P. Dekker, J Clin Microbiol 52: 2804-2812, 2014, http://dx.doi.org/10.1128/JCM.00694-14). PCR for the p019 gene was used as the reference method. Here, blind analysis of 140 characterized Enterobacteriaceae isolates using two protein extraction methods (plate extraction and tube extraction) and two peak detection methods (manual and automated) showed sensitivities and specificities ranging from 96% to 100% and from 95% to 100%, respectively (2,520 spectra analyzed). Feasible laboratory implementation methods (plate extraction and automated analysis) demonstrated 96% sensitivity and 99% specificity. All p019-positive isolates (n = 26) contained bla(KPC) and were carbapenem resistant. Retrospective analysis of an additional 720 clinical Enterobacteriaceae spectra found an similar to 11,109-Da signal in nine spectra (1.3%), including seven from p019-containing, carbapenem-resistant isolates (positive predictive value [PPV], 78%). Instrument tuning had a significant effect on assay sensitivity, highlighting important factors that must be considered as MALDI-TOF MS moves into applications beyond microbial identification. Using a large blind clinical data set, we have shown that spectra acquired for routine organism identification can also be analyzed automatically in real time at high throughput, at no additional expense to the laboratory, to enable rapid detection of potentially bla(KPC)-containing carbapenem-resistant isolates, providing early and clinically actionable results. C1 [Youn, Jung-Ho; Weingarten, Rebecca A.; Frank, Karen M.; Dekker, John P.; Lau, Anna F.] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Drake, Steven K.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Lau, AF (reprint author), NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM Anna.Lau@nih.gov FU Intramural Research Program of the National Institutes of Health FX Intramural Research Program of the National Institutes of Health provided funding to Jung-Ho Youn, Steven K. Drake, Rebecca A. Weingarten, Karen M. Frank, John P. Dekker, and Anna F. Lau. NR 22 TC 9 Z9 9 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD JAN PY 2016 VL 54 IS 1 BP 35 EP 42 DI 10.1128/JCM.01643-15 PG 8 WC Microbiology SC Microbiology GA DA1DX UT WOS:000367537600008 PM 26338858 ER PT J AU Ricardo, AC Roy, JA Tao, KX Alper, A Chen, J Drawz, PE Fink, JC Hsu, CY Kusek, JW Ojo, A Schreiber, M Fischer, MJ AF Ricardo, Ana C. Roy, Jason A. Tao, Kaixiang Alper, Arnold Chen, Jing Drawz, Paul E. Fink, Jeffrey C. Hsu, Chi-yuan Kusek, John W. Ojo, Akinlolu Schreiber, Martin Fischer, Michael J. CA CRIC Study Investigators TI Influence of Nephrologist Care on Management and Outcomes in Adults with Chronic Kidney Disease SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE chronic kidney disease; nephrology care; outcomes ID CHRONIC RENAL-INSUFFICIENCY; BASE-LINE CHARACTERISTICS; DIABETES-MELLITUS; REFERRED LATE; COHORT; MORTALITY; PATTERNS; SURVIVAL; CKD; PARTICIPANTS AB Predialysis nephrology care for adults with late stage chronic kidney disease (CKD) is associated with improved outcomes. Less is known about the effects of nephrology care in earlier stages of CKD. We aimed to evaluate the effect of nephrology care on management of CKD risk factors and complications, CKD progression, incident cardiovascular disease (CVD), and death. This was a prospective cohort study. Participants included 3855 men and women aged 21 to 74 years enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study with a mean (SD) estimated glomerular filtration rate (eGFR) at entry of 45 (17) ml/min/1.73 m(2), followed for a median of 6.6 years. The main predictor was self-reported prior contact with a nephrologist at study enrollment. Outcomes evaluated included CKD progression (a parts per thousand yen 50 % eGFR loss or end-stage renal disease), incident CVD, and death. Two-thirds (67 %) of the participants reported prior contact with a nephrologist at study enrollment. They were younger, more likely to be male, non-Hispanic white, and had lower eGFR and higher urine protein (p < 0.05). A subgroup with eGFR 30-aEuro parts per thousand < 60 ml/min/1.73 m(2) and prior contact with a nephrologist were more likely to receive pharmacologic treatment for CKD-related complications and to report angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ACEi/ARB) use. After propensity score matching (for reporting prior contact with a nephrologist vs. not) and adjusting for demographic and clinical variables, prior contact with a nephrologist was not significantly associated with CKD progression, incident CVD or death (p > 0.05). One-third of CRIC participants had not seen a nephrologist before enrollment, and this prior contact was subject to age, sex, and ethnic-related disparities. While prior nephrology care was associated with more frequent treatment of CKD complications and use of ACEi/ARB medications, there was neither an association between this care and achievement of guideline-recommended intermediate measures, nor long-term adverse outcomes. C1 [Ricardo, Ana C.] Univ Illinois, Dept Med, Div Nephrol, Chicago, IL 60612 USA. [Roy, Jason A.; Tao, Kaixiang] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Alper, Arnold; Chen, Jing] Tulane Univ, Dept Med, New Orleans, LA 70118 USA. [Drawz, Paul E.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Fink, Jeffrey C.] Univ Maryland, Dept Med, Baltimore, MD 21201 USA. [Hsu, Chi-yuan] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Kusek, John W.] NIDDK, NIH, Bethesda, MD 20892 USA. [Ojo, Akinlolu] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Schreiber, Martin] Cleveland Clin Fdn, Dept Hypertens & Nephrol, Cleveland, OH 44195 USA. [Fischer, Michael J.] Jesse Brown VA Med Ctr, Ctr Innovat Complex Chron Healthcare, Chicago, IL USA. [Fischer, Michael J.] Univ Illinois, Dept Med, Chicago, IL USA. RP Ricardo, AC (reprint author), Univ Illinois, Nephrol Sect, 820 South Wood St,Room 470 M-C 793, Chicago, IL 60612 USA. EM aricar2@uic.edu OI Fink, Jeffrey/0000-0002-5622-5052 FU National Institute of Diabetes and Digestive and Kidney Diseases [U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902]; Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award [NIH/NCATS UL1TR000003]; Johns Hopkins University [UL1 TR-000424]; University of Maryland [GCRC M01 RR-16500]; Clinical and Translational Science Collaborative of Cleveland; National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health [UL1TR000439]; NIH roadmap for Medical Research; Michigan Institute for Clinical and Health Research (MICHR) [UL1TR000433]; University of Illinois at Chicago [CTSA UL1RR029879]; Tulane University Translational Research in Hypertension and Renal Biology [P30GM103337]; Kaiser Permanente NIH/NCRR UCSF-CTSI [UL1 RR-024131]; National Institutes of Diabetes and Digestive and Kidney Diseases [1K23DK094829-01] FX Funding for the CRIC Study was obtained under cooperative agreements from the National Institute of Diabetes and Digestive and Kidney Diseases (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). In addition, this work was supported in part by: the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award NIH/NCATS UL1TR000003, Johns Hopkins University UL1 TR-000424, University of Maryland GCRC M01 RR-16500, Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH roadmap for Medical Research, Michigan Institute for Clinical and Health Research (MICHR) UL1TR000433, University of Illinois at Chicago CTSA UL1RR029879, Tulane University Translational Research in Hypertension and Renal Biology P30GM103337, Kaiser Permanente NIH/NCRR UCSF-CTSI UL1 RR-024131. A.C.R is funded by the National Institutes of Diabetes and Digestive and Kidney Diseases 1K23DK094829-01 Award. NR 36 TC 2 Z9 2 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JAN PY 2016 VL 31 IS 1 BP 22 EP 29 DI 10.1007/s11606-015-3452-x PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DA1FB UT WOS:000367540600009 PM 26138006 ER PT J AU Haas, JS Sprague, BL Klabunde, CN Tosteson, ANA Chen, JS Bitton, A Beaber, EF Onega, T Kim, JJ MacLean, CD Harris, K Yamartino, P Howe, K Pearson, L Feldman, S Brawarsky, P Schapira, MM AF Haas, Jennifer S. Sprague, Brian L. Klabunde, Carrie N. Tosteson, Anna N. A. Chen, Jane S. Bitton, Asaf Beaber, Elisabeth F. Onega, Tracy Kim, Jane J. MacLean, Charles D. Harris, Kimberly Yamartino, Phillip Howe, Kathleen Pearson, Loretta Feldman, Sarah Brawarsky, Phyllis Schapira, Marilyn M. CA PROSPR Population-Based Res Optimi TI Provider Attitudes and Screening Practices Following Changes in Breast and Cervical Cancer Screening Guidelines SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE breast cancer screening; cervical cancer screening; provider practice patterns; primary care; clinical practice guidelines ID PRIMARY-CARE-PHYSICIANS; SERVICES TASK-FORCE; UNITED-STATES; MAMMOGRAPHY; RECOMMENDATIONS; CONSISTENT; ADHERENCE; SOCIETY; MODEL AB Changes to national guidelines for breast and cervical cancer screening have created confusion and controversy for women and their primary care providers. To characterize women's primary health care provider attitudes towards screening and changes in practice in response to recent revisions in guidelines for breast and cervical cancer screening. In 2014, we distributed a confidential web and mail survey to 668 women's health care providers affiliated with the four clinical care networks participating in the three PROSPR (Population-based Research Optimizing Screening through Personalized Regimens) consortium breast cancer research centers (385 respondents; response rate 57.6 %). We assessed self-reported attitudes toward breast and cervical cancer screening, as well as practice changes in response to the most recent revisions of the U.S. Preventive Services Task Force (USPSTF) recommendations. The majority of providers believed that mammography screening was effective for reducing cancer mortality among women ages 40-74 years, and that Papanicolaou (Pap) testing was very effective for women ages 21-64 years. While the USPSTF breast and cervical cancer screening recommendations were widely perceived by the respondents as influential, 75.7 and 41.2 % of providers (for mammography and cervical cancer screening, respectively) reported screening practices in excess of those recommended by USPSTF. Provider-reported barriers to concordance with guideline recommendations included: patient concerns (74 and 36 % for breast and cervical, respectively), provider disagreement with the recommendations (50 and 14 %), health system measurement of a provider's screening practices that use conflicting measurement criteria (40 and 21 %), concern about malpractice risk (33 and 11 %), and lack of time to discuss the benefits and harms with their patients (17 and 8 %). Primary care providers do not consistently follow recent USPSTF breast and cervical cancer screening recommendations, despite noting that these guidelines are influential. C1 [Haas, Jennifer S.; Chen, Jane S.; Bitton, Asaf; Harris, Kimberly; Feldman, Sarah; Brawarsky, Phyllis] Brigham & Womens Hosp, Boston, MA 02120 USA. [Haas, Jennifer S.; Bitton, Asaf; Feldman, Sarah] Harvard Univ, Sch Med, Boston, MA USA. [Sprague, Brian L.; MacLean, Charles D.; Howe, Kathleen] Univ Vermont, Burlington, VT USA. [Tosteson, Anna N. A.; Onega, Tracy; Pearson, Loretta] Geisel Sch Med Dartmouth, Lebanon, NH USA. [Tosteson, Anna N. A.; Onega, Tracy; Pearson, Loretta] Norris Cotton Canc Ctr, Lebanon, NH USA. [Klabunde, Carrie N.] NIH, Off Dis Prevent, Off Director, Bethesda, MD 20892 USA. [Beaber, Elisabeth F.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Kim, Jane J.] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Yamartino, Phillip; Schapira, Marilyn M.] Univ Penn, Philadelphia, PA 19104 USA. [Yamartino, Phillip; Schapira, Marilyn M.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Haas, Jennifer S.] Brigham & Womens Hosp, Div Gen Med & Primary Care, Boston, MA 02120 USA. RP Haas, JS (reprint author), Brigham & Womens Hosp, Div Gen Med & Primary Care, 1620 Tremont St, Boston, MA 02120 USA. EM jhaas@partners.org FU National Cancer Institute-funded consortium, Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) [U54 CA163307, U54 CA 163313, U54 CA163303, U01CA163304, U54CA164336] FX We appreciate the input of Alan Waxman, MD, on the development of the survey. This study was conducted as part of the National Cancer Institute-funded consortium, Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) (grant numbers U54 CA163307, U54 CA 163313, U54 CA163303, U01CA163304, U54CA164336). A list of PROSPR investigators and contributing research staff is provided at: http://healthcaredelivery.cancer.gov/prospr/ NR 27 TC 6 Z9 6 U1 4 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JAN PY 2016 VL 31 IS 1 BP 52 EP 59 DI 10.1007/s11606-015-3449-5 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DA1FB UT WOS:000367540600013 PM 26129780 ER PT J AU Oni-Orisan, A Edin, ML Lee, JA Wells, MA Christensen, ES Vendrov, KC Lih, FB Tomer, KB Bai, X Taylor, JM Stouffer, GA Zeldin, DC Lee, CR AF Oni-Orisan, Akinyemi Edin, Matthew L. Lee, John Andrew Wells, Michael A. Christensen, Erin S. Vendrov, Kimberly C. Lih, Fred B. Tomer, Kenneth B. Bai, Xue Taylor, Joan M. Stouffer, George A. Zeldin, Darryl C. Lee, Craig R. TI Cytochrome P450-derived epoxyeicosatrienoic acids and coronary artery disease in humans: a targeted metabolomics study SO JOURNAL OF LIPID RESEARCH LA English DT Article DE arachidonic acid; atherosclerosis; eicosanoids; heart; inflammation; pharmacometabolomics; precision medicine ID SOLUBLE EPOXIDE HYDROLASE; ARACHIDONIC-ACID; HEART-DISEASE; ATHEROSCLEROSIS RISK; IN-VIVO; EICOSANOIDS; METABOLISM; EXPRESSION; INFLAMMATION; EPOXYGENASES AB Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) exhibit potent cardiovascular protective effects in preclinical models, and promoting the effects of EETs has emerged as a potential therapeutic strategy for coronary artery disease (CAD). The relationship between circulating LET levels and CAD extent in humans, however, remains unknown. A panel of free (unesterified) plasma eicosanoid metabolites was quantified in 162 patients referred for coronary angiography, and associations with extent of CAD [no apparent CAD (N = 39), nonobstructive CAD (N = 51), and obstructive CAD (N = 72)] were evaluated. A significant relationship between free LET levels and CAD extent was observed (P = 0.003) such that the presence of obstructive CAD was associated with lower circulating LET levels. This relationship was confirmed in multiple regression analysis where CAD extent was inversely and significantly associated with EET levels (P = 0.013), and with a biomarker of EET biosynthesis (P < 0.001), independent of clinical and demographic factors. Furthermore, quantitative enrichment analysis revealed that these associations were the most pronounced compared with other eicosanoid metabolism pathways. Collectively, these findings suggest that the presence of obstructive CAD is associated with lower LET metabolite levels secondary to suppressed LET biosynthesis. Novel strategies that promote the effects of EETs may have therapeutic promise for patients with obstructive CAD. C1 [Oni-Orisan, Akinyemi; Lee, John Andrew; Wells, Michael A.; Christensen, Erin S.; Vendrov, Kimberly C.; Lee, Craig R.] Univ N Carolina, Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC 27599 USA. [Oni-Orisan, Akinyemi; Lee, Craig R.] Univ N Carolina, Ctr Pharmacogen & Individualized Therapy, Sch Med, Chapel Hill, NC USA. [Taylor, Joan M.; Stouffer, George A.; Lee, Craig R.] Univ N Carolina, McAllister Heart Inst, Sch Med, Chapel Hill, NC USA. [Bai, Xue; Taylor, Joan M.] Univ N Carolina, Dept Pathol & Lab Med, Sch Med, Chapel Hill, NC USA. [Stouffer, George A.] Univ N Carolina, Div Cardiol, Sch Med, Chapel Hill, NC USA. [Edin, Matthew L.; Lih, Fred B.; Tomer, Kenneth B.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Lee, CR (reprint author), Univ N Carolina, Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC 27599 USA. EM craig_lee@unc.edu OI Lee, John Andrew/0000-0002-1914-7614; Lee, Craig/0000-0003-3595-5301 FU University of North Carolina at Chapel Hill Royster Society of Fellows Chancellor's Fellowship; American Heart Association [13PRE16470017]; National Institutes of Health/National Institute of Environmental Health Science [Z01 ES025034] FX This work was supported by a University of North Carolina at Chapel Hill Royster Society of Fellows Chancellor's Fellowship and an American Heart Association Predoctoral Fellowship (13PRE16470017; A.O-O.), as well as funds from the Intramural Research Program of the National Institutes of Health/National Institute of Environmental Health Science (Z01 ES025034; D.C.Z). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 50 TC 5 Z9 5 U1 1 U2 12 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD JAN PY 2016 VL 57 IS 1 BP 109 EP 119 DI 10.1194/jlr.M061697 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DA2DT UT WOS:000367606200012 PM 26555503 ER PT J AU Schiffman, M Wentzensen, N AF Schiffman, Mark Wentzensen, Nicolas TI A Suggested Approach to Simplify and Improve Cervical Screening in the United States SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Editorial Material ID HUMAN-PAPILLOMAVIRUS VACCINATION; RISK HUMAN-PAPILLOMAVIRUS; ATYPICAL SQUAMOUS-CELLS; OF-AMERICAN-PATHOLOGISTS; NEOPLASIA GRADE 3; INTRAEPITHELIAL NEOPLASIA; UNDETERMINED SIGNIFICANCE; ABSOLUTE RISK; 5-YEAR RISKS; CANCER PRECURSORS AB Cervical cancer prevention strategies in the United States have become complicated and even controversial, despite advanced understanding of carcinogenic human papillomavirus (HPV) infection as the necessary causal agent. Twenty years ago, etiologic and methodologic studies had already yielded 2 powerful preventive approaches. There are excellent vaccines to prevent the most carcinogenic types of HPV infection; reduced HPV endemicity will ultimately prevent a large fraction of cervical precancer and cancers. For prevention of cervical cancer in the interim, sensitive HPV tests that target women at risk of cancer, by detection of the DNA/RNA of approximately a dozen carcinogenic HPV types, permit early diagnosis and treatment of precancers. Although HPV vaccines and tests have continued to improve, implementation of these new HPV-based prevention methods has been relatively slow in the United States and in most places worldwide. Increasing vaccination rates is the clearest and most vital long-term priority. But, for decades to come, screening will also be important. To promote useful discussion, this commentary will raise some current critical issues in simplifying and speeding the rational introduction of HPV molecular methods into US cervical screening. C1 [Schiffman, Mark; Wentzensen, Nicolas] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. RP Schiffman, M (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Room 6E544,9609 Med Ctr Dr, Rockville, MD 20850 USA. EM schiffmm@mail.nih.gov FU Intramural NIH HHS [Z01 CP010124-12] NR 63 TC 7 Z9 7 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1089-2591 EI 1526-0976 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD JAN PY 2016 VL 20 IS 1 BP 1 EP 7 DI 10.1097/LGT.0000000000000170 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DA2AJ UT WOS:000367597400001 PM 26704326 ER PT J AU Zhang, JJ Li, DL Lang, LX Zhu, ZH Wang, L Wu, PL Niu, G Li, F Chen, XY AF Zhang, Jingjing Li, Deling Lang, Lixin Zhu, Zhaohui Wang, Ling Wu, Peilin Niu, Gang Li, Fang Chen, Xiaoyuan TI Ga-68-NOTA-Aca-BBN(7-14) PET/CT in Healthy Volunteers and Glioma Patients SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE BBN peptide; gastrin-releasing peptide receptor (GRPR); Ga-68-BBN; PET/CT; glioma ID BOMBESIN/GASTRIN-RELEASING PEPTIDE; RECEPTOR-EXPRESSING MALIGNANCIES; IN-VIVO EVALUATION; PROSTATE-CANCER; RADIATION-DOSIMETRY; BREAST-CANCER; MOUSE MODEL; ANALOGS; ANTAGONIST; TUMORS AB This work was designed to study the safety, biodistribution, and radiation dosimetry of a gastrin-releasing peptide receptor (GRPR)-targeting, Ga-68-labeled bombesin (BBN) peptide derivative PET tracer, NOTA-Aca-BBN(7-14) (denoted as Ga-68-BBN) in healthy volunteers and to assess the level of receptor expression in glioma patients. Methods: Four healthy volunteers (2 male and 2 female) underwent whole-body PET/CT at multiple time points after a bolus injection of Ga-68-BBN (111 +/- 148 MBq). Regions of interest were drawn manually over major organs, and time-activity curves were obtained. Dosimetry was calculated using the OLINDA/EXM software. Twelve patients with glioma diagnosed by contrast-enhanced MRI underwent PET/CT at 30-45 min after Ga-68-BBN injection. Within 1 wk afterward, the tumor was surgically removed and immunohistochemical staining of tumor samples against GRPR was performed and correlated with the PET/CT results. Results: Ga-68-BBN was well tolerated in all healthy volunteers, with no adverse symptoms being noticed or reported. Ga-68-BBN cleared rapidly from the circulation and was excreted mainly through the kidneys and urinary tract. The total effective dose equivalent and effective dose were 0.0335 +/- 0.0079 and 0.0276 +/- 0.0066 mSv/MBq, respectively. In glioma patients, all MRI-identified lesions showed high signal intensity on Ga-68-BBN PET/CT. SUVmax and SUVmean were 2.08 +/- 0.58 and 1.32 +/- 0.37, respectively. With normal brain tissue as background, tumor-to-background ratios were 24.0 +/- 8.85 and 13.4 +/- 4.54 based on SUVmax and SUVmean, respectively. The immunohistochemical staining confirmed a positive correlation between SUV and GRPR expression level (r(2) = 0.71, P < 0.001). Conclusion: Ga-68-BBN is a PET tracer with favorable pharmacokinetics and a favorable dosimetry profile. It has the potential to evaluate GRPR expression in glioma patients and guide GRPR-targeted therapy Of glioma. C1 [Zhang, Jingjing; Zhu, Zhaohui; Wang, Ling; Wu, Peilin; Li, Fang] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Nucl Med, Beijing 100730, Peoples R China. [Zhang, Jingjing; Zhu, Zhaohui; Wang, Ling; Wu, Peilin; Li, Fang] Peking Union Med Coll, Beijing 100021, Peoples R China. [Zhang, Jingjing; Lang, Lixin; Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD USA. [Li, Deling] Capital Med Univ, Beijing Tiantan Hosp, Dept Neurosurg, Beijing, Peoples R China. RP Li, F (reprint author), Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Nucl Med, Beijing 100730, Peoples R China. EM lifang@pumch.cn; shawn.chen@nih.gov FU Intramural Research Program of National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. This work was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. No potential conflict of interest relevant to this article was reported. NR 48 TC 2 Z9 2 U1 3 U2 6 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD JAN PY 2016 VL 57 IS 1 BP 9 EP 14 DI 10.2967/jnumed.115.165316 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DA5SL UT WOS:000367862700004 PM 26449838 ER PT J AU Rosenthal, EL Warram, JM de Boer, E Basilion, JP Biel, MA Bogyo, M Bouvet, M Brigman, BE Colson, YL DeMeester, SR Gurtner, GC Ishizawa, T Jacobs, PM Keereweer, S Liao, JC Nguyen, QT Olson, JM Paulsen, KD Rieves, D Sumer, BD Tweedle, MF Vahrmeijer, AL Weichert, JP Wilson, BC Zenn, MR Zinn, KR van Dam, GM AF Rosenthal, Eben L. Warram, Jason M. de Boer, Esther Basilion, James P. Biel, Merrill A. Bogyo, Matthew Bouvet, Michael Brigman, Brian E. Colson, Yolonda L. DeMeester, Steven R. Gurtner, Geoffrey C. Ishizawa, Takeaki Jacobs, Paula M. Keereweer, Stijn Liao, Joseph C. Nguyen, Quyen T. Olson, James M. Paulsen, Keith D. Rieves, Dwaine Sumer, Baran D. Tweedle, Michael F. Vahrmeijer, Alexander L. Weichert, Jamey P. Wilson, Brian C. Zenn, Michael R. Zinn, Kurt R. van Dam, Gooitzen M. CA ISIGS TI Successful Translation of Fluorescence Navigation During Oncologic Surgery: A Consensus Report SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE fluorescence-guided surgery; consensus report; regulatory guidance; ISIGS ID FROZEN-SECTION; 5-AMINOLEVULINIC ACID; DRUG DEVELOPMENT; BREAST-CANCER; RESECTION; HEAD; NECK; XENOGRAFTS; ANTIBODIES; MARGINS AB Navigation with fluorescence guidance has emerged in the last decade as a promising strategy to improve the efficacy of oncologic surgery. To achieve routine clinical use, the onus is on the surgical community to objectively assess the value of this technique. This assessment may facilitate both Food and Drug Administration approval of new optical imaging agents and reimbursement for the imaging procedures. It is critical to characterize fluorescence-guided procedural benefits over existing practices and to elucidate both the costs and the safety risks. This report is the result of a meeting of the International Society of Image Guided Surgery (www.isigs.org) on February 6, 2015, in Miami, Florida, and reflects a consensus of the participants' opinions. Our objective was to critically evaluate the imaging platform technology and optical imaging agents and to make recommendations for successful clinical trial development of this highly promising approach in oncologic surgery. C1 [Rosenthal, Eben L.] Stanford Univ, Dept Otolaryngol, Stanford, CA 94305 USA. [Warram, Jason M.; de Boer, Esther] Univ Alabama Birmingham, Dept Otolaryngol, Div Otolaryngol, Birmingham, AL USA. [Warram, Jason M.; Zinn, Kurt R.] Univ Alabama Birmingham, Dept Radiol, Birmingham, AL USA. [de Boer, Esther] Univ Groningen, Univ Med Ctr Groningen, Dept Surg, Groningen, Netherlands. [Basilion, James P.] Case Western Reserve Univ, Dept Radiol, NFCR Ctr Mol Imaging, Case Ctr Imaging Res, Cleveland, OH 44106 USA. [Biel, Merrill A.] Univ Minnesota, Dept Otolaryngol Head & Neck Surg, Minneapolis, MN USA. [Bogyo, Matthew] Stanford Sch Med, Dept Pathol, Stanford, CA USA. [Bogyo, Matthew] Stanford Sch Med, Dept Canc Biol Program, Stanford, CA USA. [Bouvet, Michael] Univ Calif San Diego, Dept Surg, La Jolla, CA 92093 USA. [Brigman, Brian E.] Duke Univ, Med Ctr, Dept Surg, Div Orthopaed Surg, Durham, NC 27710 USA. [Colson, Yolonda L.] Brigham & Womens Hosp, Div Thorac Dis, Boston, MA 02115 USA. [DeMeester, Steven R.] Univ So Calif, Keck Sch Med, Dept Surg, Los Angeles, CA 90033 USA. [Gurtner, Geoffrey C.] Stanford Univ, Sch Med, Div Plast & Reconstruct Surg, Hagey Lab Pediat Regenerat Med,Dept Surg, Stanford, CA 94305 USA. [Ishizawa, Takeaki] Univ Tokyo, Grad Sch Med, Dept Surg, Artificial Organ & Transplantat Surg Div, Tokyo, Japan. [Jacobs, Paula M.] NCI, Canc Imaging Program, DCTD, Bethesda, MD 20892 USA. [Keereweer, Stijn] Erasmus MC, Dept Otorhinolaryngol Head & Neck Surg, Rotterdam, Netherlands. [Liao, Joseph C.] Stanford Univ, Sch Med, Dept Urol, Stanford, CA 94305 USA. [Liao, Joseph C.] Stanford Univ, Sch Med, BioX Program, Stanford, CA 94305 USA. [Nguyen, Quyen T.] Univ Calif San Diego, Div Head & Neck Surg, San Diego, CA 92103 USA. [Olson, James M.] Fred Hutchinson Canc Res Ctr, Clin Res Div, Seattle, WA 98104 USA. [Olson, James M.] Seattle Childrens Hosp & Reg Med Ctr, Seattle, WA USA. [Paulsen, Keith D.] Dartmouth Coll, Geisel Sch Med, Dept Diagnost Radiol, Hanover, NH 03755 USA. [Rieves, Dwaine] NDA Partners LLC, Washington, DC USA. [Sumer, Baran D.] Univ Texas SW Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dept Otolaryngol, Dallas, TX 75390 USA. [Tweedle, Michael F.] Ohio State Univ, Dept Radiol, Wright Ctr Innovat Biomed Imaging, Columbus, OH 43210 USA. [Vahrmeijer, Alexander L.] Univ Med Ctr, Dept Surg, Leiden, Netherlands. [Weichert, Jamey P.] Univ Wisconsin, Dept Radiol, Madison, WI 53706 USA. [Wilson, Brian C.] UHN, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Wilson, Brian C.] Univ Toronto, Med Biophys, Toronto, ON, Canada. [Zenn, Michael R.] Duke Univ, Med Ctr, Plast & Reconstruct Surg, Durham, NC USA. [van Dam, Gooitzen M.] Univ Groningen, Univ Med Ctr Groningen, Dept Surg, Nucl Med & Mol Imaging & Intens Care, NL-9700 AB Groningen, Netherlands. RP Rosenthal, EL (reprint author), Stanford Canc Ctr, 875 Blake Wilbur Dr, Stanford, CA 94305 USA. EM elr@stanford.edu OI Zinn, Kurt/0000-0001-7463-4741 FU NCI NIH HHS [P30 CA013148, R01 CA114567, R01 CA135491] NR 20 TC 7 Z9 7 U1 2 U2 8 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD JAN PY 2016 VL 57 IS 1 BP 144 EP 150 DI 10.2967/jnumed.115.158915 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DA5SL UT WOS:000367862700025 PM 26449839 ER PT J AU Mumford, SL Browne, RW Schliep, KC Schmelzer, J Plowden, TC Michels, KA Sjaarda, LA Zarek, SM Perkins, NJ Messer, LC Radin, RG Wactawski-Wende, J Schisterman, EF AF Mumford, Sunni L. Browne, Richard W. Schliep, Karen C. Schmelzer, Jonathan Plowden, Torie C. Michels, Kara A. Sjaarda, Lindsey A. Zarek, Shvetha M. Perkins, Neil J. Messer, Lynne C. Radin, Rose G. Wactawski-Wende, Jean Schisterman, Enrique F. TI Serum Antioxidants Are Associated with Serum Reproductive Hormones and Ovulation among Healthy Women SO JOURNAL OF NUTRITION LA English DT Article DE antioxidants; estrogen; ovulation; progesterone; vitamins ID MARGINAL STRUCTURAL MODELS; OXIDATIVE STRESS; ALPHA-TOCOPHEROL; MENSTRUAL-CYCLE; ASCORBIC-ACID; PREMENOPAUSAL WOMEN; GAMMA-TOCOPHEROL; VITAMIN-E; IMMUNOHISTOCHEMICAL LOCALIZATION; MOLECULAR-MECHANISMS AB Background: Evidence is growing that the equilibrium between reactive oxygen species and antioxidants plays a vital role in women's reproductive health. Objective: The objective of this study was to evaluate variations in serum antioxidant concentrations across the menstrual cycle and associations between antioxidants and reproductive hormones and anovulation among healthy women. Methods: The BioCycle Study, a prospective cohort, followed 259 women aged 18-44 y for up to 2 menstrual cycles. Serum fat-soluble vitamin and micronutrient (alpha-tocopherol, gamma-tocopherol, retinol, lutein, lycopene, and 3-carotene), ascorbic acid, and reproductive hormone concentrations were measured 5-8 times/cycle. We used weighted linear mixed models to assess associations between antioxidants and hormone concentrations, after adjustment for age, race, body mass index, parity, sleep, pain medication use, total energy intake, concurrent hormones, serum cholesterol, F2-isoprostanes, and other antioxidants. Generalized linear models were used to identify associations with anovulation. Results: Serum antioxidant concentrations varied across the menstrual cycle. Retinol and a-tocopherol were associated with higher estradiol [RR: 1.00 pg/mL (95% Cl: 0.67, 1.34 pg/mL); RR: 0.02 pg/mL (95% Cl: 0.003, 0.03 pg/mL), respectively] and testosterone [RR: 0.61 ng/dL (95% Cl: 0.44, 0.78 ng/dL); RR: 0.01 ng/dL (95% Cl: 0.001, 0.01 ng/dL), respectively]. Ascorbic acid was associated with higher progesterone (RR: 0.15 ng/mL; 95% Cl: 0.05, 0.25 ng/mL) and with lower follicle-stimulating hormone (RR: 0.06 mIU/mL; 95% Cl: 0.09, 0.03 mIU/mL). The ratio of CI- to y-tocopherol was associated with an increased risk of anovulation (RR: 1.03; 95% Cl: 1.01, 1.06). Conclusions: These findings shed new light on the intricate associations between serum antioxidants and endogenous hormones in healthy premenopausal women and support the hypothesis that concentrations of serum vitamins affect steroidogenesis even after adjustment for oxidative stress. C1 [Mumford, Sunni L.; Schliep, Karen C.; Plowden, Torie C.; Michels, Kara A.; Sjaarda, Lindsey A.; Zarek, Shvetha M.; Perkins, Neil J.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Rockville, MD 20892 USA. [Browne, Richard W.] SUNY Buffalo, Dept Biotech, Buffalo, NY 14260 USA. [Browne, Richard W.] SUNY Buffalo, Clin Sci Lab, Buffalo, NY 14260 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Epidemiol & Environm, Buffalo, NY 14260 USA. [Schmelzer, Jonathan] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Epidemiol & Biostat, Washington, DC USA. [Plowden, Torie C.; Zarek, Shvetha M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. [Messer, Lynne C.] Portland State Univ, Sch Community Hlth, Portland, OR 97207 USA. RP Mumford, SL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Rockville, MD 20892 USA. EM mumfords@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Sjaarda, Lindsey/0000-0003-0539-8110; Michels, Kara/0000-0003-2431-2079; Schisterman, Enrique/0000-0003-3757-641X FU NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358] FX Supported by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development, contracts N01-HD-3-3355, N01-HD-3-3356, and N01-HD-3-3358. NR 53 TC 2 Z9 2 U1 0 U2 2 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD JAN PY 2016 VL 146 IS 1 BP 98 EP 106 DI 10.3945/jn.115.217620 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DA3MF UT WOS:000367701100015 PM 26581679 ER PT J AU Haskali, MB Telu, S Lee, YS Morse, CL Lu, SY Pike, VW AF Haskali, Mohammad B. Telu, Sanjay Lee, Yong-Sok Morse, Cheryl L. Lu, Shuiyu Pike, Victor W. TI An Investigation of (Diacetoxyiodo)arenes as Precursors for Preparing No-Carrier-Added [F-18]Fluoroarenes from Cyclotron-Produced [F-18]Fluoride Ion SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID DIARYLIODONIUM-SALTS; IODONIUM SALTS; IODOARENES; OXIDANT; RADIOFLUORINATION; SUCCINIMIDYL; TOSYLATES; YLIDES; ACID AB Treatment of (diacetoxyiodo)arenes (1a-1u) with cyclotron-produced [F-18]fluoride ion rapidly affords no-carrier-added [V-18]-fluoroarenes (2a-2u) in useful yields and constitutes a new method for converting substituted iodoarenes into substituted [F-18]fluoroarenes in just two steps. C1 [Haskali, Mohammad B.; Telu, Sanjay; Morse, Cheryl L.; Lu, Shuiyu; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Lee, Yong-Sok] NIH, Ctr Mol Modeling, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Pike, VW (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Room B3 C346A,10 Ctr Dr, Bethesda, MD 20892 USA. EM pikev@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (NIMH) [ZIA-MH00279, ZIA-CT000265-19] FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIMH, ZIA-MH002793; CIT, ZIA-CT000265-19). The quantum chemical study utilized PC/linux clusters at the Center for Molecular Modeling of the National Institutes of Health (http://cit.nih. gov). NR 29 TC 2 Z9 2 U1 6 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD JAN 1 PY 2016 VL 81 IS 1 BP 297 EP 302 DI 10.1021/acs.joc.5b02332 PG 6 WC Chemistry, Organic SC Chemistry GA DA3MN UT WOS:000367701900033 PM 26641128 ER PT J AU Kume, K Ishida, K Ikeda, M Takemoto, K Shimura, T Young, L Nishizuka, SS AF Kume, Kohei Ishida, Kazushige Ikeda, Miyuki Takemoto, Kazuhiro Shimura, Tsutomu Young, Lynn Nishizuka, Satoshi S. TI Systematic Protein Level Regulation via Degradation Machinery Induced by Genotoxic Drugs SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE protein dynamics; cancer cell; genotoxic drug; reverse-phase protein microarray (RPPA); correlation distance (dCor) ID UBIQUITIN-PROTEASOME SYSTEM; DNA-DAMAGE; LYSATE MICROARRAYS; HUMAN-CELLS; MOLECULAR PHARMACOLOGY; ANTICANCER DRUGS; EXPRESSION DATA; CANCER-THERAPY; GENE; PROTEOMICS AB In this study we monitored protein dynamics in response to cisplatin, 5-fluorouracil, and irinotecan with different concentrations and administration modes using "reverse-phase" protein arrays (RPPAs) in order to gain comprehensive insight into the protein dynamics induced by genotoxic drugs. Among 666 protein time-courses, 38% exhibited an increasing trend, 32% exhibited a steady decrease, and 30% fluctuated within 24 h after drug exposure. We analyzed almost 12,000 time-course pairs of protein levels based on the geometrical similarity by correlation distance (dCor). Twenty-two percent of the pairs showed dCor > 0.8, which indicates that each protein of the pair had similar dynamics. These trends were disrupted by a proteasome inhibitor, MG132, suggesting that the protein degradation system was activated in response to the drugs. Among the pairs with high dCor, the average dCor of pairs with apoptosis-related protein was significantly higher than those without, indicating that regulation of protein levels was induced by the drugs. These results suggest that the levels of numerous functionally distinct proteins may be regulated by common degradation machinery induced by genotoxic drugs. C1 [Kume, Kohei; Ishida, Kazushige; Ikeda, Miyuki; Nishizuka, Satoshi S.] Iwate Med Univ, Sch Med, Mol Therapeut Lab, Morioka, Iwate 0208505, Japan. [Kume, Kohei; Ishida, Kazushige; Ikeda, Miyuki; Nishizuka, Satoshi S.] Iwate Med Univ, Sch Med, Dept Surg, Morioka, Iwate 0208505, Japan. [Kume, Kohei; Nishizuka, Satoshi S.] Iwate Med Univ, Med Innovat Adv Sci & Technol Program MIAST, Morioka, Iwate 0208505, Japan. [Kume, Kohei; Nishizuka, Satoshi S.] Iwate Med Univ, Inst Biomed Sci, Yahaba, Iwate 0208505, Japan. [Nishizuka, Satoshi S.] Iwate Med Univ, Sch Dent, Dept Surg, Morioka, Iwate 0208505, Japan. [Takemoto, Kazuhiro] Kyushu Inst Technol, Dept Biosci & Bioinformat, Fukuoka 8208502, Japan. [Shimura, Tsutomu] Natl Inst Publ Hlth, Dept Environm Hlth, Wako, Saitama 351097, Japan. [Young, Lynn] NIH, Natl Inst Hlth NIH Lib, Div Lib Serv, Off Res Serv, Bethesda, MD 20892 USA. RP Nishizuka, SS (reprint author), Iwate Med Univ, Sch Med, Mol Therapeut Lab, Morioka, Iwate 0208505, Japan. EM snishizu@iwate-med.ac.jp FU Keiryokai Research Foundation [101]; KAKENHI [21591676]; MIAST (Medical Innovation by Advanced Science and Technology) project of the Ministry of Education, Culture, Sports, Science and Technology, Japan; Japan Prize Foundation FX This work was supported by a Keiryokai Research Foundation (101) grant to S.S.N.; a KAKENHI (21591676) Grant-in-Aid for Scientific Research (C) to S.S.N.; the MIAST (Medical Innovation by Advanced Science and Technology) project of the Ministry of Education, Culture, Sports, Science and Technology, Japan, to K.K. and S.S.N.; and a research fund from The Japan Prize Foundation to K.K. We thank Hirotoshi Nakajirna of Iwate Prefectural University for artwork. We would like to thank Cindy Clark, NIH Library Editing Service, for reviewing the manuscript. NR 58 TC 1 Z9 1 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD JAN PY 2016 VL 15 IS 1 BP 205 EP 215 DI 10.1021/acs.jproteome.5b00759 PG 11 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DA3OC UT WOS:000367706000016 PM 26625007 ER PT J AU Dumitriu, B Ito, S Feng, XM Stephens, N Yunce, M Kajigaya, S Melenhorst, JJ Rios, O Scheinberg, P Chinian, F Keyvanfar, K Battiwalla, M Wu, CO Maric, I Xi, LQ Raffeld, M Muranski, P Townsley, DM Young, NS Barrett, AJ Scheinberg, P AF Dumitriu, Bogdan Ito, Sawa Feng, Xingmin Stephens, Nicole Yunce, Muharrem Kajigaya, Sachiko Melenhorst, Joseph J. Rios, Olga Scheinberg, Priscila Chinian, Fariba Keyvanfar, Keyvan Battiwalla, Minoo Wu, Colin O. Maric, Irina Xi, Liqiang Raffeld, Mark Muranski, Pawel Townsley, Danielle M. Young, Neal S. Barrett, Austin J. Scheinberg, Phillip TI Alemtuzumab in T-cell large granular lymphocytic leukaemia: interim results from a single-arm, open-label, phase 2 study SO LANCET HAEMATOLOGY LA English DT Article ID LYMPHOPROLIFERATIVE DISORDERS; MULTIPLE-SCLEROSIS; APLASTIC-ANEMIA; LGL LEUKEMIA; THERAPY; DISEASE; MULTICENTER; EXPRESSION; CAMPATH-1H; MUTATIONS AB Background T-cell large granular lymphocytic leukaemia (T-LGL) is a lymphoproliferative disease that presents with immune-mediated cytopenias and is characterised by clonal expansion of cytotoxic CD3+ CD8+ lymphocytes. Use of methotrexate, ciclosporin, or cyclophosphamide as first therapy improves cytopenias in 50% of patients, but long-term use of these can lead to toxicity. We aimed to explore the activity and safety of alemtuzumab, an anti-CD52 monoclonal antibody, in patients with T-LGL. Methods We did this single-arm, phase 2 trial in consecutively enrolled adults with T-LGL referred to the National Institutes of Health in Bethesda, MD, USA. Alemtuzumab was given intravenously at 10 mg per day for 10 days. The primary endpoint was haematological response at 3 months after infusion. A complete response was defined as normalisation of all affected lineages, and a partial response was defined in neutropenic patients as 100% increase in the absolute neutrophil count to more than 5x10(8) cells per L, and in those with anaemia, as any increase in haemoglobin of 20 g/L or higher observed in at least two serial measurements 1 week apart and sustained for 1 month or longer without exogenous growth factors support or transfusions. Analysis was by intention to treat. We report results from the first stage of this Simon two-stage design trial; enrolment into the second stage is continuing. This study is registered with ClinicalTrials. gov, number NCT00345345. Findings From Oct 1, 2006, to March 1, 2015, we enrolled 25 patients with T-LGL. 14 patients (56%; 95% CI 35-76) had a haematological response at 3 months. Four patients with associated myelodysplastic syndrome and two who had received haemopoietic stem cell transplantation had either no response or were not evaluable, meaning 14 (74% [49-91]) of the 19 patients with classic T-LGL responded. All patients had an infusion reaction (24 [96%] patients grade 1-2, one [4%] patient grade 3), which improved with symptomatic therapy. All patients developed lymphopenia, with 22 (88%) patients having grade 3 or 4 lymphopenia. The other most common grade 3 and 4 adverse events were leukopenia (eight [32%]) and neutropenic infections (five [20%]). Seven patients died; all were non-responders. Interpretation This is the largest and only prospective study of alemtuzumab in patients with T-LGL. The activity reported with a single course of a lymphocytotoxic drug in patients with mainly relapsed and refractory disease suggests that haematological response can be achieved without continued use of oral immunosuppression. C1 [Dumitriu, Bogdan; Ito, Sawa; Feng, Xingmin; Stephens, Nicole; Yunce, Muharrem; Kajigaya, Sachiko; Melenhorst, Joseph J.; Rios, Olga; Scheinberg, Priscila; Chinian, Fariba; Keyvanfar, Keyvan; Battiwalla, Minoo; Muranski, Pawel; Townsley, Danielle M.; Young, Neal S.; Barrett, Austin J.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Wu, Colin O.] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. [Maric, Irina] NCI, Dept Lab Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Xi, Liqiang; Raffeld, Mark] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Scheinberg, Phillip] Hosp Sao Jose, Antonio Ermirio de Moraes Canc Ctr, Clin Hematol, BR-01321001 Sao Paulo, SP, Brazil. [Scheinberg, Phillip] Beneficencia Portuguesa, Sao Paulo, SP, Brazil. RP Scheinberg, P (reprint author), Hosp Sao Jose, BR-01321001 Sao Paulo, SP, Brazil. EM phillip.scheinberg@hospitalsjose.org.br FU National Institutes of Health's National Heart, Lung, and Blood Institute FX We received funding from the Intramural Research Program of the National Institutes of Health's National Heart, Lung, and Blood Institute. NR 32 TC 2 Z9 2 U1 1 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2352-3026 J9 LANCET HAEMATOL JI Lancet Haematol. PD JAN PY 2016 VL 3 IS 1 BP E22 EP E29 DI 10.1016/S2352-3026(15)00227-6 PG 8 WC Hematology SC Hematology GA DA4UT UT WOS:000367797500004 PM 26765645 ER PT J AU Prasad, V Berger, VW AF Prasad, Vinay Berger, Vance W. TI In Reply-Is There a Need for "Bias Police" in Industry-Sponsored Research? SO MAYO CLINIC PROCEEDINGS LA English DT Letter ID TRIALS C1 [Prasad, Vinay] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Berger, Vance W.] Univ Maryland Baltimore Cty, NCI, Rockville, MD USA. RP Prasad, V (reprint author), Oregon Hlth & Sci Univ, Portland, OR 97201 USA. NR 7 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0025-6196 EI 1942-5546 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD JAN PY 2016 VL 91 IS 1 BP 121 EP 121 DI 10.1016/j.mayocp.2015.10.014 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DA3KX UT WOS:000367696700021 PM 26763516 ER PT J AU Yu, DX Moore, SC Matthews, CE Xiang, YB Zhang, XL Gao, YT Zheng, W Shu, XO AF Yu, Danxia Moore, Steven C. Matthews, Charles E. Xiang, Yong-Bing Zhang, Xianglan Gao, Yu-Tang Zheng, Wei Shu, Xiao-Ou TI Plasma metabolomic profiles in association with type 2 diabetes risk and prevalence in Chinese adults SO METABOLOMICS LA English DT Article DE Metabolomics; Type 2 diabetes; Epidemiology; Prospective cohort study; Chinese populations ID DIETARY FATTY-ACIDS; CHAIN AMINO-ACIDS; INSULIN-RESISTANCE; LIFE-STYLE; FOLLOW-UP; MELLITUS; DISEASE; GLUCOSE; COHORT; GENES AB Metabolomic studies have identified several metabolites associated with type 2 diabetes (T2D) in populations of European ancestry. East Asians, a population of particular susceptibility to T2D, were generally not included in previous studies. We examined the associations of plasma metabolites with risk and prevalence of T2D in 976 Chinese men and women (40-74 years of age) who were participants of two prospective cohort studies and had no cardiovascular disease or cancer at baseline. Sixty-eight prevalent and 73 incident T2D cases were included. Non-targeted metabolomics was conducted that detected 689 metabolites with known identities and 690 unknown metabolites. Multivariable logistic and Cox regressions were used to evaluate the associations of standardized metabolites with diabetes risk and prevalence. We identified 36 known metabolites and 10 unknown metabolites associated with prevalent and/or incident T2D at false discovery rate <0.05. The known metabolites are involved in metabolic pathways of glycolysis/gluconeogenesis, branched-chain amino acids, other amino acids, fatty acids, glycerophospholipids, androgen, and bradykinin. Six metabolites showed independent associations with incident T2D: 1,5-anhydroglucitol, mannose, valine, 3-methoxytyrosine, docosapentaenoate (22:5n3), and bradykinin-hydroxy-pro(3). Each standard deviation increase in these metabolites was associated with a 40-150 % change in risk of developing diabetes (30-80 % after further adjustment for glucose). Risk prediction was significantly improved by adding these metabolites in addition to known T2D risk factors, including central obesity and glucose. These findings suggest that hexoses, branched-chain amino acids, and yet to be validated novel plasma metabolites may improve risk prediction and mechanistic understanding of T2D in Chinese populations. C1 [Yu, Danxia; Zhang, Xianglan; Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol,Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA. [Moore, Steven C.; Matthews, Charles E.] Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Xiang, Yong-Bing; Gao, Yu-Tang] Shanghai Jiao Tong Univ, Sch Med, Shanghai Canc Inst, Renji Hosp, Shanghai 200031, Peoples R China. RP Shu, XO (reprint author), Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol,Vanderbilt Epidemiol Ctr, 2525 West End Ave,Suite 600, Nashville, TN 37203 USA. EM xiao-ou.shu@vanderbilt.edu RI Moore, Steven/D-8760-2016; Zheng, Wei/O-3351-2013 OI Moore, Steven/0000-0002-8169-1661; Zheng, Wei/0000-0003-1226-070X FU US National Institutes of Health [R37 CA070867, UM1 CA182910, UM1 CA173640, R01 HL079123, NO2-CP11010-66]; Breast Cancer Research Stamp Fund; Intramural Research Program of the National Cancer Institute, National Institutes of Health FX This work was supported, in part, by the US National Institutes of Health [R37 CA070867 and UM1 CA182910 to Dr. W. Zheng, UM1 CA173640, R01 HL079123 and NO2-CP11010-66 to Dr. X.O. Shu]. This work was also supported, in part, by the Breast Cancer Research Stamp Fund, awarded through competitive peer review and the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 55 TC 0 Z9 0 U1 7 U2 21 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1573-3882 EI 1573-3890 J9 METABOLOMICS JI Metabolomics PD JAN PY 2016 VL 12 IS 1 DI 10.1007/s11306-015-0890-8 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CZ9OJ UT WOS:000367426600003 ER PT J AU Zhang, J Liu, X Yu, WX Zhang, YL Shi, C Ni, SL Liu, QL Li, XW Sun, YJ Zheng, CY Sun, HC AF Zhang, Juan Liu, Xia Yu, Weixian Zhang, Yingli Shi, Ce Ni, Shilei Liu, Qilin Li, Xiangwei Sun, Yingjian Zheng, Changyu Sun, Hongchen TI Effects of human vascular endothelial growth factor on reparative dentin formation SO MOLECULAR MEDICINE REPORTS LA English DT Article DE VEGF; formation of reparative dentin; dental pulp cells; gene therapy; mineralization ID LPS-INDUCED VEGF; MATRIX PROTEIN-1; PULP CELLS; STEM-CELLS; SIALOPROTEIN; ANGIOGENESIS; EXPRESSION; GENE; REVASCULARIZATION; DENTINOGENESIS AB It is a challenge for dentists to save dental pulp in patients with pulp disease without resorting to root canal therapy. Formation of tertiary dentin to maintain pulp vitality is a key odontoblast response to dental pulp injury. Vascular endothelial growth factor (VEGF) is the most potent angiogenic and vasculogenic factor involved in tertiary dentin formation. It was hypothesized that VEGF may be used to treat pulp diseases such as pulpitis. To explore this hypothesis, the first step was to assess whether VEGF affects dental pulp cells to promote reparative dentin formation. In the current study, an AdCMV-hVEGF vector was constructed to deliver hVEGF into dental pulp cells of exfoliated deciduous teeth (hDPCs) in vitro and dental pulp cells in a rat model in vivo. The collected data clearly demonstrated that hVEGF increased alkaline phosphatase and mineralization by enzymatic activity. RT-qPCR data demonstrated that hVEGF significantly increased the expression levels of genes commonly involved in osteogenesis/odontogenesis. Data from the in vivo assays indicated that hVEGF enhanced pulp cell proliferation and neovascularization, and markedly increased formation of reparative dentin in dental pulp. The in vitro and in vivo data suggest that hVEGF may have potential clinical applications, thus may aid in the development of novel treatment strategies for dental pulpitis. C1 [Zhang, Juan; Liu, Xia; Yu, Weixian; Zhang, Yingli; Shi, Ce; Ni, Shilei; Liu, Qilin; Li, Xiangwei; Sun, Hongchen] Jilin Univ, Jilin Hosp Stomatol, Key Lab Tooth Dev & Bone Remodeling, Changchun 130021, Jilin, Peoples R China. [Sun, Yingjian] Jilin Univ, Hosp 2, Dept Ophthalmol, Changchun 130021, Jilin, Peoples R China. [Zheng, Changyu] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Sun, HC (reprint author), Jilin Univ, Jilin Hosp Stomatol, Key Lab Tooth Dev & Bone Remodeling, 1500 Qinghua Rd, Changchun 130021, Jilin, Peoples R China. EM hcsun@mail.jlu.edu.cn FU Science and Technology Development Projects of Jilin Province [20140204018SF]; Jilin Provincial Health Department Research Projects [2012S017]; Fundamental Research Project of the Central Universities [450060491132]; Human Resources and Social Security Development Postdoctoral Research Projects of Jilin Province [20130419431]; National Natural Science Foundation of China [81271111] FX The authors would like to thank Dr Chunlin Qin (Baylor College of Dentistry, Texas A&M University Health Science Center, Dallas, TX, USA) for the donation of the DMP1 and DSP antibodies and Ms. Cindy Clark (NIH Library Editing Service, Bethesda, MD, USA) for reviewing the manuscript. The current study was supported by the Science and Technology Development Projects of Jilin Province (grant no. 20140204018SF), Jilin Provincial Health Department Research Projects (grant no. 2012S017), the Fundamental Research Project of the Central Universities (grant no. 450060491132), the 2013 Human Resources and Social Security Development Postdoctoral Research Projects of Jilin Province (grant no. 20130419431) and the National Natural Science Foundation of China (grant no. 81271111). NR 31 TC 1 Z9 1 U1 3 U2 7 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1791-2997 EI 1791-3004 J9 MOL MED REP JI Mol. Med. Rep. PD JAN PY 2016 VL 13 IS 1 BP 705 EP 712 DI 10.3892/mmr.2015.4608 PN B PG 8 WC Oncology; Medicine, Research & Experimental SC Oncology; Research & Experimental Medicine GA DA5UI UT WOS:000367867700014 PM 26647730 ER PT J AU Joag, VR McKinnon, LR Liu, J Kidane, ST Yudin, MH Nyanga, B Kimwaki, S Besel, KE Obila, JO Huibner, S Oyugi, JO Arthos, J Anzala, O Kimani, J Ostrowski, MA Kaul, R AF Joag, V. R. McKinnon, L. R. Liu, J. Kidane, S. T. Yudin, M. H. Nyanga, B. Kimwaki, S. Besel, K. E. Obila, J. O. Huibner, S. Oyugi, J. O. Arthos, J. Anzala, O. Kimani, J. Ostrowski, M. A. Kaul, R. CA Toronto HIV Res Grp TI Identification of preferential CD4(+) T-cell targets for HIV infection in the cervix SO MUCOSAL IMMUNOLOGY LA English DT Article ID CHLAMYDIA-TRACHOMATIS INFECTION; IMMUNODEFICIENCY-VIRUS TYPE-1; ACUTE SIV INFECTION; SEXUAL TRANSMISSION; MUCOSAL TRANSMISSION; IMMUNE FACTORS; EARLY EVENTS; SUSCEPTIBILITY; INTEGRINS; WOMEN AB A better understanding of the cellular targets of HIV infection in the female genital tract may inform HIV prevention efforts. Proposed correlates of cellular susceptibility include the HIV co-receptor CCR5, peripheral homing integrins, and immune activation. We used a CCR5-tropic pseudovirus to quantify HIV entry into unstimulated endocervical CD4(+) T cells collected by cytobrush. Virus entry was threefold higher into cervix-derived CD4(+) T cells than blood, but was strongly correlated between these two compartments. Cervix-derived CD4(+) T cells expressing CD69, alpha(4)beta(7), or alpha(4)beta(1) were preferential HIV targets; this enhanced susceptibility was strongly correlated with increased CCR5 expression in alpha(4)beta(+)(7) and CD69(+) CD4(+) T cells, and to a lesser extent in alpha(4)beta(+)(1) CD4(+) T cells. Direct binding of gp140 to integrins was not observed, integrin inhibitors had no effect on virus entry, and pseudotypes with an env that preferentially binds a4b7 still demonstrated enhanced entry into alpha(4)beta(+)(1) cells. In summary, a rapid and sensitive HIV entry assay demonstrated enhanced susceptibility of activated endocervical CD4(+) T cells, and those expressing alpha(4 beta 7) or alpha(4 beta 1). This may relate to increased CCR5 expression by these cell subsets, but did not appear to be due to direct interaction of alpha 4 beta(7) or alpha 4 beta(1) with HIV envelope. C1 [Joag, V. R.; Liu, J.; Kidane, S. T.; Ostrowski, M. A.; Kaul, R.] Univ Toronto, Dept Immunol, Toronto, ON, Canada. [McKinnon, L. R.] Univ KwaZulu Natal, Ctr AIDS Program Res South Africa, Durban, South Africa. [McKinnon, L. R.; Huibner, S.; Kaul, R.] Univ Toronto, Dept Med, Toronto, ON, Canada. [Yudin, M. H.; Besel, K. E.] Univ Toronto, St Michaels Hosp, Dept Obstet & Gynecol, Toronto, ON, Canada. [Nyanga, B.; Kimwaki, S.; Oyugi, J. O.; Anzala, O.] Univ Nairobi, Dept Med Microbiol, Nairobi, Kenya. [Obila, J. O.; Anzala, O.] Kenyan AIDS Vaccine Initiat, Nairobi, Kenya. [Oyugi, J. O.; Kimani, J.] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. [Arthos, J.] NIAID, Lab Immune Regulat, NIH, Bethesda, MD 20892 USA. [Ostrowski, M. A.] St Michaels Hosp, Li Ka Shing Knowledge Inst, Toronto, ON M5B 1W8, Canada. [Kaul, R.] Univ Hlth Network, Dept Med, Toronto, ON, Canada. RP Joag, VR (reprint author), Univ Toronto, Dept Immunol, Toronto, ON, Canada. EM vineet.joag@gmail.com; rupert.kaul@utoronto.ca FU Canadian Institutes of Health Research [OCH-131579, THA-11900]; Ontario HIV Treatment Network FX We acknowledge the gracious support of the study participants in Nairobi and the Kenya AIDS Control Project (KACP) staff who contributed to patient care, data management, administration, and laboratory diagnostics. We also thank Sergey Yegorov, Kamnoosh Shahabi, and Connie Kim for helpful discussions and proofreading of this manuscript. We also appreciate the support of Julie Overbaugh and Stephanie Rainwater from the University of Washington for kindly providing HIV plasmid constructs. This study was supported by the Canadian Institutes of Health Research (grant OCH-131579 to R.K.; THA-11900 to M.A.O.; and studentship to V.R.J.) and by the Ontario HIV Treatment Network (salary award to R.K.). NR 45 TC 6 Z9 6 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 EI 1935-3456 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD JAN PY 2016 VL 9 IS 1 BP 1 EP 12 DI 10.1038/mi.2015.28 PG 12 WC Immunology SC Immunology GA DA2VB UT WOS:000367653800001 PM 25872482 ER PT J AU Borthwick, LA Barron, L Hart, KM Vannella, KM Thompson, RW Oland, S Cheever, A Sciurba, J Ramalingam, TR Fisher, AJ Wynn, TA AF Borthwick, L. A. Barron, L. Hart, K. M. Vannella, K. M. Thompson, R. W. Oland, S. Cheever, A. Sciurba, J. Ramalingam, T. R. Fisher, A. J. Wynn, T. A. TI Macrophages are critical to the maintenance of IL-13-dependent lung inflammation and fibrosis SO MUCOSAL IMMUNOLOGY LA English DT Article ID CD11C(+) DENDRITIC CELLS; DUST MITE ALLERGEN; IN-VIVO DEPLETION; SCHISTOSOMA-MANSONI; GRANULOMA-FORMATION; HELMINTH INFECTION; T-CELLS; MONOCYTES; RESPONSES; TH2 AB The roles of macrophages in type 2-driven inflammation and fibrosis remain unclear. Here, using CD11b-diphtheria toxin receptor (DTR) transgenic mice and three models of interleukin 13 (IL-13)-dependent inflammation, fibrosis, and immunity, we show that CD11b(+) F4/80(+) Ly6C(+) macrophages are required for the maintenance of type 2 immunity within affected tissues but not secondary lymphoid organs. Direct depletion of macrophages during the maintenance or resolution phases of secondary Schistosoma mansoni egg-induced granuloma formation caused a profound decrease in inflammation, fibrosis, and type 2 gene expression. Additional studies with CD11c-DTR and CD11b/CD11c-DTR double-transgenic mice suggested that macrophages but not dendritic cells were critical. Mechanistically, macrophage depletion impaired effector CD4(+) T helper type 2 (Th2) cell homing and activation within the inflamed lung. Depletion of CD11b(+) F4/80(+) Ly6C(+) macrophages similarly reduced house dust mite-induced allergic lung inflammation and suppressed IL-13-dependent immunity to the nematode parasite Nippostrongylus brasiliensis. Consequently, therapeutic strategies targeting macrophages offer a novel approach to ameliorate established type 2 inflammatory diseases. C1 [Borthwick, L. A.; Fisher, A. J.] Newcastle Univ, Sch Med, Inst Cellular Med, Tissue Fibrosis & Repair Grp, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Borthwick, L. A.; Barron, L.; Hart, K. M.; Vannella, K. M.; Thompson, R. W.; Oland, S.; Cheever, A.; Sciurba, J.; Ramalingam, T. R.; Wynn, T. A.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Fisher, A. J.] Freeman Rd Hosp, Inst Transplantat, Newcastle Upon Tyne, Tyne & Wear, England. RP Wynn, TA (reprint author), NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM twynn@niaid.nih.gov OI Borthwick, Lee/0000-0003-2885-3382 FU Marie Curie international outgoing fellowship from European Union; NIH/NIAID FX We express our sincere appreciation and thanks to all of our colleagues, past and present, for their guidance and support. L.A.B. is supported by a Marie Curie international outgoing fellowship from the European Union Framework Programme 7. T.A.W. is supported by the Intramural Research Program of the NIH/NIAID. NR 49 TC 13 Z9 13 U1 4 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 EI 1935-3456 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD JAN PY 2016 VL 9 IS 1 BP 38 EP 55 DI 10.1038/mi.2015.34 PG 18 WC Immunology SC Immunology GA DA2VB UT WOS:000367653800004 PM 25921340 ER PT J AU Gorman, J Soto, C Yang, MM Davenport, TM Guttman, M Bailer, RT Chambers, M Chuang, GY DeKosky, BJ Doria-Rose, NA Druz, A Ernandes, MJ Georgiev, IS Jarosinski, MC Joyce, MG Lemmin, TM Leung, S Louder, MK McDaniel, JR Narpala, S Pancera, M Stuckey, J Wu, XL Yang, YP Zhang, BS Zhou, TQ Mullikin, JC Baxa, U Georgiou, G McDermott, AB Bonsignori, M Haynes, BF Moore, PL Morris, L Lee, KK Shapiro, L Mascola, JR Kwong, PD AF Gorman, Jason Soto, Cinque Yang, Max M. Davenport, Thaddeus M. Guttman, Miklos Bailer, Robert T. Chambers, Michael Chuang, Gwo-Yu DeKosky, Brandon J. Doria-Rose, Nicole A. Druz, Aliaksandr Ernandes, Michael J. Georgiev, Ivelin S. Jarosinski, Marissa C. Joyce, M. Gordon Lemmin, Thomas M. Leung, Sherman Louder, Mark K. McDaniel, Jonathan R. Narpala, Sandeep Pancera, Marie Stuckey, Jonathan Wu, Xueling Yang, Yongping Zhang, Baoshan Zhou, Tongqing Mullikin, James C. Baxa, Ulrich Georgiou, George McDermott, Adrian B. Bonsignori, Mattia Haynes, Barton F. Moore, Penny L. Morris, Lynn Lee, Kelly K. Shapiro, Lawrence Mascola, John R. Kwong, Peter D. CA NISC Comparative Sequencing TI Structures of HIV-1 Env V1V2 with broadly neutralizing antibodies reveal commonalities that enable vaccine design SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID B-CELL RECEPTORS; HIV-1-NEUTRALIZING ANTIBODIES; POTENT NEUTRALIZATION; CRYSTAL-STRUCTURE; ENVELOPE PROTEIN; IMMUNOGEN DESIGN; GP120; RECOGNITION; REPERTOIRE; BINDING AB Broadly neutralizing antibodies (bNAbs) against HIV-1 Env V1V2 arise in multiple donors. However, atomic-level interactions had previously been determined only with antibodies from a single donor, thus making commonalities in recognition uncertain. Here we report the cocrystal structure of V1V2 with antibody CH03 from a second donor and model Env interactions of antibody CAP256-VRC26 from a third donor. These V1 V2-directed bNAbs used strand-strand interactions between a protruding antibody loop and a V1V2 strand but differed in their N-glycan recognition. Ontogeny analysis indicated that protruding loops develop early, and glycan interactions mature over time. Altogether, the multidonor information suggested that V1V2-directed bNAbs form an 'extended class', for which we engineered ontogeny-specific antigens: Env trimers with chimeric V1V2s that interacted with inferred ancestor and intermediate antibodies. The ontogeny-based design of vaccine antigens described here may provide a general means for eliciting antibodies of a desired class. C1 [Gorman, Jason; Soto, Cinque; Yang, Max M.; Bailer, Robert T.; Chambers, Michael; Chuang, Gwo-Yu; DeKosky, Brandon J.; Doria-Rose, Nicole A.; Druz, Aliaksandr; Ernandes, Michael J.; Georgiev, Ivelin S.; Jarosinski, Marissa C.; Joyce, M. Gordon; Leung, Sherman; Louder, Mark K.; Narpala, Sandeep; Pancera, Marie; Stuckey, Jonathan; Wu, Xueling; Yang, Yongping; Zhang, Baoshan; Zhou, Tongqing; McDermott, Adrian B.; Shapiro, Lawrence; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Davenport, Thaddeus M.; Guttman, Miklos; Lee, Kelly K.] Univ Washington, Dept Med Chem, Seattle, WA 98195 USA. [DeKosky, Brandon J.; McDaniel, Jonathan R.; Georgiou, George] Univ Texas Austin, Dept Chem Engn, Austin, TX 78712 USA. [Lemmin, Thomas M.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA USA. [Mullikin, James C.; NISC Comparative Sequencing] NHGRI, NIH Intramural Sequencing Ctr NISC, NIH, Bethesda, MD 20892 USA. [Baxa, Ulrich] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, Electron Microscopy Lab, Frederick, MD USA. [Bonsignori, Mattia; Haynes, Barton F.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Moore, Penny L.; Morris, Lynn] Natl Hlth Lab Serv, Natl Inst Communicable Dis, Ctr HIV & STIs, Johannesburg, South Africa. [Moore, Penny L.; Morris, Lynn] Univ Witwatersrand, Fac Hlth Sci, Johannesburg, South Africa. [Moore, Penny L.; Morris, Lynn] Univ KwaZulu Natal, Ctr AIDS Programme Res South Africa CAPRISA, Congella, South Africa. [Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY USA. [Shapiro, Lawrence] Columbia Univ, Dept Syst Biol, New York, NY USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pdkwong@nih.gov RI Zhou, Tongqing/A-6880-2010; OI Zhou, Tongqing/0000-0002-3935-4637; McDaniel, Jonathan/0000-0001-8575-3535; Moore, Penny/0000-0001-8719-4028 FU Intramural Research Program of the Vaccine Research Center, US National Institute of Allergy and Infectious Diseases (NIAID); Division of AIDS, NIAID, NIH [1U01-AI116086-01, R21-AI112389]; Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery [OPP1033102]; IAVI; Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery grant (CHAVI-ID) [UM1 AI100645]; Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E]; US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX We thank members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center, NIH, for discussions and comments on the manuscript, and Weill Cornell Medical College, The Scripps Research Institute, Academic Medical Center and the HIV Vaccine Research and Design team comprising investigators from these three institutions for their contributions to the design and validation of near-native mimicry for soluble BG505 SOSIP.664 trimers. We thank J. Baalwa, D. Ellenberger, F. Gao, B. Hahn, K. Hong, J. Kim, F. McCutchan, D. Montefiori, L. Morris, J. Overbaugh, E. Sanders-Buell, G. Shaw, R. Swanstrom, M. Thomson, S. Tovanabutra, C. Williamson and L. Zhang for contributions to HIV-1-Env plasmids used in neutralization assessments. We thank R. Sanders for providing the PGDM1400-1412 sequences and the International AIDS Vaccine Initiative (IAVI) for PG9, PG16 and PGT141-145. Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, US National Institute of Allergy and Infectious Diseases (NIAID) (to A.B.M., J.R. Mascola and P.D.K.); the Division of AIDS, NIAID, NIH (1U01-AI116086-01 to P.L.M., L.M., J.R. Mascola and P.D.K.; R21-AI112389 to K.K.L.); the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (OPP1033102 to K.K.L.); IAVI; and the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery grant (CHAVI-ID; UM1 AI100645 to M.B. and B.F.H.). This project was funded in part with Federal funds to U.B. from the Frederick National Laboratory for Cancer Research, NIH, under contract HHSN261200800001E. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38. Modeling and molecular dynamics were carried out through the NIH's Biowulf computing cluster. NR 47 TC 27 Z9 27 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD JAN PY 2016 VL 23 IS 1 BP 81 EP 90 DI 10.1038/nsmb.3144 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DA4HO UT WOS:000367761100014 PM 26689967 ER PT J AU Sexton, JE Desmonds, T Quick, K Taylor, R Abramowitz, J Forge, A Kros, CJ Birnbaumer, L Wood, JN AF Sexton, Jane E. Desmonds, Terri Quick, Kathryn Taylor, Ruth Abramowitz, Joel Forge, Andy Kros, Corne J. Birnbaumer, Lutz Wood, John N. TI The contribution of TRPC1, TRPC3, TRPC5 and TRPC6 to touch and hearing SO NEUROSCIENCE LETTERS LA English DT Article DE Mechanosensation; TRP channels; Touch ID DORSAL-ROOT GANGLION; HAIR-CELLS; MECHANICAL HYPERALGESIA; TRPA1 CONTRIBUTES; CHANNELS; TRANSDUCER; PIEZO2; MICE; SENSATION; CURRENTS AB Transient receptor potential channels have diverse roles in mechanosensation. Evidence is accumulating that members of the canonical subfamily of TRP channels (TRPC) are involved in touch and hearing. Characteristic features of TRP channels include their high structural homology and their propensity to form heteromeric complexes which suggests potential functional redundancy. We previously showed that TRPC3 and TRPC6 double knockout animals have deficits in light touch and hearing whilst single knockouts were apparently normal. We have extended these studies to analyse deficits in global quadruple TRPC1, 3, 5 and 6 null mutant mice. We examined both touch and hearing in behavioural and electro-physiological assays, and provide evidence that the quadruple knockout mice have larger deficits than the TRPC3 TRPC6 double knockouts. Mechano-electrical transducer currents of cochlear outer hair cells were however normal. This suggests that TRPC1, TRPC3, TRPC5 and TRPC6 channels contribute to cutaneous and auditory mechanosensation in a combinatorial manner, but have no direct role in cochlear mechanotransduction. (C) 2015 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). C1 [Sexton, Jane E.; Quick, Kathryn; Wood, John N.] UCL, Mol Nocicept Grp, Wolfson Inst Biomed Res, London WC1E 6BT, England. [Desmonds, Terri; Kros, Corne J.] Univ Sussex, Sch Life Sci, Sussex Neurosci, Brighton BN1 9QG, E Sussex, England. [Taylor, Ruth; Forge, Andy] UCL Ear Inst, London WC1X 8EE, England. [Abramowitz, Joel; Birnbaumer, Lutz] Natl Inst Environm Hlth Sci, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. [Kros, Corne J.] Univ Groningen, Univ Med Ctr Groningen, Dept Otorhinolaryngol, NL-9700 RB Groningen, Netherlands. RP Sexton, JE (reprint author), UCL, Mol Nocicept Grp, Wolfson Inst Biomed Res, London WC1E 6BT, England. EM jane.sexton.09@ucl.ac.uk RI Abramowitz, Joel/A-2620-2015 FU NIH Intramural Research Program of the NIH [G (F436L, rs55687265), provided the most compelling evidence of association (P=9.35 x 10(-10), odds ratio [OR] 6.11), which was confirmed in the replication cohort (P=0.012, OR 1.86) and meta-analysis (P=1.92 x 10(-7), OR 2.5). Genes involved in E3 ubiquitin-protein ligase complex (ASB10) and cyclic nucleotide gated channelopathies (CNGB3) as well as HLA-DRB5 and HSPB2 (heat-shock protein 27) provided additional evidence of association (P < 10(-5)). Differential ATP8B4 expression was observed among the SSc patients compared to the controls (P=0.0005). ConclusionATP8B4 may represent a putative genetic risk factor for SSc and pulmonary vascular complications. C1 [Gao, Li; Cheadle, Chris; Berger, Alan E.; Rafaels, Nicholas; Vergara, Candelaria; Taub, Margaret A.; Ruczinski, Ingo; Mathai, Stephen C.; Hummers, Laura K.; Hassoun, Paul M.; Mathias, Rasika A.; Barnes, Kathleen C.] Johns Hopkins Univ, Baltimore, MD USA. [Emond, Mary J.; Louie, Tin; Nickerson, Deborah A.] Univ Washington, Seattle, WA 98195 USA. [Kim, Yoonhee] NHGRI, NIH, Baltimore, MD USA. [Rich, Stephen S.] Univ Virginia, Charlottesville, VA USA. [Bamshad, Michael J.] Univ Washington, Seattle, WA 98195 USA. [Bamshad, Michael J.] Seattle Childrens Hosp, Seattle, WA USA. RP Barnes, KC (reprint author), Johns Hopkins Asthma & Allergy Ctr, 5501 Hopkins Bayview Circle,Room 3A-62A, Baltimore, MD 21224 USA. EM kbarnes@jhmi.edu FU NHLBI [HL-102923, HL-102924, HL-102925, HL-102926, HL-103010]; NIH (National Heart, Lung, and Blood Institute) [HL-102923, R03-HL-114937, P50-HL-084946]; Gilead Sciences Research Scholars Program in Pulmonary Arterial Hypertension; National Human Genome Research Institute; Mary Beryl Patch Turnbull Scholar Program FX Supported in part by the NIH (National Heart, Lung, and Blood Institute grants R03-HL-114937 to Drs. Gao, Hassoun, and Barnes, HL-102923 to Drs. Gao and Barnes, and P50-HL-084946 to Dr. Hassoun). Dr. Gao's work was supported in part by the Gilead Sciences Research Scholars Program in Pulmonary Arterial Hypertension. Dr. Kim's work was supported in part by the Intramural Research Program of the National Human Genome Research Institute. Dr. Barnes' work was supported in part by the Mary Beryl Patch Turnbull Scholar Program. NR 46 TC 5 Z9 5 U1 2 U2 3 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 JAN PY 2016 VL 68 IS 1 BP 191 EP 200 DI 10.1002/art.39449 PG 10 WC Rheumatology SC Rheumatology GA CZ8MN UT WOS:000367353900020 PM 26473621 ER PT J AU Jiang, LW Krishnasamy, V Varano, GM Wood, BJ AF Jiang, Liwei Krishnasamy, Venkatesh Varano, Gianluca M. Wood, Bradford J. TI Hyponatremia Following High-Volume D5W Hydrodissection During Thermal Ablation SO CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Letter ID RADIOFREQUENCY ABLATION; MYELINOLYSIS; PROTECTION; PONTINE; FLUID C1 [Jiang, Liwei; Krishnasamy, Venkatesh; Varano, Gianluca M.; Wood, Bradford J.] NIH, Ctr Intervent Oncol, Ctr Clin, Bethesda, MD 20892 USA. [Jiang, Liwei] Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. RP Jiang, LW (reprint author), NIH, Ctr Intervent Oncol, Ctr Clin, Bldg 10,Room 1C351,10 Ctr Dr, Bethesda, MD 20892 USA. EM jiangl.mail@gmail.com; venkatesh.krishnasamy@nih.gov; gianluca.varano@gmail.com; bwood@cc.nih.gov FU Howard Hughes Medical Institute; Intramural NIH HHS; NCI NIH HHS [ZID BC 011242-06] NR 11 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0174-1551 EI 1432-086X J9 CARDIOVASC INTER RAD JI Cardiovasc. Interv. Radiol. PD JAN PY 2016 VL 39 IS 1 BP 146 EP 149 DI 10.1007/s00270-015-1195-z PG 4 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CZ9ZE UT WOS:000367455700022 PM 26246216 ER PT J AU Skarzynski, M Niemann, CU Lee, YS Martyr, S Maric, I Salem, D Stetler-Stevenson, M Marti, GE Calvo, KR Yuan, C Valdez, J Soto, S Farooqui, MZH Herman, SEM Wiestner, A AF Skarzynski, Martin Niemann, Carsten U. Lee, Yuh Shan Martyr, Sabrina Maric, Irina Salem, Dalia Stetler-Stevenson, Maryalice Marti, Gerald E. Calvo, Katherine R. Yuan, Constance Valdez, Janet Soto, Susan Farooqui, Mohammed Z. H. Herman, Sarah E. M. Wiestner, Adrian TI Interactions between Ibrutinib and Anti-CD20 Antibodies: Competing Effects on the Outcome of Combination Therapy SO CLINICAL CANCER RESEARCH LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; KINASE INHIBITOR IBRUTINIB; MANTLE-CELL LYMPHOMA; MAB-BASED THERAPIES; IN-VITRO; CD20 EXPRESSION; TARGETING BTK; TUMOR-CELLS; SINGLE-ARM; B-CELLS AB Purpose: Clinical trials of ibrutinib combined with anti-CD20 monoclonal antibodies (mAb) for chronic lymphocytic leukemia (CLL) report encouraging results. Paradoxically, in preclinical studies, in vitro ibrutinib was reported to decrease CD20 expression and inhibit cellular effector mechanisms. We therefore set out to investigate effects of in vivo ibrutinib treatment that could explain this paradox. Experimental Design: Patients received single-agent ibrutinib (420 mg daily) on an investigator-initiated phase II trial. Serial blood samples were collected pretreatment and during treatment for ex vivo functional assays to examine the effects on CLL cell susceptibility to anti-CD20 mAbs. Results: We demonstrate that CD20 expression on ibrutinib was rapidly and persistently downregulated (median reduction 74%, day 28, P < 0.001) compared with baseline. Concomitantly, CD20 mRNA was decreased concurrent with reduced NF-kappa B signaling. An NF-kappa B binding site in the promoter of MS4A1 (encoding CD20) and downregulation of CD20 by NF-kappa B inhibitors support a direct transcriptional effect. Ex vivo, tumor cells from patients on ibrutinib were less susceptible to antiCD20 mAb-mediated complement-dependent cytotoxicity than pretreatment cells (median reduction 75%, P < 0.001); however, opsonization by the complement protein C3d, which targets cells for phagocytosis, was relatively maintained. Expression of decay-accelerating factor (CD55) decreased on ibrutinib, providing a likely mechanism for the preserved C3d opsonization. In addition, ibrutinib significantly inhibited trogocytosis, a major contributor to antigen loss and tumor escape during mAb therapy. Conclusions: Our data indicate that ibrutinib promotes both positive and negative interactions with anti-CD20 mAbs, suggesting that successfully harnessing maximal antitumor effects of such combinations requires further investigation. (C)2015 AACR. C1 [Skarzynski, Martin; Niemann, Carsten U.; Lee, Yuh Shan; Martyr, Sabrina; Salem, Dalia; Marti, Gerald E.; Valdez, Janet; Soto, Susan; Farooqui, Mohammed Z. H.; Herman, Sarah E. M.; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Maric, Irina; Calvo, Katherine R.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Stetler-Stevenson, Maryalice; Yuan, Constance] NCI, Flow Cytometry Unit, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,CRC 3-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM wiestnera@mail.nih.gov RI Salem, Dalia/R-9314-2016 OI Salem, Dalia/0000-0002-4209-2260 FU Intramural Research Program of the NHLBI; NCI; Danish Cancer Society; Pharmacyclics FX This work was funded by the Intramural Research Program of the NHLBI and NCI. C.U. Niemann was supported by The Danish Cancer Society. Pharmacyclics provided study drug and research support. This work was also supported by the Intramural Research Program of the NHLBI. NR 50 TC 11 Z9 11 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 1 PY 2016 VL 22 IS 1 BP 86 EP 95 DI 10.1158/1078-0432.CCR-15-1304 PG 10 WC Oncology SC Oncology GA DA1IU UT WOS:000367550300013 PM 26283682 ER PT J AU Balkus, JE Brown, ER Hillier, SL Coletti, A Ramjee, G Mgodi, N Makanani, B Reid, C Martinson, F Soto-Torres, L Karim, SSA Chirenje, ZM AF Balkus, Jennifer E. Brown, Elizabeth R. Hillier, Sharon L. Coletti, Anne Ramjee, Gita Mgodi, Nyaradzo Makanani, Bonus Reid, Cheri Martinson, Francis Soto-Torres, Lydia Karim, Salim S. Abdool Chirenje, Zvavahera M. TI Oral and injectable contraceptive use and HIV acquisition risk among women in four African countries: a secondary analysis of data from a microbicide trial SO CONTRACEPTION LA English DT Article DE Hormonal contraception; HIV infection; Injectables; Oral contraceptive pills; Southern Africa; Women ID MARGINAL STRUCTURAL MODELS; SEXUALLY-TRANSMITTED INFECTIONS; HORMONAL CONTRACEPTION; EPIDEMIOLOGIC EVIDENCE; TRANSMISSION AB Objective: To assess the effect of oral and injectable contraceptive use compared to nonhormonal contraceptive use on HIV acquisition among Southern African women enrolled in a microbicide trial. Study design: This is a prospective cohort study using data from women enrolled in HIV Prevention Trials Network protocol 035. At each quarterly visit, participants were interviewed about self-reported contraceptive use and sexual behaviors and underwent HIV testing. Cox proportional hazards regression was used to assess the effect of injectable and oral hormonal contraceptive use on HIV acquisition. Results: The analysis included 2830 participants, of whom 106 became HIV infected (4.07 per 100 person-years). At baseline, 1546 (51%) participants reported using injectable contraceptives and 595 (21%) reported using oral contraceptives. HIV incidence among injectable, oral and nonhormonal contraceptive method users was 4.72, 2.68 and 3.83 per 100 person-years, respectively. Injectable contraceptive use was associated with a nonstatistically significant increased risk of HW acquisition [adjusted hazard ratio (aHR)=1.17; 95% confidence interval (Cl) 0.70, 1.96], while oral contraceptive use was associated with a nonstatistically significant decreased risk of HIV acquisition (aHR=0.76; 95% CI 0.37,1.55). Conclusion: In this secondary analysis of randomized trial data, a marginal, but nonstatistically significant, increase in HIV risk among women using injectable hormonal contraceptives was observed. No increased HIV risk was observed among women using oral contraceptives. Our findings support the World Health Organization's recommendation that women at high risk for acquiring HIV, including those using progestogen-only injectable contraception, should be strongly advised to always use condoms and other HIV prevention measures. Implications: Among Southern African women participating in an HIV prevention trial, women using injectable hormonal contraceptives had a modest increased risk of HIV acquisition; however, this association was not statistically significant. Continued research on the relationship between widely used hormonal contraceptive methods and HIV acquisition is essential. (C) 2016 Elsevier Inc. All rights reserved. C1 [Balkus, Jennifer E.; Brown, Elizabeth R.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Hillier, Sharon L.] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Hillier, Sharon L.] Univ Pittsburgh, Sch Med, Magee Womens Res Inst, Pittsburgh, PA USA. [Coletti, Anne] FHI360, Durham, NC USA. [Ramjee, Gita] South Africa Med Res Council, HIV Prevent Res Unit, Durban, South Africa. [Mgodi, Nyaradzo; Chirenje, Zvavahera M.] Univ Zimbabwe Univ Calif San Francisco Res Progra, Harare, Zimbabwe. [Makanani, Bonus] Univ Malawi, Coll Med, Blantyre, Malawi. [Reid, Cheri] Ctr Infect Dis Res Zambia, Lusaka, Zambia. [Martinson, Francis] Kamuzu Cent Hosp, Univ North Carolina Project, Lilongwe, Malawi. [Soto-Torres, Lydia] NIH, Bethesda, MD USA. [Karim, Salim S. Abdool] Univ KwaZulu Natal, Ctr AIDS Program Res South Africa, Doris Duke Med Res Inst, Nelson R Mandela Sch Med, Congella, South Africa. [Karim, Salim S. Abdool] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. RP Balkus, JE (reprint author), Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. EM jbalkus@fhcrc.org OI Abdool Karim, Salim/0000-0002-4986-2133 FU US National Institutes of Health [035]; National Institute of Allergy and Infectious Diseases (NIAID) [U01AI4674]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Drug Abuse; National Institute of Mental Health (NIMH); NIAID [U01AI068633, U01AI068615]; NICHD; NIMH FX HIV Prevention Trials Network (HPTN) 035 was funded by the US National Institutes of Health. The trial was designed and implemented by the HPTN and the Microbicide Trials Network (MTN). The HPTN (U01AI4674) has been funded by the National Institute of Allergy and Infectious Diseases (NIAID), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institute of Drug Abuse and the National Institute of Mental Health (NIMH). The MTN (U01AI068633) has been funded by NIAID, NICHD and NIMH. The Statistical Center was supported by NIAID (U01AI068615). NR 27 TC 4 Z9 4 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0010-7824 EI 1879-0518 J9 CONTRACEPTION JI Contraception PD JAN PY 2016 VL 93 IS 1 BP 25 EP 31 DI 10.1016/j.contraception.2015.10.010 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ9HV UT WOS:000367409600005 PM 26519646 ER PT J AU Archer, DF Thomas, MA Conard, J Merkatz, RB Creasy, GW Roberts, K Plagianos, M Blithe, D Sitruk-Ware, R AF Archer, D. F. Thomas, M. A. Conard, J. Merkatz, R. B. Creasy, G. W. Roberts, K. Plagianos, M. Blithe, D. Sitruk-Ware, R. TI Impact on hepatic estrogen-sensitive proteins by a 1-year contraceptive vaginal ring delivering Nestorone (R) and ethinyl estradiol SO CONTRACEPTION LA English DT Article DE Contraception; Vaginal ring; Coagulation proteins; SHBG; Nestorone; Ethinyl estradiol ID COMBINED ORAL-CONTRACEPTIVES; HORMONE-BINDING GLOBULIN; VENOUS THROMBOEMBOLISM; HEMOSTASIS VARIABLES; CROSS-OVER; MU-G; RISK; THROMBOSIS; WOMEN; METAANALYSIS AB Objectives: Estrogen-sensitive hepatic proteins were assessed in women using a contraceptive vaginal ring (CVR) delivering 150 mcg Nestorone (NES) and 15 mcg ethinyl estradiol (EE). Study design: A substudy of the Contraceptive Clinical Trials Network of the National Institute of Child Health and Human Development enrolled 129 participants, with assessments of factor VIII, fibrinogen, protein S (PS) and sex hormone binding globulin (SHBG). Thirty-six participants had used combined hormonal contraceptives (CHCs) in the cycle preceding first CVR use (recent users) and 70 had no history of recent use (nonusers). Results: Mean values at baseline were within the normal range for all four proteins but were higher for factor VIII, fibrinogen and SHBG and significantly lower for PS in recent compared to nonusers. During NES/EE CVR use, factor VIII, fibrinogen and PS were within the normal range; however, SHBG levels were increased by nearly 100% at Cycle 13. The change from baseline to final evaluation was statistically significant for all proteins in nonusers. The change in recent users was significant for factor VIII at Cycle 6 and for SHBG at Cycles 6 and 13, but not for PS or fibrinogen. Conclusion: NES/EE CVR for up to 13 cycles was associated with changes from baseline in plasma levels of factor VIII, fibrinogen and PS that were within the normal range, with SHBG levels above the normal range by Cycle 6. Nonusers of CHC before CVR showed wider changes in values versus recent users whose baseline values were increased by previous BE exposure. Implications: Recent use of CHCs demonstrated significant changes in all four measured hepatic proteins at baseline compared to nonusers. Use of the NES/EE CVR further changed these hepatic protein markers, but values remained within the normal range. Prebaseline exposure to estrogen can obscure interpretation of hepatic proteins changes associated with a second CHC. (C) 2016 Elsevier Inc. All rights reserved. C1 [Archer, D. F.] Eastern Virginia Med Sch, Dept Obstet & Gynecol, Clin Res Ctr, Norfolk, VA 23507 USA. [Thomas, M. A.] Ctr Reprod Hlth, Cincinnati, OH 45219 USA. [Conard, J.] Hotel Dieu Cochin Hosp, Dept Biol Hematol, F-75014 Paris, France. [Merkatz, R. B.; Creasy, G. W.; Roberts, K.; Plagianos, M.; Sitruk-Ware, R.] Populat Council, Ctr Biomed Res, New York, NY 10017 USA. [Blithe, D.] Eunice Kennedy Shrivel Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. RP Archer, DF (reprint author), Eastern Virginia Med Sch, Dept Obstet & Gynecol, Clin Res Ctr, Norfolk, VA 23507 USA. EM archerdf@evms.edu FU Eunice Kennedy Shriver NICHD at the National Institutes of Health [HHSN275200403366, HHSN275200403377, HHSN275200403382]; Population Council FX The study was sponsored by a grant of the Eunice Kennedy Shriver NICHD at the National Institutes of Health [contract numbers: HHSN275200403366 (Human Development Index), HHSN275200403377 (University of Cincinnati) and HHSN275200403382 (Eastern Virginia Medical School)] and the Population Council. NR 44 TC 2 Z9 2 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0010-7824 EI 1879-0518 J9 CONTRACEPTION JI Contraception PD JAN PY 2016 VL 93 IS 1 BP 58 EP 64 DI 10.1016/j.contraception.2015.09.008 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ9HV UT WOS:000367409600009 PM 26408374 ER PT J AU Basudhar, D Ridnour, LA Cheng, R Kesarwala, AH Heinecke, J Wink, DA AF Basudhar, Debashree Ridnour, Lisa A. Cheng, Robert Kesarwala, Aparna H. Heinecke, Julie Wink, David A. TI Biological signaling by small inorganic molecules SO COORDINATION CHEMISTRY REVIEWS LA English DT Review DE Nitric oxide; Nitroxyl; Carbon monoxide; Hydrogen sulfide; Hydrogen; Redox biology ID SOLUBLE GUANYLATE-CYCLASE; NITRIC-OXIDE SYNTHASE; CYTOCHROME-C-OXIDASE; CYSTATHIONINE BETA-SYNTHASE; ISCHEMIA-REPERFUSION INJURY; PROTEIN-TYROSINE NITRATION; NO-CENTER-DOT; SUPEROXIDE GENERATION CONTRIBUTES; DETERRENT AGENT CYANAMIDE; HUMAN ENDOTHELIAL-CELLS AB Small redox active molecules such as reactive nitrogen and oxygen species and hydrogen sulfide have emerged as important biological mediators that are involved in various physiological and pathophysiological processes. Advancement in understanding of cellular mechanisms that tightly regulate both generation and reactivity of these molecules is central to improved management of various disease states including cancer and cardiovascular dysfunction. Imbalance in the production of redox active molecules can lead to damage of critical cellular components such as cell membranes, proteins and DNA and thus may trigger the onset of disease. These small inorganic molecules react independently as well as in a concerted manner to mediate physiological responses. This review provides a general overview of the redox biology of these key molecules, their diverse chemistry relevant to physiological processes and their interrelated nature in cellular signaling. Published by Elsevier B.V. C1 [Basudhar, Debashree; Ridnour, Lisa A.; Cheng, Robert; Heinecke, Julie; Wink, David A.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Kesarwala, Aparna H.] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Wink, DA (reprint author), 10 Ctr Dr,Bldg 10,Room B3-B35, Bethesda, MD 20892 USA. EM wink@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute and Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute and Center for Cancer Research. NR 383 TC 6 Z9 6 U1 12 U2 41 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0010-8545 EI 1873-3840 J9 COORDIN CHEM REV JI Coord. Chem. Rev. PD JAN 1 PY 2016 VL 306 SI SI BP 708 EP 723 DI 10.1016/j.ccr.2015.06.001 PN 2 PG 16 WC Chemistry, Inorganic & Nuclear SC Chemistry GA DA0JL UT WOS:000367483300016 PM 26688591 ER PT J AU Menke, A Guallar, E Cowie, CC AF Menke, Andy Guallar, Eliseo Cowie, Catherine C. TI Metals in Urine and Diabetes in US Adults SO DIABETES LA English DT Article ID SURVEY KNHANES 2009-2010; KOREA NATIONAL-HEALTH; BLOOD LEAD LEVELS; HEAVY-METALS; CADMIUM EXPOSURE; CARDIOVASCULAR-DISEASE; MELLITUS PATIENTS; FASTING GLUCOSE; UNITED-STATES; TOXIC METALS AB Our objective was to evaluate the relationship of urine metals including barium, cadmium, cobalt, cesium, molybdenum, lead, antimony, thallium, tungsten, and uranium with diabetes prevalence. Data were from a cross-sectional study of 9,447 participants of the 1999-2010 National Health and Nutrition Examination Survey, a representative sample of the U.S. civilian noninstitutionalized population. Metals were measured in a spot urine sample, and diabetes status was determined based on a previous diagnosis or an A1C >= 6.5% (48 mmol/mol). After multivariable adjustment, the odds ratios of diabetes associated with the highest quartile of metal, compared with the lowest quartile, were 0.86 (95% CI 0.66-1.12) for barium (P-trend = 0.74 (0.51-1.09) for cadmium (P-trend = 0.35), 1.21 (0.85-1.72) for cobalt (P-trend = 0.59), 1.31 (0.90-1.91) for cesium (P-trend = 0.29), 1.76(1.24-2.50) for molybdenum (P-trend = 0.01), 0.79 (0.56-1.13) for lead (P-trend = 0.10), 1.72 (1.27-2.33) for antimony (P-trend <0.01), 0.76 (0.51-1.13) for thallium (P-trend = 0.13), 2.18 (1.51-3.15) for tungsten (P-trend < 0.01), and 1.46 (1.09-1.96) for uranium (P-trend = 0.02). Higher quartiles of barium, molybdenum, and antimony were associated with greater HOMA of insulin resistance after adjustment. Molybdenum, antimony, tungsten, and uranium were positively associated with diabetes, even at the relatively low levels seen in the U.S. population. Prospective studies should further evaluate metals as risk factors for diabetes. C1 [Menke, Andy] Social & Sci Syst Inc, Silver Spring, MD 20910 USA. [Guallar, Eliseo] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Guallar, Eliseo] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Med, Baltimore, MD USA. [Guallar, Eliseo] Johns Hopkins Bloomberg Sch Publ Hlth, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Cowie, Catherine C.] Natl Inst Hlth, Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD USA. RP Menke, A (reprint author), Social & Sci Syst Inc, Silver Spring, MD 20910 USA. EM amenke@s-3.com FU National Institute of Diabetes and Digestive and Kidney Diseases [GS10F0381L] FX This work was supported by a contract from the National Institute of Diabetes and Digestive and Kidney Diseases (GS10F0381L). NR 45 TC 5 Z9 5 U1 2 U2 11 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD JAN PY 2016 VL 65 IS 1 BP 164 EP 171 DI 10.2337/db15-0316 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CZ9NS UT WOS:000367424900019 PM 26542316 ER PT J AU Huggins, GS Berkowitz, RI Blackburn, GL Bray, GA Cheskin, L Clark, JM Coday, M Espeland, MA Evans, M Foreyt, JP Glasser, S Greenway, FL Gregg, EW Hanson, RL Hazuda, HP Hill, JO Horton, ES Jakicic, JM Jeffery, RW Johnson, KC Kahn, SE Kitzman, DW Knowler, WC Lewis, CE McCaffery, JM Michaels, SA Montez, MG Murillo, A Nathan, DM Pajewski, NM Patricio, J Peters, A Pi-Sunyer, X Pownall, H Redmon, B Regensteiner, J Steinberg, HO Wadden, TA Wagenknecht, LE Wesche-Thobaben, J Wing, RR AF Huggins, Gordon S. Berkowitz, Robert I. Blackburn, George L. Bray, George A. Cheskin, Lawrence Clark, Jeanne M. Coday, Mace Espeland, Mark A. Evans, Mary Foreyt, John P. Glasser, Stephen Greenway, Frank L. Gregg, Edward W. Hanson, Robert L. Hazuda, Helen P. Hill, James O. Horton, Edward S. Jakicic, John M. Jeffery, Robert W. Johnson, Karen C. Kahn, Steven E. Kitzman, Dalane W. Knowler, William C. Lewis, Cora E. McCaffery, Jeanne M. Michaels, Sara A. Montez, Maria G. Murillo, Anne Nathan, David M. Pajewski, Nicholas M. Patricio, Jennifer Peters, Anne Pi-Sunyer, Xavier Pownall, Henry Redmon, Bruce Regensteiner, Judy Steinberg, Helmut O. Wadden, Thomas A. Wagenknecht, Lynne E. Wesche-Thobaben, Jacqueline Wing, Rena R. CA Look AHEAD Res Grp TI Prospective Association of GLUL rs10911021 With Cardiovascular Morbidity and Mortality Among Individuals With Type 2 Diabetes: The Look AHEAD Study SO DIABETES LA English DT Article ID LIFE-STYLE INTERVENTION; GENETIC VARIANT; HEART-DISEASE; TRIAL AB Genetic studies have identified a glutamate-ammonia ligase gene (GLUL) polymorphism associated with cardiovascular disease morbidity and mortality among people with type 2 diabetes (T2D). We sought to determine whether GLUL rs10911021 is associated prospectively with adjudicated cardiovascular composite end points among overweight/obese individuals with T2D and whether a lifestyle intervention resulting in weight loss could diminish this association. Look AHEAD is a randomized, controlled trial to determine the effects of intensive lifestyle intervention (ILI), including weight loss and physical activity, relative to diabetes support and education, on cardiovascular outcomes. Look AHEAD participants included in this report were 3,845 overweight/obese individuals with T2D who provided consent for genetic analyses. Over a median of 9.6 years of follow-up, the risk (C) allele for GLUL rs10911021 was significantly associated with the primary composite end point of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina among individuals with no history of cardiovascular disease (CVD) at baseline using additive genetic models (hazard ratio 1.17(95% CI 1.01-1.36]; P = 0.032). Results appeared more consistent in recessive models and among individuals with no known history of CVD at baseline; ILI did not alter these associations. These results extend the association of GLUL rs10911021 to incident CVD morbidity and mortality in the setting of T2D. C1 [Huggins, Gordon S.] Tufts Med Ctr, MCRI Ctr Translat Genom, Boston, MA 02111 USA. [Huggins, Gordon S.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Berkowitz, Robert I.] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Blackburn, George L.] Beth Israel Deaconess Med Ctr, Dept Surg, Ctr Study Nutr Med, Boston, MA 02215 USA. [Blackburn, George L.; Nathan, David M.] Harvard Univ, Sch Med, Boston, MA USA. [Bray, George A.] Louisiana State Univ, Dept Clin Obes, Pennington Biomed Res Ctr, Baton Rouge, LA 70803 USA. [Cheskin, Lawrence] Johns Hopkins Bloomberg Sch Publ Hlth, Global Obes Prevent Ctr Johns Hopkins, Baltimore, MD USA. [Clark, Jeanne M.] Johns Hopkins Univ, Dept Med & Epidemiol, Baltimore, MD USA. [Coday, Mace] Memphis East Clin, Dept Prevent Med, Memphis, TN USA. [Espeland, Mark A.; Pajewski, Nicholas M.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Evans, Mary] NIDDKD, Dept Digest Dis & Nutr, Bethesda, MD USA. [Foreyt, John P.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Glasser, Stephen] Univ Alabama Birmingham, Dept Med, Div Prevent Med, Birmingham, AL 35294 USA. [Greenway, Frank L.] Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Gregg, Edward W.] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. [Hanson, Robert L.] NIDDKD, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. [Hazuda, Helen P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Nephrol, San Antonio, TX 78229 USA. [Hill, James O.] Univ Colorado, Anschutz Hlth & Wellness Ctr, Aurora, CO USA. [Horton, Edward S.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Horton, Edward S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Jakicic, John M.] Univ Pittsburgh, Dept Hlth & Phys Act, Pittsburgh, PA USA. [Jeffery, Robert W.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Johnson, Karen C.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Kahn, Steven E.] VA Puget Sound Hlth Care Syst, Div Metab Endocrinol & Nutr, Dept Med, Seattle, WA USA. [Kahn, Steven E.; Murillo, Anne] Univ Washington, Seattle, WA 98195 USA. [Kitzman, Dalane W.] Wake Forest Univ Hlth Sci, Dept Cardiol, Winston Salem, NC USA. [Knowler, William C.] NIDDKD, Phoenix, AZ USA. [Lewis, Cora E.] Univ Alabama Birmingham, Dept Med, Div Prevent Med, Birmingham, AL 35294 USA. [McCaffery, Jeanne M.] Brown Univ, Miriam Hosp, Alpert Sch, Dept Psychiat & Human Behav, Providence, RI USA. [Michaels, Sara A.] Northern Navajo Med Ctr, Shiprock, NM USA. [Montez, Maria G.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Nephrol, San Antonio, TX 78229 USA. [Murillo, Anne] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Nathan, David M.] Massachusetts Gen Hosp, Dept Med, Ctr Diabet, Diabet Unit, Boston, MA 02114 USA. [Patricio, Jennifer; Pi-Sunyer, Xavier] St Lukes Roosevelt Hosp, New York Obes Res Ctr, New York, NY USA. [Peters, Anne] Edward R Roybal Comprehens Hlth Ctr, Los Angeles, CA USA. [Pownall, Henry] Methodist Hosp Res Inst, Dept Cardiol, Houston, TX USA. [Redmon, Bruce] Univ Minnesota, Dept Endocrinol Med, Minneapolis, MN USA. [Regensteiner, Judy] Univ Colorado, Hlth Sci Ctr, Ctr Womens Hlth Res, Denver, CO USA. [Steinberg, Helmut O.] Univ Tennessee, Ctr Hlth Sci, Div Endocrinol Diabet & Metab, Memphis, TN 38163 USA. [Wadden, Thomas A.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Wagenknecht, Lynne E.] Wake Forest Sch Med, Dept Publ Hlth Serv, Winston Salem, NC USA. [Wesche-Thobaben, Jacqueline] Univ Pittsburgh, Phys Act & Weight Management Res Ctr, Pittsburgh, PA USA. [Wing, Rena R.] Brown Univ, Dept Psychiat & Human Behav, Miriam Hosp, Alpert Sch Med, Providence, RI 02912 USA. RP Huggins, GS (reprint author), Tufts Med Ctr, MCRI Ctr Translat Genom, Boston, MA 02111 USA. EM ghuggins@tuftsmedicalcenter.org FU National Institute of Diabetes and Digestive and Kidney Diseases [DK-57136] FX This study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (DK-57136). NR 13 TC 1 Z9 1 U1 1 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD JAN PY 2016 VL 65 IS 1 BP 297 EP 302 DI 10.2337/db15-0890 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CZ9NS UT WOS:000367424900031 ER PT J AU Cameron, D Siddiqi, N Neil, CJ Jagpal, B Bruce, M Higgins, DM He, JB Singh, S Redpath, TW Frenneaux, MP Dawson, DK AF Cameron, Donnie Siddiqi, Nishat Neil, Christopher J. Jagpal, Baljit Bruce, Margaret Higgins, David M. He, Jiabao Singh, Satnam Redpath, Thomas W. Frenneaux, Michael P. Dawson, Dana K. TI T-1 mapping for assessment of myocardial injury and microvascular obstruction at one week post myocardial infarction SO EUROPEAN JOURNAL OF RADIOLOGY LA English DT Article DE Acute myocardial infarction; Magnetic resonance imaging; Myocardium at risk; Myocardial oedema; Microvascular obstruction; T-1 mapping ID CARDIOVASCULAR MAGNETIC-RESONANCE; PROGNOSTIC-SIGNIFICANCE; EDEMA; RISK; AREA; SALVAGE; HEART; MRI; CMR; ENHANCEMENT AB Objectives: To compare 3T T-1 mapping to conventional T2-weighted (T2W) imaging for delineating myocardial oedema one week after ST-elevation myocardial infarction (STEMI), and to explore the confounding effects of microvascular obstruction (MVO) on each technique. Methods: T2W spectral attenuated inversion recovery and native T-1 mapping were applied in 10 healthy volunteers and 62 STEMI patients, and late gadolinium enhancement was included for infarct localisation at 1 week and at 6 months post-STEMI. Segmental T-1 values and T2W signal intensity ratios were calculated; oedema volumes and salvage indices were determined in patients using image thresholding a receiver operator characteristic (ROC) derived T-1 threshold, and a 25D T2W threshold; and the results were compared between patients with/without MVO (n=35127). Results: Native T-1 mapping delineated oedema with significantly better discriminatory power than T2W as indicated by ROC analysis (area-under-the-curve, ADC= 0.89 versus 0.83,p = 0.009; and sensitivity/specificity = 83183% versus 73173%). The optimal ROC threshold derived for Ti mapping was 1241 ms, which gave significantly larger oedema volumes than 25D T2W (p= 0.006); with this threshold, patients with and without MVO showed similar oedema volumes, but patients with MVO had significantly poorer salvage indices (p< 0.05) than those without. Neither method was significantly affected by MVO, the volume of which was seen to increase exponentially with infarct size. Conclusions: Native T-1 mapping at 3T can delineate oedema one week post-STEMI, showing larger oedema volumes and better discriminatory power than T2W imaging, and it is suitable for quantitative thresholding. Both techniques are robust against MVO-related magnetic susceptibility. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Cameron, Donnie; Siddiqi, Nishat; Neil, Christopher J.; Jagpal, Baljit; Bruce, Margaret; He, Jiabao; Singh, Satnam; Redpath, Thomas W.; Frenneaux, Michael P.; Dawson, Dana K.] Univ Aberdeen, Dept Cardiovasc Med, Aberdeen AB25 2ZD, Scotland. [Higgins, David M.] Philips Healthcare, Guildford GU2 8XH, Surrey, England. RP Cameron, D (reprint author), NIA, NIH, MedStar Harbor Hosp, 3001 South Hanover St, Baltimore, MD 21225 USA. EM d.cameron.09@aberdeen.ac.uk; n.siddiqi@abdn.ac.uk; ctop1@me.com; b.jagpal@abdn.ac.uk; maggie.bruce2@nhs.net; David.Higgins@philips.com; jiabao.he@abdn.ac.uk; s.singh@abdn.ac.uk; t.redpath@abdn.ac.uk; m.p.frenneaux@abdn.ac.uk; dana.dawson@abdn.ac.uk OI Cameron, Donnie/0000-0001-9841-6909 FU Medical Research Council UK [G0800901] FX This study was supported by a Medical Research Council UK grant (grant number G0800901), as a sub-study of Nitrites in Acute Myocardial Infarction. Thanks are due to Roger Staff, for invaluable advice regarding receiver operator characteristic analysis. NR 31 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0720-048X EI 1872-7727 J9 EUR J RADIOL JI Eur. J. Radiol. PD JAN PY 2016 VL 85 IS 1 BP 279 EP 285 DI 10.1016/j.ejrad.2015.10.008 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CZ8OA UT WOS:000367357800037 PM 26507864 ER PT J AU Liu, Y Yang, Y Dong, H Cutler, RG Strong, R Mattson, MP AF Liu, Yong Yang, Ying Dong, Hui Cutler, Roy G. Strong, Randy Mattson, Mark P. TI Thidoredxin-2 overexpression fails to rescue chronic high calorie diet induced hippocampal dysfunction SO EXPERIMENTAL NEUROLOGY LA English DT Article DE High calorie diet; Hippocampus; Lipid peroxidation; Mitochondria; Oxidative stress; Synaptic plasticity; Thioredoxin ID HIGH-FAT DIET; INCREASED OXIDATIVE STRESS; INDUCED INSULIN-RESISTANCE; MILD COGNITIVE IMPAIRMENT; LONG-TERM POTENTIATION; SYNAPTIC PLASTICITY; ALZHEIMERS-DISEASE; MITOCHONDRIAL DYSFUNCTION; NEUROTROPHIC FACTOR; INDUCED OBESITY AB A high calorie diet (HCD) can impair hippocampal synaptic plasticity and cognitive function in animal models. Mitochondria( thioredoxin 2 (TRX-2) is critical for maintaining intracellular redox status, but whether it can protect against HCD-induced impairment of synaptic plasticity is unknown. We found that levels of TRX-2 are reduced in the hippocampus of wild type mice maintained for 8 months on a HCD, and that the mice on the HCD exhibit impaired hippocampal synaptic plasticity (long-term potentiation at CA1 synapses) and cognitive function (novel object recognition). Transgenic mice overexpressing human TRX-2 (hTRX-2) exhibit increased resistance to diquat-induced oxidative stress in peripheral tissues. However, neither the HCD nor hTRX-2 overexpression affected levels of lipid peroxidation products (F2 isoprostanes) in the hippocampus, and hTRX-2 transgenic mice were not protected against the adverse effects of the HCD on hippocampal synaptic plasticity and cognitive function. Our findings indicate that TRX-2 overexpression does not mitigate adverse effects of a HCD on synaptic plasticity, and also suggest that oxidative stress may not be a pivotal factor in the impairment of synaptic plasticity and cognitive function caused by HCDs. Published by Elsevier Inc. C1 [Liu, Yong; Yang, Ying; Dong, Hui; Cutler, Roy G.; Mattson, Mark P.] NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. [Yang, Ying] Wuhan Univ, Zhongnan Hosp, Dept Neurol, Wuhan 430072, Peoples R China. [Strong, Randy] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78245 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. EM mark.mattson@nih.gov OI Liu, Yong/0000-0003-1278-7114 FU Intramural Research Program of the National Institute on Aging [AG000315-14] FX This research was supported by the Intramural Research Program of the National Institute on Aging (AG000315-14). NR 66 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 EI 1090-2430 J9 EXP NEUROL JI Exp. Neurol. PD JAN PY 2016 VL 275 BP 126 EP 132 DI 10.1016/j.expneurol.2015.10.002 PN 1 PG 7 WC Neurosciences SC Neurosciences & Neurology GA CZ9MA UT WOS:000367420500014 PM 26476179 ER PT J AU Visco, AG Brubaker, L Jelovsek, JE Wilson, TS Norton, P Zyczynski, HM Spino, C Sirls, L Nguyen, JN Rahn, DD Meikle, SF Nolen, TL AF Visco, Anthony G. Brubaker, Linda Jelovsek, J. Eric Wilson, Tracey S. Norton, Peggy Zyczynski, Halina M. Spino, Cathie Sirls, Larry Nguyen, John N. Rahn, David D. Meikle, Susie F. Nolen, Tracy L. CA Pelvic Floor Disorders Network TI Adherence to Oral Therapy for Urgency Urinary Incontinence: Results from the Anticholinergic Versus Botox Comparison (ABC) Trial SO FEMALE PELVIC MEDICINE AND RECONSTRUCTIVE SURGERY LA English DT Article DE medication adherence; onabotulinumtoxinA; botox; botulinum toxin; urgency incontinence; anticholinergic medication; randomized clinical trials; ABC trial ID OVERACTIVE BLADDER; MEDICATION ADHERENCE; OAB-Q; PERSISTENCE AB Objectives: Medication adherence with urgency urinary incontinence (UUI) treatment is challenging and the best assessment methodology is uncertain. We sought to describe adherence with anticholinergic (AC) versus placebo (P) by comparing pill counts and MEMSCAP event data and to identify factors associated with adherence. Methods: The randomized controlled AC versus Botox Comparison trial of women with moderate to severe idiopathic UUI included 126 participants initiating AC plus P bladder injection and 121 receiving P pills plus Botox injection. Adherence data on 243 participants (124 AC and 119 P) were calculated by pill count and MEMSCAP data for each 2-month interval during the 6-month study that allowed for dose escalation/drug change. Overall composite adherence estimates were calculated using the average of both methods and weighted by the duration of each 2-month interval. Results: Treatment groups had no significant differences in dosing duration (P = 0.76) or mean adherence (AC, 83.3% [16.8] vs P, 84.8% [13.8]). Only 53% of women met the dichotomous outcome of more than 80% adherence during all intervals. Correlation between adherence by pill counts versus MEMSCAP decreased over time with pill counts demonstrating higher adherence than MEMSCAP (r = 0.53, 0.50, and 0.36 for each 2-month interval). Lower adherence was associated with higher baseline incontinence severity and better UUI quality of life for the AC group and with current smoking status in both groups. Conclusions: Adherence using pill counts and MEMSCAP was reasonably correlated and similar in both the AC and P groups. In the AC group, higher baseline incontinence severity and better UUI Quality of Life were associated with decreased adherence. Smokers were less adherent. C1 [Visco, Anthony G.] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27707 USA. [Brubaker, Linda] Loyola Univ, Stritch Sch Med, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Brubaker, Linda] Loyola Univ, Stritch Sch Med, Dept Urol, Chicago, IL 60611 USA. [Jelovsek, J. Eric] Cleveland Clin, Obstet Gynecol & Womens Hlth Inst, Cleveland, OH USA. [Wilson, Tracey S.] Univ Alabama Birmingham, Dept Urol, Birmingham, AL USA. [Norton, Peggy] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Zyczynski, Halina M.] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Spino, Cathie] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Sirls, Larry] OUWB Sch Med, Beaumont Hlth Syst, Dept Urol, Royal Oak, MI USA. [Nguyen, John N.] Kaiser Permanente, Dept Obstet & Gynecol, Downey, CA USA. [Rahn, David D.] Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. [Meikle, Susie F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Gynecol Hlth & Dis Branch, NIH, Bethesda, MD USA. [Nolen, Tracy L.] RTI Int, Res Triangle Pk, NC USA. RP Visco, AG (reprint author), Duke Univ, Med Ctr, Dept Obstet & Gynecol, Div Urogynecol & Reconstruct Pelv Surg, 5324 McFarland Dr,Suite 310, Durham, NC 27707 USA. EM anthony.visco@duke.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, (Duke) [2-U10-HD04267-12]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, (Loyola) [U10-HD054136]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, (UAB) [2-U10-HD041261-11]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, (Utah) [U10-HD041250]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, (Cleveland Clinic) [2-U10-HD054215-06]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, (UCSD) [2-U10-HD054214-06]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, (Pittsburgh) [1-U10-HD069006-01]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, (UTSW) [2-U10-HD054241-06]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, (University of Michigan) [U01-HD41249]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, (RTI) [1-U01-HD069010-01]; National Institutes of Health Office of Research on Women's Health FX Supported by grants from The Eunice Kennedy Shriver National Institute of Child Health and Human Development, (Duke: 2-U10-HD04267-12; Loyola: U10-HD054136; UAB: 2-U10-HD041261-11; Utah: U10-HD041250; Cleveland Clinic: 2-U10-HD054215-06; UCSD: 2-U10-HD054214-06; Pittsburgh: 1-U10-HD069006-01; UTSW: 2-U10-HD054241-06; University of Michigan: U01-HD41249; RTI: 1-U01-HD069010-01) and the National Institutes of Health Office of Research on Women's Health. NR 18 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 2151-8378 J9 FEMALE PELVIC MED RE JI Female Pelvic Med. Reconstr. Surg. PD JAN-FEB PY 2016 VL 22 IS 1 BP 24 EP 28 DI 10.1097/SPV.0000000000000215 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DA1KJ UT WOS:000367554400006 PM 26516810 ER PT J AU Rahman, F Wang, N Yin, XY Ellinor, PT Lubitz, SA LeLorier, PA McManus, DD Sullivan, LM Seshadri, S Vasan, RS Benjamin, EJ Magnani, JW AF Rahman, Faisal Wang, Na Yin, Xiaoyan Ellinor, Patrick T. Lubitz, Steven A. LeLorier, Paul A. McManus, David D. Sullivan, Lisa M. Seshadri, Sudha Vasan, Ramachandran S. Benjamin, Emelia J. Magnani, Jared W. TI Atrial flutter: Clinical risk factors and adverse outcomes in the Framingham Heart Study SO HEART RHYTHM LA English DT Article DE Atrial flutter; Atrial fibrillation; Risk factors; Outcomes; Epidemiology ID RADIOFREQUENCY CATHETER ABLATION; MYOCARDIAL-INFARCTION; THROMBOEMBOLIC RISK; NATURAL-HISTORY; FIBRILLATION; POPULATION; COHORT; METAANALYSIS; DISEASE; STROKE AB BACKGROUND Few epidemiologic cohort studies have evaluated atrial flutter (flutter) as an arrhythmia distinct from atrial fibrillation (AF). OBJECTIVE The purpose of this study was to examine the clinical correlates of flutter and its associated outcomes to distinguish them from those associated with AF in the Framingham Heart Study. METHODS We reviewed and adjudicated electrocardiograms (ECGs) previously classified as flutter or AF/flutter and another 100 ECGs randomly selected from AF cases. We examined the clinical correlates of flutter by matching up to 5 AF and 5 referents to each flutter case using a nested case referent design. We determined the 10-year outcomes associated with flutter with Cox models. RESULTS During mean follow-up of 33.0 +/- 12.2 years, 112 participants (mean age 72 +/- 10 years, 30% women) developed flutter. In multivariable analyses, smoking (odds ratio [OR] 2.84, 95% confidence interval [CI] 1.54-5.23), increased PR interval (OR 1.28 per SD, 95% CI 1.03-1.60), myocardial infarction (OR 2.25, 95% CI 1.05-4.80) and heart failure (OR 5.22, 95% CI 1.26-21.64) were associated with incident flutter. In age- and sex-adjusted models, flutter (vs referents) was associated with 10-year increased risk of AF (hazard ratio [HR] 5.01, 95% CI 3.14-7.99), myocardial infarction (HR 3.05, 95% CI 1.42-6.59), heart failure (HR 4.14, 95% CI 1.90-8.99), stroke (HR 2.17, 95% CI 1.13-4.17), and mortality (HR 2.00, 95% CI 1.44-2.79). CONCLUSION We identified the clinical correlates associated with flutter and observed that flutter was associated with multiple adverse outcomes. C1 [Rahman, Faisal] Boston Univ, Med Ctr, Dept Med, Boston, MA 02118 USA. [Wang, Na] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA 02118 USA. [Yin, Xiaoyan; Sullivan, Lisa M.] Boston Univ, Dept Biostat, Boston, MA 02118 USA. [Ellinor, Patrick T.; Lubitz, Steven A.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Benjamin, Emelia J.; Magnani, Jared W.] Boston Univ, Sch Med, Sect Cardiovasc Med, Dept Med, Boston, MA 02118 USA. [LeLorier, Paul A.] Louisiana State Univ, Sch Med, Dept Med, New Orleans, LA USA. [McManus, David D.; Seshadri, Sudha; Vasan, Ramachandran S.; Benjamin, Emelia J.; Magnani, Jared W.] NHLBI, Framingham, MA USA. [McManus, David D.; Seshadri, Sudha; Vasan, Ramachandran S.; Benjamin, Emelia J.; Magnani, Jared W.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [McManus, David D.] Univ Massachusetts, Dept Med, Worcester, MA 01605 USA. [McManus, David D.] Univ Massachusetts, Dept Quantitat Hlth Sci, Worcester, MA 01605 USA. [McManus, David D.] Worcester Polytech Inst, Dept Biomed Engn, Worcester, MA 01609 USA. [Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Magnani, JW (reprint author), Boston Univ, Sch Med, Sect Cardiovasc Med, 88 E Newton St, Boston, MA 02118 USA. EM jmagnani@bu.edu OI Seshadri, Sudha/0000-0001-6135-2622; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Institutes of Health [R03AG045075, K23HL114724, KL2RR031981, NS17950, N01-HC-25195, 6R01-NS17950, 2R01HL092577, HHSN268201500001I, 1R01 HL102214, R01HL104156, K24HL105780]; Doris Duke Charitable Foundation Clinical Scientist Development Award [2014105]; American Heart Association Established Investigator Award [13EIA14220013] FX This work was supported by National Institutes of Health Grant R03AG045075 to Dr. Magnani; Grant K23HL114724 to Dr. Lubitz; Grant KL2RR031981 to Dr. McManus; Grant NS17950 to Dr. Seshadri; Grant N01-HC-25195 to Dr. Vasan; Grants 6R01-NS17950 and 2R01HL092577 to Drs. Ellinor and Benjamin; Grant HHSN268201500001I to Dr. Benjamin; Grant 1R01 HL102214 to Dr. Benjamin; Grants R01HL104156 and K24HL105780 to Dr Ellinor; Doris Duke Charitable Foundation Clinical Scientist Development Award 2014105 to Dr. Lubitz; and American Heart Association Established Investigator Award 13EIA14220013 to Dr. Ellinor) NR 38 TC 4 Z9 4 U1 3 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 EI 1556-3871 J9 HEART RHYTHM JI Heart Rhythm PD JAN PY 2016 VL 13 IS 1 BP 233 EP 240 DI 10.1016/j.hrthm.2015.07.031 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CZ9CA UT WOS:000367394200038 PM 26226213 ER PT J AU Kendall, PC Cummings, CM Villabo, MA Narayanan, MK Treadwell, K Birmaher, B Compton, S Piacentini, J Sherrill, J Walkup, J Gosch, E Keeton, C Ginsburg, G Suveg, C Albano, AM AF Kendall, Philip C. Cummings, Colleen M. Villabo, Marianne A. Narayanan, Martina K. Treadwell, Kimberli Birmaher, Boris Compton, Scott Piacentini, John Sherrill, Joel Walkup, John Gosch, Elizabeth Keeton, Courtney Ginsburg, Golda Suveg, Cindy Albano, Anne Marie TI Mediators of Change in the Child/Adolescent Anxiety Multimodal Treatment Study SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE anxiety; youth; anxious self-talk; coping; mediators ID COGNITIVE-BEHAVIORAL THERAPY; SELF-STATEMENT QUESTIONNAIRE; RANDOMIZED CLINICAL-TRIAL; DISORDERS INTERVIEW SCHEDULE; CHILDRENS AUTOMATIC THOUGHTS; CHILDHOOD ANXIETY; ANXIOUS YOUTH; PSYCHOSOCIAL TREATMENTS; NEGATIVE AFFECTIVITY; CONTENT-SPECIFICITY AB Objective: Test changes in (a) coping efficacy and (b) anxious self-talk as potential mediators of treatment gains at 3-month follow-up in the Child/Adolescent Anxiety Multimodal Treatment Study (CAMS). Method: Participants were 488 youth (ages 7-17; 50.4% male) randomized to cognitive-behavioral therapy (CBT; Coping cat program), pharmacotherapy (sertraline), their combination, or pill placebo. Participants met Diagnostic and Statistical Manual for Mental Disorders-Fourth Edition (DSM-IV) criteria for generalized anxiety disorder, social phobia, and/or separation anxiety disorder. Coping efficacy (reported ability to manage anxiety provoking situations) was measured by youth and parent reports on the Coping Questionnaire, and anxious self-talk was measured by youth report on the Negative Affectivity Self-Statement Questionnaire. Outcome was measured using the Pediatric Anxiety Rating Scale (completed by Independent Evaluators blind to condition). For temporal precedence, residualized treatment gains were assessed at 3-month follow-up. Results: Residualized gains in coping efficacy mediated gains in the CBT, sertraline, and combination conditions. In the combination condition, some unique effect of treatment remained. Treatment assignment was not associated with a reduction in anxious self-talk, nor did anxious self-talk predict changes in anxiety symptoms. Conclusions: The findings suggest that improvements in coping efficacy are a mediator of treatment gains. Anxious self-talk did not emerge as a mediator. C1 [Kendall, Philip C.; Cummings, Colleen M.] Temple Univ, Dept Psychol, Philadelphia, PA 19122 USA. [Villabo, Marianne A.] Ctr Child & Adolescent Mental Hlth, Dept Psychol, Oslo, Norway. [Narayanan, Martina K.] Norwegian Ctr Child Behav Dev, Dept Psychol, Oslo, Norway. [Treadwell, Kimberli] Univ Connecticut, Dept Psychol, Storrs, CT USA. [Birmaher, Boris] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. [Compton, Scott] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC 27706 USA. [Piacentini, John] Univ Calif Los Angeles, Dept Psychiat & Behav Sci, Los Angeles, CA 90024 USA. [Sherrill, Joel] NIH, Child & Adolescent Mental Hlth, Bethesda, MD 20892 USA. [Walkup, John] Cornell Univ, Dept Child & Adolescent Psychiat, Ithaca, NY 14853 USA. [Gosch, Elizabeth] Philadelphia Coll Osteopath Med, Dept Psychol, Philadelphia, PA USA. [Keeton, Courtney; Ginsburg, Golda] Johns Hopkins Univ, Dept Child & Adolescent Psychiat, Baltimore, MD 21218 USA. [Suveg, Cindy] Univ Georgia, Dept Psychol, Athens, GA 30602 USA. [Albano, Anne Marie] Columbia Univ, Dept Child & Adolescent Psychiat, New York, NY 10027 USA. RP Kendall, PC (reprint author), Temple Univ, Dept Psychol, 1301 North 13th St, Philadelphia, PA 19122 USA. EM pkendall@temple.edu FU Pfizer Pharmaceuticals; Pettit Foundation; Tourette Association of America; National Institute of Mental Health; Eli Lilly; Pfizer; Abbott; Shire; Tourette Syndrome-Center for Disease Control and Prevention; American Academy of Child and Adolescent Psychiatry, American Psychiatric Association; Hartwell Foundation; Tourette Syndrome Association; National Institutes of Mental Health [MH063747, MH64003, MH 64088, MH64089, MH64092] FX Philip C. Kendall receives royalties from sales of treatment materials related to anxiety in youth. He publishes and distributes the program that was included in the study. Boris Birmaher receives royalties from American Psychiatric Association, Random House, UpToDate. John Piacentini receives research support from Pfizer Pharmaceuticals, Pettit Foundation, Tourette Association of America; publication royalties from Oxford University Press and Guilford Press; travel support and speaking honoraria from Tourette Association, International OCD Foundation; speaking honoraria from Trichtillomania Learning Center. John Walkup has received free drug/placebo from the following pharmaceutical companies for National Institute of Mental Health funded studies Eli Lilly (2003); Pfizer (2007); Abbott (2005). John Walkup was paid for a one time consultation with Shire (2011). John Walkup is a paid speaker for the Tourette Syndrome-Center for Disease Control and Prevention outreach educational programs; American Academy of Child and Adolescent Psychiatry, American Psychiatric Association. John Walkup receives royalties for books on Tourette syndrome from Guilford Press and Oxford Press. John Walkup receives grant funding from the Hartwell Foundation and the Tourette Syndrome Association, and is an unpaid advisor to Anxiety Disorders Association of America, Consumer Reports, and Trichtillomania Learning Center.; This research was supported by an National Institutes of Mental Health grants (MH063747 to Philip C. Kendall; MH64003 to Boris Birmaher; MH64003 to Scott Compton; MH 64088 to John Piacentini; MH64089 to John Walkup; MH64092 to Albano). The authors thank David Kenny for his contributions. NR 74 TC 6 Z9 6 U1 9 U2 28 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X EI 1939-2117 J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD JAN PY 2016 VL 84 IS 1 BP 1 EP 14 DI 10.1037/a0039773 PG 14 WC Psychology, Clinical SC Psychology GA CZ9OM UT WOS:000367426900001 PM 26460572 ER PT J AU Lewis, AL Dreher, MR O'Byrne, V Grey, D Caine, M Dunn, A Tang, YQ Hall, B Fowers, KD Johnson, CG Sharma, KV Wood, BJ AF Lewis, Andrew L. Dreher, Matthew R. O'Byrne, Vincent Grey, David Caine, Marcus Dunn, Anthony Tang, Yiqing Hall, Brenda Fowers, Kirk D. Johnson, Carmen Gacchina Sharma, Karun V. Wood, Bradford J. TI DC BeadM1 (TM) : towards an optimal transcatheter hepatic tumour therapy SO JOURNAL OF MATERIALS SCIENCE-MATERIALS IN MEDICINE LA English DT Article ID DRUG-ELUTING BEADS; UNRESECTABLE HEPATOCELLULAR-CARCINOMA; TRANSARTERIAL CHEMOEMBOLIZATION TACE; LIVER METASTASES; TECHNICAL RECOMMENDATIONS; ARTERIAL EMBOLIZATION; IN-VITRO; DOXORUBICIN; IRINOTECAN; CANCER AB Clinical use of DC Bead (TM) loaded with doxorubicin (DEBDOX (TM)) or irinotecan (DEBIRI (TM)), for the treatment of primary and secondary tumours of the liver respectively, is showing great promise. Recently there has been a tendency to select smaller bead size ranges to treat tumours in an effort to allow more drug dose to be administered, improve tumoural penetration and resultant drug delivery and tumour coverage. Herein we describe the development and performance characterisation of a new DC Bead size range (DC BeadM1 (TM), 70-150 mu m) capable of an increased bead delivery in the distal vasculature, corresponding to greater tumour coverage and drug dose delivered. Both unloaded and drug loaded DC BeadM1 were shown to have a greater density of distal volume of penetration although the ultimate distal level of penetration was the same as that of the 100-300 mu m beads in an in vitro penetration model. Elution of doxorubicin was slower than irinotecan elution, but it was similar when comparing the same drug elution from 70 to 150 mu m compared to 100-300 mu m beads. Radiopaque versions of 70-150 and 100-300 mu m beads were prepared in order to evaluate distribution ex vivo using mu-CT and doxorubicin distribution using epifluorescent microscopy. Liver distribution of the radiopaque versions of the beads was shown to be more distal and efficient at filling smaller vessels with the DC BeadM1 and correspondingly more beads were found per vessel histologically with a larger area of drug coverage with the smaller size range. This study indicates that the smaller (70-150 mu m) beads should permit an increased dose of drug to be administered to both hypervascular and hypovascular tumours as compared to 100-300 mu m beads. C1 [Lewis, Andrew L.; Dreher, Matthew R.; O'Byrne, Vincent; Grey, David; Caine, Marcus; Dunn, Anthony; Tang, Yiqing; Hall, Brenda; Fowers, Kirk D.] Biocompatibles UK Ltd, Camberley GU15 3YL, England. [Johnson, Carmen Gacchina; Sharma, Karun V.; Wood, Bradford J.] NIH, Dept Radiol & Imaging Sci, Ctr Intervent Oncol, Ctr Clin, Bethesda, MD 20892 USA. [Sharma, Karun V.] Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Lewis, AL (reprint author), Biocompatibles UK Ltd, Riverside Way,Watchmoor Pk, Camberley GU15 3YL, England. EM andrew.lewis@biocompatibles.com NR 56 TC 4 Z9 4 U1 6 U2 9 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-4530 EI 1573-4838 J9 J MATER SCI-MATER M JI J. Mater. Sci.-Mater. Med. PD JAN PY 2016 VL 27 IS 1 AR 13 DI 10.1007/s10856-015-5629-6 PG 12 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA CZ9OA UT WOS:000367425700013 PM 26676859 ER PT J AU Walters, KA D'Agnillo, F Sheng, ZM Kindrachuk, J Schwartzman, LM Kuestner, RE Chertow, DS Golding, BT Taubenberger, JK Kash, JC AF Walters, Kathie-Anne D'Agnillo, Felice Sheng, Zong-Mei Kindrachuk, Jason Schwartzman, Louis M. Kuestner, Rolf E. Chertow, Daniel S. Golding, Basil T. Taubenberger, Jeffery K. Kash, John C. TI 1918 pandemic influenza virus and Streptococcus pneumoniae co-infection results in activation of coagulation and widespread pulmonary thrombosis in mice and humans SO JOURNAL OF PATHOLOGY LA English DT Article DE 1918 influenza; Streptococcus pneumoniae; co-infection; inflammation; extrinsic pathway of coagulation; pulmonary thrombosis ID NEUTROPHIL EXTRACELLULAR TRAPS; BACTERIAL PNEUMONIA; IMMUNE-RESPONSE; HOST IMMUNE; INFECTION; PATHOGENESIS; LUNG; NETS; PATHOGENICITY; NEURAMINIDASE AB To study bacterial co-infection following 1918 H1N1 influenza virus infection, mice were inoculated with the 1918 influenza virus, followed by Streptococcus pneumoniae (SP) 72 h later. Co-infected mice exhibited markedly more severe disease, shortened survival time and more severe lung pathology, including widespread thrombi. Transcriptional profiling revealed activation of coagulation only in co-infected mice, consistent with the extensive thrombogenesis observed. Immunohistochemistry showed extensive expression of tissue factor (F3) and prominent deposition of neutrophil elastase on endothelial and epithelial cells in co-infected mice. Lung sections of SP-positive 1918 autopsy cases showed extensive thrombi and prominent staining for F3 in alveolar macrophages, monocytes, neutrophils, endothelial and epithelial cells, in contrast to co-infection-positive 2009 pandemic H1N1 autopsy cases. This study reveals that a distinctive feature of 1918 influenza virus and SP co-infection in mice and humans is extensive expression of tissue factor and activation of the extrinsic coagulation pathway leading to widespread pulmonary thrombosis. Copyright (c) 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. C1 [Walters, Kathie-Anne; Kuestner, Rolf E.] Inst Syst Biol, Seattle, WA USA. [D'Agnillo, Felice; Golding, Basil T.] US FDA, Lab Biochem & Vasc Biol, Div Hematol Res & Review, Ctr Biol Evaluat & Res,Off Blood Res & Review, Silver Spring, MD USA. [Kindrachuk, Jason; Chertow, Daniel S.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Sheng, Zong-Mei; Schwartzman, Louis M.; Chertow, Daniel S.; Taubenberger, Jeffery K.; Kash, John C.] NIAID, NIH, Infect Dis Lab, Viral Pathogenesis & Evolut Sect, Bethesda, MD 20892 USA. RP Taubenberger, JK (reprint author), NIAID, NIH, Infect Dis Lab, 33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov; kashj@niaid.nih.gov OI Kindrachuk, Jason/0000-0002-3305-7084 FU Intramural Research Programmes of the National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID); Defense Threat Reduction Agency [HDTRA-1-08-C-0023] FX This study was supported by the Intramural Research Programmes of the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID). KAW and REK were supported by the Defense Threat Reduction Agency (Contract No. HDTRA-1-08-C-0023). We thank Dr David Morens at NIAID/NIH for helpful discussions. Animal care was performed by the Comparative Medicine Branch, NIH/NIAID. NR 38 TC 1 Z9 1 U1 3 U2 12 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 JAN PY 2016 VL 238 IS 1 BP 85 EP 97 DI 10.1002/path.4638 PG 13 WC Oncology; Pathology SC Oncology; Pathology GA CZ7QW UT WOS:000367295800010 PM 26383585 ER PT J AU Engelholm, LH Melander, MC Hald, A Persson, M Madsen, DH Jurgensen, HJ Johansson, K Nielsen, C Norregaard, KS Ingvarsen, SZ Kjaer, A Trovik, CS Laerum, OD Bugge, TH Eide, J Behrendt, N AF Engelholm, Lars H. Melander, Maria C. Hald, Andreas Persson, Morten Madsen, Daniel H. Jurgensen, Henrik J. Johansson, Kristina Nielsen, Christoffer Norregaard, Kirstine S. Ingvarsen, Signe Z. Kjaer, Andreas Trovik, Clement S. Laerum, Ole D. Bugge, Thomas H. Eide, Johan Behrendt, Niels TI Targeting a novel bone degradation pathway in primary bone cancer by inactivation of the collagen receptor uPARAP/Endo180 SO JOURNAL OF PATHOLOGY LA English DT Article DE bone cancer; collagen; matrix metalloprotease; matrix degradation; osteosarcoma; uPARAP/Endo180 ID PLASMINOGEN-ACTIVATOR RECEPTOR; BREAST-CANCER; MONOCLONAL-ANTIBODIES; EXTRACELLULAR-MATRIX; ENDOCYTIC RECEPTOR; MANNOSE RECEPTOR; METASTASIS; ENDO180; OSTEOSARCOMA; EXPRESSION AB In osteosarcoma, a primary mesenchymal bone cancer occurring predominantly in younger patients, invasive tumour growth leads to extensive bone destruction. This process is insufficiently understood, cannot be efficiently counteracted and calls for novel means of treatment. The endocytic collagen receptor, uPARAP/Endo180, is expressed on various mesenchymal cell types and is involved in bone matrix turnover during normal bone growth. Human osteosarcoma specimens showed strong expression of this receptor on tumour cells, along with the collagenolytic metalloprotease, MT1-MMP. In advanced tumours with ongoing bone degeneration, sarcoma cells positive for these proteins formed a contiguous layer aligned with the degradation zones. Remarkably, osteoclasts were scarce or absent from these regions and quantitative analysis revealed that this scarcity marked a strong contrast between osteosarcoma and bone metastases of carcinoma origin. This opened the possibility that sarcoma cells might directly mediate bone degeneration. To examine this question, we utilized a syngeneic, osteolytic bone tumour model with transplanted NCTC-2472 sarcoma cells in mice. When analysed in vitro, these cells were capable of degrading the protein component of surface-labelled bone slices in a process dependent on MMP activity and uPARAP/Endo180. Systemic treatment of the sarcoma-inoculated mice with a mouse monoclonal antibody that blocks murine uPARAP/Endo180 led to a strong reduction of bone destruction. Our findings identify sarcoma cell-resident uPARAP/Endo180 as a central player in the bone degeneration of advanced tumours, possibly following an osteoclast-mediated attack on bone in the early tumour stage. This points to uPARAP/Endo180 as a promising therapeutic target in osteosarcoma, with particular prospects for improved neoadjuvant therapy. Copyright (c) 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. C1 [Engelholm, Lars H.; Melander, Maria C.; Hald, Andreas; Jurgensen, Henrik J.; Johansson, Kristina; Nielsen, Christoffer; Norregaard, Kirstine S.; Ingvarsen, Signe Z.; Laerum, Ole D.; Behrendt, Niels] Rigshosp, BRIC, Finsen Lab, Copenhagen, Denmark. [Engelholm, Lars H.; Melander, Maria C.; Hald, Andreas; Persson, Morten; Jurgensen, Henrik J.; Johansson, Kristina; Nielsen, Christoffer; Norregaard, Kirstine S.; Ingvarsen, Signe Z.; Kjaer, Andreas; Laerum, Ole D.; Behrendt, Niels] Univ Copenhagen, DK-2200 Copenhagen, Denmark. [Persson, Morten; Kjaer, Andreas] Rigshosp, Dept Clin Physiol Nucl Med & PET, Copenhagen, Denmark. [Persson, Morten; Kjaer, Andreas] Rigshosp, Cluster Mol Imaging, Copenhagen, Denmark. [Madsen, Daniel H.; Bugge, Thomas H.] NIH, Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodelling Sect, Bethesda, MD 20892 USA. [Trovik, Clement S.] Haukeland Hosp, Dept Oncol Orthopaed, N-5021 Bergen, Norway. [Laerum, Ole D.] Univ Bergen, Gade Lab Pathol, Dept Clin Med, N-5020 Bergen, Norway. [Eide, Johan] Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway. RP Behrendt, N (reprint author), Univ Copenhagen, Rigshosp, BRIC, Finsen Lab, Ole Maaloes Vej 5, DK-2200 Copenhagen N, Denmark. EM niels.behrendt@finsenlab.dk OI Norregaard, Kirstine Sandal/0000-0002-1299-0991; Madsen, Daniel Hargboel/0000-0002-3183-6201; Kjaer, Andreas/0000-0002-2706-5547; Engelholm, Lars/0000-0002-6616-1232 FU Danish Cancer Society; Danish Medical Research Council; Danish National Advanced Technology Foundation; Danish Cancer Research Foundation; Lundbeck Foundation; Novo Nordisk Foundation; AP Moller Foundation; Danish National Research Foundation (Danish-Chinese Centre for Proteases and Cancer); Intramural Research Programme of the National Institutes of Health (NIH), NIDCR, USA; European Community's Seventh Framework Programme FP7 [201279]; Grosserer Alfred Nielsen og Hustrus Foundation; Copenhagen University Hospital FX The excellent technical assistance of Katharina H Stegmann, Lotte B Frederiksen, Lene K Callesen and Bendik Nordanger is gratefully acknowledged. Dr Sanjiv S Gambhir is thanked for the generous gift of the pFU-L2T vector. Senior Statistician Ib Jarle Christensen is thanked for data evaluation and statistical advice. This study was supported by the Danish Cancer Society, the Danish Medical Research Council, the Danish National Advanced Technology Foundation, the Danish Cancer Research Foundation, the Lundbeck Foundation, the Novo Nordisk Foundation, the AP Moller Foundation, the Danish National Research Foundation (Danish-Chinese Centre for Proteases and Cancer), the Intramural Research Programme of the National Institutes of Health (NIH), NIDCR, USA, the European Community's Seventh Framework Programme FP7/2007-2011 (Grant No. 201279) and the Grosserer Alfred Nielsen og Hustrus Foundation. DHM and HJJ received personal fellowship grants from Copenhagen University Hospital. NR 60 TC 2 Z9 3 U1 1 U2 3 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 JAN PY 2016 VL 238 IS 1 BP 120 EP 133 DI 10.1002/path.4661 PG 14 WC Oncology; Pathology SC Oncology; Pathology GA CZ7QW UT WOS:000367295800013 PM 26466547 ER PT J AU van der Stap, DKD Rider, LG Alexanderson, H Huber, AM Gualano, B Gordon, P van der Net, J Mathiesen, P Johnson, LG Ernste, FC Feldman, BM Houghton, KM Singh-Grewal, D Kutzbach, AG Munters, LA Takken, T AF van der Stap, Djamilla K. D. Rider, Lisa G. Alexanderson, Helene Huber, Adam M. Gualano, Bruno Gordon, Patrick van der Net, Janjaap Mathiesen, Pernille Johnson, Liam G. Ernste, Floranne C. Feldman, Brian M. Houghton, Kristin M. Singh-Grewal, Davinder Kutzbach, Abraham Garcia Munters, Li Alemo Takken, Tim CA Int Myositis Assessment TI Proposal for a Candidate Core Set of Fitness and Strength Tests for Patients with Childhood or Adult Idiopathic Inflammatory Myopathies SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE EXERCISE; FITNESS; MYOSITIS; OUTCOME MEASURES; INSTRUMENTS ID MYOSITIS ASSESSMENT SCALE; INCLUSION-BODY MYOSITIS; HOME EXERCISE PROGRAM; JUVENILE DERMATOMYOSITIS; MUSCLE FUNCTION; INTERNATIONAL CONSENSUS; FUNCTIONAL INDEX-2; OUTCOME ASSESSMENT; FOLLOW-UP; POLYMYOSITIS AB Objective. Currently there are no evidence-based recommendations regarding fitness and strength tests for patients with childhood or adult idiopathic inflammatory myopathies (IIM). This hinders clinicians and researchers in choosing the appropriate fitness-or muscle strength-related outcome measures for these patients. Through a Delphi survey, we aimed to identify a candidate core set of fitness and strength tests for children and adults with IIM. Methods. Fifteen experts participated in a Delphi survey that consisted of 5 stages to achieve a consensus. Using an extensive search of published literature and through the work of experts, a candidate core set based on expert opinion and clinimetrics properties was developed. Members of the International Myositis Assessment and Clinical Studies Group were invited to review this candidate core set during the final stage, which led to a final candidate core set. Results. A core set of fitness-and strength-related outcome measures was identified for children and adults with IIM. For both children and adults, different tests were identified and selected for maximal aerobic fitness, submaximal aerobic fitness, anaerobic fitness, muscle strength tests, and muscle function tests. Conclusion. The core set of fitness-and strength-related outcome measures provided by this expert consensus process will assist practitioners and researchers in deciding which tests to use in patients with IIM. This will improve the uniformity of fitness and strength tests across studies, thereby facilitating the comparison of study results and therapeutic exercise program outcomes among patients with IIM. C1 [van der Stap, Djamilla K. D.] Free Univ Amsterdam, Fac Human Movement Sci, Amsterdam, Netherlands. [van der Stap, Djamilla K. D.; van der Net, Janjaap; Takken, Tim] Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Child Dev & Exercise Ctr, NL-3508 AB Utrecht, Netherlands. [Rider, Lisa G.] NIEHS, Environm Autoimmun Grp, NIH, Bethesda, MD USA. [Ernste, Floranne C.] Mayo Clin, Div Rheumatol, Dept Internal Med, Rochester, MN USA. [Munters, Li Alemo] Vanderbilt Univ, Dept Med, Div Rheumatol & Immunol, Nashville, TN 37235 USA. [Alexanderson, Helene] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden. [Alexanderson, Helene] Karolinska Inst, Div Phys Therapy, Stockholm, Sweden. [Alexanderson, Helene; Munters, Li Alemo] Karolinska Univ Hosp, Orthoped Rheumatol Unit, Phys Therapy Clin, Stockholm, Sweden. [Huber, Adam M.] IWK Hlth Ctr, Halifax, NS, Canada. [Huber, Adam M.] Dalhousie Univ, Halifax, NS, Canada. [Feldman, Brian M.] Univ Toronto, Dept Pediat, Toronto, ON, Canada. [Feldman, Brian M.] Univ Toronto, Dept Med, Toronto, ON, Canada. [Feldman, Brian M.] Univ Toronto, Inst Hlth Policy Management & Evaluat, Toronto, ON, Canada. [Feldman, Brian M.] Hosp Sick Children, Div Rheumatol, Toronto, ON M5G 1X8, Canada. [Houghton, Kristin M.] British Columbia Childrens Hosp, Vancouver, BC V6H 3V4, Canada. [Houghton, Kristin M.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Gualano, Bruno] Univ Sao Paulo, Sao Paulo, Brazil. [Gordon, Patrick] Kings Coll Hosp London, Dept Rheumatol, London, England. [Mathiesen, Pernille] Rigshosp, Dept Paediat, Paediat Rheumatol Clin, DK-2100 Copenhagen, Denmark. [Johnson, Liam G.] Univ Victoria, Coll Sport & Exercise Sci, ISEAL, Victoria, BC V8W 2Y2, Canada. [Johnson, Liam G.] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Melbourne, Vic 3010, Australia. [Singh-Grewal, Davinder] Sydney Childrens Hosp Network Randwick & Westmead, Sydney, NSW, Australia. [Singh-Grewal, Davinder] Univ Western Sydney, Dept Paediat, Sydney, NSW, Australia. [Singh-Grewal, Davinder] Univ Sydney, Sch Paediat & Child Hlth, Sydney, NSW 2006, Australia. [Singh-Grewal, Davinder] Univ New S Wales, Discipline Child & Maternal Hlth, Sydney, NSW 2052, Australia. [Singh-Grewal, Davinder] John Hunter Childrens Hosp, Newcastle, NSW, Australia. [Kutzbach, Abraham Garcia] Univ Francisco Marroquin, Sch Med, Guatemala City, Guatemala. RP Takken, T (reprint author), Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Child Dev & Exercise Ctr, KB 02-056-0,POB 85090, NL-3508 AB Utrecht, Netherlands. EM t.takken@umcutrecht.nl RI Gualano, Bruno /C-7190-2012; OI Houghton, Kristin/0000-0001-7174-1007; Chinoy, Hector/0000-0001-6492-1288 FU Intramural Research Program of the National Institute of Environmental Health Sciences, US National Institutes of Health FX Supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, US National Institutes of Health. NR 42 TC 1 Z9 1 U1 0 U2 1 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X EI 1499-2752 J9 J RHEUMATOL JI J. Rheumatol. PD JAN PY 2016 VL 43 IS 1 BP 169 EP 176 DI 10.3899/jrheum.150270 PG 8 WC Rheumatology SC Rheumatology GA DA0AN UT WOS:000367459200023 PM 26568594 ER PT J AU Trabert, B Xu, X Falk, RT Guillemette, C Stanczyk, FZ McGlynn, KA AF Trabert, Britton Xu, Xia Falk, Roni T. Guillemette, Chantal Stanczyk, Frank Z. McGlynn, Katherine A. TI Assay reproducibility of serum androgen measurements using liquid chromatography-tandem mass spectrometry SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE Reproducibility; Serum androgen assay; Liquid chromatography tandem mass spectrometry; Metabolites; Endogenous hormones ID ENDOMETRIAL CANCER-RISK; PROSTATE-CANCER; POSTMENOPAUSAL WOMEN; ENDOGENOUS ESTROGENS; STEROID-HORMONES; SEX-HORMONES; METABOLITES; TESTOSTERONE; OVARIAN; BREAST AB Background: Valid and precise measures of androgen concentrations are needed for etiologic studies of hormonally-related cancers. We developed a high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) method with two sample preparations to measure 11 androgens, including adrenal and gonadal androgenic precursors and their 5 alpha-reduced metabolites. Methods: Androgen levels were measured in serum from 20 healthy volunteers (5 men, 10 premenopausal women, 5 postmenopausal women). Two blinded, randomized aliquots per individual were assayed in each of three batches. A fourth batch of samples was measured at an external laboratory using comparable methodology to measure 9 of the 11 androgens. Coefficients of variation (CV) and intraclass correlation coefficients (ICC) were calculated from the individual components of variance. Comparability of 9 androgens across laboratories was assessed using Spearman ranked correlations, Deming regression and bias plots. Results: The laboratory CVs were <5% and ICCs were uniformly high (>95%) for all androgens measured across sex/menopausal status groups. Spearman ranked correlations for 9 hormones measured in the comparison laboratory were high (>0.85), suggesting good agreement. Conclusion: Our high-performance LC-MS/MS assays of 11 androgens, including adrenal and gonadal androgenic precursors and their 5 alpha-reduced metabolites demonstrated excellent laboratory reproducibility, and good comparability with an established method that measured 9 of the 11 hormones tested. The serum androgen metabolite assays are suitable for use in epidemiologic research. Published by Elsevier Ltd. C1 [Trabert, Britton; Falk, Roni T.; McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Xu, Xia] Leidos Biomed Res Inc, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Guillemette, Chantal] Univ Laval, Ctr Hosp Univ Quebec CHUQ Res Ctr, Pharmacogen Lab, Quebec City, PQ, Canada. [Stanczyk, Frank Z.] Univ So Calif, Keck Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. [Stanczyk, Frank Z.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. RP Trabert, B (reprint author), 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM britton.trabert@nih.gov RI Trabert, Britton/F-8051-2015 FU Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics; National Cancer Institute, Department of Health and Human Services FX This work was supported by the Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services. NR 24 TC 2 Z9 2 U1 2 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD JAN PY 2016 VL 155 BP 56 EP 62 DI 10.1016/j.jsbmb.2015.09.032 PN A PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CZ9NJ UT WOS:000367424000007 PM 26416142 ER PT J AU Bailey, AL Lauck, M Sibley, SD Friedrich, TC Kuhn, JH Freimer, NB Jasinska, AJ Phillips-Conroy, JE Jolly, CJ Marx, PA Apetrei, C Rogers, J Goldberg, TL O'Connor, DH AF Bailey, Adam L. Lauck, Michael Sibley, Samuel D. Friedrich, Thomas C. Kuhn, Jens H. Freimer, Nelson B. Jasinska, Anna J. Phillips-Conroy, Jane E. Jolly, Clifford J. Marx, Preston A. Apetrei, Cristian Rogers, Jeffrey Goldberg, Tony L. O'Connor, David H. TI Zoonotic Potential of Simian Arteriviruses SO JOURNAL OF VIROLOGY LA English DT Review ID HEMORRHAGIC-FEVER; NONHUMAN-PRIMATES; EBOLA-VIRUS; WILD; EMERGENCE; MONKEYS; DISEASE; TRANSMISSION; PATHOGENESIS; PHYLOGENY AB Wild nonhuman primates are immediate sources and long-term reservoirs of human pathogens. However, ethical and technical challenges have hampered the identification of novel blood-borne pathogens in these animals. We recently examined RNA viruses in plasma from wild African monkeys and discovered several novel, highly divergent viruses belonging to the family Arteriviridae. Close relatives of these viruses, including simian hemorrhagic fever virus, have caused sporadic outbreaks of viral hemorrhagic fever in captive macaque monkeys since the 1960s. However, arterivirus infection in wild nonhuman primates had not been described prior to 2011. The arteriviruses recently identified in wild monkeys have high sequence and host species diversity, maintain high viremia, and are prevalent in affected populations. Taken together, these features suggest that the simian arteriviruses may be "preemergent" zoonotic pathogens. If not, this would imply that biological characteristics of RNA viruses thought to facilitate zoonotic transmission may not, by themselves, be sufficient for such transmission to occur. C1 [Bailey, Adam L.; Lauck, Michael; O'Connor, David H.] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53706 USA. [Bailey, Adam L.; Lauck, Michael; Sibley, Samuel D.; Friedrich, Thomas C.; Rogers, Jeffrey; Goldberg, Tony L.; O'Connor, David H.] Wisconsin Natl Primate Res Ctr, Madison, WI USA. [Sibley, Samuel D.; Friedrich, Thomas C.; Goldberg, Tony L.] Univ Wisconsin, Dept Pathobiol Sci, Madison, WI 53706 USA. [Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD USA. [Freimer, Nelson B.; Jasinska, Anna J.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Ctr Neurobehav Genet, Los Angeles, CA 90024 USA. [Phillips-Conroy, Jane E.] Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. [Phillips-Conroy, Jane E.] Washington Univ, Dept Anthropol, St Louis, MO 63130 USA. [Jolly, Clifford J.] NYU, Dept Anthropol, New York, NY 10003 USA. [Marx, Preston A.] Tulane Natl Primate Res Ctr, Covington, LA USA. [Marx, Preston A.] Tulane Sch Publ Hlth & Trop Med, Dept Trop Med, New Orleans, LA USA. [Apetrei, Cristian] Univ Pittsburgh, Ctr Vaccine Res, Pittsburgh, PA USA. [Apetrei, Cristian] Univ Pittsburgh, Dept Microbiol & Mol Genet, Pittsburgh, PA USA. [Rogers, Jeffrey] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. RP O'Connor, DH (reprint author), Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53706 USA. EM doconnor@primate.wisc.edu OI Friedrich, Thomas/0000-0001-9831-6895; Kuhn, Jens H./0000-0002-7800-6045 FU National Institutes of Health (NIH) [R01AI077376-01, R01AI084787, R01RR025781, P01AI088564]; National Science Foundation (NSF) [NSF1029302, NSF1029323, NSF1029451]; NIH-NSF Ecology of Infectious Diseases program [TW009237]; UK Economic and Social Research Council [TW009237]; Wisconsin Partnership Program through the Wisconsin Center for Infectious Diseases; Office of Research Infrastructure Programs (ORIP) [P51RR000167, R01OD010980]; Research Facilities Improvement Program [RR15459-01, RR020141-01]; University of Wisconsin's Medical Scientist Training Program (MSTP) [T32 GM008692]; National Research Service Award (NRSA) through the Microbes in Health and Disease (MHD) training program at the University of Wisconsin-Madison [T32 AI55397]; University of Wisconsin, Department of Pathology and Laboratory Medicine; WNPRC; U.S. National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200700016I] FX This work was funded by the National Institutes of Health (NIH) (R01AI077376-01, R01AI084787, R01RR025781, P01AI088564), the National Science Foundation (NSF) (NSF1029302, NSF1029323, NSF1029451), and the joint NIH-NSF Ecology of Infectious Diseases program and the UK Economic and Social Research Council (TW009237), and by the Wisconsin Partnership Program through the Wisconsin Center for Infectious Diseases. All animal research was approved by the appropriate wildlife authorities and Institutional Animal Care and Use Committees. This publication was made possible in part by grants (P51RR000167, a component of the NIH, to the Wisconsin National Primate Research Center [WNPRC], University of Wisconsin-Madison, and R01OD010980, formerly R01RR016300, to the University of California Los Angeles [UCLA]) from the Office of Research Infrastructure Programs (ORIP). This research was conducted in part at a facility constructed with support from the Research Facilities Improvement Program, grant numbers RR15459-01 and RR020141-01. A.L.B. performed this work with support from the University of Wisconsin's Medical Scientist Training Program (MSTP) (grant T32 GM008692) and a National Research Service Award (NRSA) through the Microbes in Health and Disease (MHD) training program at the University of Wisconsin-Madison (T32 AI55397). We thank the University of Wisconsin, Department of Pathology and Laboratory Medicine, and the WNPRC for funding and the use of its facilities and services. We thank the Department of Environmental Affairs, South Africa; Department of Tourism, Environmental and Economic Affairs, Free State Province; the Ezemvelo KZN Wildlife in KwaZulu Natal Province; and Department of Economic Development and Environmental Affairs, Eastern Cape. This work was also funded in part through Battelle Memorial Institute's prime contract with the U.S. National Institute of Allergy and Infectious Diseases (NIAID) under contract HHSN272200700016I. Subcontractors to Battelle Memorial Institute who performed this work are: J.H.K., an employee of Tunnell Government Services, Inc. This publication's contents are solely the responsibility of the author(s) and do not necessarily represent the official views of ORIP, NIH, U.S. Department of Health and Human Services, or of the institutions and companies affiliated with the authors. The funders of this research had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 4 Z9 4 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2016 VL 90 IS 2 BP 630 EP 635 DI 10.1128/JVI.01433-15 PG 6 WC Virology SC Virology GA DA1AE UT WOS:000367527900002 PM 26559828 ER PT J AU Martins, AN Waheed, AA Ablan, SD Huang, W Newton, A Petropoulos, CJ Brindeiro, RDM Freed, EO AF Martins, Angelica N. Waheed, Abdul A. Ablan, Sherimay D. Huang, Wei Newton, Alicia Petropoulos, Christos J. Brindeiro, Rodrigo D. M. Freed, Eric O. TI Elucidation of the Molecular Mechanism Driving Duplication of the HIV-1 PTAP Late Domain SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; GAG CLEAVAGE SITES; RESOURCE-LIMITED SETTINGS; RECOMBINANT VACCINIA VIRUS; DRUG-RESISTANCE; PROTEASE INHIBITORS; TYPE-1 GAG; VIRAL FITNESS; AMINO-ACID; ANTIRETROVIRAL THERAPY AB HIV-1 uses cellular machinery to bud from infected cells. This cellular machinery is comprised of several multiprotein complexes known as endosomal sorting complexes required for transport (ESCRTs). A conserved late domain motif, Pro-Thr-Ala-Pro (PTAP), located in the p6 region of Gag (p6(Gag)), plays a central role in ESCRT recruitment to the site of virus budding. Previous studies have demonstrated that PTAP duplications are selected in HIV-1-infected patients during antiretroviral therapy; however, the consequences of these duplications for HIV-1 biology and drug resistance are unclear. To address these questions, we constructed viruses carrying a patient-derived PTAP duplication with and without drug resistance mutations in the viral protease. We evaluated the effect of the PTAP duplication on viral release efficiency, viral infectivity, replication capacity, drug susceptibility, and Gag processing. In the presence of protease inhibitors, we observed that the PTAP duplication in p6Gag significantly increased the infectivity and replication capacity of the virus compared to those of viruses bearing only resistance mutations in protease. Our biochemical analysis showed that the PTAP duplication, in combination with mutations in protease, enhances processing between the nucleocapsid and p6 domains of Gag, resulting in more complete Gag cleavage in the presence of protease inhibitors. These results demonstrate that duplication of the PTAP motif in p6Gag confers a selective advantage in viral replication by increasing Gag processing efficiency in the context of protease inhibitor treatment, thereby enhancing the drug resistance of the virus. These findings highlight the interconnected role of PTAP duplications and protease mutations in the development of resistance to antiretroviral therapy. IMPORTANCE Resistance to current drug therapy limits treatment options in many HIV-1-infected patients. Duplications in a Pro-Thr-Ala-Pro (PTAP) motif in the p6 domain of Gag are frequently observed in viruses derived from patients on protease inhibitor (PI) therapy. However, the reason that these duplications arise and their consequences for virus replication remain to be established. In this study, we examined the effect of PTAP duplication on PI resistance in the context of wild-type protease or protease bearing PI resistance mutations. We observe that PTAP duplication markedly enhances resistance to a panel of PIs. Biochemical analysis reveals that the PTAP duplication reverses a Gag processing defect imposed by the PI resistance mutations in the context of PI treatment. The results provide a long-sought explanation for why PTAP duplications arise in PI-treated patients. C1 [Martins, Angelica N.; Waheed, Abdul A.; Ablan, Sherimay D.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Huang, Wei; Newton, Alicia; Petropoulos, Christos J.] Monogram Biosci, San Francisco, CA USA. [Brindeiro, Rodrigo D. M.] Univ Fed Rio de Janeiro, Mol Virol Lab, Rio De Janeiro, Brazil. RP Freed, EO (reprint author), NCI, Virus Cell Interact Sect, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21701 USA. EM efreed@nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH; Intramural AIDS Targeted Antiviral Program FX Work in the E. O. Freed laboratory is supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH, and by the Intramural AIDS Targeted Antiviral Program. NR 77 TC 4 Z9 4 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2016 VL 90 IS 2 BP 768 EP 779 DI 10.1128/JVI.01640-15 PG 12 WC Virology SC Virology GA DA1AE UT WOS:000367527900014 PM 26512081 ER PT J AU Fontana, J Keller, PW Urano, E Ablan, SD Steven, AC Freed, EO AF Fontana, Juan Keller, Paul W. Urano, Emiko Ablan, Sherimay D. Steven, Alasdair C. Freed, Eric O. TI Identification of an HIV-1 Mutation in Spacer Peptide 1 That Stabilizes the Immature CA-SP1 Lattice SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; MATURATION INHIBITOR BEVIRIMAT; VIRION MATURATION; RECONSTRUCTIONS; POLYMORPHISMS; TOMOGRAPHY; PARTICLE; PROTEIN; PA-457; MICROSCOPY AB Upon release of HIV-1 particles from the infected cell, the viral protease cleaves the Gag polyprotein at specific sites, triggering maturation. During this process, which is essential for infectivity, the capsid protein (CA) reassembles into a conical core. Maturation inhibitors (MIs) block HIV-1 maturation by interfering with protease-mediated CA-spacer peptide 1 (CA-SP1) processing, concomitantly stabilizing the immature CA-SP1 lattice; virions from MI-treated cells retain an immature-like CA-SP1 lattice, whereas mutational abolition of cleavage at the CA-SP1 site results in virions in which the CA-SP1 lattice converts to a mature-like form. We previously reported that propagation of HIV-1 in the presence of MI PF-46396 selected for assembly-defective, compound-dependent mutants with amino acid substitutions in the major homology region (MHR) of CA. Propagation of these mutants in the absence of PF-46396 resulted in the acquisition of second-site compensatory mutations. These included a Thr-to-Ile substitution at SP1 residue 8 (T8I), which results in impaired CA-SP1 processing. Thus, the T8I mutation phenocopies PF-46396 treatment in terms of its ability to rescue the replication defect imposed by the MHR mutations and to impede CA-SP1 processing. Here, we use cryo-electron tomography to show that, like MIs, the T8I mutation stabilizes the immature-like CA-SP1 lattice. These results have important implications for the mechanism of action of HIV-1 MIs; they also suggest that T8I may provide a valuable tool for structural definition of the CA-SP1 boundary region, which has thus far been refractory to high-resolution analysis, apparently because of conformational flexibility in this region of Gag. IMPORTANCE HIV-1 maturation involves dissection of the Gag polyprotein by the viral protease and assembly of a conical capsid enclosing the viral ribonucleoprotein. Maturation inhibitors (MIs) prevent the final cleavage step at the site between the capsid protein (CA) and spacer peptide 1 (SP1), apparently by binding at this site and denying the protease access. Additionally, MIs stabilize the immature-like CA-SP1 lattice, preventing release of CA into the soluble pool. We previously found that T8I, a mutation in SP1, rescues a PF-46396-dependent CA mutant and blocks CA-SP1 cleavage. In this study, we imaged T8I virions by cryo-electron tomography and showed that T8I mutants, like MI-treated virions, contain an immature CA-SP1 lattice. These results lay the groundwork needed to understand the structure of the CA-SP1 interface region and further illuminate the mechanism of action of MIs. C1 [Fontana, Juan; Keller, Paul W.; Steven, Alasdair C.] NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. [Urano, Emiko; Ablan, Sherimay D.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov; efreed@nih.gov RI Fontana, Juan/A-9138-2009 OI Fontana, Juan/0000-0002-9084-2927 FU HHS\ National Institutes of Health (NIH) \ Intramural Research Program [AR041166, BC010778]; Intramural AIDS Targeted Antiviral Program FX HHS vertical bar National Institutes of Health (NIH) vertical bar Intramural Research Program provided funding to Alasdair C. Steven and Eric O. Freed under grant numbers AR041166 and BC010778.; Funding was also provided by the Intramural AIDS Targeted Antiviral Program. NR 43 TC 4 Z9 5 U1 1 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2016 VL 90 IS 2 BP 972 EP 978 DI 10.1128/JVI.02204-15 PG 7 WC Virology SC Virology GA DA1AE UT WOS:000367527900030 ER PT J AU Dyer, KD Drummond, RA Rice, TA Percopo, CM Brenner, TA Barisas, DAG Karpe, KA Moore, ML Rosenberg, HF AF Dyer, Kimberly D. Drummond, Rebecca A. Rice, Tyler A. Percopo, Caroline M. Brenner, Todd A. Barisas, Derek A. G. Karpe, Kendal A. Moore, Martin L. Rosenberg, Helene F. TI Priming of the Respiratory Tract with Immunobiotic Lactobacillus plantarum Limits Infection of Alveolar Macrophages with Recombinant Pneumonia Virus of Mice (rK2-PVM) SO JOURNAL OF VIROLOGY LA English DT Article ID LETHAL PNEUMOVIRUS INFECTION; INFLUENZA-A VIRUS; MOUSE LUNG-TISSUE; SYNCYTIAL VIRUS; DENDRITIC CELLS; T-CELLS; REVERSE GENETICS; INNATE IMMUNITY; HOST-DEFENSE; DISEASE AB Pneumonia virus of mice (PVM) is a natural rodent pathogen that replicates in bronchial epithelial cells and reproduces many clinical and pathological features of the more severe forms of disease associated with human respiratory syncytial virus. In order to track virus-target cell interactions during acute infection in vivo, we developed rK2-PVM, bacterial artificial chromosome-based recombinant PVM strain J3666 that incorporates the fluorescent tag monomeric Katushka 2 (mKATE2). The rK2-PVM pathogen promotes lethal infection in BALB/c mice and elicits characteristic cytokine production and leukocyte recruitment to the lung parenchyma. Using recombinant virus, we demonstrate for the first time PVM infection of both dendritic cells (DCs; CD11c(+) major histocompatibility complex class II+) and alveolar macrophages (AMs; CD11c(+) sialic acid-binding immunoglobulin-like lectin F+) in vivo and likewise detect mKATE2(+) DCs in mediastinal lymph nodes from infected mice. AMs support both active virus replication and production of infectious virions. Furthermore, we report that priming of the respiratory tract with immunobiotic Lactobacillus plantarum, a regimen that results in protection against the lethal inflammatory sequelae of acute respiratory virus infection, resulted in differential recruitment of neutrophils, DCs, and lymphocytes to the lungs in response to rK2-PVM and a reduction from similar to 40% to <10% mKATE2(+) AMs in association with a 2-log drop in the release of infectious virions. In contrast, AMs from L. plantarum-primed mice challenged with virus ex vivo exhibited no differential susceptibility to rK2-PVM. Although the mechanisms underlying Lactobacillus-mediated viral suppression remain to be fully elucidated, this study provides insight into the cellular basis of this response. IMPORTANCE Pneumonia virus of mice (PVM) is a natural mouse pathogen that serves as a model for severe human respiratory syncytial virus disease. Wehave developed a fully functional recombinant PVM strain with a fluorescent reporter protein (rK2-PVM) that permits us to track infection of target cells in vivo. With rK2-PVM, we demonstrate infection of leukocytes in the lung, notably, dendritic cells and alveolar macrophages. Alveolar macrophages undergo productive infection and release infectious virions. Wehave shown previously that administration of immunobiotic Lactobacillus directly to the respiratory mucosa protects mice from the lethal sequelae of PVM infection in association with profound suppression of the virus-induced inflammatory response. We show here that Lactobacillus administration also limits infection of leukocytes in vivo and results in diminished release of infectious virions from alveolar macrophages. This is the first study to provide insight into the cellular basis of the antiviral impact of immunobiotic L. plantarum. C1 [Dyer, Kimberly D.; Rice, Tyler A.; Percopo, Caroline M.; Brenner, Todd A.; Barisas, Derek A. G.; Karpe, Kendal A.; Rosenberg, Helene F.] NIAID, Inflammat Immunobiol Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Drummond, Rebecca A.] NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Moore, Martin L.] Emory Univ, Sch Med, Div Pediat Infect Dis, Atlanta, GA USA. [Moore, Martin L.] Childrens Healthcare Atlanta, Atlanta, GA USA. RP Rosenberg, HF (reprint author), NIAID, Inflammat Immunobiol Sect, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov OI Brenner, Todd/0000-0003-0541-2234; Drummond, Rebecca/0000-0001-5424-7074 FU NIH [1R01AI087798, 1U19AI095227]; Division of Intramural Research funding [AI000943] FX This work was funded by NIH grants 1R01AI087798 and 1U19AI095227 to M.L.M. and Division of Intramural Research funding AI000943 to H.F.R. NR 75 TC 2 Z9 2 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2016 VL 90 IS 2 BP 979 EP 991 DI 10.1128/JVI.02279-15 PG 13 WC Virology SC Virology GA DA1AE UT WOS:000367527900031 PM 26537680 ER PT J AU Cerqueira, C Pang, YYS Day, PM Thompson, CD Buck, CB Lowy, DR Schiller, JT AF Cerqueira, Carla Pang, Yuk-Ying S. Day, Patricia M. Thompson, Cynthia D. Buck, Christopher B. Lowy, Douglas R. Schiller, John T. TI A Cell-Free Assembly System for Generating Infectious Human Papillomavirus 16 Capsids Implicates a Size Discrimination Mechanism for Preferential Viral Genome Packaging SO JOURNAL OF VIROLOGY LA English DT Article ID VIRUS-LIKE PARTICLES; IN-VITRO; NUCLEAR IMPORT; PROTEIN L2; BOVINE PAPILLOMAVIRUS; GAMMA SECRETASE; POLYOMA TYPE; PLASMID DNA; LIFE-CYCLE; TYPE-16 L1 AB We have established a cell-free in vitro system to study human papillomavirus type 16 (HPV16) assembly, a poorly understood process. L1/L2 capsomers, obtained from the disassembly of virus-like particles (VLPs), were incubated with nuclear extracts to provide access to the range of cellular proteins that would be available during assembly within the host cell. Incorporation of a reporter plasmid "pseudogenome" was dependent on the presence of both nuclear extract and ATP. Unexpectedly, L1/L2 VLPs that were not disassembled prior to incubation with a reassembly mixture containing nuclear extract also encapsidated a reporter plasmid. As with HPV pseudoviruses (PsV) generated intracellularly, infection by cell-free particles assembled in vitro required the presence of L2 and was susceptible to the same biochemical inhibitors, implying the cell-free assembled particles use the infectious pathway previously described for HPV16 produced in cell culture. Using biochemical and electron microscopy analyses, we observed that, in the presence of nuclear extract, intact VLPs partially disassemble, providing a mechanistic explanation to how the exogenous plasmid was packaged by these particles. Further, we provide evidence that capsids containing an <8-kb pseudogenome are resistant to the disassembly/reassembly reaction. Our results suggest a novel size discrimination mechanism for papillomavirus genome packaging in which particles undergo iterative rounds of disassembly/reassembly, seemingly sampling DNA until a suitably sized DNA is encountered, resulting in the formation of a stable virion structure. IMPORTANCE Little is known about papillomavirus assembly biology due to the difficulties in propagating virus in vitro. The cell-free assembly method established in this paper reveals a new mechanism for viral genome packaging and will provide a tractable system for further dissecting papillomavirus assembly. The knowledge gained will increase our understanding of virus-host interactions, help to identify new targets for antiviral therapy, and allow for the development of new gene delivery systems based on in vitro-generated papillomavirus vectors. C1 [Cerqueira, Carla; Pang, Yuk-Ying S.; Day, Patricia M.; Thompson, Cynthia D.; Buck, Christopher B.; Lowy, Douglas R.; Schiller, John T.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Schiller, JT (reprint author), NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. EM schillej@mail.nih.gov FU National Cancer Institute, National Institutes of Health FX This work was supported by intramural funding from the National Cancer Institute, National Institutes of Health. NR 64 TC 2 Z9 2 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2016 VL 90 IS 2 BP 1096 EP 1107 DI 10.1128/JVI.02497-15 PG 12 WC Virology SC Virology GA DA1AE UT WOS:000367527900041 ER PT J AU Liu, XQ Cohen, JI AF Liu, XueQiao Cohen, Jeffrey I. TI Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Promotes EBV Reactivation through Activation of the p38 Mitogen-Activated Protein Kinase SO JOURNAL OF VIROLOGY LA English DT Article ID HERPES-SIMPLEX-VIRUS; GROWTH-FACTOR-BETA; SIGNAL-TRANSDUCTION; GENE-EXPRESSION; TRANSCRIPTION FACTOR; MEMBRANE-PROTEINS; RNA INTERFERENCE; LEUCINE-ZIPPER; JNK PATHWAY; BZLF1 GENE AB Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus associated with both B cell and epithelial cell malignancies. EBV infection of B cells triggers activation of several signaling pathways that are critical for cell survival, virus latency, and growth transformation. To identify EBV proteins important for regulating cell signaling, we used a proteomic approach to screen viral proteins for AP-1 and NF-kappa B promoter activity in AP-1-and NF-kappa B-luciferase reporter assays. We found that EBV BGLF2 activated AP-1 but not NF-kappa B reporter activity. Expression of EBV BGLF2 in cells activated p38 and c-Jun N-terminal kinase (JNK), both of which are important for mitogen-activated protein kinase (MAPK) signaling. Deletion of the carboxyl-terminal 66 amino acids of BGLF2 reduced the ability of BGLF2 to activate JNK and p38. Expression of BGLF2 enhanced BZLF1 expression in latently EBV-infected lymphoblastoid cell lines, and knockdown of BGLF2 reduced EBV reactivation induced by IgG cross-linking. Expression of BGLF2 induced BZLF1 expression and virus production in EBV-infected gastric carcinoma cells. BGLF2 enhanced BZLF1 expression and EBV production by activating p38; chemical inhibition of p38 and MAPK/ERK kinases 1 and 2 (MEK1/2) reduced expression of BZLF1 and virus production induced by BGLF2. In summary, the EBV tegument protein BGLF2, which is delivered to the cell at the onset of virus infection, activates the AP-1 pathway and enhances EBV reactivation and virus production. IMPORTANCE Epstein-Barr virus (EBV) is associated with both B cell and epithelial cell malignancies, and the virus activates multiple signaling pathways important for its persistence in latently infected cells. We identified a viral tegument protein, BGLF2, which activates members of the mitogen-activated protein kinase signaling pathway. Expression of BGLF2 increased expression of EBV BZLF1, which activates a switch from latent to lytic virus infection, and increased production of EBV. Inhibition of BGFL2 expression or inhibition of p38/MAPK, which is activated by BGLF2, reduced virus reactivation from latency. These results indicate that a viral tegument protein which is delivered to cells upon infection activates signaling pathways to enhance virus production and facilitate virus reactivation from latency. C1 [Liu, XueQiao; Cohen, Jeffrey I.] NIAID, Med Virol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIAID, Med Virol Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID) FX Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID) provided funding to XueQiao Liu and Jeffrey I Cohen. NR 63 TC 3 Z9 3 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2016 VL 90 IS 2 BP 1129 EP 1138 DI 10.1128/JVI.01410-15 PG 10 WC Virology SC Virology GA DA1AE UT WOS:000367527900044 ER PT J AU Moore, IN Lamirande, EW Paskel, M Donahue, D Kenney, H Qin, J Subbarao, K AF Moore, Ian N. Lamirande, Elaine W. Paskel, Myeisha Donahue, Danielle Kenney, Heather Qin, Jing Subbarao, Kanta TI Severity of Clinical Disease and Pathology in Ferrets Experimentally Infected with Influenza Viruses Is Influenced by Inoculum Volume (vol 88, pg 13879, 2014) SO JOURNAL OF VIROLOGY LA English DT Correction C1 [Moore, Ian N.; Lamirande, Elaine W.; Paskel, Myeisha; Kenney, Heather; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Donahue, Danielle] NINDS, Mouse Imaging Facil, NIH, Bethesda, MD 20892 USA. [Qin, Jing] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Moore, IN (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2016 VL 90 IS 2 BP 1153 EP 1153 DI 10.1128/JVI.02806-15 PG 1 WC Virology SC Virology GA DA1AE UT WOS:000367527900049 PM 26719560 ER PT J AU Martins, NMC Bergmann, JH Shono, N Kimura, H Larionov, V Masumoto, H Earnshaw, WC AF Martins, Nuno M. C. Bergmann, Jan H. Shono, Nobuaki Kimura, Hiroshi Larionov, Vladimir Masumoto, Hiroshi Earnshaw, William C. TI Epigenetic engineering shows that a human centromere resists silencing mediated by H3K27me3/K9me3 SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID HUMAN ARTIFICIAL CHROMOSOMES; POLYCOMB RESPONSE ELEMENT; HISTONE H3.3 REPLACEMENT; INNER KINETOCHORE PLATE; ALPHA-SATELLITE DNA; RNA-POLYMERASE-II; CENP-A; HUMAN GENOME; FUNCTIONAL CENTROMERES; ACTIVE CHROMATIN AB Centromeres are characterized by the centromere-specific H3 variant CENP-A, which is embedded in chromatin with a pattern characteristic of active transcription that is required for centromere identity. It is unclear how centromeres remain transcriptionally active despite being flanked by repressive pericentric heterochromatin. To further understand centrochromatin's response to repressive signals, we nucleated a Polycomb-like chromatin state within the centromere of a human artificial chromosome (HAC) by tethering the methyltransferase EZH2. This led to deposition of the H3K27me3 MARK and PRC1 repressor binding. Surprisingly, this state did not abolish HAC centromere function or transcription, and this apparent resistance was not observed on a noncentromeric locus, where transcription was silenced. Directly tethering the READER/repressor PRC1 bypassed this resistance, inactivating the centromere. We observed analogous responses when tethering the heterochromatin EDITOR Suv39h1-methyltransferase domain (centromere resistance) or READER HP1 alpha (centromere inactivation), respectively. Our results reveal that the HAC centromere can resist repressive pathways driven by H3K9me3/H3K27me3 and may help to explain how centromeres are able to resist inactivation by flanking heterochromatin. C1 [Martins, Nuno M. C.; Bergmann, Jan H.; Earnshaw, William C.] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland. [Shono, Nobuaki; Masumoto, Hiroshi] Kazusa DNA Res Inst, Dept Frontier Res, Lab Cell Engn, Kisarazu 2920818, Japan. [Shono, Nobuaki] Nagoya Univ, Grad Sch Sci, Div Biol Sci, Nagoya, Aichi 4648602, Japan. [Kimura, Hiroshi] Tokyo Inst Technol, Grad Sch Biosci & Biotechnol, Yokohama, Kanagawa 2268501, Japan. [Larionov, Vladimir] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Earnshaw, WC (reprint author), Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland. EM bill.earnshaw@ed.ac.uk RI Shono, Nobuaki/C-4130-2017; OI Shono, Nobuaki/0000-0002-9060-1074; Martins, Nuno/0000-0003-3953-9313 FU Wellcome Trust [107022, 080458]; Ministry of Education, Culture, Sports, Science and Technology of Japan KAKENHI Grants [23247030, 23114008]; Kazusa DNA Research Institute Foundation; Japan Society for the Promotion of Science; Ministry of Education, Culture, Sports, Science and Technology of Japan; National Institutes of Health, National Cancer Institute, Center for Cancer Research; Fundacao para a Ciencia e a Tecnologia [SFRH/BD/62092/2009]; [077707]; [092076] FX We thank Irina Stancheva, Patrick Heun, Philipp Voigt, and Nadine Vincenten for critical discussions and feedback on the manuscript. We thank Alexander Kagansky for the design and construction of the TetR-EYFP-Suv39h1SET expression construct. This work was funded by the Wellcome Trust, of which W.C.E. is a Principal Research Fellow (Grant 107022). The Wellcome Trust Centre for Cell Biology is supported by core grants 077707 and 092076. Additional experiments were supported by Ministry of Education, Culture, Sports, Science and Technology of Japan KAKENHI Grants 23247030 and 23114008 and the Kazusa DNA Research Institute Foundation (H.M.); grants-in-aid from the Japan Society for the Promotion of Science and the Ministry of Education, Culture, Sports, Science and Technology of Japan (H.K.); and the intramural research program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (V.L.). N.M.C.M. was funded by a PhD studentship from the Fundacao para a Ciencia e a Tecnologia (SFRH/BD/62092/2009), and J.H.B. was funded by a PhD studentship from the Wellcome Trust (080458). NR 102 TC 4 Z9 5 U1 2 U2 6 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JAN 1 PY 2016 VL 27 IS 1 BP 177 EP 196 DI 10.1091/mbc.E15-08-0605 PG 20 WC Cell Biology SC Cell Biology GA CZ7CB UT WOS:000367256400015 PM 26564795 ER PT J AU Ntai, I LeDuc, RD Fellers, RT Erdmann-Gilmore, P Davies, SR Rumsey, J Early, BP Thomas, PM Li, SQ Compton, PD Ellis, MJC Ruggles, KV Fenyo, D Boja, ES Rodriguez, H Townsend, RR Kelleher, NL AF Ntai, Ioanna LeDuc, Richard D. Fellers, Ryan T. Erdmann-Gilmore, Petra Davies, Sherri R. Rumsey, Jeanne Early, Bryan P. Thomas, Paul M. Li, Shunqiang Compton, Philip D. Ellis, Matthew J. C. Ruggles, Kelly V. Fenyoe, David Boja, Emily S. Rodriguez, Henry Townsend, R. Reid Kelleher, Neil L. TI Integrated Bottom-Up and Top-Down Proteomics of Patient-Derived Breast Tumor Xenografts SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID INTERMEDIATE-FILAMENTS; PROTEIN; CANCER; COMBINATION; SEPARATION; ORBITRAP; BIOLOGY; LESIONS AB Bottom-up proteomics relies on the use of proteases and is the method of choice for identifying thousands of protein groups in complex samples. Top-down proteomics has been shown to be robust for direct analysis of small proteins and offers a solution to the "peptide-to-protein" inference problem inherent with bottom-up approaches. Here, we describe the first large-scale integration of genomic, bottom-up and top-down proteomic data for the comparative analysis of patient-derived mouse xenograft models of basal and luminal B human breast cancer, WHIM2 and WHIM16, respectively. Using these well-characterized xenograft models established by the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium, we compared and contrasted the performance of bottom-up and top-down proteomics to detect cancer-specific aberrations at the peptide and proteoform levels and to measure differential expression of proteins and proteoforms. Bottom-up proteomic analysis of the tumor xenografts detected almost 10 times as many coding nucleotide polymorphisms and peptides resulting from novel splice junctions than top-down. For proteins in the range of 0-30 kDa, where quantitation was performed using both approaches, bottom-up proteomics quantified 3,519 protein groups from 49,185 peptides, while top-down proteomics quantified 982 proteoforms mapping to 358 proteins. Examples of both concordant and discordant quantitation were found in a similar to 60:40 ratio, providing a unique opportunity for top-down to fill in missing information. The two techniques showed complementary performance, with bottom-up yielding eight times more identifications of 0-30 kDa proteins in xenograft proteomes, but failing to detect differences in certain post-translational modifications (PTMs), such as phosphorylation pattern changes of alpha-endosulfine. This work illustrates the potency of a combined bottom-up and top-down proteomics approach to deepen our knowledge of cancer biology, especially when genomic data are available. C1 [LeDuc, Richard D.; Fellers, Ryan T.; Early, Bryan P.; Thomas, Paul M.; Compton, Philip D.; Kelleher, Neil L.] Northwestern Univ, Prote Ctr Excellence, Evanston, IL 60208 USA. [Ntai, Ioanna; Kelleher, Neil L.] Northwestern Univ, Dept Chem, Evanston, IL 60208 USA. [Thomas, Paul M.; Kelleher, Neil L.] Northwestern Univ, Dept Mol Biosci, Evanston, IL 60208 USA. [Erdmann-Gilmore, Petra; Davies, Sherri R.; Rumsey, Jeanne; Li, Shunqiang; Compton, Philip D.; Townsend, R. Reid] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA. [Ellis, Matthew J. C.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Ruggles, Kelly V.; Fenyoe, David] NYU, Sch Med, Ctr Hlth Informat & Bioinformat, New York, NY 10016 USA. [Ruggles, Kelly V.; Fenyoe, David] NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY 10016 USA. [Boja, Emily S.; Rodriguez, Henry] NCI, Off Canc Clin Prote Res, Bethesda, MD 20892 USA. RP Townsend, RR (reprint author), Washington Univ, St Louis, MO 63110 USA. EM rtownsend@wustl.edu; n-kelleher@northwestern.edu RI Thomas, Paul/A-6233-2011; Compton, Philip/A-9921-2013; OI Thomas, Paul/0000-0003-2887-4765; Compton, Philip/0000-0001-5212-7175; Fenyo, David/0000-0001-5049-3825; Ruggles, Kelly/0000-0002-0152-0863 FU National Institute of General Medical Sciences (NLK) [GM067193]; Federal Funds from National Cancer Institute (Office of Cancer Clinical Proteomics Research), National Institutes of Health [HHSN261200800001E]; National Science Foundation [ABI-1062432] FX This work was supported by Award No. GM067193 from the National Institute of General Medical Sciences (NLK), Federal Funds from the National Cancer Institute (Office of Cancer Clinical Proteomics Research), National Institutes of Health, under Contract No. HHSN261200800001E, and the Office for Research at Northwestern University. This research was also partially supported by the National Science Foundation under grant no. ABI-1062432 to Indiana University (RDL). The content of this publication does not necessarily reflect the views of 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. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation, the National Institutes of Health, the National Center for Genome Analysis Support, Northwestern University, or Indiana University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 35 TC 8 Z9 9 U1 3 U2 18 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD JAN PY 2016 VL 15 IS 1 BP 45 EP 56 DI 10.1074/mcp.M114.047480 PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DA0BF UT WOS:000367461000004 PM 26503891 ER PT J AU Ren, SC Shao, YP Zhao, XJ Hong, CS Wang, FB Lu, X Li, J Ye, GZ Yan, M Zhuang, ZP Xu, CL Xu, GW Sun, YH AF Ren, Shancheng Shao, Yaping Zhao, Xinjie Hong, Christopher S. Wang, Fubo Lu, Xin Li, Jia Ye, Guozhu Yan, Min Zhuang, Zhengping Xu, Chuanliang Xu, Guowang Sun, Yinghao TI Integration of Metabolomics and Transcriptomics Reveals Major Metabolic Pathways and Potential Biomarker Involved in Prostate Cancer SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID GLYCINE-N-METHYLTRANSFERASE; TERT-BUTYL ETHER; SPHINGOSINE 1-PHOSPHATE; EXPRESSION ANALYSIS; CELL MIGRATION; PROGRESSION; SPHINGOSINE-1-PHOSPHATE; TRANSFERASE; METASTASIS; RECEPTOR AB Prostate cancer is a highly prevalent tumor affecting millions of men worldwide, but poor understanding of its pathogenesis has limited effective clinical management of patients. In addition to transcriptional profiling or transcriptomics, metabolomics is being increasingly utilized to discover key molecular changes underlying tumorigenesis. In this study, we integrated transcriptomics and metabolomics to analyze 25 paired human prostate cancer tissues and adjacent noncancerous tissues, followed by further validation of our findings in an additional cohort of 51 prostate cancer patients and 16 benign prostatic hyperplasia patients. We found several altered pathways aberrantly expressed at both metabolic and transcriptional levels, including cysteine and methionine metabolism, nicotinamide adenine dinucleotide metabolism, and hexosamine biosynthesis. Additionally, the metabolite sphingosine demonstrated high specificity and sensitivity for distinguishing prostate cancer from benign prostatic hyperplasia, particularly for patients with low prostate specific antigen level (0-10 ng/ml). We also found impaired sphingosine-1-phosphate receptor 2 signaling, downstream of sphingosine, representing a loss of tumor suppressor gene and a potential key oncogenic pathway for therapeutic targeting. By integrating metabolomics and transcriptomics, we have provided both a broad picture of the molecular perturbations underlying prostate cancer and a preliminary study of a novel metabolic signature, which may help to discriminate prostate cancer from normal tissue and benign prostatic hyperplasia. C1 [Ren, Shancheng; Wang, Fubo; Xu, Chuanliang; Sun, Yinghao] Second Mil Med Univ, Shanghai Changhai Hosp, Dept Urol, Shanghai, Peoples R China. [Shao, Yaping; Zhao, Xinjie; Lu, Xin; Li, Jia; Ye, Guozhu; Yan, Min; Xu, Guowang] Chinese Acad Sci, Dalian Inst Chem Phys, Key Lab Separat Sci Analyt Chem, Dalian 116023, Peoples R China. [Hong, Christopher S.; Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Xu, GW (reprint author), Second Mil Med Univ, Shanghai Changhai Hosp, Dept Urol, Shanghai, Peoples R China. EM xugw@dicp.ac.cn; sunyh@medmail.com.cn FU National Basic Research Program of China [2012CB518303, 2012CB518306]; National Natural Science Foundation of China [21435006, 21321064, 81430058, 81101946, 81472397]; Shanghai Pujiang Program [12PJD008]; Prostate Cancer Foundation; Shanghai Municipal Health and Family Planning Commission [XYQ2013077]; Shanghai Municipal Education Commission; National Institute of Neurological Disorders and Stroke at the National Institutes of Health (Bethesda, MD) FX The work was supported by the National Basic Research Program (No. 2012CB518303, 2012CB518306) of China, the Key Program (21435006), the Creative Research Group project (No. 21321064) and general projects (81430058, 81101946, 81472397) from the National Natural Science Foundation of China, the Shanghai Pujiang Program (12PJD008), Prostate Cancer Foundation Young Investigator Award, Shanghai Municipal Health and Family Planning Commission Outstanding Young Investigator (XYQ2013077), Shanghai Municipal Education Commission. Additional support was provided by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (Bethesda, MD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 57 TC 2 Z9 2 U1 9 U2 50 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD JAN PY 2016 VL 15 IS 1 BP 154 EP 163 DI 10.1074/mcp.M115.052381 PG 10 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DA0BF UT WOS:000367461000011 PM 26545398 ER PT J AU Razzoli, M Frontini, A Gurney, A Mondini, E Cubuk, C Katz, LS Cero, C Bolan, PJ Dopazo, J Vidal-Puig, A Cinti, S Bartolomucci, A AF Razzoli, Maria Frontini, Andrea Gurney, Allison Mondini, Eleonora Cubuk, Cankut Katz, Liora S. Cero, Cheryl Bolan, Patrick J. Dopazo, Joaquin Vidal-Puig, Antonio Cinti, Saverio Bartolomucci, Alessandro TI Stress-induced activation of brown adipose tissue prevents obesity in conditions of low adaptive thermogenesis SO MOLECULAR METABOLISM LA English DT Article DE Subordinate; Energy expenditure; UCP1; P2RX5; Purinergic ID VESICULAR NUCLEOTIDE TRANSPORTER; DIFFERENTIAL REGULATION; PSYCHOSOCIAL STRESS; WHITE ADIPOCYTES; BEIGE ADIPOCYTES; NERVOUS-SYSTEM; MESSENGER-RNA; SOCIAL DEFEAT; ADULT HUMANS; JOB STRAIN AB Background: Stress-associated conditions such as psychoemotional reactivity and depression have been paradoxically linked to either weight gain or weight loss. This bi-directional effect of stress is not understood at the functional level. Here we tested the hypothesis that pre-stress level of adaptive thermogenesis and brown adipose tissue (BAT) functions explain the vulnerability or resilience to stress-induced obesity. Methods: We used wt and triple beta 1, beta 2, beta 3-Adrenergic Receptors knockout (beta-less) mice exposed to a model of chronic subordination stress (CSS) at either room temperature (22 degrees C) or murine thermoneutrality (30 degrees C). A combined behavioral, physiological, molecular, and immunohistochemical analysis was conducted to determine stress-induced modulation of energy balance and BAT structure and function. Immortalized brown adipocytes were used for in vitro assays. Results: Departing from our initial observation that beta ARs are dispensable for cold-induced BAT browning, we demonstrated that under physiological conditions promoting low adaptive thermogenesis and BAT activity (e.g. thermoneutrality or genetic deletion of the beta ARs), exposure to CSS acted as a stimulus for BAT activation and thermogenesis, resulting in resistance to diet-induced obesity despite the presence of hyperphagia. Conversely, in wt mice acclimatized to room temperature, and therefore characterized by sustained BAT function, exposure to CSS increased vulnerability to obesity. Exposure to CSS enhanced the sympathetic innervation of BAT in wt acclimatized to thermoneutrality and in bless mice. Despite increased sympathetic innervation suggesting adrenergic-mediated browning, norepinephrine did not promote browning in beta ARs knockout brown adipocytes, which led us to identify an alternative sympathetic/brown adipocytes purinergic pathway in the BAT. This pathway is downregulated under conditions of low adaptive thermogenesis requirements, is induced by stress, and elicits activation of UCP1 in wt and beta-less brown adipocytes. Importantly, this purinergic pathway is conserved in human BAT. Conclusion: Our findings demonstrate that thermogenesis and BAT function are determinant of the resilience or vulnerability to stress-induced obesity. Our data support a model in which adrenergic and purinergic pathways exert complementary/synergistic functions in BAT, thus suggesting an alternative to beta ARs agonists for the activation of human BAT. (C) 2015 The Authors. Published by Elsevier GmbH. C1 [Razzoli, Maria; Gurney, Allison; Cero, Cheryl; Bartolomucci, Alessandro] Univ Minnesota, Dept Integrat Biol & Physiol, Minneapolis, MN 55455 USA. [Frontini, Andrea; Mondini, Eleonora; Cinti, Saverio] Univ Politecn Marche, Ctr Obes, Dept Expt & Clin Med, I-60020 Ancona, Italy. [Cubuk, Cankut; Dopazo, Joaquin] Ctr Invest Principe Felipe, Computat Genom Dept, Valencia 46012, Spain. [Katz, Liora S.] NIDDK, NIH, Bethesda, MD 20892 USA. [Bolan, Patrick J.] Univ Minnesota, Dept Radiol, Minneapolis, MN 55455 USA. [Bolan, Patrick J.] Univ Minnesota, Ctr Magnet Resonance Res, Minneapolis, MN 55455 USA. [Vidal-Puig, Antonio] Univ Cambridge, Metab Res Labs, Cambridge CB2 0QQ, England. [Vidal-Puig, Antonio] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. RP Bartolomucci, A (reprint author), Univ Minnesota, Dept Integrat Biol & Physiol, 2231 6th St SE, Minneapolis, MN 55455 USA. EM abartolo@umn.edu FU British Heart Foundation [PG/12/53/29714]; Medical Research Council [MC_G0802535, MC_UU_12012/2]; NIA NIH HHS [R01 AG043972]; NIBIB NIH HHS [P41 EB015894]; NIDDK NIH HHS [R01 DK102496] NR 82 TC 5 Z9 5 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2212-8778 J9 MOL METAB JI Mol. Metab. PD JAN PY 2016 VL 5 IS 1 BP 19 EP 33 DI 10.1016/j.molmet.2015.10.005 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CZ9WO UT WOS:000367448200004 PM 26844204 ER PT J AU Lo, B AF Lo, Bernice TI The requirement of iron transport for lymphocyte function SO NATURE GENETICS LA English DT Editorial Material ID PROTEINS AB Iron is essential in multiple cellular processes and is especially critical for cellular respiration and division. A new study identified a mutation affecting the iron import receptor TfR1 as the cause of a human primary immunodeficiency, illuminating the importance of iron in immune cell function. C1 [Lo, Bernice] NIAID, Mol Dev, Immune Syst Sect, Lab Immunol,Clin Genom Program,US Natl Inst Hlth, Bethesda, MD 20892 USA. [Lo, Bernice] Sidra Med & Res Ctr, Div Translat Med, Doha, Qatar. RP Lo, B (reprint author), NIAID, Mol Dev, Immune Syst Sect, Lab Immunol,Clin Genom Program,US Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lob21@niaid.nih.gov NR 12 TC 0 Z9 0 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JAN PY 2016 VL 48 IS 1 BP 10 EP 11 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA CZ7BQ UT WOS:000367255300007 PM 26711111 ER PT J AU Zhou, Q Wang, HY Schwartz, DM Stoffels, M Park, YH Zhang, Y Yang, D Demirkaya, E Takeuchi, M Tsai, WXL Lyons, JJ Yu, XM Ouyang, C Chen, C Chin, DT Zaal, K Chandrasekharappa, SC Hanson, EP Yu, Z Mullikin, JC Hasni, SA Wertz, IE Ombrello, AK Stone, DL Hoffmann, P Jones, A Barham, BK Leavis, HL van Royen-Kerkof, A Sibley, C Batu, ED Gul, A Siegel, RM Boehm, M Milner, JD Ozen, S Gadina, M Chae, J Laxer, RM Kastner, DL Aksentijevich, I AF Zhou, Qing Wang, Hongying Schwartz, Daniella M. Stoffels, Monique Park, Yong Hwan Zhang, Yuan Yang, Dan Demirkaya, Erkan Takeuchi, Masaki Tsai, Wanxia Li Lyons, Jonathan J. Yu, Xiaomin Ouyang, Claudia Chen, Celeste Chin, David T. Zaal, Kristien Chandrasekharappa, Settara C. Hanson, Eric P. Yu, Zhen Mullikin, James C. Hasni, Sarfaraz A. Wertz, Ingrid E. Ombrello, Amanda K. Stone, Deborah L. Hoffmann, Patrycja Jones, Anne Barham, Beverly K. Leavis, Helen L. van Royen-Kerkof, Annet Sibley, Cailin Batu, Ezgi D. Guel, Ahmet Siegel, Richard M. Boehm, Manfred Milner, Joshua D. Ozen, Seza Gadina, Massimo Chae, JaeJin Laxer, Ronald M. Kastner, Daniel L. Aksentijevich, Ivona TI Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease SO NATURE GENETICS LA English DT Article ID NF-KAPPA-B; SYSTEMIC-LUPUS-ERYTHEMATOSUS; NLRP3 INFLAMMASOME; RHEUMATOID-ARTHRITIS; AUTOIMMUNE-DISEASES; GERMLINE MUTATIONS; TUMOR SUPPRESSION; LUBAC DEFICIENCY; UBIQUITIN; ASSOCIATION AB Systemic autoinflammatory diseases are driven by abnormal activation of innate immunity(1). Herein we describe a new disease caused by high-penetrance heterozygous germline mutations in TNFAIP3, which encodes the NF-kappa B regulatory protein A20, in six unrelated families with early-onset systemic inflammation. The disorder resembles Behcet's disease, which is typically considered a polygenic disorder with onset in early adulthood(2). A20 is a potent inhibitor of the NF-kappa B signaling pathway(3). Mutant, truncated A20 proteins are likely to act through haploinsufficiency because they do not exert a dominant-negative effect in overexpression experiments. Patient-derived cells show increased degradation of I kappa B alpha and nuclear translocation of the NF-kappa B p65 subunit together with increased expression of NF-kappa B-mediated proinflammatory cytokines. A20 restricts NF-kappa B signals via its deubiquitinase activity. In cells expressing mutant A20 protein, there is defective removal of Lys63-linked ubiquitin from TRAF6, NEMO and RIP1 after stimulation with tumor necrosis factor (TNF). NF-kappa B-dependent proinflammatory cytokines are potential therapeutic targets for the patients with this disease. C1 [Zhou, Qing; Wang, Hongying; Stoffels, Monique; Park, Yong Hwan; Takeuchi, Masaki; Chen, Celeste; Chin, David T.; Ombrello, Amanda K.; Stone, Deborah L.; Hoffmann, Patrycja; Jones, Anne; Barham, Beverly K.; Chae, JaeJin; Kastner, Daniel L.; Aksentijevich, Ivona] NHGRI, Inflammatory Dis Sect, Bethesda, MD 20892 USA. [Schwartz, Daniella M.] Natl Inst Arthrit & Musculoskeletal & Skin Dis, Mol Immunol & Inflammat Branch, Bethesda, MD USA. [Zhang, Yuan; Lyons, Jonathan J.; Yu, Xiaomin; Milner, Joshua D.] Lab Allerg Dis, Natl Inst Allergy & Infect Dis, Genet & Pathogenesis Allergy Sect, Bethesda, MD USA. [Yang, Dan; Yu, Zhen; Boehm, Manfred] Lab Cardiovasc Regenerat Med Natl Heart Lung, Bethesda, MD USA. [Yang, Dan; Yu, Zhen; Boehm, Manfred] Blood Inst, Bethesda, MD USA. [Demirkaya, Erkan] Gulhane Mil Med Acad, FMF Arthrit Vasculitis & Orphan Dis Res Ctr FAVOR, Ankara, Turkey. [Tsai, Wanxia Li; Gadina, Massimo] Natl Inst Arthrit & Musculoskeletal & Skin Dis, Translat Immunol Sect, Bethesda, MD USA. [Ouyang, Claudia; Hanson, Eric P.; Siegel, Richard M.] Natl Inst Arthrit & Musculoskeletal & Skin Dis, Autoimmun Branch, Bethesda, MD USA. [Zaal, Kristien] Natl Inst Arthrit & Musculoskeletal & Skin Dis, Light Imaging Sect, Bethesda, MD USA. [Chandrasekharappa, Settara C.] NHGRI, Canc Genet & Comparat Genom Branch, Bethesda, MD 20892 USA. [Mullikin, James C.] NHGRI, Natl Inst Hlth Intramural Sequencing Ctr, Bethesda, MD 20892 USA. [Hasni, Sarfaraz A.] Natl Inst Arthrit & Musculoskeletal & Skin Dis, Syst Autoimmune Branch, Bethesda, MD USA. [Wertz, Ingrid E.] Genentech Inc, Dept Mol Oncol, San Francisco, CA USA. [Leavis, Helen L.] Univ Med Ctr Utrecht, Dept Med Microbiol, Utrecht, Netherlands. [van Royen-Kerkof, Annet] Univ Med Ctr Utrecht, Dept Pediat Immunol, Utrecht, Netherlands. [Sibley, Cailin] Oregon Hlth & Sci Univ, Div Arthrit & Rheumat Dis, Portland, OR 97201 USA. [Batu, Ezgi D.; Ozen, Seza] Hacettepe Univ, Dept Pediat Rheumatol, Ankara, Turkey. [Guel, Ahmet] Istanbul Univ, Dept Internal Med, Istanbul, Turkey. [Laxer, Ronald M.] Univ Toronto, Hosp Sick Children, Div Rheumatol, Toronto, ON M5G 1X8, Canada. RP Aksentijevich, I (reprint author), NHGRI, Inflammatory Dis Sect, Bethesda, MD 20892 USA. EM aksentii@mail.nih.gov RI Yu, Xiaomin/I-6407-2016; OI Schwartz, Daniella/0000-0002-1660-8438; Lyons, Jonathan/0000-0002-2346-8189 FU Intramural Research Programs of the National Human Genome Research Institute; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Diseases; US National Institutes of Health Clinical Center; Research Fellowship Program for International Researchers - Scientific and Technological Research Council of Turkey (TUBITAK) [B.14.2.TBT.0.06.01-219-84] FX We thank V. Dixit for helpful discussions. We also thank all the patients and their families, and the healthy children and adult controls, for their enthusiastic support during this research study. This research was supported by the Intramural Research Programs of the National Human Genome Research Institute, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious Diseases, and the US National Institutes of Health Clinical Center. S.O. received royalties for consulting and speaking from Novartis and SOBI. H.L.L. received royalties for consulting from Baxter. E.D. was recipient of the Research Fellowship Program for International Researchers, which is supported by the Scientific and Technological Research Council of Turkey (TUBITAK; B.14.2.TBT.0.06.01-219-84). NR 48 TC 31 Z9 31 U1 7 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JAN PY 2016 VL 48 IS 1 BP 67 EP + DI 10.1038/ng.3459 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA CZ7BQ UT WOS:000367255300015 PM 26642243 ER PT J AU Zaragoza, B Chen, X Oppenheim, JJ Baeyens, A Gregoire, S Chader, D Gorochov, G Miyara, M Salomon, BL AF Zaragoza, Bruno Chen, Xin Oppenheim, Joost J. Baeyens, Audrey Gregoire, Sylvie Chader, Driss Gorochov, Guy Miyara, Makoto Salomon, Benoit L. TI Suppressive activity of human regulatory T cells is maintained in the presence of TNF SO NATURE MEDICINE LA English DT Letter ID RHEUMATOID-ARTHRITIS; ALPHA THERAPY; EXPRESSION C1 [Zaragoza, Bruno; Baeyens, Audrey; Gregoire, Sylvie; Chader, Driss; Gorochov, Guy; Miyara, Makoto; Salomon, Benoit L.] Univ Paris 06, Sorbonne Univ, Ctr Immunol & Malad Infect CIMI Paris, INSERM,CNRS, 91 Bd Hop, Paris, France. [Chen, Xin] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Basic Sci Program, Frederick, MD USA. [Chen, Xin; Oppenheim, Joost J.] NCI, Lab Mol Immunoregulat, Canc Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Gorochov, Guy; Miyara, Makoto] Hop La Pitie Salpetriere, AP HP, Dept Immunol, Paris, France. [Chen, Xin] Univ Macau, State Key Lab Qual Res Chinese Med, Inst Chinese Med Sci, Macau, Peoples R China. RP Salomon, BL (reprint author), Univ Paris 06, Sorbonne Univ, Ctr Immunol & Malad Infect CIMI Paris, INSERM,CNRS, 91 Bd Hop, Paris, France. EM benoit.salomon@upmc.fr RI Chen, Xin/I-6601-2015; OI Chen, Xin/0000-0002-2628-4027; Salomon, Benoit/0000-0001-9673-5578 NR 12 TC 5 Z9 6 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD JAN PY 2016 VL 22 IS 1 BP 16 EP + DI 10.1038/nm.4019 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DA1YA UT WOS:000367590700006 PM 26735402 ER PT J AU Hickman, HD AF Hickman, Heather D. TI Illuminating inflammasome activity in vivo SO NATURE MEDICINE LA English DT Editorial Material ID LYMPH-NODES; CELL RESPONSES; MACROPHAGES; VIRUSES; ASC AB Sentinel macrophages in the lymph node provide a first line of defense against invading viruses. A new study visualizes inflammasome activation in virally infected nodal macrophages in mice and shows that this activation augments both innate and adaptive immunity. C1 [Hickman, Heather D.] NIAID, Viral Dis Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Hickman, HD (reprint author), NIAID, Viral Dis Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. EM hhickman@mail.nih.gov NR 12 TC 0 Z9 0 U1 4 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD JAN PY 2016 VL 22 IS 1 BP 22 EP 23 DI 10.1038/nm.4026 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DA1YA UT WOS:000367590700009 PM 26735405 ER PT J AU Klebanoff, CA Rosenberg, SA Restifo, NP AF Klebanoff, Christopher A. Rosenberg, Steven A. Restifo, Nicholas P. TI Prospects for gene-engineered T cell immunotherapy for solid cancers SO NATURE MEDICINE LA English DT Article ID CHIMERIC-ANTIGEN-RECEPTOR; GROWTH-FACTOR RECEPTOR; STEM-CELLS; ADOPTIVE IMMUNOTHERAPY; METASTATIC MELANOMA; ESTABLISHED TUMORS; ANTI-PD-1 ANTIBODY; SLEEPING-BEAUTY; PD-1 BLOCKADE; LUNG-CANCER AB Adoptive transfer of receptor-engineered T cells has produced impressive results in treating patients with B cell leukemias and lymphomas. This success has captured public imagination and driven academic and industrial researchers to develop similar 'off-the-shelf' receptors targeting shared antigens on epithelial cancers, the leading cause of cancer-related deaths. However, the successful treatment of large numbers of people with solid cancers using this strategy is unlikely to be straightforward. Receptor-engineered T cells have the potential to cause lethal toxicity from on-target recognition of normal tissues, and there is a paucity of truly tumor-specific antigens shared across tumor types. Here we offer our perspective on how expanding the use of genetically redirected T cells to treat the majority of patients with solid cancers will require major technical, manufacturing and regulatory innovations centered around the development of autologous gene therapies targeting private somatic mutations. C1 [Klebanoff, Christopher A.; Rosenberg, Steven A.; Restifo, Nicholas P.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Klebanoff, CA (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM klebanoc@mail.nih.gov; restifo@nih.gov FU Intramural Research Program of the National Cancer Institute, Center for Cancer Research of the US National Institutes of Health (NIH) [ZIA BC011586, ZIA BC010763]; NIH Center for Regenerative Medicine FX This work was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research of the US National Institutes of Health (NIH) (ZIA BC011586 and ZIA BC010763) and the NIH Center for Regenerative Medicine. Additional support was provided by generous gifts from L. Jinyuan of the Tiens Charitable Foundation and the Milstein Family Foundation. NR 140 TC 41 Z9 42 U1 37 U2 102 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD JAN PY 2016 VL 22 IS 1 BP 26 EP 36 DI 10.1038/nm.4015 PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DA1YA UT WOS:000367590700012 PM 26735408 ER PT J AU Moten, A Schafer, D Fletcher, EH Montgomery, E AF Moten, Asad Schafer, Daniel Fletcher, Erica H. Montgomery, Elizabeth TI Randomised controlled trials as a driving force of evidence-based public health on the population level SO PERSPECTIVES IN PUBLIC HEALTH LA English DT Editorial Material ID POLICY C1 [Moten, Asad] HealthNovat Int, Houston, TX 77004 USA. Univ Oxford, Oxford OX1 2JD, England. NIH, Bethesda, MD USA. Univ Texas Med Branch, Galveston, TX USA. Texas Childrens Hosp, Houston, TX 77030 USA. Harvard Belfer Ctr Sci & Int Affairs, Cambridge, England. RP Moten, A (reprint author), HealthNovat Int, Houston, TX 77004 USA. NR 15 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1757-9139 EI 1757-9147 J9 PERSPECT PUBLIC HEAL JI Perspect. Public Health PD JAN PY 2016 VL 136 IS 1 BP 25 EP 27 DI 10.1177/1757913915616731 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CZ9GC UT WOS:000367404800016 PM 26702115 ER PT J AU Tageja, N Groninger, H AF Tageja, Nishant Groninger, Hunter TI Chemotherapy-induced nausea and vomiting: an overview and comparison of three consensus guidelines SO POSTGRADUATE MEDICAL JOURNAL LA English DT Review DE ONCOLOGY; PALLIATIVE CARE ID PLACEBO-CONTROLLED TRIAL; HIGH-DOSE CISPLATIN; DOUBLE-BLIND; ANTAGONIST APREPITANT; CANCER-PATIENTS; RECEPTOR ANTAGONISTS; ANTIEMETIC THERAPY; DELAYED EMESIS; PREVENTION; TOLERABILITY AB Chemotherapy-induced nausea and vomiting (CINV) remains one of the most debilitating toxicities associated with cancer treatment. In recent decades, significant strides have been made in our understanding of the pathophysiology of CINV, making way to more effective targeted pharmacotherapies, especially 5-hydroxytryptamine3 receptor antagonists and neurokinin-1 (NK-1) receptor antagonists. As much as 70%-80% of CINV can be prevented with appropriate administration of available antiemetics. Nevertheless, fear of CINV still may diminish cancer treatment adherence. To assimilate and summarise the rapidly growing body of clinical research literature on CINV, three professional organisationsthe Multinational Association of Supportive Care in Cancer/European Society for Medical Oncology, the American Society of Clinical Oncology and the National Comprehensive Cancer Networkhave created CINV management guidelines. While these respective guidelines are developed from similar consensus processes using similar clinical research literature, their results demonstrate several key differences in recommended strategies. This article aims to provide an overview of CINV pathophysiology, compare and contrast three expert guidelines and offer considerations for future clinical and research challenges. C1 [Tageja, Nishant] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Groninger, Hunter] MedStar Washington Hosp Ctr, Dept Med, Sect Palliat Care, Washington, DC USA. RP Groninger, H (reprint author), MedStar Washington Hosp Ctr, Dept Med, Sect Palliat Care, 110 Irving St NW, Washington, DC USA. EM hunter.groninger@medstar.net NR 34 TC 2 Z9 2 U1 2 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0032-5473 EI 1469-0756 J9 POSTGRAD MED J JI Postgrad. Med. J. PD JAN PY 2016 VL 92 IS 1083 BP 34 EP 40 DI 10.1136/postgradmedj-2014-132969 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA DA0HR UT WOS:000367478700007 PM 26561590 ER PT J AU Slaughter, AJ Koehly, LM AF Slaughter, Andrew J. Koehly, Laura M. TI Multilevel models for social networks: Hierarchical Bayesian approaches to exponential random graph modeling SO SOCIAL NETWORKS LA English DT Article DE Multilevel networks; Hierarchical models; Exponential random graph models; Autoregressive models ID LOGISTIC-REGRESSION; UNCERTAINTY; SAMPLER AB In many applications, researchers may be interested in studying patterns of dyadic relationships that involve multiple groups, with a focus on modeling the systematic patterns within groups and how these structural patterns differ across groups. A number of different models - many of them potentially quite powerful - have been developed that allow for researchers to study these differences. However, as with any set of models, these are limited in ways that constrain the types of questions researchers may ask, such as those involving the variance in group-wise structural features. In this paper, we demonstrate some of the ways in which multilevel models based on a hierarchical Bayesian approach might be used to further develop and extend existing exponential random graph models to address such constraints. These include random coefficient extensions to the standard ERGM for sets of multiple unconnected or connected networks and examples of multilevel models that allow for the estimation of structural entrainment among connected groups. We demonstrate the application of these models to real-world and simulated data sets. Published by Elsevier B.V. C1 [Slaughter, Andrew J.] US Army Res Inst Behav & Social Sci, Arlington, VA 22202 USA. [Koehly, Laura M.] NHGRI, Bethesda, MD USA. RP Slaughter, AJ (reprint author), US Army Res Inst Behav & Social Sci, Arlington, VA 22202 USA. EM andrew.j.slaughter.civ@mail.mil; koehlyl@mail.nih.gov FU Breast Cancer Research Program, The University of Texas M.D. Anderson Cancer Center; Intramural Research Program of the National Human Genome Research Institute at the National Institutes of Health [ZIA HG200335]; US Army Research Institute for the Behavioral and Social Sciences FX The Circle of Friends study, which provided exemplar data, was supported by the Breast Cancer Research Program, The University of Texas M.D. Anderson Cancer Center. We would like to thank Karen Basen-Engquist for her assistance in obtaining the Circle of Friends data. The completion of this manuscript was supported by the Intramural Research Program of the National Human Genome Research Institute at the National Institutes of Health (ZIA HG200335 to Laura M. Koehly) and the US Army Research Institute for the Behavioral and Social Sciences. The views, opinions, and/or findings contained in this article are solely those of the authors and should not be construed as an official Department of the Army or DOD position, policy, or decision, unless so designated by other documentation. NR 42 TC 1 Z9 2 U1 2 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-8733 EI 1879-2111 J9 SOC NETWORKS JI Soc. Networks PD JAN PY 2016 VL 44 BP 334 EP 345 DI 10.1016/j.socnet.2015.11.002 PG 12 WC Anthropology; Sociology SC Anthropology; Sociology GA CZ9NI UT WOS:000367423900030 ER PT J AU Floto, RA Olivier, KN Saiman, L Daley, CL Herrmann, JL Nick, JA Noone, PG Bilton, D Corris, P Gibson, RL Hempstead, SE Koetz, K Sabadosa, KA Sermet-Gaudelus, I Smyth, AR van Ingen, J Wallace, RJ Winthrop, KL Marshall, BC Haworth, CS AF Floto, R. Andres Olivier, Kenneth N. Saiman, Lisa Daley, Charles L. Herrmann, Jean-Louis Nick, Jerry A. Noone, Peadar G. Bilton, Diana Corris, Paul Gibson, Ronald L. Hempstead, Sarah E. Koetz, Karsten Sabadosa, Kathryn A. Sermet-Gaudelus, Isabelle Smyth, Alan R. van Ingen, Jakko Wallace, Richard J. Winthrop, Kevin L. Marshall, Bruce C. Haworth, Charles S. TI US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis SO THORAX LA English DT Article DE Cystic Fibrosis; Bacterial Infection ID COMPLEX LUNG-DISEASE; RAPIDLY GROWING MYCOBACTERIA; ANTI-PSEUDOMONAL ANTIBIOTICS; DESORPTION IONIZATION-TIME; FLIGHT MASS-SPECTROMETRY; INNO-LIPA-MYCOBACTERIA; GASTROESOPHAGEAL-REFLUX DISEASE; HUMAN-IMMUNODEFICIENCY-VIRUS; AVIUM COMPLEX; PULMONARY-DISEASE AB Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with pre-existing inflammatory lung disease such as cystic fibrosis (CF). Pulmonary disease caused by NTM has emerged as a major threat to the health of individuals with CF but remains difficult to diagnose and problematic to treat. In response to this challenge, the US Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) convened an expert panel of specialists to develop consensus recommendations for the screening, investigation, diagnosis and management of NTM pulmonary disease in individuals with CF. Nineteen experts were invited to participate in the recommendation development process. Population, Intervention, Comparison, Outcome (PICO) methodology and systematic literature reviews were employed to inform draft recommendations. An anonymous voting process was used by the committee to reach consensus. All committee members were asked to rate each statement on a scale of: 0, completely disagree, to 9, completely agree; with 80% or more of scores between 7 and 9 being considered good' agreement. Additionally, the committee solicited feedback from the CF communities in the USA and Europe and considered the feedback in the development of the final recommendation statements. Three rounds of voting were conducted to achieve 80% consensus for each recommendation statement. Through this process, we have generated a series of pragmatic, evidence-based recommendations for the screening, investigation, diagnosis and treatment of NTM infection in individuals with CF as an initial step in optimising management for this challenging condition. C1 [Floto, R. Andres] Univ Cambridge, Cambridge Inst Med Res, Cambridge CB2 0XY, England. [Floto, R. Andres; Haworth, Charles S.] Papworth Hosp, Cambridge Ctr Lung Infect, Cambridge CB3 8RE, England. [Olivier, Kenneth N.] NHLBI, Cardiovasc Pulm Branch, NIH, Bethesda, MD 20892 USA. [Saiman, Lisa] Columbia Univ, Med Ctr, Dept Pediat, Pediat Infect Dis, New York, NY USA. [Daley, Charles L.] Natl Jewish Hlth, Div Mycobacterial & Resp Infect, Denver, CO USA. [Herrmann, Jean-Louis] Versailles St Quentin Univ, UFR Simone Veil, INSERM U1173, St Quentin En Yvelines, France. [Herrmann, Jean-Louis] Hop Raymond Poincare, AP HP, Microbiol Serv, Garches, France. [Nick, Jerry A.] Natl Jewish Hlth, Dept Med, Denver, CO USA. [Noone, Peadar G.] Univ N Carolina, Chapel Hill, NC USA. [Bilton, Diana] Royal Brompton Hosp, Dept Resp Med, London SW3 6LY, England. [Corris, Paul] Freeman Rd Hosp, Dept Resp Med, Newcastle Upon Tyne, Tyne & Wear, England. [Gibson, Ronald L.] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. [Hempstead, Sarah E.; Sabadosa, Kathryn A.] Geisel Sch Med Dartmouth, Dartmouth Inst Hlth Policy & Clin Practice, Lebanon, NH USA. [Koetz, Karsten] Sahlgrens Univ Hosp, Dept Pediat, Gothenburg, Sweden. [Sermet-Gaudelus, Isabelle] Univ Paris 05, Hop Necker Enfants Malad, Serv Pneumopediat, Paris, France. [Smyth, Alan R.] Univ Nottingham, Div Child Hlth Obstet & Gynaecol, Nottingham NG7 2RD, England. [van Ingen, Jakko] Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, NL-6525 ED Nijmegen, Netherlands. [Wallace, Richard J.] Univ Texas Hlth Sci Ctr, Dept Microbiol, Tyler, TX USA. [Winthrop, Kevin L.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Marshall, Bruce C.] Cyst Fibrosis Fdn, Bethesda, MD USA. RP Floto, RA (reprint author), Univ Cambridge, Cambridge Inst Med Res, Cambridge Biomed Campus,Hills Rd, Cambridge CB2 0XY, England. EM arf27@cam.ac.uk RI van Ingen, Jakko/D-5526-2014; OI van Ingen, Jakko/0000-0002-0581-2003; Andres, Rodrigo/0000-0002-2188-5659; Smyth, Alan/0000-0001-5494-5438 FU Cystic Fibrosis Foundation; European Cystic Fibrosis Society; Wellcome Trust; Cambridge NIHR BRC; Intramural programme of the National Heart, Lung, and Blood Institute, NIH; Vaincre La Mucoviscidose [VLMIC1014, RF20120600689]; Region Ile-de-France Domaine d'Interet Majeur Maladies Infectieuses et Emergentes; CF Foundation Clinical Research Award [NICK13A0]; Imperial College London NIHR Respiratory BRU FX Cystic Fibrosis Foundation; European Cystic Fibrosis Society, The Wellcome Trust and Cambridge NIHR BRC (RAF); Intramural programme of the National Heart, Lung, and Blood Institute, NIH (KNO); Vaincre La Mucoviscidose (VLMIC1014 and RF20120600689) and the Region Ile-de-France Domaine d'Interet Majeur Maladies Infectieuses et Emergentes (J-LH); CF Foundation Clinical Research Award (NICK13A0) (JAN); Imperial College London NIHR Respiratory BRU (DB). NR 189 TC 21 Z9 21 U1 3 U2 14 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 EI 1468-3296 J9 THORAX JI Thorax PD JAN PY 2016 VL 71 SU 1 BP 1 EP 22 DI 10.1136/thoraxjnl-2015-207360 PG 22 WC Respiratory System SC Respiratory System GA DA0DA UT WOS:000367465700001 PM 26666259 ER PT J AU Conde-Agudelo, A Romero, R AF Conde-Agudelo, Agustin Romero, Roberto TI Cervical phosphorylated insulin-like growth factor binding protein-1 test for the prediction of preterm birth: a systematic review and metaanalysis SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Review DE biomarker; common pathway of parturition; fetal fibronectin; predictive value; prematurity; preterm labor ID DIAGNOSTIC-TEST ACCURACY; FETAL FIBRONECTIN TEST; ACTIM PARTUS TEST; BIOCHEMICAL MARKERS; BEDSIDE TEST; SYMPTOMATIC WOMEN; TWIN PREGNANCIES; MID-PREGNANCY; DELIVERY; LABOR AB OBJECTIVE: To assess the accuracy of the cervical phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) test to predict preterm birth in women with and without symptoms of preterm labor through the use of formal methods for systematic reviews and metaanalytic techniques. DATA SOURCES: PubMed, Embase, Cinahl, Lilacs, and Medion (all from inception to June 30, 2015), reference lists, conference proceedings, and Google scholar. STUDY ELIGIBILITY CRITERIA: Cohort or cross-sectional studies that reported on the predictive accuracy of the cervical phIGFBP-1 test for preterm birth. STUDY APPRAISAL AND SYNTHESIS METHODS: Two reviewers independently selected studies, assessed the risk of bias, and extracted the data. Summary receiver-operating characteristic curves, pooled sensitivities and specificities, and summary likelihood ratios were generated. RESULTS: Forty-three studies met the inclusion criteria, of which 15 provided data on asymptomatic women (n = 6583) and 34 on women with an episode of preterm labor (n = 3620). Among asymptomatic women, the predictive accuracy of the cervical phIGFBP-1 test for preterm birth at <37, <34, and <32 weeks of gestation was minimal, with pooled sensitivities and specificities and summary positive and negative likelihood ratios ranging from 14% to 47%, 76% to 93%, 1.5 to 4.4, and 0.6 to 1.0, respectively. Among women with an episode of preterm labor, the test had a low predictive performance for delivery within 7 and 14 days of testing, and preterm birth at <34 and <37 weeks of gestation with pooled sensitivities and specificities and summary positive and negative likelihood ratios that varied between 60% and 68%, 77% and 81%, 2.7 and 3.5, and 0.4 and 0.5, respectively. A negative test result in women with an episode of preterm labor had a low to moderate accuracy to identify women who are not at risk for delivering within the next 48 hours (summary negative likelihood ratio of 0.28 in all women and 0.23 in women with singleton gestations). CONCLUSION: Cervical phIGFBP-1 has the potential utility to identify patients with an episode of preterm labor who will not deliver within 48 hours. However, its overall predictive ability for the identification of symptomatic and asymptomatic women at risk for preterm birth is limited. C1 [Conde-Agudelo, Agustin; Romero, Roberto] NICHHD, Perinatol Res Branch, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Conde-Agudelo, Agustin; Romero, Roberto] NICHHD, Perinatol Res Branch, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH,Dept Hlth & Human Serv, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Dept Mol Obstet & Genet, Detroit, MI USA. RP Romero, R (reprint author), NICHHD, Perinatol Res Branch, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM romeror@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. NR 76 TC 3 Z9 3 U1 2 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 BP 57 EP 73 DI 10.1016/j.ajog.2015.06.060 PG 17 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SM UT WOS:000367093000008 PM 26149828 ER PT J AU Al-kouatly, HB Vilboux, T Fries, MH Young, A Mullikin, JC Malicdan, MCV Stephen, J Huizing, M Gahl, WA Wapner, RJ AF Al-kouatly, Huda B. Vilboux, Thierry Fries, Melissa H. Young, Alice Mullikin, Jim C. Malicdan, May Christine V. Stephen, Joshi Huizing, Marjan Gahl, William A. Wapner, Ronald J. TI Prenatal whole exome sequencing identifies genetic causes of congenital heart disease in fetuses with normal karyotype and normal microarray SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Al-kouatly, Huda B.; Vilboux, Thierry; Young, Alice; Mullikin, Jim C.; Malicdan, May Christine V.; Stephen, Joshi; Huizing, Marjan; Gahl, William A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Al-kouatly, Huda B.; Fries, Melissa H.] Medstar Washington Hosp Ctr, Dept Obstet & Gynecol, Washington, DC USA. [Vilboux, Thierry] Inova Hlth Syst, Inova Translat Med Inst, Falls Church, VA USA. [Wapner, Ronald J.] Columbia Univ, Med Ctr, Dept Obstet & Gynecol, New York, NY USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 104 BP S71 EP S72 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800105 ER PT J AU Anderson, S AF Anderson, Sarah TI Is fetal tachycardia in the setting of intrapartum fever associated with neonatal morbidity? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Anderson, Sarah] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 346 BP S195 EP S195 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800342 ER PT J AU Boyle, A Preslar, JP Hogue, CJ Silver, RM Reddy, UM Goldenberg, RL Dudley, DJ AF Boyle, Annelee Preslar, Jessica P. Hogue, Carol J. Silver, Robert M. Reddy, Uma M. Goldenberg, Robert L. Dudley, Donald J. CA SCRN Investigators TI Clinical management of stillbirth SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Boyle, Annelee; Dudley, Donald J.] Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. [Preslar, Jessica P.; Hogue, Carol J.] Emory Univ, Sch Med, Atlanta, GA USA. [Preslar, Jessica P.; Hogue, Carol J.] Emory Univ, Sch Publ Hlth, Atlanta, GA USA. [Silver, Robert M.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Reddy, Uma M.; SCRN Investigators] Eunice Kennedy Shriver NICHD, Bethesda, MD USA. [Goldenberg, Robert L.] Columbia Univ, Med Ctr, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 373 BP S208 EP S208 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800368 ER PT J AU Casey, B AF Casey, Brian TI Effect of treatment of maternal subclinical hypothyroidism or hypothyroxinemia on IQ in offspring SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Casey, Brian] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. NR 0 TC 6 Z9 6 U1 2 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 2 BP S2 EP S2 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800003 ER PT J AU Costantine, M AF Costantine, Maged TI Rates of severe maternal and neonatal adverse outcomes according to predicted likelihood of vaginal delivery SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Costantine, Maged] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 428 BP S235 EP S236 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800422 ER PT J AU Downes, KL Shenassa, ED Grantz, KL AF Downes, Katheryne Leah Shenassa, Edmond D. Grantz, Katherine L. TI Duration of labor associated with placental abruption SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Downes, Katheryne Leah; Shenassa, Edmond D.] Univ Maryland, College Pk, MD 20742 USA. [Grantz, Katherine L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 692 BP S365 EP S366 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800685 ER PT J AU Esplin, M AF Esplin, Michael TI The use of serial cervical length and quantitative fetal fibronectin to identify nulliparous women at risk of subsequent spontaneous preterm birth SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Esplin, Michael] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Network NuMoM2b, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 6 BP S4 EP S5 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800007 ER PT J AU Froehlich, RJ AF Froehlich, Rosemary J. TI The association of estimated fetal weight and cesarean delivery in women attempting vaginal delivery at term SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Froehlich, Rosemary J.] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 735 BP S385 EP S386 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800726 ER PT J AU Gibbins, KJ Sjaarda, LA Branch, DW Mumford, SL Perkins, NJ Schisterman, EF Silver, RM AF Gibbins, Karen J. Sjaarda, Lindsay A. Branch, D. Ware Mumford, Sunni L. Perkins, Neil J. Schisterman, Enrique F. Silver, Robert M. TI Recurrent pregnancy loss in women with and without anti-phospholipid antibodies SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Gibbins, Karen J.; Branch, D. Ware; Silver, Robert M.] Univ Utah Hlth Sci & Intermt Healthcare, Salt Lake City, UT USA. [Sjaarda, Lindsay A.; Mumford, Sunni L.; Perkins, Neil J.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 354 BP S199 EP S199 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800350 ER PT J AU Grantz, K Kim, S Grobman, W Newman, R Owen, J Skupski, D Grewal, J Chien, E Wing, D Wapner, R Ranzini, A Hinkle, S Hediger, M Louis, GB Albert, P AF Grantz, Katherine Kim, Sungduk Grobman, William Newman, Roger Owen, John Skupski, Daniel Grewal, Jagteshwar Chien, Edward Wing, Deborah Wapner, Ronald Ranzini, Angela Hinkle, Stefanie Hediger, Mary Louis, Germaine Buck Albert, Paul TI Does the addition of fetal growth velocity improve the precision of sonographic birthweight estimation? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Grantz, Katherine; Kim, Sungduk; Grewal, Jagteshwar; Hinkle, Stefanie; Hediger, Mary; Louis, Germaine Buck; Albert, Paul] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Grobman, William] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Newman, Roger] Med Univ S Carolina, Dept Obstet & Gynecol, Charleston, SC 29425 USA. [Owen, John] Univ Alabama Birmingham, Ctr Womens Reprod Hlth, Birmingham, AL USA. [Skupski, Daniel] New York Presbyterian Queens, Dept Obstet & Gynecol, Flushing, NY USA. [Chien, Edward] Case Western Reserve Univ, MetroHlth Med Ctr, Cleveland, OH 44106 USA. Univ Calif Irvine, Irvine, CA USA. [Wapner, Ronald] Columbia Univ, Dept Obstet & Gynecol, Med Ctr, New York, NY USA. [Ranzini, Angela] St Peters Univ Hosp, New Brunswick, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 112 BP S78 EP S78 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800113 ER PT J AU Gyamfi-Bannerman, C AF Gyamfi-Bannerman, Cynthia TI Antenatal Late Preterm Steroids (ALPS): a randomized trial to reduce neonatal respiratory morbidity SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Gyamfi-Bannerman, Cynthia] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 1 BP S2 EP S2 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800002 ER PT J AU Halfon, JK Small, M Bagambe, P Rulisa, S AF Halfon, Johanna K. Small, Maria Bagambe, Patrick Rulisa, Stephen TI Post-cesarean section peritonitis at a referral hospital in Rwanda SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Halfon, Johanna K.; Small, Maria] Duke Univ, Durham, NC USA. [Halfon, Johanna K.] NIH, Fogarty Int Ctr, VECD Consortium, Bethesda, MD 20892 USA. [Bagambe, Patrick; Rulisa, Stephen] Univ Teaching Hosp Kigali, Kigali, Rwanda. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 855 BP S445 EP S445 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800844 ER PT J AU Hauth, JC AF Hauth, John C. TI Early intrapartum fetal heart rate patterns and neonatal outcomes in nulliparas SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Hauth, John C.] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 197 BP S120 EP S121 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800196 ER PT J AU Manuck, TA Watkins, S Esplin, MS Parry, S Zhang, HP Huang, H Biggio, JR Bukowski, R Saade, G Andrews, W Baldwin, D Sadovsky, Y Reddy, U Ilekis, J Varner, MW Jorde, LB Yandell, M AF Manuck, Tracy A. Watkins, Scott Esplin, M. Sean Parry, Samuel Zhang, Heping Huang, Hao Biggio, Joseph R. Bukowski, Radek Saade, George Andrews, William Baldwin, Don Sadovsky, Yoel Reddy, Uma Ilekis, John Varner, Michael W. Jorde, Lynn B. Yandell, Mark TI Gene set enrichment investigation of maternal exome variation in spontaneous preterm birth (SPTB) SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 Univ N Carolina, Chapel Hill, NC USA. Univ Utah, Salt Lake City, UT USA. Intermt Healthcare, Salt Lake City, UT USA. Genom & Prote Network Preterm Birth Res GPN, Bethesda, MD USA. Univ Penn, Philadelphia, PA 19104 USA. Yale Univ, New Haven, CT USA. Univ Alabama Birmingham, Birmingham, AL USA. Univ Texas Med Branch, Galveston, TX 77555 USA. Univ Pittsburgh, Pittsburgh, PA USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 242 BP S142 EP S143 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800238 ER PT J AU Manuck, TA Watkins, S Esplin, MS Parry, S Zhang, HP Huang, H Biggio, JR Bukowski, R Saade, G Andrews, W Baldwin, D Sadovsky, Y Reddy, U Ilekis, J Varner, MW Yandell, M Jorde, LB AF Manuck, Tracy A. Watkins, Scott Esplin, M. Sean Parry, Samuel Zhang, Heping Huang, Hao Biggio, Joseph R. Bukowski, Radek Saade, George Andrews, William Baldwin, Don Sadovsky, Yoel Reddy, Uma Ilekis, John Varner, Michael W. Yandell, Mark Jorde, Lynn B. TI Genetic variation may influence response to 17-alpha hydroxyprogesterone caproate (17P) for recurrent preterm birth (PTB) prevention SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Manuck, Tracy A.] Univ N Carolina, Chapel Hill, NC USA. [Manuck, Tracy A.; Watkins, Scott; Esplin, M. Sean; Varner, Michael W.; Yandell, Mark; Jorde, Lynn B.] Univ Utah, Salt Lake City, UT USA. [Manuck, Tracy A.; Esplin, M. Sean; Varner, Michael W.] Intermt Healthcare, Salt Lake City, UT USA. [Manuck, Tracy A.; Esplin, M. Sean; Parry, Samuel; Zhang, Heping; Huang, Hao; Biggio, Joseph R.; Bukowski, Radek; Saade, George; Andrews, William; Baldwin, Don; Sadovsky, Yoel; Reddy, Uma; Ilekis, John; Varner, Michael W.] Genom & Prote Network Preterm Birth Res GPN, Bethesda, MD USA. [Parry, Samuel; Baldwin, Don] Univ Penn, Philadelphia, PA 19104 USA. [Zhang, Heping; Huang, Hao; Bukowski, Radek] Yale Univ, New Haven, CT USA. [Biggio, Joseph R.; Andrews, William] Univ Alabama Birmingham, Birmingham, AL USA. [Saade, George] Univ Texas Med Branch, Galveston, TX 77555 USA. [Sadovsky, Yoel] Univ Pittsburgh, Pittsburgh, PA USA. [Reddy, Uma; Ilekis, John] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 12 BP S9 EP S10 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800013 ER PT J AU Miller, ES AF Miller, Emily S. TI Is duration of operative vaginal delivery associated with adverse obstetric outcomes? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Miller, Emily S.] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 223 BP S133 EP S133 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800220 ER PT J AU Oh, KJ Romero, R Yoon, BH AF Oh, Kyung Joon Romero, Roberto Yoon, Bo Hyun TI Preterm labor in twin gestations: a point of care test to identify impending preterm delivery and intra-amniotic infection SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Oh, Kyung Joon; Yoon, Bo Hyun] Seoul Natl Univ, Seoul, South Korea. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 664 BP S352 EP S352 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800658 ER PT J AU Page, JM AF Page, Jessica M. CA SCRN Eunice Kennedy Shriver NICHD TI What proportion of stillbirths are potentially preventable? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Page, Jessica M.] Univ Utah, Salt Lake City, UT USA. [SCRN Eunice Kennedy Shriver NICHD] NICHD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 419 BP S231 EP S232 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800413 ER PT J AU Page, JM AF Page, Jessica M. CA SCRN Eunice Kennedy Shriver NICHD TI Optimal evaluation for stillbirth: Stillbirth Collaborative Research Network SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Page, Jessica M.] Univ Utah, Salt Lake City, UT USA. [SCRN Eunice Kennedy Shriver NICHD] NICHD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 25 BP S18 EP S18 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800026 ER PT J AU Parry, S AF Parry, Samuel TI Lack of value of uterine artery Doppler screening to predict fetal growth restriction in nulliparous women SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Parry, Samuel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NuMoM2b Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 305 BP S174 EP S175 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800301 ER PT J AU Peaceman, A AF Peaceman, Alan TI Effect of treatment of maternal subclinical hypothyroidism and hypothyroxinemia on pregnancy outcomes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Peaceman, Alan] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 2 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 356 BP S200 EP S200 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800352 ER PT J AU Rice, MM AF Rice, Madeline Murguia TI Adverse pregnancy outcomes and child cardiometabolic health SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Rice, Madeline Murguia] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 63 BP S45 EP S46 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800064 ER PT J AU Romero, S Esplin, MS Parry, S Zhang, HP Huang, H Biggio, JR Bukowski, R Saade, G Andrews, W Baldwin, D Sadovsky, Y Reddy, U Ilekis, J Varner, MW Manuck, TA AF Romero, Stephanie Esplin, M. Sean Parry, Samuel Zhang, Heping Huang, Hao Biggio, Joseph R. Bukowski, Radek Saade, George Andrews, William Baldwin, Don Sadovsky, Yoel Reddy, Uma Ilekis, John Varner, Michael W. Manuck, Tracy A. TI Optimal duration of antenatal corticosteroid (ACS) exposure and neonatal outcomes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Romero, Stephanie] Univ S Florida, Tampa, FL USA. [Romero, Stephanie; Esplin, M. Sean; Parry, Samuel; Zhang, Heping; Huang, Hao; Biggio, Joseph R.; Bukowski, Radek; Saade, George; Andrews, William; Baldwin, Don; Sadovsky, Yoel; Reddy, Uma; Ilekis, John; Varner, Michael W.; Manuck, Tracy A.] Genom & Prote Network Preterm Birth Res, Bethesda, MD USA. [Esplin, M. Sean; Varner, Michael W.; Manuck, Tracy A.] Univ Utah, Salt Lake City, UT USA. [Esplin, M. Sean; Varner, Michael W.; Manuck, Tracy A.] Intermt Healthcare, Salt Lake City, UT USA. [Parry, Samuel; Baldwin, Don] Univ Penn, Philadelphia, PA 19104 USA. [Zhang, Heping; Huang, Hao; Bukowski, Radek] Yale Univ, New Haven, CT USA. [Biggio, Joseph R.; Andrews, William] Univ Alabama Birmingham, Birmingham, AL USA. [Saade, George] Univ Texas Med Branch, Galveston, TX 77555 USA. [Sadovsky, Yoel] Univ Pittsburgh, Pittsburgh, PA USA. [Reddy, Uma; Ilekis, John] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Manuck, Tracy A.] Univ N Carolina, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 528 BP S285 EP S286 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800522 ER PT J AU Saade, G AF Saade, George TI Using pattern-recognition software to evaluate intrapartum fetal heart rate (FHR) tracings SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Saade, George] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 666 BP S352 EP S353 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800660 ER PT J AU Saade, G AF Saade, George TI Intrapartum risk stratification for early-onset neonatal sepsis SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Saade, George] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 213 BP S128 EP S129 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800211 ER PT J AU Skupski, DW Owen, J Kim, S Albert, P Grantz, KL AF Skupski, Daniel W. Owen, John Kim, Sungduk Albert, Paul Grantz, Katherine Laughon TI The NICHD Fetal Growth Studies: Development of a contemporary formula for estimating gestational age from ultrasound fetal biometrics SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Skupski, Daniel W.] New York Presbyterian Queens, Flushing, NY USA. [Owen, John] Univ Alabama Birmingham, Birmingham, AL USA. [Kim, Sungduk; Albert, Paul; Grantz, Katherine Laughon] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 105 BP S74 EP S74 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800106 ER PT J AU Tita, A AF Tita, Alan TI Late intrapartum FHR patterns and their relationship to neonatal outcomes in nulliparas SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Tita, Alan] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 711 BP S373 EP S374 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800704 ER PT J AU Tita, A AF Tita, Alan TI Time from diagnosis to hospitalization for preeclampsia (PE): patient characteristics and outcomes in a multicenter nulliparous cohort SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Tita, Alan] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 483 BP S264 EP S265 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800477 ER PT J AU Varner, M AF Varner, Michael TI Does maternal replacement therapy improve neonatal outcomes in maternal subclinical hypothyroidism or hypothyroxinemia? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Varner, Michael] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 823 BP S428 EP S429 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800812 ER PT J AU Varner, M AF Varner, Michael TI Do subsequent pregnancies following the diagnosis of mild gestational diabetes increase the risk of maternal cardiometabolic disorders? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Varner, Michael] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 294 BP S168 EP S169 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800290 ER PT J AU Wiegand, S Swortwood, MJ Huestis, MA Vora, NL AF Wiegand, Samantha Swortwood, Madeleine J. Huestis, Marilyn A. Vora, Neeta L. TI Quantification of naloxone and metabolites in cord blood of prenatally-exposed newborns and correlations with maternal concentrations SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 Univ N Carolina, Chapel Hill, NC USA. NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 120 BP S84 EP S84 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800121 ER PT J AU Yee, LM AF Yee, Lynn M. TI Delayed pushing is associated with increased frequency of cesarean delivery and NICU admission SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 36th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2016 CL Atlanta, GA SP Soc Maternal Fetal Med C1 [Yee, Lynn M.] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2016 VL 214 IS 1 SU S MA 200 BP S121 EP S122 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CZ4SK UT WOS:000367092800198 ER PT J AU Carr, NJ Cecil, TD Mohamed, F Sobin, LH Sugarbaker, PH Gonzalez-Moreno, S Taflampas, P Chapman, S Moran, BJ AF Carr, Norman J. Cecil, Thomas D. Mohamed, Faheez Sobin, Leslie H. Sugarbaker, Paul H. Gonzalez-Moreno, Santiago Taflampas, Panos Chapman, Sara Moran, Brendan J. TI A Consensus for Classification and Pathologic Reporting of Pseudomyxoma Peritonei and Associated Appendiceal Neoplasia The Results of the Peritoneal Surface Oncology Group International (PSOGI) Modified Delphi Process SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article ID OVARIAN MUCINOUS TUMORS; SIGNET-RING CELLS; CLINICOPATHOLOGICAL ANALYSIS; INTRAPERITONEAL CHEMOTHERAPY; PROPOSED CLASSIFICATION; CYTOREDUCTIVE SURGERY; EPITHELIAL NEOPLASMS; PROGNOSTIC-FACTORS; COLORECTAL-CANCER; SERRATED LESIONS C1 [Carr, Norman J.; Cecil, Thomas D.; Mohamed, Faheez; Taflampas, Panos; Moran, Brendan J.] Peritoneal Malignancy Inst, Basingstoke, Hants, England. [Carr, Norman J.; Cecil, Thomas D.; Mohamed, Faheez; Taflampas, Panos; Moran, Brendan J.] North Hampshire Hosp, Basingstoke, Hants, England. [Carr, Norman J.; Chapman, Sara] Southampton Univ Hosp, Cellular Pathol, Southampton SO42 7RT, Hants, England. [Sobin, Leslie H.] NCI, Frederick Natl Lab Canc Res, Rockville, MD USA. [Sugarbaker, Paul H.] Washington Hosp Ctr, Washington Canc Inst, Washington, DC 20010 USA. [Gonzalez-Moreno, Santiago] MD Anderson Canc Ctr, Surg Oncol, Madrid, Spain. RP Carr, NJ (reprint author), Southampton Univ Hosp, Cellular Pathol, Tremona Rd, Southampton SO42 7RT, Hants, England. EM n.j.carr@soton.ac.uk FU Pelican Cancer Foundation FX Financial support for the Basingstoke Conference was generously provided by the Pelican Cancer Foundation. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 46 TC 18 Z9 18 U1 6 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD JAN PY 2016 VL 40 IS 1 BP 14 EP 26 PG 13 WC Pathology; Surgery SC Pathology; Surgery GA CZ5IG UT WOS:000367135400003 PM 26492181 ER PT J AU King, RL Dao, LN McPhail, ED Jaffe, ES Said, J Swerdlow, SH Sattler, CA Ketterling, RP Sidhu, JS Hsi, ED Karikehalli, S Jiang, LY Gibson, SE Ondrejka, SL Nicolae, A Macon, WR Dasari, S Castellar, EP Feldman, AL AF King, Rebecca L. Dao, Linda N. McPhail, Ellen D. Jaffe, Elaine S. Said, Jonathan Swerdlow, Steven H. Sattler, Christopher A. Ketterling, Rhett P. Sidhu, Jagmohan S. Hsi, Eric D. Karikehalli, Shridevi Jiang, Liuyan Gibson, Sarah E. Ondrejka, Sarah L. Nicolae, Alina Macon, William R. Dasari, Surendra Castellar, Edgardo Parrilla Feldman, Andrew L. TI Morphologic Features of ALK-negative Anaplastic Large Cell Lymphomas With DUSP22 Rearrangements SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article ID PERIPHERAL T-CELL; TRANSLOCATIONS; EXPRESSION; DISEASE; ALCL C1 [King, Rebecca L.; Dao, Linda N.; McPhail, Ellen D.; Sattler, Christopher A.; Ketterling, Rhett P.; Macon, William R.; Feldman, Andrew L.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Dasari, Surendra] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Jaffe, Elaine S.; Nicolae, Alina] NCI, Hematopathol Sect, Pathol Lab, Bethesda, MD 20892 USA. [Said, Jonathan] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol, Los Angeles, CA 90095 USA. [Swerdlow, Steven H.; Gibson, Sarah E.] Univ Pittsburgh, Med Ctr, Div Hematopathol, Pittsburgh, PA USA. [Sidhu, Jagmohan S.] United Hlth Serv Hosp, Dept Pathol & Lab Med, Johnson City, TN USA. [Karikehalli, Shridevi] Centrex Clin Labs, Dept Pathol & Lab Med, Utica, NY USA. [Hsi, Eric D.; Ondrejka, Sarah L.] Cleveland Clin, Dept Clin Pathol, Cleveland, OH 44106 USA. [Jiang, Liuyan] Mayo Clin, Dept Pathol & Lab Med, Jacksonville, FL 32224 USA. [Castellar, Edgardo Parrilla] Duke Univ, Dept Pathol, Durham, NC 27706 USA. RP Feldman, AL (reprint author), Mayo Clin, Dept Lab Med & Pathol, Hilton Bldg,Room 8-00F,200 First St SW, Rochester, MN 55905 USA. EM feldman.andrew@mayo.edu FU National Cancer Institute [R01 CA177734, P50 CA97274]; National Center for Advancing Translational Science [UL1 TR000135]; Predolin Foundation; Abbvie; Eli Lilly; Cellerant Therapeutics FX Supported by Award Numbers R01 CA177734 (A.L.F.) and P50 CA97274 (University of Iowa/Mayo Clinic Lymphoma SPORE) from the National Cancer Institute, by Award Number UL1 TR000135 (Mayo Clinic CTSA) from the National Center for Advancing Translational Science, and by the Predolin Foundation. S.H.S. has accepted a speaker honorarium and meeting travel expenses from Chugai Pharmaceutical Co. E.D.H. has received a speaker honorarium from Seattle Genetics and sponsored research support from Abbvie, Eli Lilly, and Cellerant Therapeutics. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 20 TC 3 Z9 4 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD JAN PY 2016 VL 40 IS 1 BP 36 EP 43 PG 8 WC Pathology; Surgery SC Pathology; Surgery GA CZ5IG UT WOS:000367135400005 PM 26379151 ER PT J AU Larson, JC Allstadt, SD Fan, TM Khanna, C Lunghofer, PJ Hansen, RJ Gustafson, DL Legendre, AM Galyon, GD LeBlanc, AK Martin-Jimenez, T AF Larson, Jeanne C. Allstadt, Sara D. Fan, Timothy M. Khanna, Chand Lunghofer, Paul J. Hansen, Ryan J. Gustafson, Daniel L. Legendre, Alfred M. Galyon, Gina D. LeBlanc, Amy K. Martin-Jimenez, Tomas TI Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs SO AMERICAN JOURNAL OF VETERINARY RESEARCH LA English DT Article ID RENAL-ALLOGRAFT SURVIVAL; MAMMALIAN TARGET; CANINE MODEL; WHOLE-BLOOD; CELL-LINES; SIROLIMUS; PATHWAY; CYCLOSPORINE; EVEROLIMUS; STABILITY AB OBJECTIVE To determine the pharmacokinetics of orally administered rapamycin in healthy dogs. ANIMALS 5 healthy purpose-bred hounds. PROCEDURES The study consisted of 2 experiments. In experiment 1, each dog received rapamycin (0.1 mg/kg, PO) once; blood samples were obtained immediately before and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after administration. In experiment 2, each dog received rapamycin (0.1 mg/kg, PO) once daily for 5 days; blood samples were obtained immediately before and at 3, 6, 24, 27, 30, 48, 51, 54, 72, 75, 78, 96, 96.5, 97, 98, 100, 102, 108, 120, 144, and 168 hours after the first dose. Blood rapamycin concentration was determined by a validated liquid chromatography-tandem mass spectrometry assay. Pharma-cokinetic parameters were determined by compartmental and non-compartmental analyses. RESULTS Mean +/- SD blood rapamycin terminal half-life, area under the concentration-time curve from 0 to 48 hours after dosing, and maximum concentration were 38.7 +/- 12.7 h, 140 +/- 23.9 ng.h/mL, and 8.39 +/- 1.73 ng/mL, respectively, for experiment 1, and 99.5 +/- 89.5 h, 126 +/- 27.1 ng.h/mL, and 5.49 +/- 1.99 ng/mL, respectively, for experiment 2. Pharmacokinetic parameters for rapamycin after administration of 5 daily doses differed significantly from those after administration of 1 dose. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that oral administration of low-dose (0.1 mg/kg) rapamycin to healthy dogs achieved blood concentrations measured in nanograms per milliliter. The optimal dose and administration frequency of rapamcyin required to achieve therapeutic effects in tumor-bearing dogs, as well as toxicity after chronic dosing, need to be determined. C1 [Larson, Jeanne C.; Allstadt, Sara D.; Legendre, Alfred M.; Galyon, Gina D.; LeBlanc, Amy K.] Univ Tennessee, Coll Vet Med, Dept Small Anim Clin Sci, Knoxville, TN 37996 USA. [Martin-Jimenez, Tomas] Univ Tennessee, Coll Vet Med, Dept Biomed & Diagnost Sci, Knoxville, TN 37996 USA. [Fan, Timothy M.] Univ Illinois, Coll Vet Med, Dept Vet Clin Med, Urbana, IL 61801 USA. [Khanna, Chand] NCI, NIH, Ctr Canc Res, Comparat Oncol Program, Bethesda, MD 20892 USA. [Lunghofer, Paul J.; Hansen, Ryan J.; Gustafson, Daniel L.] Colorado State Univ, Flint Anim Canc Ctr, Ft Collins, CO 80523 USA. RP Larson, JC (reprint author), Univ Tennessee, Coll Vet Med, Dept Small Anim Clin Sci, POB 1071, Knoxville, TN 37996 USA. EM jeannelarsondvm@gmail.com FU University of Tennessee Center of Excellence in Livestock Disease and Human Health; Department of Small Animal Clinical Sciences Companion Animal and Oncology Funds; University of Colorado Cancer Center Support Grant FX Supported in part by the University of Tennessee Center of Excellence in Livestock Disease and Human Health and the Department of Small Animal Clinical Sciences Companion Animal and Oncology Funds. Pharmacokinetic analysis was performed in the Pharmacology Shared Resource with support from a University of Colorado Cancer Center Support Grant. NR 26 TC 3 Z9 3 U1 1 U2 5 PU AMER VETERINARY MEDICAL ASSOC PI SCHAUMBURG PA 1931 N MEACHAM RD SUITE 100, SCHAUMBURG, IL 60173-4360 USA SN 0002-9645 EI 1943-5681 J9 AM J VET RES JI Am. J. Vet. Res. PD JAN PY 2016 VL 77 IS 1 BP 65 EP 71 PG 7 WC Veterinary Sciences SC Veterinary Sciences GA CZ7CJ UT WOS:000367257200007 PM 26709938 ER PT J AU Lloyd, JR Jayasekara, PS Jacobson, KA AF Lloyd, John R. Jayasekara, P. Suresh Jacobson, Kenneth A. TI Characterization of polyamidoamino (PAMAM) dendrimers using in-line reversed phase LC electrospray ionization mass spectrometry SO ANALYTICAL METHODS LA English DT Article ID POLY(AMIDOAMINE) DENDRIMERS; COMPLEXES; SILICA AB Generation 3 (G3) PAMAM dendrimers are symmetrical, highly branched polymers widely reported in the scientific literature as therapeutic agents themselves or as carrier scaffolds for various therapeutic agents. A large number of analytical techniques have been applied to study PAMAM dendrimers, but one that has been missing is in-line reversed phase LC electrospray ionization mass spectrometry (RP/LC/ESI/MS). To translate PAMAM dendrimers into therapeutic agents, a better understanding of their purity, stability and structure is required, and in-line RP/LC/ESI/MS is widely applied to all three of these analytical questions. In this study, we developed a robust in-line RP/LC/ESI/MS method for assessing stability, purity and structure of the G3 PAMAM dendrimers, and we also examined the reasons why previous attempts at method development failed. Using the RP/LC/ESI/MS method we uncovered several unique aspects of the chemistry of G3 PAMAM dendrimers. They are interconverted between two isomeric forms by dialysis, and under higher concentration levels there is an inter-molecular displacement reaction resulting, which degrades PAMAM dendrimers. Purification of G3 dendrimers by RP/LC was also previously unreported; so we slightly modified the LC/MS method for isolating individual components from a complex dendrimer mixture. Thus, we have developed a robust, comprehensive method for characterizing PAMAM dendrimers and their degradation. C1 [Lloyd, John R.; Jayasekara, P. Suresh; Jacobson, Kenneth A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Jayasekara, P. Suresh] Walter Reed Army Inst Res, Div Expt Therapeut, Silver Spring, MD 20910 USA. RP Jacobson, KA (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural Research Program of the NIH, NIDDK FX We thank the Intramural Research Program of the NIH, NIDDK for support. NR 32 TC 1 Z9 1 U1 1 U2 15 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1759-9660 EI 1759-9679 J9 ANAL METHODS-UK JI Anal. Methods PY 2016 VL 8 IS 2 BP 263 EP 269 DI 10.1039/c5ay01995h PG 7 WC Chemistry, Analytical; Food Science & Technology; Spectroscopy SC Chemistry; Food Science & Technology; Spectroscopy GA CZ6XF UT WOS:000367243600005 PM 26997980 ER PT J AU McSpadden, KE Patrick, H Oh, AY Yaroch, AL Dwyer, LA Nebeling, LC AF McSpadden, Kate E. Patrick, Heather Oh, April Y. Yaroch, Amy L. Dwyer, Laura A. Nebeling, Linda C. TI The association between motivation and fruit and vegetable intake: The moderating role of social support SO APPETITE LA English DT Article DE Fruit and vegetable intake; Motivation; Social support ID SELF-DETERMINATION THEORY; INTRINSIC MOTIVATION; AUTONOMY SUPPORT; PSYCHOSOCIAL PREDICTORS; INTERVENTIONS; CONSUMPTION; BEHAVIOR; HEALTH; DIETARY; ADULTS AB Despite knowing that fruit and vegetable (FV) intake promotes health and well-being, few U.S. adults meet current guidelines. Thus, understanding people's motivation for FV intake is important for predicting dietary behavior. Applying self-determination theory, the goal of this study was to examine the role of social support as a potential moderator of the link between autonomous and controlled motivations and FV intake. Cross-sectional data from 2959 adults in the United States were analyzed. Autonomous motivation and perceived social support were positively associated with FV intake, while controlled motivation was negatively associated with FV intake. Additionally, there was evidence that the negative association between controlled motivation and FV intake was attenuated by higher levels of perceived social support. Findings suggest the need for a more comprehensive approach to understanding the role of motivation in health behaviors like FV intake and the potential roles played by friends and family in these motivational processes. (C) 2015 Elsevier Ltd. All rights reserved. C1 [McSpadden, Kate E.; Oh, April Y.; Dwyer, Laura A.; Nebeling, Linda C.] NCI, Behav Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Yaroch, Amy L.] Gretchen Swanson Ctr Nutr, Omaha, NE 68114 USA. [Patrick, Heather] Envolve PeopleCare, Bethesda, MD USA. RP Dwyer, LA (reprint author), NCI, Behav Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM laura.dwyer@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 52 TC 2 Z9 2 U1 5 U2 17 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-6663 EI 1095-8304 J9 APPETITE JI Appetite PD JAN 1 PY 2016 VL 96 BP 87 EP 94 DI 10.1016/j.appet.2015.08.031 PG 8 WC Behavioral Sciences; Nutrition & Dietetics SC Behavioral Sciences; Nutrition & Dietetics GA CZ5AH UT WOS:000367114000012 PM 26321416 ER PT J AU Hubbard, RR Palmberg, A Lydecker, J Green, B Kelly, NR Trapp, S Bean, MK AF Hubbard, Rebecca R. Palmberg, Allison Lydecker, Janet Green, Brooke Kelly, Nichole R. Trapp, Stephen Bean, Melanie K. TI Culturally-Based Communication about Health, Eating, and Food: Development and validation of the CHEF scale SO APPETITE LA English DT Article DE Ethnic identity; Race; Obesity; Racism; Culture; Food choices ID COLLEGE-STUDENTS; SELF-EFFICACY; AFRICAN-AMERICAN; SOCIAL SUPPORT; RACIAL-DISCRIMINATION; EMERGING ADULTHOOD; CHILDHOOD OBESITY; BEHAVIOR-CHANGE; BLOOD-PRESSURE; IDENTITY AB Ethnic minority populations in the United States are disproportionately affected by obesity. To address this disparity, research has begun to investigate the role of culture, ethnicity, and experiences with racism on food choices and health interventions. The aim of the current study was to develop and evaluate a new scale measuring the extent to which individuals' culture, as they perceive it, influences perceptions of food-related health messages. A diverse sample of 422 college students responded to the item pool, as well as surveys on race-related stress, self-efficacy in making healthy food choices, ethnic identity, and social support for health-related behaviors. Exploratory and confirmatory factor analyses produced a five-factor model: Connection (the extent to which food connected individuals with their culture), Authority (beliefs that health care providers were familiar with individuals' cultural foods), Unhealthy Food Perceptions (beliefs that individuals' cultural foods were perceived as unhealthy), Healthy Food Perceptions (beliefs that others perceive individuals' cultural foods to be healthy), and Social Value (the extent to which social relationships are improved by shared cultural food traditions). Authority and Healthy Food Perceptions were related to individuals' confidence in their ability to make healthy food choices. Authority was inversely correlated with negative coping with racism-related events. Ethnic identity was significantly correlated with all but Unhealthy Food Perceptions. Race/ethnicity differences were identified for Healthy Food Perceptions, Unhealthy Food Perceptions, Social Value, Connection, but not Authority. Applications and suggestions for further research using the Culturally-based Communication about Health, Eating, and Food (CHEF) Scale are proposed. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Hubbard, Rebecca R.; Palmberg, Allison; Lydecker, Janet; Green, Brooke; Kelly, Nichole R.] Virginia Commonwealth Univ, Dept Psychol, Richmond, VA 23284 USA. [Lydecker, Janet] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. [Kelly, Nichole R.] USUHS, Dept Med & Clin Psychol, DoD, Bethesda, MD 20814 USA. [Kelly, Nichole R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,DHHS, Bethesda, MD 20814 USA. [Bean, Melanie K.] Virginia Commonwealth Univ, Dept Pediat, Childrens Hosp Richmond, Richmond, VA 23298 USA. [Trapp, Stephen] Univ S Florida, Dept Child & Family Studies, Coll Behav & Community Sci, Tampa, FL 33612 USA. RP Hubbard, RR (reprint author), 1525 E 53rd St,Suite 503, Chicago, IL 60615 USA. EM hubbardrr@gmail.com RI Lydecker, Janet/B-3349-2016 OI Lydecker, Janet/0000-0001-6425-514X NR 54 TC 1 Z9 1 U1 6 U2 21 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-6663 EI 1095-8304 J9 APPETITE JI Appetite PD JAN 1 PY 2016 VL 96 BP 399 EP 407 DI 10.1016/j.appet.2015.09.024 PG 9 WC Behavioral Sciences; Nutrition & Dietetics SC Behavioral Sciences; Nutrition & Dietetics GA CZ5AH UT WOS:000367114000049 PM 26409643 ER PT J AU Swortwood, MJ Carlier, J Ellefsen, KN Wohlfarth, A Diao, XX Concheiro-Guisan, M Kronstrand, R Huestis, MA AF Swortwood, Madeleine J. Carlier, Jeremy Ellefsen, Kayla N. Wohlfarth, Ariane Diao, Xingxing Concheiro-Guisan, Marta Kronstrand, Robert Huestis, Marilyn A. TI In vitro, in vivo and in silico metabolic profiling of -pyrrolidinopentiothiophenone, a novel thiophene stimulant SO BIOANALYSIS LA English DT Article DE alpha-PVT; hepatocytes; high-resolution MS; metabolism; novel psychoactive substances; synthetic cathinone ID CHROMATOGRAPHY-MASS-SPECTROMETRY; HUMAN LIVER-MICROSOMES; DRUG ALPHA-PYRROLIDINOVALEROPHENONE; DESIGNER DRUG; TOXICOLOGICAL DETECTION; BATH SALTS; 3,4-METHYLENEDIOXYPYROVALERONE MDPV; SYNTHETIC CATHINONES; HUMAN HEPATOCYTES; ADB-FUBINACA AB Background: Little or no pharmacological or toxicological data are available for novel psychoactive substances when they first emerge, making their identification and interpretation in biological matrices challenging. Materials & methods: A new synthetic cathinone, alpha-pyrrolidinopentiothiophenone (alpha-PVT), was incubated with hepatocytes and samples were analyzed using liquid chromatography coupled to a Q Exactive(TM) Orbitrap mass spectrometer. Authentic urine specimens from suspected -PVT cases were also analyzed. Scans were data mined with Compound Discoverer for identification and structural elucidation of metabolites. Results/conclusion: Seven alpha-PVT metabolites were identified in hepatocyte incubations, and in the authentic urine samples, also with an additional monohydroxylated product and a glucuronide of low intensity. alpha-PVT dihydroxypyrrolidinyl, alpha-PVT 2-ketopyrrolidinyl, alpha-PVT hydroxythiophenyl and alpha-PVT thiophenol had the most intense in vivo signals. C1 [Swortwood, Madeleine J.; Carlier, Jeremy; Ellefsen, Kayla N.; Wohlfarth, Ariane; Diao, Xingxing; Concheiro-Guisan, Marta; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Ellefsen, Kayla N.] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. [Wohlfarth, Ariane] Natl Board Forens Med, Linkoping, Sweden. [Concheiro-Guisan, Marta] CUNY John Jay Coll Criminal Justice, Dept Sci, New York, NY 10019 USA. [Kronstrand, Robert] Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linkoping, Sweden. [Kronstrand, Robert] Linkoping Univ, Fac Hlth Sci, Dept Med & Hlth Sci, Linkoping, Sweden. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health FX This research was funded by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. 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 45 TC 11 Z9 11 U1 6 U2 11 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1757-6180 EI 1757-6199 J9 BIOANALYSIS JI Bioanalysis PY 2016 VL 8 IS 1 BP 65 EP 82 DI 10.4155/bio.15.237 PG 18 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA CZ3NZ UT WOS:000367012500008 PM 26648097 ER PT J AU Krishnamurthy, VN Naeem, M Murphy, TP Cerezo, J Jordan, PG Goldberg, SH Ershow, AG Hirsch, AT Oldenburg, N Cutlip, DE AF Krishnamurthy, Venkataramu N. Naeem, Muhammad Murphy, Timothy P. Cerezo, Joselyn Jordan, Paul Gaither Goldberg, Suzanne H. Ershow, Abby G. Hirsch, Alan T. Oldenburg, Niki Cutlip, Donald E. TI The effect of gender on outcomes of aortoiliac artery interventions for claudication SO CLINICAL IMAGING LA English DT Article DE Peripheral arterial disease; Gender differences; Aortoiliac stent; Vessel diameter ID PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY; ENDOLUMINAL REVASCULARIZATION CLEVER; CARDIOVASCULAR RISK-FACTORS; INFRARENAL AORTIC DIAMETER; COMMON FEMORAL-ARTERY; OCCLUSIVE DISEASE; ILIAC ARTERIES; CORONARY ANGIOPLASTY; VASCULAR-DISEASE; ABDOMINAL-AORTA AB Objective: To explore the relationship between gender, native artery diameters, and outcomes of stent revascularization (ST) in the "Claudication: Exercise versus Endoluminal Revascularization" trial. Methods: A comparative analysis was performed of the impact of gender, age, weight, height, body mass index, and body surface area on revascularization-outcomes at baseline-and 6-months in 55 arterial segments-of aorta, common iliac artery, and external iliac artery (EIA). Results: Women demonstrated smaller diameter of the EIA. However, the clinical outcomes of revascularization were not negatively affected by the gender-based differences. Conclusion: Gender-based differences are unlikely to significantly impact outcome of ST. Published by Elsevier Inc. C1 [Krishnamurthy, Venkataramu N.] VA Ann Arbor Hlth Syst, Serv Radiol, Ann Arbor, MI 48105 USA. [Naeem, Muhammad; Murphy, Timothy P.; Cerezo, Joselyn; Jordan, Paul Gaither] Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch,Vasc Dis Res Ctr, Dept Diagnost Imaging,Div Vasc & Intervent Radiol, Providence, RI 02903 USA. [Goldberg, Suzanne H.] NHLBI, Nutr Branch, Div Cardiovasc Dis, NIH, Bethesda, MD 20892 USA. [Ershow, Abby G.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Hirsch, Alan T.; Oldenburg, Niki] Univ Minnesota, Sch Med, Div Cardiovasc, Minneapolis, MN 55455 USA. [Hirsch, Alan T.; Oldenburg, Niki] Univ Minnesota, Sch Med, Lillehei Heart Inst, Minneapolis, MN 55455 USA. [Cutlip, Donald E.] Harvard Clin Res Inst, Clin Invest, Boston, MA USA. RP Krishnamurthy, VN (reprint author), VA Ann Arbor Hlth Syst, 2215 Fuller Rd,Mail Code 114, Ann Arbor, MI 48105 USA. EM venkkris@umich.edu; mnaeem@Lifespan.org; TMurphy@Lifespan.org; jvcerezol@gmail.com; pjordan@Lifespan.org; ErshowA@nhIbi.nih.gov; hirsc005@umn.edu; olden019@umn.edu; don.cutlip@hcri.harvard.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda MD; NIH Office for Research on Women's Health FX The study was funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda MD and co-funded by the NIH Office for Research on Women's Health. NR 43 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 0899-7071 EI 1873-4499 J9 CLIN IMAG JI Clin. Imaging PD JAN-FEB PY 2016 VL 40 IS 1 BP 96 EP 100 DI 10.1016/j.clinimag.2015.09.003 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CZ6ME UT WOS:000367214600013 PM 26439658 ER PT J AU Cicala, C Nawaz, F Jelicic, K Arthos, J Fauci, AS AF Cicala, Claudia Nawaz, Fatima Jelicic, Katija Arthos, James Fauci, Anthony S. TI HIV-1 gp120: A Target for Therapeutics and Vaccine Design SO CURRENT DRUG TARGETS LA English DT Article DE HIV-1; gp120; transmission; signal transduction; integrin; alpha 4 beta 7 ID IMMUNODEFICIENCY-VIRUS TYPE-1; T-CELL DEPLETION; RECOMBINANT GLYCOPROTEIN-120 VACCINE; HIGH ENDOTHELIAL VENULES; ACUTE SIV INFECTION; INTESTINAL INTRAEPITHELIAL LYMPHOCYTES; EPIDERMAL LANGERHANS CELLS; MUCOSAL HOMING RECEPTOR; MACROPHAGE-TROPIC HIV; INTEGRIN ALPHA(4)BETA(7) AB Although extraordinary progress has been made in the treatment and prevention of HIV infection, the AIDS pandemic continues to rage globally with 2.1 million infections and 1.6 million AIDS-related deaths reported in 2013. Until an effective vaccine is developed, new strategies for treatment and prevention are needed. Regarding the prevention of HIV infection, a major focus of prevention research in general and vaccine research in particular involves the interaction of the HIV-1 envelope protein gp120 with cell-surface receptors, with the hope that a greater understanding of these interactions will lead to the development of novel strategies aimed at preventing and even treating HIV-1 infection. Particular attention has been directed toward gaining a more precise understanding of the early events in transmission focusing on that critical window of time when HIV first establishes infection in the host. Here we describe some of the recent findings involving HIV-1 envelope interactions with cell surface receptors that are relevant to transmission and which may represent new opportunities to develop strategies to prevent HIV infection. C1 [Cicala, Claudia; Nawaz, Fatima; Jelicic, Katija; Arthos, James; Fauci, Anthony S.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Cicala, C (reprint author), NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. EM ccicala@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. NR 169 TC 0 Z9 0 U1 2 U2 12 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-4501 EI 1873-5592 J9 CURR DRUG TARGETS JI Curr. Drug Targets PY 2016 VL 17 IS 1 BP 122 EP 135 DI 10.2174/1389450116666150825120735 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CY9QT UT WOS:000366742100012 PM 26302793 ER PT J AU Bao, W Li, SS Chavarro, JE Tobias, DK Zhu, YY Hu, FB Zhang, CL AF Bao, Wei Li, Shanshan Chavarro, Jorge E. Tobias, Deirdre K. Zhu, Yeyi Hu, Frank B. Zhang, Cuilin TI Low Carbohydrate-Diet Scores and Long-term Risk of Type 2 Diabetes Among Women With a History of Gestational Diabetes Mellitus: A Prospective Cohort Study SO DIABETES CARE LA English DT Article ID CORONARY-HEART-DISEASE; TOTAL-ENERGY-INTAKE; LOW-FAT DIETS; PHYSICAL-ACTIVITY; WEIGHT-LOSS; GLUCOSE-INTOLERANCE; RANDOMIZED-TRIAL; QUESTIONNAIRE; METAANALYSIS; PREGNANCY AB OBJECTIVE Low-carbohydrate diets (LCDs) may improve short-term glycemic control in patients with gestational diabetes mellitus (GDM), but the long-term effect on progression from GDM to type 2 diabetes mellitus (T2DM) is unknown. We aimed to examine the long-term risk of T2DM in association with a low-carbohydrate dietary pattern among women with a history of GDM. RESEARCH DESIGN AND METHODS Overall, 4,502 women with a history of GDM from the Nurses' Health Study II (NHSII) cohort, as part of the Diabetes & Women's Health (DWH) study, were followed up from 1991 to 2011. Overall, animal, or vegetable LCD scores, which represent adherence to different low-carbohydrate dietary patterns, were calculated using diet intake information assessed every 4 years since 1991 by validated food-frequency questionnaires. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs. RESULTS We documented 722 incident cases of T2DM during 68,897 person-years of observation. The multivariable-adjusted HRs (95% CIs) of T2DM, comparing the highest with lowest quintiles, were 1.36 (1.04-1.78) for overall LCD score (P = 0.003 for trend), 1.40 (1.06-1.84) for animal LCD score (P = 0.004 for trend), and 1.19 (0.91-1.55) for vegetable LCD score (P = 0.50 for trend). CONCLUSIONS Among women with a history of GDM, a low-carbohydrate dietary pattern, particularly with high protein and fat intake mainly from animal-source foods, is associated with higher T2DM risk, whereas a low-carbohydrate dietary pattern with high protein and fat intake from plant-source foods is not significantly associated with risk of T2DM. C1 [Bao, Wei; Li, Shanshan; Zhu, Yeyi; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20892 USA. [Bao, Wei] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA USA. [Chavarro, Jorge E.; Tobias, Deirdre K.; Hu, Frank B.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Chavarro, Jorge E.; Hu, Frank B.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chavarro, Jorge E.; Hu, Frank B.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Chavarro, Jorge E.; Tobias, Deirdre K.; Hu, Frank B.] Harvard Univ, Sch Med, Boston, MA USA. [Tobias, Deirdre K.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20892 USA. EM zhangcu@mail.nih.gov OI Bao, Wei/0000-0002-7301-5786 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN275201000020C]; National Institutes of Health [DK-58845, CA-50385, P30-DK-46200, UM1-CA-176726]; American Diabetes Association [7-12-MN-34] FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract no. HHSN275201000020C). The Nurses' Health Study II was funded by research grants DK-58845, CA-50385, P30-DK-46200, and UM1-CA-176726 from the National Institutes of Health. D.K.T. was supported by a mentored fellowship from the American Diabetes Association (no. 7-12-MN-34). NR 47 TC 4 Z9 4 U1 1 U2 12 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 JAN PY 2016 VL 39 IS 1 BP 43 EP 49 DI 10.2337/dc15-1642 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CZ8EA UT WOS:000367331800022 PM 26577416 ER PT J AU Klingensmith, GJ Pyle, L Nadeau, KJ Barbour, LA Goland, RS Willi, SM Linder, B White, NH AF Klingensmith, Georgeanna J. Pyle, Laura Nadeau, Kristen J. Barbour, Linda A. Goland, Robin S. Willi, Steven M. Linder, Barbara White, Neil H. CA TODAY Study Grp TI Pregnancy Outcomes in Youth With Type 2 Diabetes: The TODAY Study Experience SO DIABETES CARE LA English DT Article ID MATERNAL OBESITY; UNITED-STATES; CONGENITAL-ANOMALIES; ADOLESCENTS; RISK; GROWTH; BIRTH; WOMEN AB OBJECTIVE We evaluated pregnancy outcomes, maternal and fetal/neonatal, during the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study. RESEARCH DESIGN AND METHODS The TODAY study was a randomized controlled trial comparing three treatment options for youth with type 2 diabetes. Informed consent included the requirement for contraception, including abstinence; this was reinforced at each visit. Following informed consent, self-reported data related to the mother's prenatal care and delivery and the infant's health were retrospectively collected. When permitted, maternal medical records and infant birth records were reviewed. RESULTS Of the 452 enrolled female participants, 46 (10.2%) had 63 pregnancies. Despite continued emphasis on adequate contraception, only 4.8% of the pregnant participants reported using contraception prior to pregnancy. The mean age at first pregnancy was 18.4 years; the mean diabetes duration was 3.17 years. Seven pregnancies were electively terminated; three pregnancies had no data reported. Of the remaining 53 pregnancies, 5 (9.4%) resulted in early pregnancy loss, and 7 (13%) resulted in loss with inadequate pregnancy duration data. Two pregnancies ended in stillbirth, at 27 and 37 weeks, and 39 ended with a live-born infant. Of the live-born infants, six (15.4%) were preterm and eight (20.5%) had a major congenital anomaly. CONCLUSIONS Despite diabetes-specific information recommending birth control and the avoidance of pregnancy, 10% of the study participants became pregnant. Pregnancies in youth with type 2 diabetes may be especially prone to result in congenital anomalies. Reasons for the high rate of congenital anomalies are uncertain, but may include poor metabolic control and extreme obesity. C1 [Klingensmith, Georgeanna J.] Univ Colorado, Barbara Davis Ctr Diabet, Sch Med, Aurora, CO USA. [Klingensmith, Georgeanna J.] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO USA. [Pyle, Laura] George Washington Univ, Ctr Biostat, Rockville, MD 20852 USA. [Nadeau, Kristen J.] Univ Colorado, Sch Med, Div Pediat Endocrinol, Dept Pediat, Aurora, CO USA. [Barbour, Linda A.] Univ Colorado, Sch Med, Dept Med, Div Endocrinol, Aurora, CO USA. [Barbour, Linda A.] Univ Colorado, Sch Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, Aurora, CO USA. [Goland, Robin S.] Columbia Univ, Naomi Berrie Diabet Ctr, New York, NY USA. [Willi, Steven M.] Childrens Hosp Philadelphia, Dept Endocrinol & Diabet, Philadelphia, PA 19104 USA. [Linder, Barbara] NIDDKD, NIH, Bethesda, MD USA. [White, Neil H.] Washington Univ, Sch Med, Dept Pediat, Div Endocrinol & Diabet, St Louis, MO 63110 USA. RP Pyle, L (reprint author), George Washington Univ, Ctr Biostat, Rockville, MD 20852 USA. EM laura.pyle@ucdenver.edu OI Zeitler, Philip/0000-0001-5756-7858 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health Office of the Director [U01-DK-61212, U01-DK-61230, U01-DK-61239, U01-DK-61242, U01-DK-61254]; National Center for Research Resources General Clinical Research Centers Program [M01-RR-00036, M01-RR00043-45, M01-RR00069, M01-RR00084, M01-RR01066, M01-RR00125, M01-RR14467]; National Center for Research Resources Clinical and Translational Science Awards [UL1-RR-024134, UL1-RR-024139, UL1-RR-024153, UL1-RR-024989, UL1-RR-024992, UL1-RR-025758, UL1-RR-025780] FX This work was completed with funding from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institutes of Health Office of the Director (OD) through grants U01-DK-61212, U01-DK-61230, U01-DK-61239, U01-DK-61242, and U01-DK-61254; from the National Center for Research Resources General Clinical Research Centers Program grants M01-RR-00036 (Washington University School of Medicine in St. Louis), M01-RR00043-45 (Children's Hospital Los Angeles), M01-RR00069 (University of Colorado Denver), M01-RR00084 (Children's Hospital of Pittsburgh), M01-RR01066 (Massachusetts General Hospital), M01-RR00125 (Yale University), and M01-RR14467 (University of Oklahoma Health Sciences Center); and from the National Center for Research Resources Clinical and Translational Science Awards UL1-RR-024134 (Children's Hospital of Philadelphia), UL1-RR-024139 (Yale University), UL1-RR-024153 (Children's Hospital of Pittsburgh), UL1-RR-024989 (Case Western Reserve University), UL1-RR-024992 (Washington University in St. Louis), UL1-RR-025758 (Massachusetts General Hospital), and UL1-RR-025780 (University of Colorado Denver). NR 31 TC 3 Z9 3 U1 0 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 JAN PY 2016 VL 39 IS 1 BP 122 EP 129 DI 10.2337/dc15-1206 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CZ8EA UT WOS:000367331800034 PM 26628417 ER PT J AU Weinreb, JC Barentsz, JO Choyke, PL Cornud, F Haider, MA Macura, KJ Margolis, D Schnall, MD Shtern, F Tempany, CM Thoeny, HC Verma, S AF Weinreb, Jeffrey C. Barentsz, Jelle O. Choyke, Peter L. Cornud, Francois Haider, Masoom A. Macura, Katarzyna J. Margolis, Daniel Schnall, Mitchell D. Shtern, Faina Tempany, Clare M. Thoeny, Harriet C. Verma, Sadna TI PI-RADS Prostate Imaging - Reporting and Data System: 2015, Version 2 SO EUROPEAN UROLOGY LA English DT Article DE Prostate mpMRI; Prostate MRI; Magnetic resonance imaging; Prostate; Prostate cancer ID PELVIC PHASED-ARRAY; HIGH B-VALUE; DIFFUSION-WEIGHTED IMAGES; COMPUTER-AIDED DIAGNOSIS; RADICAL PROSTATECTOMY; 3 TESLA; CANCER DETECTION; PERIPHERAL ZONE; MULTIPARAMETRIC MRI; ENDORECTAL COIL AB The Prostate Imaging - Reporting and Data System Version 2 (PI-RADS (TM) v2) is the product of an international collaboration of the American College of Radiology (ACR), European Society of Uroradiology (ESUR), and AdMetech Foundation. It is designed to promote global standardization and diminish variation in the acquisition, interpretation, and reporting of prostate multiparametric magnetic resonance imaging (mpMRI) examination, and it is based on the best available evidence and expert consensus opinion. It establishes minimum acceptable technical parameters for prostate mpMRI, simplifies and standardizes terminology and content of reports, and provides assessment categories that summarize levels of suspicion or risk of clinically significant prostate cancer that can be used to assist selection of patients for biopsies and management. It is intended to be used in routine clinical practice and also to facilitate data collection and outcome monitoring for research. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Weinreb, Jeffrey C.] Yale Univ, Sch Med, New Haven, CT 06520 USA. [Barentsz, Jelle O.] Radboudumc, Nijmegen, Netherlands. [Choyke, Peter L.] NIH, Bethesda, MD 20892 USA. [Cornud, Francois] Univ Paris 05, Paris, France. [Haider, Masoom A.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Macura, Katarzyna J.] Johns Hopkins Univ, Baltimore, MD USA. [Margolis, Daniel] Univ Calif Los Angeles, Los Angeles, CA USA. [Schnall, Mitchell D.] Univ Penn, Philadelphia, PA 19104 USA. [Shtern, Faina] AdMeTech Fdn, Boston, MA USA. [Tempany, Clare M.] Harvard Univ, Boston, MA 02115 USA. [Thoeny, Harriet C.] Univ Hosp Bern, CH-3010 Bern, Switzerland. [Verma, Sadna] Univ Cincinnati, Cincinnati, OH USA. RP Weinreb, JC (reprint author), Yale Univ, Sch Med, New Haven, CT 06520 USA. EM jeffrey.weinreb@yale.edu NR 81 TC 98 Z9 106 U1 6 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD JAN PY 2016 VL 69 IS 1 BP 16 EP 40 DI 10.1016/j.eururo.2015.08.052 PG 25 WC Urology & Nephrology SC Urology & Nephrology GA CZ4KX UT WOS:000367073100011 PM 26427566 ER EF