FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Moriya, Y Hagino, Y Hall, SF Hen, R Ikeda, K Kasahara, Y Sora, I Uhl, GR AF Moriya, Yuki Hagino, Yoko Hall, Scott F. Hen, Rene Ikeda, Kazutaka Kasahara, Yoshiyuki Sora, Ichiro Uhl, George R. TI Methamphetamine induced changes of monoamine neurotransmission in 5-HT1B KO mice SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 30th Seoul World Congress of the International-College-of-Neuropsychopharmacology (CINP) CY JUL 03-07, 2016 CL Seoul, SOUTH KOREA SP Int Coll Neuropsychopharmacol C1 [Moriya, Yuki; Ikeda, Kazutaka] Tokyo Metropolitan Inst Med Sci, Tokyo, Japan. [Hagino, Yoko; Hall, Scott F.] Univ Toledo, Pharm & Pharmaceut Sci, 2801 W Bancroft St, Toledo, OH 43606 USA. [Hen, Rene] Columbia Univ, New York, NY 10027 USA. [Kasahara, Yoshiyuki] Tohoku Univ, Sendai, Miyagi 980, Japan. [Sora, Ichiro] Kobe Univ, Kobe, Hyogo, Japan. [Uhl, George R.] NIDA, Mol Neurobiol Branch, IRP, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2016 VL 19 SU 1 MA PM309 BP 159 EP 159 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DW8PI UT WOS:000383917600425 ER PT J AU Wang, JB Sushchyk, S Xi, ZX AF Wang, Jia Bei Sushchyk, Sarah Xi, Zheng-Xiong TI Combination of levo-tetrahydropalmatine and low dose naltrexone: a promising treatment for the prevention of cocaine relapse SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 30th Seoul World Congress of the International-College-of-Neuropsychopharmacology (CINP) CY JUL 03-07, 2016 CL Seoul, SOUTH KOREA SP Int Coll Neuropsychopharmacol C1 [Wang, Jia Bei; Sushchyk, Sarah] Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Sushchyk, Sarah; Xi, Zheng-Xiong] NIDA, Mol Targets & Medicat Discovery Branch, Intramural Res Program, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2016 VL 19 SU 1 MA PM312 BP 160 EP 160 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DW8PI UT WOS:000383917600428 ER PT J AU Hattori, S Hagihara, H Huang, FL Huang, KP Inagaki, H Kameyama, T Kuruhashi, H Miyakawa, T Ouchi, Y Takamiya, Y AF Hattori, Satoko Hagihara, Hideo Huang, Freesia L. Huang, Kuo-Ping Inagaki, Hidehito Kameyama, Toshiki Kuruhashi, Hiroki Miyakawa, Tsuyoshi Ouchi, Yuya Takamiya, Yoshihiro TI Deficiency of neurogranin, a susceptible gene for schizophrenia, causes behavioral phenotypes related to schizophrenia and immaturity of the dentate gyrus in mice SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 30th Seoul World Congress of the International-College-of-Neuropsychopharmacology (CINP) CY JUL 03-07, 2016 CL Seoul, SOUTH KOREA SP Int Coll Neuropsychopharmacol C1 [Hattori, Satoko; Hagihara, Hideo; Inagaki, Hidehito; Kameyama, Toshiki; Kuruhashi, Hiroki; Miyakawa, Tsuyoshi; Ouchi, Yuya; Takamiya, Yoshihiro] Fujita Hlth Univ, Toyoake, Aichi, Japan. [Huang, Freesia L.; Huang, Kuo-Ping] NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2016 VL 19 SU 1 MA PM374 BP 185 EP 186 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DW8PI UT WOS:000383917600491 ER PT J AU Tsai, SY Ciesielski, J Su, TP AF Tsai, Shang-Yi Ciesielski, Jenna Su, Tsung-Ping TI Myristic Acid Hitchhiking on Sigma-1 Receptor to Fend Off Neurodegeneration SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 30th Seoul World Congress of the International-College-of-Neuropsychopharmacology (CINP) CY JUL 03-07, 2016 CL Seoul, SOUTH KOREA SP Int Coll Neuropsychopharmacol C1 [Tsai, Shang-Yi; Ciesielski, Jenna; Su, Tsung-Ping] NIDA, Cellular Pathobiol Sect, Integrat Neurosci Res Branch, Intramural Res Program,NIH,DHHS, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2016 VL 19 SU 1 MA PT582 BP 260 EP 260 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DW8PI UT WOS:000383917600696 ER PT J AU Unruh, ML Larive, B Eggers, PW Garg, AX Gassman, JJ Finkelstein, FO Kimmel, PL Chertow, GM AF Unruh, Mark L. Larive, Brett Eggers, Paul W. Garg, Amit X. Gassman, Jennifer J. Finkelstein, Fredric O. Kimmel, Paul L. Chertow, Glenn M. CA FHN Trial Grp TI The effect of frequent hemodialysis on self-reported sleep quality: Frequent Hemodialysis Network Trials SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE daily hemodialysis; frequent hemodialysis; nocturnal hemodialysis; patient-reported outcome; sleep quality ID STAGE RENAL-DISEASE; NOCTURNAL HEMODIALYSIS; HOME HEMODIALYSIS; MEDICAL OUTCOMES; CLINICAL-TRIAL; DOUBLE-BLIND; SYMPTOMS; IMPACT; DISTURBANCES; DEPRESSION AB Background. Many patients who receive maintenance hemodialysis experience poor sleep. Uncontrolled studies suggest frequent hemodialysis improves sleep quality, which is a strong motivation for some patients to undertake the treatment. We studied the effects of frequent in-center ('daily') and nocturnal home hemodialysis on self-reported sleep quality in two randomized trials. Methods. Participants were randomly assigned to frequent (six times per week) or conventional (three times per week) hemodialysis in the Frequent Hemodialysis Network Daily (n = 245) and Nocturnal (n = 87) Trials. We used the Medical Outcomes Study Sleep Problems Index II (SPI II), a validated and reliable instrument in patients with end-stage renal disease, to measure self-reported sleep quality. The SPI II is scored from 0-100, with a higher value indicating poorer quality of sleep. A mean relative decline in SPI II would suggest improved sleep quality. The primary sleep outcome was the change in the SPI II score over 12 months. Results. In the Daily Trial, after adjustment for baseline SPI II, subjects randomized to frequent as compared with conventional in-center hemodialysis experienced a 4.2 [95% confidence interval (CI) 0.4-8.0] point adjusted mean relative decline in SPI II at 4 months and a 2.6 (95% CI -2.3-7.5) point adjusted mean relative decline at 12 months. In the Nocturnal Trial, subjects randomized to frequent nocturnal as compared with conventional home hemodialysis experienced 2.9 (95% CI -3.4-9.3) and 4.5 (95% CI -3.2-12.2) point mean relative declines at Months 4 and 12, respectively. Conclusions. Although a possible benefit of frequent in-center hemodialysis was observed at 4 months, neither frequent in-center hemodialysis nor home nocturnal hemodialysis demonstrated significant improvements in self-reported sleep quality compared with conventional hemodialysis at 12 months. C1 [Unruh, Mark L.] Univ New Mexico, Sch Med, Div Nephrol, Albuquerque, NM 87131 USA. [Larive, Brett; Gassman, Jennifer J.] Cleveland Clin Fdn, Dept Quantitat Hlth Sci, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Eggers, Paul W.] NIDDK, Kidney Epidemiol Program, NIH, Bethesda, MD 20892 USA. [Eggers, Paul W.] NIDDK, Urol Epidemiol Program, NIH, Bethesda, MD 20892 USA. [Garg, Amit X.] Western Univ, Div Nephrol, London, ON, Canada. [Finkelstein, Fredric O.] Yale Univ, Sch Med, Dept Med, Hosp St Raphael, New Haven, CT 06510 USA. [Kimmel, Paul L.] NIDDK, Div Kidney Urol & Hematol Dis, Bethesda, MD 20892 USA. [Chertow, Glenn M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. RP Unruh, ML (reprint author), Univ New Mexico, Sch Med, Div Nephrol, Albuquerque, NM 87131 USA. EM mlunruh@salud.unm.edu FU NIH, National Institute of Diabetes and Digestive and Kidney Diseases; Center for Medicare and Medical Services; NIH Research Foundation; Amgen; Baxter; Dialysis Clinics; DaVita; Dialysis Clinics Inc; Fresenius Medical Care; Renal Advantage; RRI; Satellite Healthcare FX Members of the FHN Trial Group are Achinger S., Anderson S., Appel L., Apruzzes R., Atwal J., Augustine B., Ayus J., Bardsley J., Bay W., Beach S., Beck G., Bharti B., Briggs J., Bullas R., Burkart J., Burrowes J., Cabezon E., Callegari J., Carter M., Champagne J., Chan C., Chan W., Chang J., Chertow G., Cheung A., Copland M., Coplon N., Coppley A., Daugirdas J., Dellagrottaglie S., Depner T., Derse A., Dominguez A., Doss S., Eggers P., Eknoyan G., Escalada R., Fensterer A., Finkelstein F., Fofie Y., Franzwa B., Frome R., Fu Z., Garg A., Gassman J., Gayda P., Geller N., Geronemus R., Goodman W., Gorodetskaya I., Gotch F., Greene T., Greenwood R., Grimm R., Gutierrez M., Hall Y., Handelman G., Henderson L., Hernandez A., Higgins H., Hilkin A., Hostetter T., Hoy C., Humphreys M., Hunsicker L., James S., Kariisa M., Kaufman A., Kaufman T., Kaysen G., Ke S., Keene R., Kimmel P., Kliger A., Kotanko P., Kramer C., Kuhlmann M., Kwan S., Kwok S., Lacson E., Larive B., Leavell E., Lemus D., Levin A., Levin N., Li M., Lilli K., Lindsay R., Lockridge R., Luan J., MacKrell J., Manaster R., Mandaci O., Mathew R., Mauck V., Mazzorato A., McCulloch C., McGrath-Chong M., McLeroy S., Mehta R., Meisels I., Miller B., Mohr P., Moossavi S., Nabali A., Narva A., Nissenson A., Ornt D., Painter P., Pepas J., Peterson C., Pierratos A., Pipkin M., Prichard S., Rajagopalan S., Ramos R., Rashid M., Rastogi A., Regozo K., Riley J., Rivas M., Rocco M., Rodriquez R., Roecker E., Roger D., Rogers J., Salusky I., Sanz G., Sanz J., Schiller-Moran B., Schlarb J., Schuessler R., Schulman G., Schweitzer S., Sergeyeva O., Shah S., Sherer S., Sika M., Sioson L., Skelton R., Smith M., Snell C., Somers D., Sonico J., Spanner E., Star R., Steigerwald D., Stokes J., Suri R., Suter M., Tamura M., Tarallo M., Tichy M., Ting G., Tran T., Ulloa D., Unruh M., Vassalotti J., Wallace W., Waterman E., Wei J., Weiss B., West J., Wiggins K., and Winchester J. This work was supported by the NIH, National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Medicare and Medical Services and the NIH Research Foundation. Contributors to the NIH Foundation in support of the FHN trials included Amgen, Baxter, and Dialysis Clinics. Additional support was provided by DaVita, Dialysis Clinics Inc, Fresenius Medical Care, Renal Advantage, RRI, and Satellite Healthcare. NR 30 TC 1 Z9 1 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 EI 1460-2385 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD JUN PY 2016 VL 31 IS 6 BP 984 EP 991 DI 10.1093/ndt/gfw062 PG 9 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA DT1AG UT WOS:000381213500023 PM 27190356 ER PT J AU Wang, RS Gabriel, SE Ward, MM AF Wang, Runsheng Gabriel, Sherine E. Ward, Michael M. TI Progression of Nonradiographic Axial Spondyloarthritis to Ankylosing Spondylitis A Population-Based Cohort Study SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID INFLAMMATORY BACK-PAIN; FOLLOW-UP; UNDIFFERENTIATED SPONDYLOARTHRITIS; RADIOGRAPHIC SACROILIITIS; DIAGNOSTIC-CRITERIA; HLA-B27; DISEASE; CLASSIFICATION AB Objective. The long-term outcome of patients with nonradiographic axial spondyloarthritis (SpA) is unclear, particularly whether few or most progress to ankylosing spondylitis (AS). Our objective was to examine the progression to AS in a population-based inception cohort of patients with nonradiographic axial SpA. Methods. The Rochester Epidemiology Project (REP) is a longstanding population-based study of health in the residents of Olmsted County, Minnesota. We searched the REP from 1985 to 2010 using diagnostic and procedural codes for back pain, HLA-B27, and magnetic resonance imaging of the pelvis, and we performed detailed chart reviews to identify subjects who fulfilled the Assessment of SpondyloArthritis international Society classification criteria for axial SpA but did not have AS. We followed these subjects from disease onset to March 15, 2015, and used survival analysis to measure the time to progression to AS. Results. After screening 2,151 patients, we identified 83 subjects with new-onset nonradiographic axial SpA. Over a mean follow-up of 10.6 years, progression to AS occurred in 16 patients. The probability that the condition would remain as nonradiographic axial SpA at 5, 10, and 15 years was 93.6%, 82.7%, and 73.6%, respectively. There was more frequent and more rapid progression among subjects in the imaging arm (n = 18) than among those in the clinical arm (n = 65) (28% versus 17%; hazard ratio 3.50 [95% confidence interval 1.15-10.6], P = 0.02). Conclusion. Progression to AS occurred in a minority (26%) of patients with nonradiographic axial SpA over as long as 15 years of follow-up. This suggests that the classification criteria for nonradiographic axial SpA identifies many patients in whom the condition is unlikely to progress to AS or that nonradiographic axial SpA represents a prolonged prodromal state that takes longer to evolve to AS and thus requires longer follow-up. C1 [Wang, Runsheng; Ward, Michael M.] NIAMSD, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Bethesda, MD 20892 USA. [Gabriel, Sherine E.] Mayo Clin, Rochester, MN USA. RP Ward, MM (reprint author), NIAMSD, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH; NIH (National Institute on Aging) [R01-AG-034676]; NIH (National Center for Advancing Translational Sciences Clinical and Translational Science Award) [UL1-TR-000135] FX Supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH. The current study used data from the Rochester Epidemiology Project, which is supported by the NIH (National Institute on Aging award R01-AG-034676 and National Center for Advancing Translational Sciences Clinical and Translational Science Award Program grant UL1-TR-000135). NR 22 TC 5 Z9 5 U1 4 U2 4 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 JUN PY 2016 VL 68 IS 6 BP 1415 EP 1421 DI 10.1002/art.39542 PG 7 WC Rheumatology SC Rheumatology GA DW2TB UT WOS:000383493600015 PM 26663907 ER PT J AU Tektonidou, MG Dasgupta, A Ward, MM AF Tektonidou, Maria G. Dasgupta, Abhijit Ward, Michael M. TI Risk of End-Stage Renal Disease in Patients With Lupus Nephritis, 1971-2015 A Systematic Review and Bayesian Meta-Analysis SO ARTHRITIS & RHEUMATOLOGY LA English DT Review ID SOCIOECONOMIC-STATUS; ERYTHEMATOSUS; MORTALITY; SURVIVAL; EPIDEMIOLOGY; MORBIDITY; COHORT; ASSOCIATION; PREDNISONE; MANAGEMENT AB Objective. End-stage renal disease (ESRD) is a major consequence of lupus nephritis, but how this risk has changed over time is unknown. We conducted this systematic review to examine changes in ESRD among adults with lupus nephritis from 1971 to 2015 and to estimate risks of ESRD among contemporary patients. Methods. We searched PubMed, Embase, and the Cochrane Database of Systematic Reviews for cohort studies and clinical trials on ESRD in adults with lupus nephritis. We analyzed studies from developed and developing countries separately. The outcome was probability of ESRD at 5, 10, and 15 years of lupus nephritis. Results. We included 187 articles that reported on 18,309 patients. In developed countries, the 5-year risk of ESRD decreased from 16% (95% confidence interval [95% CI] 14-17%) in 1970-1979 to 11% (95% CI 10-12%) in the mid-1990s and then plateaued. ESRD risks at 10 years and 15 years showed steeper declines in the 1970s and 1980s but also plateaued in 1993-1997, with a notable increase in the late 2000s. The decrease in risk after 1980 coincided with increased use of cyclophosphamide. The 15-year ESRD risk was higher in developing countries than in developed countries. Patients with class IV lupus nephritis had the greatest risk of ESRD, with a 15-year risk of 44% during the 2000s. Conclusion. Risks of ESRD in lupus nephritis improved between the 1970s and the mid-1990s and then plateaued, with an increase in the late 2000s. This pattern suggests limitations in the effectiveness of, or access to, current treatments. C1 [Tektonidou, Maria G.] Univ Athens, Sch Med, Athens, Greece. [Dasgupta, Abhijit; Ward, Michael M.] NIAMSD, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr,MSC 1468, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMSD, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr,MSC 1468, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH FX Supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH. NR 41 TC 3 Z9 3 U1 0 U2 1 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 JUN PY 2016 VL 68 IS 6 BP 1432 EP 1441 DI 10.1002/art.39594 PG 10 WC Rheumatology SC Rheumatology GA DW2TB UT WOS:000383493600017 PM 26815601 ER PT J AU Ward, MM Deodhar, A Reveille, JD Caplan, L AF Ward, Michael M. Deodhar, Atul Reveille, John D. Caplan, Liron TI Treatment of patients with nonradiographic axial spondyloarthritis who have negative magnetic resonance imaging results and normal C-reactive protein levels at baseline: comment on the article by Ward et al Reply SO ARTHRITIS & RHEUMATOLOGY LA English DT Letter ID PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; EFFICACY; SACROILIITIS; ADALIMUMAB C1 [Ward, Michael M.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Deodhar, Atul] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Reveille, John D.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Caplan, Liron] Denver Vet Affairs Med Ctr, Aurora, CO USA. [Caplan, Liron] Univ Colorado, Aurora, CO USA. RP Ward, MM (reprint author), NIAMSD, NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 AR041153-04] NR 8 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD JUN PY 2016 VL 68 IS 6 BP 1563 EP 1564 DI 10.1002/art.39524 PG 3 WC Rheumatology SC Rheumatology GA DW2TB UT WOS:000383493600033 PM 26636978 ER PT J AU Ceovic, R Desnica, L Pulanic, D Seiwerth, RS Ilic, I Grce, M Stipetic, MM Pulanic, TK Bilic, E Bilic, E Milosevic, M Vrhovac, R Nemet, D Pavletic, SZ AF Ceovic, Romana Desnica, Lana Pulanic, Drazen Seiwerth, Ranka Serventi Ilic, Ivana Grce, Magdalena Stipetic, Marinka Mravak Pulanic, Tajana Klepac Bilic, Ervina Bilic, Ernest Milosevic, Milan Vrhovac, Radovan Nemet, Damir Pavletic, Steven Z. TI High frequency of cutaneous manifestations including vitiligo and alopecia areata in a prospective cohort of patients with chronic graft-vs-host disease SO CROATIAN MEDICAL JOURNAL LA English DT Article ID BONE-MARROW-TRANSPLANTATION; CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; OF-THE-LITERATURE; CLINICAL-TRIALS; CELL TRANSPLANTATION; LABORATORY MARKERS; TOTAL LEUKODERMA; RISK-FACTORS; CRITERIA AB Aim To determine the frequency and the characteristics of cutaneous manifestations, especially vitiligo and alopecia areata, in patients with chronic graft-vs-host disease (cGVHD). Methods 50 patients with cGVHD were prospectively enrolled in the observational study protocol and evaluated by an experienced dermatologist. The evaluation was focused on the clinical spectrum of skin and adnexal involvement, and the cutaneous GVHD score was determined according to National Institutes of Health (NIH) Consensus criteria. The presence of vitiligo, alopecia, xerosis, nail changes, and dyspigmentation was also assessed. Results Out of 50 cGVHD patients, 28 (56%) had skin involvement, and 27 of them (96%) had hypo and/or hyperpigmentations. 11 patients (39%) had a mild cutaneous NIH cGVHD score, 22% moderate, and 39% severe. 15 (30%) patients had nail changes and 10 (20%) had vitiligo or alopecia areata. Univariate analysis showed that patients with vitiligo/alopecia areata received more lines of prior systemic immunosuppressive therapy (P=0.043), had lower Karnofsky performance status (P=0.028), and had a higher B-cell number (P=0.005), platelet count (P=0.022), and total protein (P=0.024). Vitiligo and alopecia areata were associated with higher NIH skin score (P=0.001), higher intensity of immunosuppressive treatment (P=0.020), and total body irradiation conditioning (P=0.040). Multivariate regression model showed that patients with higher NIH skin scoring were 3.67 times more likely to have alopecia and/or vitiligo (odds ratio 3.67; 95% confidence interval 1.26-10.73), controlled for all other factors in the model (age at study entry, number of B-cells, platelet count, and global NIH score). Conclusion These data indicate that vitiligo and alopecia areata occur more frequently in cGVHD than previously reported. C1 [Ceovic, Romana] Univ Hosp Ctr Zagreb, Dept Dermatol & Venereol, Zagreb, Croatia. [Ceovic, Romana; Pulanic, Drazen; Bilic, Ervina; Bilic, Ernest; Vrhovac, Radovan; Nemet, Damir] Univ Zagreb, Sch Med, Zagreb, Croatia. [Desnica, Lana; Pulanic, Drazen; Seiwerth, Ranka Serventi; Vrhovac, Radovan; Nemet, Damir] Univ Hosp Ctr Zagreb, Div Hematol, Dept Internal Med, Zagreb, Croatia. [Pulanic, Drazen; Nemet, Damir] JJ Strossmayer Univ Osijek, Fac Med Osijek, Osijek, Croatia. [Ilic, Ivana] Univ Hosp Ctr Zagreb, Dept Pathol & Cytol, Zagreb, Croatia. [Grce, Magdalena] Rudjer Boskovic Inst, Div Mol Med, Zagreb, Croatia. [Stipetic, Marinka Mravak] Univ Zagreb, Sch Dent Med, Zagreb, Croatia. [Stipetic, Marinka Mravak] Univ Hosp Ctr Zagreb, Clin Dept Oral Med, Univ Dent Clin, Zagreb, Croatia. [Pulanic, Tajana Klepac] Community Hlth Ctr Zagreb East, Dept Gynecol, Zagreb, Croatia. [Bilic, Ervina] Univ Hosp Ctr Zagreb, Dept Neurol, Zagreb, Croatia. [Bilic, Ernest] Univ Hosp Ctr Zagreb, Dept Pediat Hematol & Oncol, Zagreb, Croatia. [Milosevic, Milan] Univ Zagreb, Sch Med, Andrija Stampar Sch Publ Hlth, Zagreb, Croatia. [Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ceovic, R (reprint author), Univ Zagreb, Sch Med, Dept Dermatol & Venereol, Salata 4, HR-10000 Zagreb, Croatia.; Ceovic, R (reprint author), Univ Hosp Ctr Zagreb, Salata 4, HR-10000 Zagreb, Croatia. EM romana.ceovic@zg.t-com.hr OI Grce, Magdalena/0000-0001-6178-8418 FU Unity Through Knowledge Fund project entitled "Clinical and Biological Factors Determining Severity and Activity of Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation" FX This work is funded by the Unity Through Knowledge Fund project entitled "Clinical and Biological Factors Determining Severity and Activity of Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation." NR 24 TC 0 Z9 0 U1 5 U2 5 PU MEDICINSKA NAKLADA PI ZAGREB PA VLASKA 69, HR-10000 ZAGREB, CROATIA SN 0353-9504 EI 1332-8166 J9 CROAT MED J JI Croat. Med. J. PD JUN PY 2016 VL 57 IS 3 BP 229 EP 238 DI 10.3325/cmj.2016.57.229 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DW0EE UT WOS:000383312900004 PM 27374824 ER PT J AU Durakovic, N Krecak, I Peric, Z Milosevic, M Desnica, L Pulanic, D Pusic, I Kusec, V Vrhovac, R Pavletic, SZ Nemet, D AF Durakovic, Nadira Krecak, Ivan Peric, Zinaida Milosevic, Milan Desnica, Lana Pulanic, Drazen Pusic, Iskra Kusec, Vesna Vrhovac, Radovan Pavletic, Steven Z. Nemet, Damir TI Glycoprotein YKL-40: a novel biomarker of chronic graft-vs-host disease activity and severity? SO CROATIAN MEDICAL JOURNAL LA English DT Article ID CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; HUMAN CARTILAGE GLYCOPROTEIN-39; BONE-MARROW-TRANSPLANTATION; CHILDRENS ONCOLOGY GROUP; ACUTE MYELOID-LEUKEMIA; CHITIN-BINDING LECTIN; NECROSIS-FACTOR-ALPHA; CLINICAL-TRIALS; SERUM YKL-40 AB Aim To investigate whether increased YKL-40 levels positively correlate with graft-vs-host disease (cGVHD) activity and severity and if YKL-40 could serve as a disease biomarker. Methods This case-control study was conducted at the University Hospital Centre Zagreb from July 2013 to October 2015. 56 patients treated with hematopoietic stem cell transplantation (HSCT) were included:35 patients with cGVHD and 21 without cGVHD. There was no difference between groups in age, sex, median time from transplant to study enrollment, intensity of conditioning, type of donor, or source of stem cells. Blood samples were collected at study enrollment and YKL-40 levels were measured with ELISA. Disease activity was estimated using Clinician's Impression of Activity and Intensity of Immunosuppression scales and disease severity using Global National Institutes of Health (NIH) score. Results YKL-40 levels were significantly higher in cGVHD patients than in controls (P=0.003). The difference remained significant when patients with myelofibrosis were excluded from the analysis (P=0.017). YKL-40 level significantly positively correlated with disease severity (P<0.001; correlation coefficient 0.455), and activity estimated using Clinician's Impression of Activity (P=0.016; correlation coefficient 0.412) but not using Intensity of Immunosuppression (P=0.085; correlation coefficient 0.296). Conclusion YKL-40 could be considered a biomarker of cGVHD severity and activity. However, validation in a larger group of patients is warranted, as well as longitudinal testing of YKL-40 levels in patients at risk of developing cGVHD. C1 [Durakovic, Nadira; Peric, Zinaida; Milosevic, Milan; Pulanic, Drazen; Vrhovac, Radovan; Nemet, Damir] Univ Zagreb, Sch Med, Zagreb, Croatia. [Durakovic, Nadira; Desnica, Lana; Vrhovac, Radovan; Nemet, Damir] Univ Hosp Ctr Zagreb, Div Hematol, Dept Internal Med, Kispaticeva 12, Zagreb 10000, Croatia. [Krecak, Ivan] Gen Hosp Sibenik, Shibenik, Croatia. [Pulanic, Drazen; Nemet, Damir] JJ Strossmayer Univ Osijek, Fac Med Osijek, Osijek, Croatia. [Pusic, Iskra] Washington Univ, Sch Med, Dept Med, Div Oncol,Sect Bone Marrow Transplant & Leukemia, St Louis, MO 63110 USA. [Kusec, Vesna] Univ Hosp Ctr Zagreb, Clin Dept Lab Diag, Zagreb, Croatia. [Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Durakovic, N (reprint author), Univ Hosp Ctr Zagreb, Div Hematol, Dept Internal Med, Kispaticeva 12, Zagreb 10000, Croatia. EM nadira@mef.hr FU Unity Through Knowledge Fund project entitled "Clinical And Biological Factors Determining Severity and Activity of Chronic Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation" FX This work was funded by the Unity Through Knowledge Fund project entitled "Clinical And Biological Factors Determining Severity and Activity of Chronic Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation". NR 53 TC 0 Z9 0 U1 1 U2 1 PU MEDICINSKA NAKLADA PI ZAGREB PA VLASKA 69, HR-10000 ZAGREB, CROATIA SN 0353-9504 EI 1332-8166 J9 CROAT MED J JI Croat. Med. J. PD JUN PY 2016 VL 57 IS 3 BP 239 EP 246 DI 10.3325/cmj.2016.57.239 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA DW0EE UT WOS:000383312900005 PM 27374825 ER PT J AU Vukic, T Smith, SR Kelecic, DL Desnica, L Prenc, E Pulanic, D Vrhovac, R Nemet, D Pavletic, SZ AF Vukic, Tamara Smith, Sean Robinson Kelecic, Dina Ljubas Desnica, Lana Prenc, Ema Pulanic, Drazen Vrhovac, Radovan Nemet, Damir Pavletic, Steven Z. TI Joint and fascia! chronic graft-vs-host disease: correlations with clinical and laboratory parameters SO CROATIAN MEDICAL JOURNAL LA English DT Article ID CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; STEM-CELL TRANSPLANTATION; CHRONIC GVHD; NEPHROTIC SYNDROME; RISK-FACTORS; WALK TEST; CRITERIA; TRIALS; DIAGNOSIS AB Aim To determine if there are correlations between joint and fascial chronic graft-vs-host disease (cGVHD) with clinical findings, laboratory parameters, and measures of functional capacity. Methods 29 patients were diagnosed with cGVHD based on National Institutes of Health (NIH) Consensus Criteria at the University Hospital Centre Zagreb from October 2013 to October 2015. Physical examination, including functional measures such as 2-minute walk test and hand grip strength, as well as laboratory tests were performed. The relationship between these evaluations and the severity of joint and fascial cGVHD was tested by logistical regression analysis. Results 12 of 29 patients (41.3%) had joint and fascial cGVHD diagnosed according to NIH Consensus Criteria. There was a significant positive correlation of joint and fascial cGVHD and skin cGVHD (P<0.001), serum C3 complement level (P=0.045), and leukocytes (P=0.032). There was a significant negative correlation between 2-minute walk test (P=0.016), percentage of cytotoxic T cells CD3+/CD8+ (P=0.022), serum albumin (P=0.047), and Karnofsky score (P<0.001). Binary logistic regression model found that a significant predictor for joint and fascial cGVHD was cGVHD skin involvement (odds ratio, 7.79; 95 confidence interval 1.87-32.56; P=0.005). Conclusion Joint and fascial cGVHD manifestations correlated with multiple laboratory measurements, clinical features, and cGVHD skin involvement, which was a significant predictor for joint and fascial cGVHD. C1 [Vukic, Tamara] Univ Hosp Ctr Zagreb, Dept Rehabil & Orthopaed Aids, Bozidareviceva 11, Zagreb 10000, Croatia. [Smith, Sean Robinson] Univ Michigan, Dept Phys Med & Rehabil, Ann Arbor, MI 48109 USA. [Kelecic, Dina Ljubas] Univ Hosp Ctr Zagreb, Clin Unit Clin Nutr, Dept Internal Med, Zagreb, Croatia. [Desnica, Lana; Pulanic, Drazen; Vrhovac, Radovan; Nemet, Damir] Univ Hosp Ctr Zagreb, Div Hematol, Dept Internal Med, Zagreb, Croatia. [Prenc, Ema] Croatian Cooperat Grp Hematol Dis CroHem, Zagreb, Croatia. [Pulanic, Drazen; Vrhovac, Radovan; Nemet, Damir] Univ Zagreb, Sch Med, Zagreb, Croatia. [Pulanic, Drazen; Nemet, Damir] JJ Strossmayer Univ Osijek, Fac Med Osijek, Osijek, Croatia. [Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Vukic, T (reprint author), Univ Hosp Ctr Zagreb, Dept Rehabil & Orthopaed Aids, Bozidareviceva 11, Zagreb 10000, Croatia. EM tvukic555@yahoo.com FU Unity Through Knowledge Fund (UKF) project entitled "Clinical and Biological Factors Determining Severity and Activity of Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation"; Center for Cancer Research, the Intramural Research Program of the National Cancer Institute, National Institutes of Health, USA FX This study was funded by the Unity Through Knowledge Fund (UKF) project entitled "Clinical and Biological Factors Determining Severity and Activity of Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation." In part it was also supported by by the Center for Cancer Research, the Intramural Research Program of the National Cancer Institute, National Institutes of Health, USA The opinions expressed here are those of the authors and do not represent the official position of the NIH or the U.S. Government. NR 34 TC 0 Z9 0 U1 1 U2 1 PU MEDICINSKA NAKLADA PI ZAGREB PA VLASKA 69, HR-10000 ZAGREB, CROATIA SN 0353-9504 EI 1332-8166 J9 CROAT MED J JI Croat. Med. J. PD JUN PY 2016 VL 57 IS 3 BP 266 EP 275 DI 10.3325/cmj.2016.57.266 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DW0EE UT WOS:000383312900008 PM 27374828 ER PT J AU Katic, M Pirsl, F Steinberg, SM Dobbin, M Curtis, LM Pulanic, D Desnica, L Titarenko, I Pavletic, SZ AF Katic, Masenjka Pirsl, Filip Steinberg, Seth M. Dobbin, Marnie Curtis, Lauren M. Pulanic, Drazen Desnica, Lana Titarenko, Irina Pavletic, Steven Z. TI Vitamin D levels and their associations with survival and major disease outcomes in a, large cohort of patients with chronic graft-vs-host disease SO CROATIAN MEDICAL JOURNAL LA English DT Article ID CONSENSUS DEVELOPMENT PROJECT; SERUM 25-HYDROXYVITAMIN D; WORKING GROUP-REPORT; STEM-CELL TRANSPLANTATION; D DEFICIENCY; CLINICAL-TRIALS; CHRONIC GVHD; RENAL-FAILURE; CANCER; CRITERIA AB Aim To identify the factors associated with vitamin D status in patients with chronic graft-vs-host disease (cGVHD) and evaluate the association between serum vitamin D (25(OH) D) levels and cGVHD characteristics and clinical outcomes defined by the National Institutes of Health (NIH) criteria. Methods 310 cGVHD patients enrolled in the NIH cGVHD natural history study (clinicaltrials.gov: NCT00092235) were analyzed. Univariate analysis and multiple logistic regression were used to determine the associations between various parameters and 25(OH)D levels, dichotomized into categorical variables: <= 20 and >20 ng/mL, and as a continuous parameter. Multiple logistic regression was used to develop a predictive model for low vitamin D. Survival analysis and association between cGVHD outcomes and 25(OH)D as a continuous as well as categorical variable: <= 20 and >20 ng/mL; <50 and >= 50 ng/mL, and among three ordered categories: <= 20, 20-50, and >= 50 ng/mL, was performed. Results 69 patients (22.3%) had serum 25(OH)D <= 20 ng/mL. Univariate analysis showed that supplement intake, nutritional status (severely malnourished, moderately malnourished, well-nourished), race (African-American, other), and estimated creatinine clearance (eCCr) were associated with 25(OH)D levels. A predictive model was developed based on supplement intake, nutritional status, race, and eCCr, accurately predicting 77.9% of patients with 25(OH) D <= 20 and 65.2% of those with 25(OH)D >20 ng/mL. No association was found between vitamin D and major cGVHD characteristics, but patients with 25(OH)D <= 20 ng/mL had somewhat decreased survival. Conclusion Nutritional status and adequate supplementation are important to maintain 25(OH)D >20 ng/mL in cGVHD patients. Intervention studies and more research is needed to reveal the underlying mechanism of vitamin D metabolism in cGVHD setting. C1 [Katic, Masenjka; Pirsl, Filip; Curtis, Lauren M.; Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Katic, Masenjka] Jamnica Dd, Zagreb, Croatia. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, NIH, Rockville, MD USA. [Dobbin, Marnie] NIH, Dept Clin Nutr, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Pulanic, Drazen; Desnica, Lana] Univ Hosp Ctr Zagreb, Div Hematol, Dept Internal Med, Zagreb, Croatia. [Pulanic, Drazen] Univ Zagreb, Sch Med, Zagreb, Croatia. [Pulanic, Drazen] JJ Strossmayer Univ Osijek, Fac Med Osijek, Osijek, Croatia. [Titarenko, Irina] NIH, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. RP Katic, M (reprint author), Trg 101 Brigade HV 2, Zagreb, Croatia. EM mashakatic@gmail.com FU intramural program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, MD, USA FX This study was funded by the intramural program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, MD, USA. Jamnica d.d. has not been involved at any stage in the scientific part of the study, its design, analysis or choice where to publish the results. No financial support has been received by Jamnica d.d. for this study. NR 36 TC 0 Z9 0 U1 1 U2 1 PU MEDICINSKA NAKLADA PI ZAGREB PA VLASKA 69, HR-10000 ZAGREB, CROATIA SN 0353-9504 EI 1332-8166 J9 CROAT MED J JI Croat. Med. J. PD JUN PY 2016 VL 57 IS 3 BP 276 EP 286 DI 10.3325/cmj.2016.57.276 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DW0EE UT WOS:000383312900009 PM 27374829 ER PT J AU Berger, VW AF Berger, Vance W. TI SEQUENCE GENERATION AND ALLOCATION CONCEALMENT SO JOURNAL OF EVIDENCE-BASED DENTAL PRACTICE LA English DT Letter ID JADAD SCORE C1 [Berger, Vance W.] NCI, 9609 Med Ctr Dr, Rockville, MD 20850 USA. [Berger, Vance W.] Univ Maryland Baltimore Cty, Biometry Res Grp, NIH, 9609 Med Ctr Dr, Rockville, MD 20850 USA. RP Berger, VW (reprint author), NCI, 9609 Med Ctr Dr, Rockville, MD 20850 USA.; Berger, VW (reprint author), Univ Maryland Baltimore Cty, Biometry Res Grp, NIH, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM vb78c@nih.gov NR 6 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-3382 EI 1532-3390 J9 J EVID-BASED DENT PR JI J. Evid.-Based Dent. Pract. PD JUN PY 2016 VL 16 IS 2 BP 145 EP 146 DI 10.1016/j.jebdp.2016.03.001 PG 2 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DW0VL UT WOS:000383361000019 PM 27449850 ER PT J AU Chlanda, P Mekhedov, E Waters, H Schwartz, CL Fischer, ER Ryham, RJ Cohen, FS Blank, PS Zimmerberg, J AF Chlanda, Petr Mekhedov, Elena Waters, Hang Schwartz, Cindi L. Fischer, Elizabeth R. Ryham, Rolf J. Cohen, Fredric S. Blank, Paul S. Zimmerberg, Joshua TI The hemifusion structure induced by influenza virus haemagglutinin is determined by physical properties of the target membranes SO NATURE MICROBIOLOGY LA English DT Article ID LIPID-BILAYERS; A VIRUS; FUSION; CHOLESTEROL; TRANSPORT; ENERGY AB Influenza A virus haemagglutinin conformational change drives the membrane fusion of viral and endosomal membranes at low pH. Membrane fusion proceeds through an intermediate called hemifusion(1,2). For viral fusion, the hemifusion structures are not determined(3). Here, influenza virus-like particles(4) carrying wildtype haemagglutinin or haemagglutinin hemifusion mutant G1S(5) and liposome mixtures were studied at low pH by Volta phase plate cryo-electron tomography, which improves the signal-to-noise ratio close to focus. We determined two distinct hemifusion structures: a hemifusion diaphragm and a novel structure termed a 'lipidic junction'. Liposomes with lipidic junctions were ruptured with membrane edges stabilized by haemagglutinin. The rupture frequency and hemifusion diaphragm diameter were not affected by G1S mutation, but decreased when the cholesterol level in the liposomes was close to physiological concentrations. We propose that haemagglutinin induces a merger between the viral and target membranes by one of two independent pathways: a rupture-insertion pathway leading to the lipidic junction and a hemifusion-stalk pathway leading to a fusion pore. The latter is relevant under the conditions of influenza virus infection of cells. Cholesterol concentration functions as a pathway switch because of its negative spontaneous curvature in the target bilayer, as determined by continuum analysis. C1 [Chlanda, Petr; Mekhedov, Elena; Waters, Hang; Blank, Paul S.; Zimmerberg, Joshua] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Integrat Biophys, Bethesda, MD 20892 USA. [Schwartz, Cindi L.; Fischer, Elizabeth R.] NIAID, Rocky Mt Labs, Electron Microscopy Unit, NIH, Hamilton, MT 59840 USA. [Ryham, Rolf J.] Fordham Univ, Dept Math, Bronx, NY 10458 USA. [Cohen, Fredric S.] Rush Univ, Dept Mol Biophys & Physiol, Chicago, IL 60612 USA. RP Chlanda, P; Zimmerberg, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Integrat Biophys, Bethesda, MD 20892 USA. EM chlandap@mail.nih.gov; zimmerbj@mail.nih.gov FU Division of Intramural Research of the Intramural Program of the National Institutes of Health FX The authors thank V. Nair for assistance with the Krios transmission electron microscope at Rocky Mountain Laboratories Microscopy Unit, National Institute of Allergy and Infectious Diseases, National Institutes of Health. The authors also thank L.-A. Carlson, L. Chernomordik, I. Morales and T. Reese for critical reading of the manuscript. This work was supported by the Division of Intramural Research of the Intramural Program of the National Institutes of Health. NR 38 TC 1 Z9 1 U1 13 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND EI 2058-5276 J9 NAT MICROBIOL JI NAT. MICROBIOL PD JUN PY 2016 VL 1 IS 6 AR 16050 DI 10.1038/NMICROBIOL.2016.50 PG 8 WC Microbiology SC Microbiology GA DW4ID UT WOS:000383605500008 PM 27572837 ER PT J AU Li, CJ Hatta, M Burke, DF Ping, JH Zhang, Y Ozawa, M Taft, AS Das, SC Hanson, AP Song, JS Imai, M Wilker, PR Watanabe, T Watanabe, S Ito, M Iwatsuki-Horimoto, K Russell, CA James, SL Skepner, E Maher, EA Neumann, G Klimov, AI Kelso, A McCauley, J Wang, DY Shu, YL Odagiri, T Tashiro, M Xu, XY Wentworth, DE Katz, JM Cox, NJ Smith, DJ Kawaoka, Y AF Li, Chengjun Hatta, Masato Burke, David F. Ping, Jihui Zhang, Ying Ozawa, Makoto Taft, Andrew S. Das, Subash C. Hanson, Anthony P. Song, Jiasheng Imai, Masaki Wilker, Peter R. Watanabe, Tokiko Watanabe, Shinji Ito, Mutsumi Iwatsuki-Horimoto, Kiyoko Russell, Colin A. James, Sarah L. Skepner, Eugene Maher, Eileen A. Neumann, Gabriele Klimov, Alexander I. Kelso, Anne McCauley, John Wang, Dayan Shu, Yuelong Odagiri, Takato Tashiro, Masato Xu, Xiyan Wentworth, David E. Katz, Jacqueline M. Cox, Nancy J. Smith, Derek J. Kawaoka, Yoshihiro TI Selection of antigenically advanced variants of seasonal influenza viruses SO NATURE MICROBIOLOGY LA English DT Article ID BINDING-PROPERTIES; STRAIN SELECTION; A VIRUSES; HEMAGGLUTININ; VACCINE; EVOLUTION; DRIFT; A(H3N2); H1N1; SPECIFICITY AB Influenza viruses mutate frequently, necessitating constant updates of vaccine viruses. To establish experimental approaches that may complement the current vaccine strain selection process, we selected antigenic variants from human H1N1 and H3N2 influenza virus libraries possessing random mutations in the globular head of the haemagglutinin protein ( which includes the antigenic sites) by incubating them with human and/or ferret convalescent sera to human H1N1 and H3N2 viruses. We also selected antigenic escape variants from human viruses treated with convalescent sera and from mice that had been previously immunized against human influenza viruses. Our pilot studies with past influenza viruses identified escape mutants that were antigenically similar to variants that emerged in nature, establishing the feasibility of our approach. Our studies with contemporary human influenza viruses identified escape mutants before they caused an epidemic in 2014-2015. This approach may aid in the prediction of potential antigenic escape variants and the selection of future vaccine candidates before they become widespread in nature. C1 [Li, Chengjun; Hatta, Masato; Ping, Jihui; Zhang, Ying; Ozawa, Makoto; Taft, Andrew S.; Das, Subash C.; Hanson, Anthony P.; Song, Jiasheng; Imai, Masaki; Wilker, Peter R.; Maher, Eileen A.; Neumann, Gabriele; Kawaoka, Yoshihiro] Univ Wisconsin, Sch Vet Med, Influenza Res Inst, Dept Pathobiol Sci, Madison, WI 53711 USA. [Burke, David F.; James, Sarah L.; Skepner, Eugene; Smith, Derek J.] Univ Cambridge, Dept Zool, Downing St, Cambridge CB2 3EJ, England. [Burke, David F.; Russell, Colin A.; James, Sarah L.; Skepner, Eugene; Smith, Derek J.] WHO, Collaborating Ctr Modelling Evolut & Control Emer, Cambridge CB2 3EJ, England. [Ozawa, Makoto; Kawaoka, Yoshihiro] Univ Tokyo, Inst Med Sci, Int Res Ctr Infect Dis, Dept Special Pathogens, Tokyo 1088639, Japan. [Imai, Masaki] Iwate Univ, Fac Agr, Dept Vet Med, Morioka, Iwate 0208550, Japan. [Watanabe, Tokiko; Watanabe, Shinji; Kawaoka, Yoshihiro] ERATO Infect Induced Host Responses Project, Saitama 3320012, Japan. [Ito, Mutsumi; Iwatsuki-Horimoto, Kiyoko; Kawaoka, Yoshihiro] Univ Tokyo, Inst Med Sci, Div Virol, Dept Microbiol & Immunol, Tokyo 1088639, Japan. [Russell, Colin A.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Russell, Colin A.] Univ Cambridge, Dept Vet Med, Cambridge CB3 0ES, England. [Klimov, Alexander I.; Xu, Xiyan; Wentworth, David E.; Katz, Jacqueline M.; Cox, Nancy J.] Ctr Dis Control & Prevent, Influenza Div, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30033 USA. [Kelso, Anne] Peter Doherty Inst Infect & Immun, WHO Collaborating Ctr Reference & Res Influenza V, Melbourne, Vic 3000, Australia. [McCauley, John] Natl Inst Med Res, MRC, Div Virol, Mill Hill, London NW7 1AA, England. [Wang, Dayan; Shu, Yuelong] Natl Inst Viral Dis Control & Prevent, Chinese Natl Influenza Ctr, Chinese Ctr Dis Control & Prevent, Beijing 102206, Peoples R China. [Odagiri, Takato; Tashiro, Masato] Natl Inst Infect Dis, Influenza Virus Res Ctr, Tokyo 2080011, Japan. [Smith, Derek J.] Erasmus MC, Dept Virol, NL-3000 CA Rotterdam, CA, Netherlands. RP Kawaoka, Y (reprint author), Univ Wisconsin, Sch Vet Med, Influenza Res Inst, Dept Pathobiol Sci, Madison, WI 53711 USA.; Smith, DJ (reprint author), Univ Cambridge, Dept Zool, Downing St, Cambridge CB2 3EJ, England.; Smith, DJ (reprint author), WHO, Collaborating Ctr Modelling Evolut & Control Emer, Cambridge CB2 3EJ, England.; Kawaoka, Y (reprint author), Univ Tokyo, Inst Med Sci, Int Res Ctr Infect Dis, Dept Special Pathogens, Tokyo 1088639, Japan.; Kawaoka, Y (reprint author), ERATO Infect Induced Host Responses Project, Saitama 3320012, Japan.; Kawaoka, Y (reprint author), Univ Tokyo, Inst Med Sci, Div Virol, Dept Microbiol & Immunol, Tokyo 1088639, Japan.; Smith, DJ (reprint author), Erasmus MC, Dept Virol, NL-3000 CA Rotterdam, CA, Netherlands. EM dsmith@zoo.cam.ac.uk; kawaokay@svm.vetmed.wisc.edu FU Bill & Melinda Gates Foundation Global Health Grant [OPPGH5383]; National Institute of Allergy and Infectious Diseases (NIAID) Public Health Service research grants (USA); ERATO(Japan Science and Technology Agency); Center for Research on Influenza Pathogenesis (CRIP) - NIAID [HHSN266200700010C, HHSN272201400008C]; Japan Initiative for Global Research Network on Infectious Diseases; Ministry of Education, Culture, Sports, Science, and Technology, Japan; Ministry of Health, Labour and Welfare, Japan; Strategic Basic Research Program of the Japan Science and Technology Agency; Japan Agency for Medical Research and Development (AMED); Royal Society; Netherlands Organisation for Scientific Research (NWO) VICI grant; European Union (EU) FP7 programme EMPERIE [223498]; European Union (EU) FP7 programme ANTIGONE [278976]; Human Frontier Science Program (HFSP) programme grant [P0050/2008]; Wellcome [087982AIA]; NIH Director's Pioneer Award [DP1-OD000490-01]; CamGrid, the University of Cambridge distributed computer system; Australian Government Department of Health FX The authors thank S. Watson for scientific editing and P. Jester for technical support. This work was supported by the Bill & Melinda Gates Foundation Global Health Grant OPPGH5383; National Institute of Allergy and Infectious Diseases (NIAID) Public Health Service research grants (USA); ERATO(Japan Science and Technology Agency); the Center for Research on Influenza Pathogenesis (CRIP) funded by the NIAID contracts HHSN266200700010C and HHSN272201400008C; the Japan Initiative for Global Research Network on Infectious Diseases; Grants-in-Aid for Specially Promoted Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan; Grants-in-Aid from the Ministry of Health, Labour and Welfare, Japan; grants from the Strategic Basic Research Program of the Japan Science and Technology Agency and by the Advanced Research & Development Programs for Medical Innovation from the Japan Agency for Medical Research and Development (AMED). C.A.R. was supported by a University Research Fellowship from the Royal Society. The authors acknowledge a Netherlands Organisation for Scientific Research (NWO) VICI grant, European Union (EU) FP7 programmes EMPERIE (223498) and ANTIGONE (278976); Human Frontier Science Program (HFSP) programme grant P0050/2008; Wellcome 087982AIA and NIH Director's Pioneer Award DP1-OD000490-01. D.F.B. and D.J.S. acknowledge support from CamGrid, the University of Cambridge distributed computer system. The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health. The origins of the HA and NA gene sequences used in this study are recognized in Supplementary Table 25. The content of this report is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Note: The methods used in this manuscript could potentially select for variants of A(H1N1)pdm09 viruses that could escape vaccine-based immunity; therefore, our manuscript was reviewed by the CDC's Institutional Biosecurity Board, which concluded this study does not constitute Dual Use Research of Concern (DURC). The selection of antigenic escape variants was completed before the US Government issued a Research Funding Pause on 17 October 2014, on selected gain-of-function research on influenza, MERS and SARS viruses. NR 38 TC 0 Z9 0 U1 11 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND EI 2058-5276 J9 NAT MICROBIOL JI NAT. MICROBIOL PD JUN PY 2016 VL 1 IS 6 AR 16058 DI 10.1038/NMICROBIOL.2016.58 PG 10 WC Microbiology SC Microbiology GA DW4ID UT WOS:000383605500012 PM 27572841 ER PT J AU Foster, JC Nan, B Shen, L Kaciroti, N Taylor, JMG AF Foster, Jared C. Nan, Bin Shen, Lei Kaciroti, Niko Taylor, Jeremy M. G. TI Permutation Testing for Treatment-Covariate Interactions and Subgroup Identification SO STATISTICS IN BIOSCIENCES LA English DT Article DE Permutation tests; Treatment-covariate interactions; Subgroup analysis; Personalized medicine ID CLINICAL-TRIALS AB We consider the problem of using permutation-based methods to test for treatment-covariate interactions from randomized clinical trial data. Testing for interactions is common in the field of personalized medicine, as subgroups with enhanced treatment effects arise when treatment-by-covariate interactions exist. Asymptotic tests can often be performed for simple models, but in many cases, more complex methods are used to identify subgroups, and non-standard test statistics proposed, and asymptotic results may be difficult to obtain. In such cases, it is natural to consider permutation-based tests, which shuffle selected parts of the data in order to remove one or more associations of interest; however, in the case of interactions, it is generally not possible to remove only the associations of interest by simple permutations of the data. We propose a number of alternative permutation-based methods, designed to remove only the associations of interest, but preserving other associations. These methods estimate the interaction term in a model, then create data that "looks like" the original data except that the interaction term has been permuted. The proposed methods are shown to outperform traditional permutation methods in a simulation study. In addition, the proposed methods are illustrated using data from a randomized clinical trial of patients with hypertension. C1 [Foster, Jared C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. [Nan, Bin; Kaciroti, Niko; Taylor, Jeremy M. G.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Shen, Lei] Eli Lilly, Global Stat Sci, Adv Analyt, Indianapolis, IN USA. RP Foster, JC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. EM jared.foster@nih.gov; bnan@umich.edu; shen_lei@lilly.com; nicola@umich.edu; jmgt@umich.edu OI Kaciroti, Niko/0000-0001-8843-8231 FU Intramural NIH HHS [Z99 HD999999]; NCI NIH HHS [T32 CA083654, R01 CA129102]; NIA NIH HHS [R01 AG036802] NR 15 TC 1 Z9 1 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1867-1764 EI 1867-1772 J9 STAT BIOSCI JI Stat. Biosci. PD JUN PY 2016 VL 8 IS 1 BP 77 EP 98 DI 10.1007/s12561-015-9125-9 PG 22 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DW2IX UT WOS:000383467200006 PM 27606036 ER PT J AU Wang, SJ Li, MC AF Wang, Sue-Jane Li, Ming-Chung TI Impacts of Predictive Genomic Classifier Performance on Subpopulation-Specific Treatment Effects Assessment SO STATISTICS IN BIOSCIENCES LA English DT Article DE Composite genomic biomarker; Cross-validated machine learning voting algorithm; Pharmacogenomics; Positive or negative predictive value; Prevalence; Subpopulation treatment effect ID ADAPTIVE SIGNATURE DESIGN; CELL LUNG-CANCER; CLINICAL-TRIALS; GENE SIGNATURE AB We consider three (strong, moderate and mild) predictive biomarker scenarios with varying prevalence. As such, there is no treatment effect in the biomarker negative (g(-)) patient subpopulation. Relative to g(-), there is a four-fold profound treatment effect in the biomarker positive (g(+)) patient subpopulation, a strongly predictive scenario; a three-fold large g(+) subpopulation treatment effect, a moderately predictive scenario; and a two-fold modest g(+) subpopulation treatment effect, a mildly predictive scenario. In this paper, we focus on binary endpoint in prescribing treatment effect. Using a Breiman's (Mach. Learn. 24:123-140, 1996) machine learning voting algorithm via a k-fold cross-validated approach applied by Freidlin et al. (Clin. Cancer Res. 16:691-698, 2010), a predictive biomarker may be developed. We consider development or discovery of a genomic biomarker using microarray gene expressions data in randomized controlled trials and validate the biomarker's predictive performance in an independent data set. We investigate the classification performance characteristics of a binary genomic composite biomarker (expected to be predictive of treatment effects) including sensitivity, specificity, accuracy, positive predictive value and negative predictive value as a function of true sensitive prevalence. In doing so, we report the finding based on three representative tuning parameter sets with varying degree of rigor in their choices of the parameters ranging from highly rigorous, moderately rigorous to mildly rigorous. We articulate the rationales on the choices of tuning parameter sets. We also study the impacts of misclassification of genomic biomarker classifiers on their assessment of treatment effects in the positive and negative patient subpopulations, and all-comer patients. We elucidate via simulation studies on approaches to improve sensitivity when a biomarker is highly specific but poorly sensitive, a scenario that is most likely to lead to an incorrect test conclusion of an applicable significant treatment effect in a specific patient subpopulation or both positive and negative subpopulations. We explore when it will be beneficial to develop a binary predictive biomarker and conclude that hypothesis test inferences for the g(+) subpopulation treatment effect in the dual hypotheses setting (all-comer and g(+) alone) cannot be relied upon if the biomarker classifier is only highly specific and poorly sensitive or resulting in poor negative predictive value. The converse dual hypotheses (all-comer and g-alone) have the same concern, viz. highly sensitive and poorly specific or resulting in poor positive predictive value. In addition, we compare the predictive performance of a biomarker classifier between use of direct selection and selection from a candidate pool shedding favorable lights of direct selection approach where biological or mechanistic plausibility can be relied upon. Further research is needed if accurate classifier is required irrespective of prevalence level. C1 [Wang, Sue-Jane] US FDA, CDER, OTS, Off Biostat, Mailstop WO 21,Room 3562,10903 New Hampshire, Silver Spring, MD 20993 USA. [Wang, Sue-Jane] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Off Biostat, Silver Spring, MD USA. [Li, Ming-Chung] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. RP Wang, SJ (reprint author), US FDA, CDER, OTS, Off Biostat, Mailstop WO 21,Room 3562,10903 New Hampshire, Silver Spring, MD 20993 USA. EM suejane.wang@fda.hhs.gov NR 14 TC 3 Z9 3 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1867-1764 EI 1867-1772 J9 STAT BIOSCI JI Stat. Biosci. PD JUN PY 2016 VL 8 IS 1 BP 129 EP 158 DI 10.1007/s12561-013-9092-y PG 30 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DW2IX UT WOS:000383467200008 ER PT J AU Meiering, EM Aravind, L AF Meiering, Elizabeth M. Aravind, L. TI Editorial overview: Sequences and topology: Protein function - synthesizing information from sequence, structure and disorder SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Editorial Material C1 [Meiering, Elizabeth M.] Univ Waterloo, Dept Chem, Waterloo, ON N2L 3G1, Canada. [Aravind, L.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Meiering, EM (reprint author), Univ Waterloo, Dept Chem, Waterloo, ON N2L 3G1, Canada. EM meiering@uwaterloo.ca; aravind@mail.nih.gov NR 0 TC 0 Z9 0 U1 4 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X EI 1879-033X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD JUN PY 2016 VL 38 BP VII EP IX DI 10.1016/j.sbi.2016.06.016 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DV9ZY UT WOS:000383301900002 PM 27400813 ER PT J AU Oria, RB Murray-Kolb, LE Scharf, RJ Pendergast, LL Lang, DR Kolling, GL Guerrant, RL AF Oria, Reinaldo B. Murray-Kolb, Laura E. Scharf, Rebecca J. Pendergast, Laura L. Lang, Dennis R. Kolling, Glynis L. Guerrant, Richard L. TI Early-life enteric infections: relation between chronic systemic inflammation and poor cognition in children SO NUTRITION REVIEWS LA English DT Review DE cognition; enteric infections; environmental enteropathy; intestinal microbiome; malnutrition ID EARLY-CHILDHOOD DIARRHEA; LOW-INCOME COUNTRIES; BLOOD-BRAIN-BARRIER; INTESTINAL BACTERIAL OVERGROWTH; INNATE IMMUNE-RESPONSES; NITRIC-OXIDE SYNTHASE; HUMAN GUT MICROBIOTA; FATTY LIVER-DISEASE; MAL-ED COHORT; YOUNG-CHILDREN AB The intestinal microbiota undergoes active remodeling in the first 6 to 18 months of life, during which time the characteristics of the adult microbiota are developed. This process is strongly influenced by the early diet and enteric pathogens. Enteric infections and malnutrition early in life may favor microbiota dysbiosis and small intestinal bacterial overgrowth, resulting in intestinal barrier dysfunction and translocation of intestinal bacterial products, ultimately leading to low-grade, chronic, subclinical systemic inflammation. The leaky gut-derived low-grade systemic inflammation may have profound consequences on the gut-liver-brain axis, compromising normal growth, metabolism, and cognitive development. This review examines recent data suggesting that early-life enteric infections that lead to intestinal barrier disruption may shift the intestinal microbiota toward chronic systemic inflammation and subsequent impaired cognitive development. C1 [Oria, Reinaldo B.] Univ Fed Ceara, Lab Tissue Healing Ontogeny & Nutr, Inst Biomed, Fac Med, Fortaleza, Ceara, Brazil. [Oria, Reinaldo B.] Univ Fed Ceara, Fac Med, Dept Morphol, Fortaleza, Ceara, Brazil. [Murray-Kolb, Laura E.] Penn State Univ, University Pk, PA 16802 USA. [Scharf, Rebecca J.; Kolling, Glynis L.; Guerrant, Richard L.] Univ Virginia, Dept Med, Div Infect Dis & Int Hlth, Ctr Global Hlth, Charlottesville, VA USA. [Pendergast, Laura L.] Temple Univ, Sch Psychol Program, Philadelphia, PA 19122 USA. [Lang, Dennis R.] Fdn Natl Inst Hlth, Bethesda, MD USA. RP Oria, RB (reprint author), Univ Fed Ceara, Fac Med, Dept Morphol, Fortaleza, Ceara, Brazil.; Oria, RB (reprint author), Univ Fed Ceara, Fac Med, Inst Biomed, Fortaleza, Ceara, Brazil. EM rbo5u@virginia.edu FU Bill & Melinda Gates Foundation; Foundation for the National Institutes of Health; Fogarty International Center; National Institutes of Health; Doris Duke Charitable Foundation Clinical Scientist Development award FX The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) is carried out as a collaborative project supported by the Bill & Melinda Gates Foundation, the Foundation for the National Institutes of Health, and the Fogarty International Center, National Institutes of Health. R.J.S. is a recipient of Doris Duke Charitable Foundation Clinical Scientist Development award. NR 179 TC 1 Z9 1 U1 6 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0029-6643 EI 1753-4887 J9 NUTR REV JI Nutr. Rev. PD JUN PY 2016 VL 74 IS 6 BP 374 EP 386 DI 10.1093/nutrit/nuw008 PG 13 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DV9RK UT WOS:000383278600002 PM 27142301 ER PT J AU Grobman, WA Lai, YL Iams, JD Reddy, UM Mercer, BM Saade, G Tita, AT Rouse, DJ Sorokin, Y Wapner, RJ Leveno, KJ Blackwell, SC Esplin, S Tolosa, JE Thorp, JM Caritis, SN AF Grobman, William A. Lai, Yinglei Iams, Jay D. Reddy, Uma M. Mercer, Brian M. Saade, George Tita, Alan T. Rouse, Dwight J. Sorokin, Yoram Wapner, Ronald J. Leveno, Kenneth J. Blackwell, Sean C. Esplin, Sean Tolosa, Jorge E. Thorp, John M. Caritis, Steve N. CA Eunice Kennedy Shriver Natl Inst Human Dev Maternal-Fetal TI Prediction of Spontaneous Preterm Birth Among Nulliparous Women With a Short Cervix SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE cervical length; obstetric ultrasound; prediction; spontaneous preterm birth ID WEEKS GESTATION; RISK-FACTORS; LENGTH; DELIVERY AB Objectives-The purpose of this study was to evaluate whether demographic and sonographic factors associated with spontaneous preterm birth among nulliparous women with a cervical length of less than 30 mm could be combined into an accurate prediction model for spontaneous preterm birth. Methods-We conducted a secondary analysis of a trial of nulliparous women with a singleton gestation and a cervical length of less than 30 mm on transvaginal sonography between 16 and 22 weeks who lacked other risk factors for spontaneous (eg, prior cervical excisional procedure) or medically indicated (eg, chronic hypertension) preterm birth, who were randomized to either 17 alpha-hydroxyprogesterone caproate treatment or a placebo. Risk factors associated with spontaneous preterm birth within the entire cohort were identified by univariable analysis. Factors significantly associated (P < .05) with spontaneous preterm birth were included in a multivariable logistic regression analysis to determine whether an accurate prediction model could be developed. Results-Of the 657 randomized patients, 109 (16.6%) had spontaneous preterm birth before 37 weeks' gestation. Logistic regression analysis revealed only cervical length (odds ratio, 1.06 per 1-mm decrease; 95% confidence interval, 1.02-1.10) to be associated with spontaneous preterm birth. The area under the receiver operating characteristic curve based on this regression was low (0.63; 95% confidence interval, 0.58-0.69). Results were similar for the outcome of spontaneous preterm birth before 34 weeks. Conclusions-An accurate prediction model for spontaneous preterm birth among nulliparous women with a short cervix could not be developed. C1 [Grobman, William A.] Northwestern Univ, Dept Obstet, Chicago, IL 60611 USA. [Grobman, William A.] Northwestern Univ, Dept Gynecol, Chicago, IL 60611 USA. [Lai, Yinglei] George Washington Univ, Ctr Biostat, Washington, DC USA. [Iams, Jay D.] Ohio State Univ, Columbus, OH 43210 USA. [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Mercer, Brian M.] Case Western Reserve Univ, Metrohlth Med Ctr, Cleveland, OH USA. [Saade, George] Univ Texas Med Branch, Galveston, TX 77555 USA. [Tita, Alan T.] Univ Alabama Birmingham, Birmingham, AL USA. [Rouse, Dwight J.] Brown Univ, Providence, RI 02912 USA. [Sorokin, Yoram] Wayne State Univ, Detroit, MI USA. [Wapner, Ronald J.] Columbia Univ, New York, NY USA. [Leveno, Kenneth J.] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. [Blackwell, Sean C.] Houston Childrens Mem Hermann Hosp, Univ Texas Hlth Sci Ctr, Houston, TX USA. [Esplin, Sean] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [Tolosa, Jorge E.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Thorp, John M.] Univ N Carolina, Chapel Hill, NC USA. [Caritis, Steve N.] Univ Pittsburgh, Pittsburgh, PA USA. RP Grobman, WA (reprint author), Northwestern Univ, Dept Obstet & Gynecol, 250 Super St,Suite 05-2175, Chicago, IL 60611 USA. EM w-grobman@northwestern.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD21410, UL1 RR024153, UL1 TR000005, HD27869, HD27915, HD27917, HD34116, HD34208, 5UL1RR025764, HD36801, HD40500, HD40512, HD40544, M01 RR00080, UL1 RR024989, HD40545, HD40560, HD40485, HD53097, HD53118] FX We thank the subcommittee members who participated in protocol development and coordination between clinical research centers (Gail Mallett, RN, BSN, CCRC, and Cynthia Milluzzi, RN), protocol/data management and statistical analysis (Elizabeth Thom, PhD), and protocol development and oversight (Catherine Y. Spong, MD). The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; HD21410, UL1 RR024153, UL1 TR000005, HD27869, HD27915, HD27917, HD34116, HD34208, 5UL1RR025764, HD36801, HD40500, HD40512, HD40544, M01 RR00080, UL1 RR024989 [National Center for Research Resources), HD40545, HD40560, HD40485, HD53097, and HD53118). Comments and views of the authors do not necessarily represent views of the NICHD. NR 13 TC 0 Z9 0 U1 1 U2 1 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 EI 1550-9613 J9 J ULTRAS MED JI J. Ultrasound Med. PD JUN 1 PY 2016 VL 35 IS 6 BP 1293 EP 1297 DI 10.7863/ultra.15.08035 PG 5 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA DU8YY UT WOS:000382504100020 PM 27151903 ER PT J AU Dioguardi, CC Uslu, B Haynes, M Kurus, M Gul, M Miao, DQ De Santis, L Ferrari, M Bellone, S Santin, A Giulivi, C Hoffman, G Usdin, K Johnson, J AF Dioguardi, Carola Conca Uslu, Bahar Haynes, Monique Kurus, Meltem Gul, Mehmet Miao, De-Qiang De Santis, Lucia Ferrari, Maurizio Bellone, Stefania Santin, Alessandro Giulivi, Cecilia Hoffman, Gloria Usdin, Karen Johnson, Joshua TI Granulosa cell and oocyte mitochondrial abnormalities in a mouse model of fragile X primary ovarian insufficiency SO MOLECULAR HUMAN REPRODUCTION LA English DT Article DE fragile X primary ovarian insufficiency; fragile X premutation; ovary; oocyte; follicle; fertility; atresia; mitochondria ID FMR1 MESSENGER-RNA; TREMOR ATAXIA SYNDROME; TREMOR/ATAXIA-SYNDROME; PREMUTATION CARRIERS; PROTEIN EXPRESSION; FULL MUTATION; REPEAT; WOMEN; DYSFUNCTION; FUSION AB STUDY HYPOTHESIS: We hypothesized that the mitochondria of granulosa cells (GC) and/or oocytes might be abnormal in a mouse model of fragile X premutation (FXPM). STUDY FINDING: Mice heterozygous and homozygous for the FXPM have increased death (atresia) of large ovarian follicles, fewer corpora lutea with a gene dosage effect manifesting in decreased litter size(s). Furthermore, granulosa cells (GC) and oocytes of FXPM mice have decreased mitochondrial content, structurally abnormal mitochondria, and reduced expression of critical mitochondrial genes. Because this mouse allele produces the mutant Fragile X mental retardation 1 (Fmr1) transcript and reduced levels of wild-type (WT) Fmr1 protein (FMRP), but does not produce a Repeat Associated Non-ATG Translation (RAN)-translation product, our data lend support to the idea that Fmr1 mRNA with large numbers of CGG-repeats is intrinsically deleterious in the ovary. WHAT IS KNOWN ALREADY: Mitochondrial dysfunction has been detected in somatic cells of human and mouse FXPM carriers and mitochondria are essential for oogenesis and ovarian follicle development, FX-associated primary ovarian insufficiency (FXPOI) is seen in women with FXPM alleles. These alleles have 55-200 CGG repeats in the 5' UTR of an X-linked gene known as FMR1. The molecular basis of the pathology seen in this disorder is unclear but is thought to involve either some deleterious consequence of overexpression of RNA with long CGG-repeat tracts or of the generation of a repeat-associated non-AUG translation (RAN translation) product that is toxic. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Analysis of ovarian function in a knock-in FXPM mouse model carrying 130 CGG repeats was performed as follows on WT, PM/+, and PM/PM genotypes. Histomorphometric assessment of follicle and corpora lutea numbers in ovaries from 8-month-old mice was executed, along with litter size analysis. Mitochondrial DNA copy number was quantified in oocytes and GC using quantitative PCR, and cumulus granulosa mitochondrial content was measured by flow cytometric analysis after staining of cells with Mitotracker dye. Transmission electron micrographs were prepared of GC within small growing follicles and mitochondrial architecture was compared. Quantitative RT-PCR analysis of key genes involved in mitochondrial structure and recycling was performed. MAIN RESULTS AND THE ROLE OF CHANCE: A defect was found in follicle survival at the large antral stage in PM/+ and PM/PM mice. Litter size was significantly decreased in PM/PM mice, and corpora lutea were significantly reduced in mice of both mutant genotypes. Mitochondrial DNA copy number was significantly decreased in GC and metaphase II eggs in mutants. Flow cytometric analysis revealed that PM/+ and PM/PM animals lack the cumulus GC that harbor the greatest mitochondrial content as found in wild-type animals. Electron microscopic evaluation of GC of small growing follicles revealed mitochondrial structural abnormalities, including disorganized and vacuolar cristae. Finally, aberrant mitochondrial gene expression was detected. Mitofusin 2 (Mfn2) and Optic atrophy 1 (Opa1), genes involved in mitochondrial fusion and structure, respectively, were significantly decreased in whole ovaries of both mutant genotypes. Mitochondrial fission factor 1 (Mff1) was significantly decreased in PM/+ and PM/PM GC and eggs compared with wild-type controls. LIMITATIONS, REASONS FOR CAUTION: Data from the mouse model used for these studies should be viewed with some caution when considering parallels to the human FXPOI condition. WIDER IMPLICATIONS OF THE FINDINGS: Our data lend support to the idea that Fmr1 mRNA with large numbers of CGG-repeats is intrinsically deleterious in the ovary. FXPM disease states, including FXPOI, may share mitochondrial dysfunction as a common underlying mechanism. LARGE SCALE DATA: Not applicable. C1 [Dioguardi, Carola Conca; Uslu, Bahar; Haynes, Monique; Miao, De-Qiang; Bellone, Stefania; Santin, Alessandro; Johnson, Joshua] Yale Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT 06510 USA. [Dioguardi, Carola Conca; Uslu, Bahar; Haynes, Monique; Miao, De-Qiang; Johnson, Joshua] Yale Sch Med, Div Reprod Endocrinol & Infertil, New Haven, CT 06510 USA. [Dioguardi, Carola Conca] Univ Vita Salute San Raffaele, IRCCS San Raffaele Hosp, Milan, Italy. [Kurus, Meltem] Izmir Katip Celebi Univ, Sch Med, Dept Histol & Embryol, Izmir, Turkey. [Gul, Mehmet] Inonu Univ, Sch Med, Dept Histol & Embryol, Malatya, Turkey. [De Santis, Lucia] Univ Vita Salute San Raffaele, IRCCS San Raffaele Hosp, Dept Obstet & Gynecol, IVF Unit, Milan, Italy. [Ferrari, Maurizio] Univ Vita Salute San Raffaele, IRCCS San Raffaele Hosp, Lab Clin Mol Biol & Cytogenet, Milan, Italy. [Bellone, Stefania; Santin, Alessandro] Yale Sch Med, Div Gynecol Oncol, New Haven, CT USA. [Giulivi, Cecilia] Univ Calif Davis, MIND Inst, Dept Mol Biosci, Davis, CA 95616 USA. [Hoffman, Gloria] Morgan State Univ, Dept Biol, Baltimore, MD 21239 USA. [Usdin, Karen] NIDDK, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Johnson, J (reprint author), Yale Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT 06510 USA.; Johnson, J (reprint author), Yale Sch Med, Div Reprod Endocrinol & Infertil, New Haven, CT 06510 USA. EM josh.johnson@yale.edu RI Uslu, Bahar/H-4903-2016 FU National Institutes of Health (NIH) [R21 071873]; Albert McKern Fund for Perinatal Research; NIH; TUBITAK FX These studies were supported by National Institutes of Health (NIH) R21 071873 (J.J., G.H.), The Albert McKern Fund for Perinatal Research (J.J.), NIH Intramural Funds (K.U.), and a TUBITAK Research Fellowship Award (B.U.). NR 58 TC 7 Z9 7 U1 6 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1360-9947 EI 1460-2407 J9 MOL HUM REPROD JI Mol. Hum. Reprod. PD JUN PY 2016 VL 22 IS 6 BP 384 EP 396 DI 10.1093/molehr/gaw023 PG 13 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA DT0XF UT WOS:000381205600002 ER PT J AU Qiu, ZP Qin, J Zhou, Y AF Qiu, Zhiping Qin, Jing Zhou, Yong TI Composite Estimating Equation Method for the Accelerated Failure Time Model with Length-biased Sampling Data SO SCANDINAVIAN JOURNAL OF STATISTICS LA English DT Article DE accelerated failure time model; composite estimating equation; kernel smoothing; length-biased sampling data; rank estimator ID RIGHT-CENSORED DATA; LINEAR RANK-TESTS; PREVALENT COHORT; SURVIVAL-DATA; PARTIAL LIKELIHOOD; REGRESSION-MODELS; TRUNCATED DATA; STATIONARITY; COVARIABLES; DEMENTIA AB Length-biased sampling data are often encountered in the studies of economics, industrial reliability, epidemiology, genetics and cancer screening. The complication of this type of data is due to the fact that the observed lifetimes suffer from left truncation and right censoring, where the left truncation variable has a uniform distribution. In the Cox proportional hazards model, Huang & Qin (Journal of the American Statistical Association, 107, 2012, p. 107) proposed a composite partial likelihood method which not only has the simplicity of the popular partial likelihood estimator, but also can be easily performed by the standard statistical software. The accelerated failure time model has become a useful alternative to the Cox proportional hazards model. In this paper, by using the composite partial likelihood technique, we study this model with length-biased sampling data. The proposed method has a very simple form and is robust when the assumption that the censoring time is independent of the covariate is violated. To ease the difficulty of calculations when solving the non-smooth estimating equation, we use a kernel smoothed estimation method (Heller; Journal of the American Statistical Association, 102, 2007, p. 552). Large sample results and a re-sampling method for the variance estimation are discussed. Some simulation studies are conducted to compare the performance of the proposed method with other existing methods. A real data set is used for illustration. C1 [Qiu, Zhiping] Huaqiao Univ, Sch Math Sci, Quanzhou, Peoples R China. [Qiu, Zhiping] Shanghai Univ Finance & Econ, Sch Stat & Management, Shanghai, Peoples R China. [Qin, Jing] NIAID, Biostat Res Branch, Bethesda, MD USA. [Zhou, Yong] Chinese Acad Sci, Inst Appl Math, Beijing 100190, Peoples R China. RP Zhou, Y (reprint author), Chinese Acad Sci, Inst Appl Math, Beijing 100190, Peoples R China. EM yzhou@amss.ac.cn FU National Natural Science Foundation of China (NSFC) [71271128]; National Natural Science Foundation of China [71331006]; NCMIS, Key Laboratory of RCSDS, AMSS, CAS [2008DP173182]; Shanghai First-class Discipline A; IRTSHUFE, PCSIRT [IRT13077]; Natural Science Foundation of Fujian Province, China [2015J01583] FX The authors are grateful to the editor, associate editor, three anonymous reviewers for their insightful comments and suggestions, and the professor Jing Ning for the R codes, which greatly improved this article. Zhou's work was supported by the National Natural Science Foundation of China (NSFC) (71271128), State Key Program of National Natural Science Foundation of China(71331006), NCMIS, Key Laboratory of RCSDS, AMSS, CAS(2008DP173182) and Shanghai First-class Discipline A and IRTSHUFE, PCSIRT (IRT13077). Qiu's work was supported by the Natural Science Foundation of Fujian Province, China (grant no. 2015J01583). NR 50 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0303-6898 EI 1467-9469 J9 SCAND J STAT JI Scand. J. Stat. PD JUN PY 2016 VL 43 IS 2 BP 396 EP 415 DI 10.1111/sjos.12182 PG 20 WC Statistics & Probability SC Mathematics GA DU9QV UT WOS:000382553500011 ER PT J AU Hughes, MF Ross, DG Starr, JM Scollon, EJ Wolansky, MJ Crofton, KM DeVito, MJ AF Hughes, Michael F. Ross, David G. Starr, James M. Scollon, Edward J. Wolansky, Marcelo J. Crofton, Kevin M. DeVito, Michael J. TI Environmentally relevant pyrethroid mixtures: A study on the correlation of blood and brain concentrations of a mixture of pyrethroid insecticides to motor activity in the rat SO TOXICOLOGY LA English DT Article DE Pesticide; Pyrethroid; Neurotoxicity; Mixture; Dosimetry ID IN-VITRO METABOLISM; ACOUSTIC STARTLE RESPONSE; CYTOCHROME-P450 ISOFORMS; HYDROLYTIC METABOLISM; SUBSTRATE-SPECIFICITY; DELTAMETHRIN; LIVER; TOXICITY; CARBOXYLESTERASES; PESTICIDES AB Human exposure to multiple pyrethroid insecticides may occur because of their broad use on crops and for residential pest control. To address the potential health risk from co-exposure to pyrethroids, it is important to understand their disposition and toxicity in target organs such as the brain, and surrogates such as the blood when administered as a mixture. The objective of this study was to assess the correlation between blood and brain concentrations of pyrethroids and neurobehavioral effects in the rat following an acute oral administration of the pyrethroids as a mixture. Male Long-Evans rats were administered a mixture of P-cyfluthrin, cypermethrin, deltamethrin, esfenvalerate and cis- and transpermethrin in corn oil at seven dose levels. The pyrethroid with the highest percentage in the dosing solution was trans-permethrin (31% of total mixture dose) while deltamethrin and esfenvalerate had the lowest percentage (3%). Motor activity of the rats was then monitored for 1 h. At 3.5 h post-dosing, the animals were euthanized and blood and brain were collected. These tissues were extracted and analyzed for parent pyrethroid using HPLC-tandem mass spectrometry. Cypermethrin and cis-permethrin were the predominate pyrethroids detected in blood and brain, respectively, at all dosage levels. The relationship of total pyrethroid concentration between blood and brain was linear (r = 0.93). The pyrethroids with the lowest fraction in blood were trans-permethrin and beta-cyfluthrin and in brain were deltamethrin and esfenvalerate. The relationship between motor activity of the treated rats and summed pyrethroid blood and brain concentration was described using a sigmoidal E-max model with the Effective Concentrations being more sensitive for brain than blood. The data suggests summed pyrethroid rat blood concentration could be used as a surrogate for brain concentration as an aid to study the neurotoxic effects of pyrethroids administered as a mixture under the conditions used in this study. Published by Elsevier Ireland Ltd. C1 [Hughes, Michael F.; Ross, David G.; Scollon, Edward J.; Crofton, Kevin M.; DeVito, Michael J.] US EPA, Off Res & Dev, Natl Hlth & Environm Effects Res Lab, MD B105-03, Res Triangle Pk, NC 27709 USA. [Starr, James M.] US EPA, Off Res & Dev, Natl Exposure Res Lab, MD B105-03, Res Triangle Pk, NC 27709 USA. [Wolansky, Marcelo J.] CNR, Res Triangle Pk, NC USA. [Scollon, Edward J.] Syngenta Crop Protect, Greensboro, NC USA. [Wolansky, Marcelo J.] Univ Buenos Aires, Buenos Aires, DF, Argentina. [Wolansky, Marcelo J.] Argentine NRC Inst IQUIBICEN, Buenos Aires, DF, Argentina. [Crofton, Kevin M.] US EPA, Off Res & Dev, Natl Ctr Computat Toxicol, MD B105-03, Res Triangle Pk, NC 27709 USA. [DeVito, Michael J.] NIEHS, Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. RP Hughes, MF (reprint author), US EPA, MD B105-03, Res Triangle Pk, NC 27709 USA. EM hughes.michaelf@epa.gov FU internal US Environmental Protection Agency, Office of Research and Development funds FX The authors thank FMC Corporation, Bayer CropScience and DuPont Crop Protection for providing the pyrethroids used in this study. The authors also thank Drs. Hisham El-Masri, Jane Ellen Simmons and Nicole Tulve for their review of an earlier version of this manuscript. This research was supported by internal US Environmental Protection Agency, Office of Research and Development funds. NR 44 TC 2 Z9 2 U1 8 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD JUN 1 PY 2016 VL 359 BP 19 EP 28 DI 10.1016/j.tox.2016.06.013 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA DT5TM UT WOS:000381545500003 PM 27330022 ER PT J AU Lopez-Class, M Cubbins, L Loving, AM AF Lopez-Class, Maria Cubbins, Lisa Loving, Ashley McClure TI Considerations of Methodological Approaches in the Recruitment and Retention of Immigrant Participants SO JOURNAL OF RACIAL AND ETHNIC HEALTH DISPARITIES LA English DT Article DE Latino; Immigration; Effective strategies for recruitment and retention ID BREAST-CANCER RISK; NATIONAL-SURVEY; AMERICAN LIFE; AFRICAN-AMERICANS; CLINICAL-TRIALS; ASIAN-AMERICAN; MENTAL-HEALTH; LATINO; CHILDREN; DESIGN AB Objective This study aims to identify effective strategies related to recruitment and retention of immigrant survey participants. Methodology The study used a multi-mode approach in, first, conducting a literature review of recent articles on surveys that either targeted immigrants or included large numbers of immigrants in their samples. Next, six surveys were reviewed that either targeted or included large numbers of immigrants. Finally, expert opinions on immigration were gathered regarding recruitment and retention of immigrant survey participants. Results Although immigrants may be difficult to recruit due to limited English proficiency, mistrust of strangers, and/or high mobility, many of these challenges can be overcome by adopting the same strategies used when surveying ethnically diverse populations (e.g., snowballing versus advertisement, establishing a personal connection with data collectors). Nonetheless, a few practices were identified as most relevant for recruitment and retention of immigrant populations, including involving local community organizations relevant to immigrants, translation of materials tailored to the vernacular language of the various ethnicities, and customizing nonmonetary incentives to the specific ethnicity. Conclusions Based on the reviews and expert interviews, multiple strategies have been shown to be effective in recruiting and retaining immigrant participants. C1 [Lopez-Class, Maria] NICHHD, NIH, Bethesda, MD 20892 USA. [Cubbins, Lisa] Battelle Mem Inst, Seattle, WA 98109 USA. [Loving, Ashley McClure] 24346 N 72nd Way, Scottsdale, AZ 85255 USA. RP Lopez-Class, M (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. EM lopezclassm@mail.nih.gov NR 54 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 2197-3792 EI 2196-8837 J9 J RACIAL ETHN HEALTH JI J. Racial Ethn. Health Disparities PD JUN PY 2016 VL 3 IS 2 BP 267 EP 280 DI 10.1007/s40615-015-0139-2 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DT5FY UT WOS:000381508200011 PM 27271068 ER PT J AU Fairhurst, RM Dondorp, AM AF Fairhurst, Rick M. Dondorp, Arjen M. TI Artemisinin-Resistant Plasmodium falciparum Malaria SO MICROBIOLOGY SPECTRUM LA English DT Article ID CHINA-MYANMAR BORDER; SUB-SAHARAN AFRICA; K13 PROPELLER GENE; PARASITE CLEARANCE; DIHYDROARTEMISININ-PIPERAQUINE; WESTERN CAMBODIA; IN-VITRO; K13-PROPELLER POLYMORPHISMS; SOUTHEAST-ASIA; MOLECULAR MARKER AB For more than five decades, Southeast Asia (SEA) has been fertile ground for the emergence of drug-resistant Plasmodium falciparum malaria. After generating parasites resistant to chloroquine, sulfadoxine, pyrimethamine, quinine, and mefloquine, this region has now spawned parasites resistant to artemisinins, the world's most potent antimalarial drugs. In areas where artemisinin resistance is prevalent, artemisinin combination therapies (ACTs)-the first-line treatments for malaria-are failing fast. This worrisome development threatens to make malaria practically untreatable in SEA, and threatens to compromise global endeavors to eliminate this disease. A recent series of clinical, in vitro, genomics, and transcriptomics studies in SEA have defined in vivo and in vitro phenotypes of artemisinin resistance, identified its causal genetic determinant, explored its molecular mechanism, and assessed its clinical impact. Specifically, these studies have established that artemisinin resistance manifests as slow parasite clearance in patients and increased survival of early-ring-stage parasites in vitro; is caused by single nucleotide polymorphisms in the parasite's K13 gene, is associated with an upregulated "unfolded protein response" pathway that may antagonize the pro-oxidant activity of artemisinins, and selects for partner drug resistance that rapidly leads to ACT failures. In SEA, clinical studies are urgently needed to monitor ACT efficacy where K13 mutations are prevalent, test whether new combinations of currently available drugs cure ACT failures, and advance new antimalarial compounds through preclinical pipelines and into clinical trials. Intensifying these efforts should help to forestall the spread of artemisinin and partner drug resistance from SEA to sub-Saharan Africa, where the world's malaria transmission, morbidity, and mortality rates are highest. C1 [Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Dondorp, Arjen M.] Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok 10400, Thailand. [Dondorp, Arjen M.] Univ Oxford, Ctr Trop Med, Nuffield Dept Med, Oxford OX3 7BN, England. RP Fairhurst, RM (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM rfairhurst@niaid.nih.gov NR 88 TC 4 Z9 4 U1 12 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA EI 2165-0497 J9 MICROBIOL SPECTR JI Microbiol. Spectr. PD JUN PY 2016 VL 4 IS 3 AR UNSP EI10-0013-2016 DI 10.1128/microbiolspec.EI10-0013-2016 PG 16 WC Microbiology SC Microbiology GA DT9GD UT WOS:000381803300017 ER PT J AU Roche, PA Cresswell, P AF Roche, Paul A. Cresswell, Peter TI Antigen Processing and Presentation Mechanisms in Myeloid Cells SO MICROBIOLOGY SPECTRUM LA English DT Article ID MHC-CLASS-II; HUMAN DENDRITIC CELLS; INVARIANT CHAIN COMPLEXES; HLA-DR MOLECULES; CROSS-PRESENTATION; IN-VIVO; INTRACELLULAR-TRANSPORT; ENDOPLASMIC-RETICULUM; INFLAMMATORY STIMULI; CATHEPSIN-S AB Unlike B cells, CD8-positive and CD4-positive T cells of the adaptive immune system do not recognize intact foreign proteins but instead recognize polypeptide fragments of potential antigens. These antigenic peptides are expressed on the surface of antigen presenting cells bound to MHC class I and MHC class II proteins. Here, we review the basics of antigen acquisition by antigen presenting cells, antigen proteolysis into polypeptide fragments, antigenic peptide binding to MHC proteins, and surface display of both MHC class I-peptide and MHC class II-peptide complexes. C1 [Roche, Paul A.] NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Cresswell, Peter] Yale Univ, Sch Med, Dept Immunobiol, Howard Hughes Med Inst, 333 Cedar St, New Haven, CT 06520 USA. RP Cresswell, P (reprint author), Yale Univ, Sch Med, Dept Immunobiol, Howard Hughes Med Inst, 333 Cedar St, New Haven, CT 06520 USA. EM peter.cresswell@yale.edu NR 104 TC 3 Z9 3 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA EI 2165-0497 J9 MICROBIOL SPECTR JI Microbiol. Spectr. PD JUN PY 2016 VL 4 IS 3 AR UNSP MCHD-0008-2015 DI 10.1128/microbiolspec.MCHD-0008-2015 PG 14 WC Microbiology SC Microbiology GA DT9GD UT WOS:000381803300031 ER PT J AU Raczynska, JE Wlodawer, A Jaskolski, M AF Raczynska, Joanna E. Wlodawer, Alexander Jaskolski, Mariusz TI Prior knowledge or freedom of interpretation? A critical look at a recently published classification of "novel" Zn binding sites SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE Zn coordination; crystal structure; stereochemistry; protein data bank (PDB) ID CRYSTAL-STRUCTURES; PROTEIN AB In a recently published article (Yao, Flight, Rouchka, and Moseley, Proteins 2015;83:1470-1487) the authors proposed novel Zn coordination patterns in protein structures, apparently discovered using an unprejudiced approach to the information collected in the Protein data Bank (PDB), which they advocated as superior to the prior-knowledge-informed paradigm. In our assessment of those propositions we demonstrate here that most, if not all, of the "new" coordination geometries are fictitious, as they are based on incorrectly interpreted protein crystal structures, which in themselves are often not error-free. The flaws of interpretation include partial or wrong Zn sites, missed or wrong ligands, ignored crystal symmetry and ligands, etc. In conclusion, we warn against using this and similar meta-analyses that ignore chemical and crystallographic knowledge, and emphasize the importance of safeguarding structural databases against bad apples. (C) 2016 Wiley Periodicals, Inc. C1 [Raczynska, Joanna E.; Jaskolski, Mariusz] Polish Acad Sci, Inst Bioorgan Chem, Ctr Biocrystallog Res, Poznan, Poland. [Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Jaskolski, Mariusz] Adam Mickiewicz Univ, Dept Crystallog, Fac Chem, Poznan, Poland. RP Jaskolski, M (reprint author), Adam Mickiewicz Univ, Dept Crystallog, Fac Chem, Poznan, Poland. EM mariuszj@amu.edu.pl FU DesInMBL grant from the National Centre for Research and Development within the JPIAMR initiative; National Science Centre [2013/10/M/NZ1/00251]; intramural research program of the NIH, National Cancer Institute, Center for Cancer Research FX MJ and JR were supported in part by the DesInMBL grant from the National Centre for Research and Development within the JPIAMR initiative. The research of MJ was supported in part by a grant (2013/10/M/NZ1/00251) from the National Science Centre. AW was supported by the intramural research program of the NIH, National Cancer Institute, Center for Cancer Research. NR 16 TC 5 Z9 5 U1 3 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 EI 1097-0134 J9 PROTEINS JI Proteins PD JUN PY 2016 VL 84 IS 6 BP 770 EP 776 DI 10.1002/prot.25024 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DT0GB UT WOS:000381160100005 PM 26914344 ER PT J AU Barna, BP McPeek, M Malur, A Fessler, MB Wingard, CJ Dobbs, L Verbanac, KM Bowling, M Judson, MA Thomassen, MJ AF Barna, Barbara P. McPeek, Matthew Malur, Anagha Fessler, Michael B. Wingard, Christopher J. Dobbs, Larry Verbanac, Kathryn M. Bowling, Mark Judson, Marc A. Thomassen, Mary Jane TI Elevated MicroRNA-33 in Sarcoidosis and a Carbon Nanotube Model of Chronic Granulomatous Disease SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE carbon nanotube; murine model; sarcoidosis; microRNA; lipid transporters ID ALVEOLAR MACROPHAGES; PULMONARY SARCOIDOSIS; LUNG INFLAMMATION; MICE; CHOLESTEROL; MIR-33; ABCG1; ATHEROSCLEROSIS; HOMEOSTASIS; DEFICIENCY AB We established a murine model of multiwall carbon nanotube (MWCNT)-induced chronic granulomatous disease, which resembles human sarcoidosis pathology. At 60 days after oropharyngeal MWCNT instillation, bronchoalveolar lavage (BAL) cells from wild-type mice exhibit an M1 phenotype with elevated proinflammatory cytokines and reduced peroxisome proliferator-activated receptor gamma (PPAR gamma)-characteristics also present in human sarcoidosis. Based upon MWCNT-associated PPARg deficiency, we hypothesized that the PPARg target gene, ATP-binding cassette (ABC) G1, a lipid transporter with antiinflammatory properties, might also be repressed. Results after MWCNT instillation indicated significantly repressed ABCG1, but, surprisingly, lipid transporter ABCA1 was also repressed, suggesting a possible second pathway. Exploration of potential regulators revealed that microRNA (miR)-33, a lipid transporter regulator, was strikingly elevated (13.9 fold) in BAL cells from MWCNT-instilled mice but not sham control mice. Elevated miR-33 was also detected in murine granulomatous lung tissue. In vitro studies confirmed that lentivirus-miR-33 overexpression repressed both ABCA1 and ABCG1 (but not PPARg) in cultured murine alveolar macrophages. BAL cells of patients with sarcoidosis also displayed elevated miR-33 together with reduced ABCA1 and ABCG1 messenger RNA and protein compared with healthy control subjects. Moreover, miR-33 was elevated within sarcoidosis granulomatous tissue. The findings suggest that alveolar macrophage miR-33 is up-regulated by proinflammatory cytokines and may perpetuate chronic inflammatory granulomatous disease by repressing antiinflammatory functions of ABCA1 and ABCG1 lipid transporters. The results also suggest two possible pathways for transporter dysregulation in granulomatous disease-one associated with intrinsic PPARg status and the other with miR-33 up-regulation triggered by environmental challenges, such as MWCNT. C1 [Barna, Barbara P.; McPeek, Matthew; Malur, Anagha; Bowling, Mark; Thomassen, Mary Jane] East Carolina Univ, Div Pulm Crit Care & Sleep Med, Greenville, NC USA. [Fessler, Michael B.] NIEHS, Immun Inflammat & Dis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Wingard, Christopher J.] East Carolina Univ, Dept Physiol, Greenville, NC USA. [Dobbs, Larry] East Carolina Univ, Dept Pathol, Greenville, NC USA. [Verbanac, Kathryn M.] East Carolina Univ, Dept Surg, Greenville, NC USA. [Judson, Marc A.] Albany Med Coll, Div Pulm & Crit Care, Albany, NY 12208 USA. RP Thomassen, MJ (reprint author), East Carolina Univ, 3E-149 Brody Bldg, Greenville, NC 27834 USA. EM thomassenm@ecu.edu FU National Institutes of Health (NIH) [ES022462, HL077652]; North Carolina Biotechnology Center Instrumentation grant; NIH Intramural Research Program, National Institute of Environmental Health Sciences [Z01 ES102005] FX This work was supported by National Institutes of Health (NIH) grants ES022462 and HL077652 (M.J.T.), North Carolina Biotechnology Center Instrumentation grant (M.J.T.), and NIH Intramural Research Program, National Institute of Environmental Health Sciences grant Z01 ES102005 (M.B.F.). NR 30 TC 2 Z9 2 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1044-1549 EI 1535-4989 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD JUN 1 PY 2016 VL 54 IS 6 BP 865 EP 871 DI 10.1165/rcmb.2015-0332OC PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA DT7XQ UT WOS:000381702000012 PM 26641802 ER PT J AU Mensah, GA AF Mensah, George A. TI HEALTH INEQUITIES IN HYPERTENSION AND RELATED ORGAN DAMAGE SO ETHNICITY & DISEASE LA English DT Editorial Material DE Hypertension; Organ Damage; Blood Pressure C1 [Mensah, George A.] NHLBI, Ctr Translat Res & Implementat Sci, NIH, One Rockledge Ctr,6705 Rockledge Dr,Suite 6070, Bethesda, MD 20892 USA. [Mensah, George A.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD USA. RP Mensah, GA (reprint author), NHLBI, Ctr Translat Res & Implementat Sci, NIH, One Rockledge Ctr,6705 Rockledge Dr,Suite 6070, Bethesda, MD 20892 USA. EM George.Mensah@nih.gov NR 12 TC 0 Z9 0 U1 0 U2 0 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X EI 1945-0826 J9 ETHNIC DIS JI Ethn. Dis. PD SUM PY 2016 VL 26 IS 3 BP 263 EP 265 DI 10.18865/ed.26.3.263 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DS5DK UT WOS:000380800800001 PM 27440962 ER PT J AU Wright, JT Fine, LJ AF Wright, Jackson T., Jr. Fine, Lawrence J. TI SPRINT AND IMPLICATIONS FOR TARGET ORGAN PROTECTION IN AFRICAN AMERICANS SO ETHNICITY & DISEASE LA English DT Editorial Material DE SPRINT; Cardiovascular Disease; Hypertension; Systolic Blood Pressure; African American ID PRESSURE INTERVENTION TRIAL; SYSTOLIC BLOOD-PRESSURE; DISEASE C1 [Wright, Jackson T., Jr.] Univ Hosp Case Med Ctr, Div Nephrol & Hypertens, Cleveland, OH USA. [Fine, Lawrence J.] NHLBI, Div Cardiovasc Sci, Bethesda, MD USA. RP Wright, JT (reprint author), Case Western Reserve Univ, Dept Med, 11100 Euclid St,Bolwell Suite 200, Cleveland, OH 44106 USA. EM Jackson.wright@case.edu NR 7 TC 0 Z9 0 U1 0 U2 0 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X EI 1945-0826 J9 ETHNIC DIS JI Ethn. Dis. PD SUM PY 2016 VL 26 IS 3 BP 271 EP 274 DI 10.18865/ed.26.3.271 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DS5DK UT WOS:000380800800003 PM 27440964 ER PT J AU Mensah, GA AF Mensah, George A. TI HYPERTENSION AND TARGET ORGAN DAMAGE: DON'T BELIEVE EVERYTHING YOU THINK! SO ETHNICITY & DISEASE LA English DT Editorial Material DE Hypertension; Organ Damage; Blood Pressure ID PREVALENCE; COUNTRIES; BLACKS C1 [Mensah, George A.] NHLBI, Ctr Translat Res & Implementat Sci, NIH, One Rockledge Ctr,6705 Rockledge Dr,Suite 6070, Bethesda, MD 20892 USA. [Mensah, George A.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD USA. RP Mensah, GA (reprint author), NHLBI, Ctr Translat Res & Implementat Sci, NIH, One Rockledge Ctr,6705 Rockledge Dr,Suite 6070, Bethesda, MD 20892 USA. EM George.Mensah@nih.gov NR 13 TC 0 Z9 0 U1 1 U2 1 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X EI 1945-0826 J9 ETHNIC DIS JI Ethn. Dis. PD SUM PY 2016 VL 26 IS 3 BP 275 EP 278 DI 10.18865/ed.26.3.275 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DS5DK UT WOS:000380800800004 PM 27440965 ER PT J AU Norris, KC Mensah, GA Boulware, LE Lu, JL Ma, JZ Streja, E Molnar, MZ Kalantar-Zadeh, K Kovesdy, CP AF Norris, Keith C. Mensah, George A. Boulware, L. Ebony Lu, Jun L. Ma, Jennie Z. Streja, Elani Molnar, Miklos Z. Kalantar-Zadeh, Kamyar Kovesdy, Csaba P. TI AGE, RACE AND CARDIOVASCULAR OUTCOMES IN AFRICAN AMERICAN VETERANS SO ETHNICITY & DISEASE LA English DT Article DE Race; African American; Age; Mortality; Coronary Heart Disease; Stroke; Incidence; Chronic Kidney Disease ID CHRONIC KIDNEY-DISEASE; US VETERANS; LARGE COHORT; DIALYSIS PATIENTS; APOL1 VARIANTS; ASSOCIATION; MORTALITY; HEALTH; DISPARITIES; SURVIVAL AB Background: In the general population, compared wtih their White peers, African Americans suffer premature all-cause and cardiovascular (CV) deaths, attributed in part to reduced access to care and lower socioeconomic status. Prior reports indicated younger (aged 35 to 44 years) African Americans had a signficantly greater age-adjusted risk of death. Recent studies suggest that in a more egalitarian health care structure than typical United States (US) health care structures, African Americans may have similar or even better CV outcomes, but the impact of age is less well-known. Methods: We examined age stratified all-cause mortality, and incident coronary heart disease (CHD) and ischemic stroke in 3,072,966 patients (547,441 African American and 2,525,525 White) with an estimated glomerular filtration rate (eGFR)>60 mL/min/1.73m(2) receiving care from the US Veterans Health Administration. Outcomes were examined in Cox models adjusted for demographics, comorbidities, kidney function, blood pressure, socioeconomics and indicators of the quality of health care delivery. Results: African Americans had an overall 30% lower all-cause mortality (P<.001) and 29% lower incidence of CHD (P<.001) and higher incidence of ischemic stroke (aHR, 95% CI: 1.16, 1.13-1.18, P<.001). The lower rates of mortality and CHD were strongest in younger African Americans and attenuated across patients aged >= 70 years. Stroke rates did not differ by race in persons aged < 70 years. Conclusions: Among patients with normal eGFR and receiving care in the Veterans Health Administration, younger African Americans had lower all-cause mortality and incidence of CHD and similar rates of stroke, independent of demographic, comorbidity and socioeconomic differences. The lower all-cause mortality persisted but attenuated with increasing age and the lower incidence of CHD ended at aged >= 80 years. The higher incidence of ischemic stroke in African Americans was driven by increasing risk in patients aged >= 70 years suggesting that the improved cardiovascular outcomes were most dramatic for younger African Americans. C1 [Norris, Keith C.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Mensah, George A.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Boulware, L. Ebony] Duke Univ, Dept Med, Durham, NC 27706 USA. [Lu, Jun L.; Molnar, Miklos Z.; Kovesdy, Csaba P.] Univ Tennessee, Heath Sci Ctr, Knoxville, TN 37996 USA. [Ma, Jennie Z.] Univ Virginia, Charlottesville, VA 22903 USA. [Streja, Elani; Kalantar-Zadeh, Kamyar] Univ Calif Irvine, Irvine, CA USA. [Kovesdy, Csaba P.] Memphis VA Med Ctr, Memphis, TN USA. RP Kovesdy, CP (reprint author), Memphis VA Med Ctr, Div Nephrol, 1030 Jefferson Ave, Memphis, TN 38104 USA. EM csaba.kovesdy@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development, VA Information Resource Center [SDR 02-237, 98-004]; National Institutes of Health [TR000124, MD000182, AG021684]; [R01DK096920] FX This study was supported by grant R01DK096920 to CPK and KKZ and is the result of work supported with resources and the use of facilities at the Memphis VA Medical Center and the Long Beach VA Medical Center. Support for VA/CMS data is provided by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development, VA Information Resource Center (Project Numbers SDR 02-237 and 98-004). Dr Norris is supported by National Institutes of Health grants TR000124, MD000182 and AG021684. NR 43 TC 1 Z9 1 U1 0 U2 0 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X EI 1945-0826 J9 ETHNIC DIS JI Ethn. Dis. PD SUM PY 2016 VL 26 IS 3 BP 305 EP 314 DI 10.18865/ed.26.3.305 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DS5DK UT WOS:000380800800008 PM 27440969 ER PT J AU Boyington, JEA Maihle, NJ Rice, TK Gonzalez, JE Hess, CA Makala, LH Jeffe, DB Ogedegbe, G Rao, DC Davila-Roman, VG Pace, BS Jean-Louis, G Boutjdir, M AF Boyington, Josephine E. A. Maihle, Nita J. Rice, Treva K. Gonzalez, Juan E. Hess, Caryl A. Makala, Levi H. Jeffe, Donna B. Ogedegbe, Gbenga Rao, Dabeeru C. Davila-Roman, Victor G. Pace, Betty S. Jean-Louis, Girardin Boutjdir, Mohamed TI A PERSPECTIVE ON PROMOTING DIVERSITY IN THE BIOMEDICAL RESEARCH WORKFORCE: THE NATIONAL HEART, LUNG, AND BLOOD INSTITUTE'S PRI DE PROGRAM SO ETHNICITY & DISEASE LA English DT Review DE Diversity; Workforce; Biomedical Research; NHLBI ID BLACK-AND-WHITE; RACIAL DISPARITIES; INCREASE DIVERSITY; HEALTH DISPARITIES; JUNIOR FACULTY; UNITED-STATES; DISEASE; RACE; ETHNICITY; SURVIVAL AB Aspiring junior investigators from groups underrepresented in the biomedical sciences face various challenges as they pursue research independence. However, the biomedical research enterprise needs their participation to effectively address critical research issues such as health disparities and health inequities. In this article, we share a research education and mentoring initiative that seeks to address this challenge: Programs to Increase Diversity among Individuals Engaged in Health Related Research (PRIDE), funded by the National Heart, Lung, and Blood Institute (NHLBI). This longitudinal research-education and mentoring program occurs through summer institute programs located at US-based academic institutions. Recruited participants are exposed to didactic and lab-based research-skill enhancement experiences, with year-round mentoring over the course of two years. Mentor-mentee matching is based on shared research interests to promote congruence and to enhance skill acquisition. Program descriptions and sample narratives of participants' perceptions of PRIDE's impact on their career progress are showcased. Additionally, we highlight the overall program design and structure of four of seven funded summer institutes that focus on cardiovascular disease, related conditions, and health disparities. Mentees' testimonials about the value of the PRIDE mentoring approach in facilitating career development are also noted. Meeting the clinical and research needs of an increasingly diverse US population is an issue of national concern. The PRIDE initiative, which focuses on increasing research preparedness and professional development of groups underrepresented in the biomedical research workforce, with an emphasis on mentoring as the critical approach, provides a robust model that is impacting the careers of future investigators. C1 [Boyington, Josephine E. A.] NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Maihle, Nita J.] Med Coll Georgia, Georgia Canc Ctr, Augusta, GA 30912 USA. [Rice, Treva K.; Rao, Dabeeru C.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Rice, Treva K.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Gonzalez, Juan E.] Univ Texas Dallas, Sch Nat Sci & Math, Richardson, TX 75083 USA. [Hess, Caryl A.] Augusta Univ, Off Leadership Dev, Augusta, GA USA. [Makala, Levi H.] Med Coll Georgia, Dept Med, Div Hematol & Oncol, Augusta, GA 30912 USA. [Jeffe, Donna B.; Davila-Roman, Victor G.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Ogedegbe, Gbenga; Jean-Louis, Girardin] NYU, Sch Med, Ctr Healthful Behav Change, Global Inst Publ Hlth, New York, NY 10003 USA. [Davila-Roman, Victor G.] Washington Univ, Sch Med, Dept Anesthesiol, St Louis, MO 63110 USA. [Davila-Roman, Victor G.] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. [Pace, Betty S.] Augusta Univ, Div Pediat Hematol Oncol, Augusta, GA USA. [Boutjdir, Mohamed] SUNY, Dept Med, Brooklyn, NY USA. RP Boyington, JEA (reprint author), NHLBI, Clin Applicat & Prevent Branch, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. EM Boyingtonje@mail.nih.gov OI Jean-Louis, Girardin/0000-0001-6777-2724 FU National Heart, Lung, and Blood Institute [R25HL-08-5042, R25HL-10-5446, R25HL-10-5444, R25HL-08-5070, R25HL-10-6365, R25HL-08-5040, R25HL-10-5400, R25-HL-10-5408] FX Funding support for the PRIDE summer institutes program staff was provided by the National Heart, Lung, and Blood Institute grants R25HL-08-5042 and R25HL-10-5446 (M Boutjdir, PI), R25HL-10-5444 (G Jean-Louis, G Ogedegbe, PIs), R25HL-08-5070 and R25HL-10-6365 (BS Pace, PI, NJ Maihle, L. Makala), R25HL-08-5040 and R25HL-10-5400 (DC Rao, PI and VG Davila-Roman PI), and R25-HL-10-5408 (TK Rice, PI). NR 38 TC 2 Z9 2 U1 1 U2 1 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X EI 1945-0826 J9 ETHNIC DIS JI Ethn. Dis. PD SUM PY 2016 VL 26 IS 3 BP 379 EP 386 DI 10.18865/ed.26.3.379 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DS5DK UT WOS:000380800800017 PM 27440978 ER PT J AU Lopez-Class, M Peprah, E Zhang, XZ Kaufmann, PG Engelgau, MM AF Lopez-Class, Maria Peprah, Emmanuel Zhang, Xinzhi Kaufmann, Peter G. Engelgau, Michael M. TI A STRATEGIC FRAMEWORK FOR UTILIZING LATE-STAGE (T4) TRANSLATION RESEARCH TO ADDRESS HEALTH INEQUITIES SO ETHNICITY & DISEASE LA English DT Review DE Framework; Health Inequities; Translation Research ID UNITED-STATES; HEART-DISEASE; ETHNIC DISPARITIES; CARE; EQUITY; STROKE; TRENDS; IMPLEMENTATION; DISSEMINATION; INTEGRATION AB Achieving health equity requires that every person has the opportunity to attain their full health potential and no one is disadvantaged from achieving this potential because of social position or other socially determined circumstances. Inequity experienced by populations of lower socioeconomic status is reflected in differences in health status and mortality rates, as well as in the distribution of disease, disability and illness across these population groups. This article gives an overview of the health inequities literature associated with heart, lung, blood and sleep (HLBS) disorders. We present an ecological framework that provides a theoretical foundation to study late-stage T4 translation research that studies implementation strategies for proven effective interventions to address health inequities. C1 [Lopez-Class, Maria; Peprah, Emmanuel; Engelgau, Michael M.] NIH, Ctr Translat Res & Implementat, Bethesda, MD USA. [Zhang, Xinzhi] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD USA. [Kaufmann, Peter G.] NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Lopez-Class, M (reprint author), Ctr Translat Res & Implementat, 6701 Rockledge Dr, Bethesda, MD 20817 USA. EM lope-zclassm@mail.nih.gov NR 49 TC 0 Z9 0 U1 1 U2 1 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X EI 1945-0826 J9 ETHNIC DIS JI Ethn. Dis. PD SUM PY 2016 VL 26 IS 3 BP 387 EP 394 DI 10.18865/ed.26.3.387 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DS5DK UT WOS:000380800800018 PM 27440979 ER PT J AU Peprah, E Lopez-Class, M Shero, S John-Sowah, J Engelgau, M AF Peprah, Emmanuel Lopez-Class, Maria Shero, Susan John-Sowah, Joylene Engelgau, Michael TI A GLOBAL PERSPECTIVE ON USING IMPLEMENTATION RESEARCH TO ADDRESS HYPERTENSION-ASSOCIATED TARGET ORGAN DAMAGE SO ETHNICITY & DISEASE LA English DT Review DE Hypertension; Target Organ Damage; Implementation Research; Global Health ID INCOME COUNTRIES; BLOOD-PRESSURE; INTERVENTION; PREVENTION; PREVALENCE; DISEASE; BURDEN; MIDDLE; TRIAL; SALT AB Hypertension, a major risk factor for cardiovascular disease, imposes a significant public health burden and challenge to address it worldwide. Scaling up delivery of proven, effective interventions for hypertension could significantly advance the goal of reducing the global burden. Although significant progress has been made in many countries, some lament that large-scale initiatives focused on reducing blood pressure in global populations have not effectively addressed this challenge. Late-stage implementation research plays a critical role in determining effective and sustainable scale-up of these initiatives. In this article, we briefly discuss some of the global initiatives that have been funded by the National Heart, Lung, and Blood Institute of the US National Institutes of Health. Intervention delivery strategies in low resource settings must have demonstrated effectiveness and consideration for the social, cultural and physical context (eg, access, affordability, and availability of medications) in which a program is being delivered in order to be sustainable nationally and globally. Hence, the use of implementation research is central to determining sustainable delivery of evidence-based and tailored interventions focused on hypertension control. The sustained control of hypertension in global populations holds tremendous potential for reducing morbidity, premature mortality, and the adverse economic impact of cardiovascular disease in all regions. C1 [Peprah, Emmanuel; Lopez-Class, Maria; Shero, Susan; John-Sowah, Joylene; Engelgau, Michael] NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Peprah, E (reprint author), Ctr Translat Res & Implementat Sci, One Rockledge Ctr,6705 Rockledge Dr,Suite 6070, Bethesda, MD 20892 USA.; Peprah, E (reprint author), NHLBI, NIH, One Rockledge Ctr,6705 Rockledge Dr,Suite 6070, Bethesda, MD 20892 USA. EM emmanuel.peprah@nih.gov NR 19 TC 0 Z9 0 U1 0 U2 0 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X EI 1945-0826 J9 ETHNIC DIS JI Ethn. Dis. PD SUM PY 2016 VL 26 IS 3 BP 395 EP 398 DI 10.18865/ed.26.3.395 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DS5DK UT WOS:000380800800019 PM 27440980 ER PT J AU White, WB Srinivasan, A Nelson, C Fahmy, N Henderson, F AF White, Wendy Brown Srinivasan, Asoka Nelson, Cheryl Fahmy, Nimr Henderson, Frances TI CAPACITY-BUILDING FOR CAREER PATHS IN PUBLIC HEALTH AND BIOMEDICAL RESEARCH FOR UNDERGRADUATE MINORITY STUDENTS: A JACKSON HEART STUDY SUCCESS MODEL SO ETHNICITY & DISEASE LA English DT Review DE Mentor; Cardiovascular Disease; Undergraduate; Training ID C-REACTIVE PROTEIN; AFRICAN-AMERICANS; RISK-FACTORS; CARDIOVASCULAR-DISEASE; NATRIURETIC PEPTIDE; SCIENCES AB Objective: This article chronicles the building of individual student capacity as well as faculty and institutional capacity, within the context of a population-based, longitudinal study of African Americans and cardiovascular disease. The purpose of this article is to present preliminary data documenting the results of this approach. Design: The JHS Scholars program is designed, under the organizational structure of the Natural Sciences Division at Tougaloo College, to provide solid preparation in quantitative skills through: good preparation in mathematics and the sciences; a high level of reading comprehension; hands-on learning experiences; and mentoring and counseling to sustain the motivation of the students to pursue further studies. Setting: This program is on the campus of a private Historically Black College in Mississippi. Participants: The participants in the program are undergraduate students. Main Outcome Measures: Data, which included information on major area of study, institution attended, degrees earned and position in the workforce, were analyzed using STATA 14. Results: Of 167 scholars, 46 are currently enrolled, while 118 have graduated. One half have completed graduate or professional programs, including; medicine, public health, pharmacy, nursing, and biomedical science; approximately one-fourth (25.4 %) are enrolled in graduate or professional programs; and nearly one tenth (9.3%) completed graduate degrees in law, education, business or English. Conclusions: These data could assist other institutions in understanding the career development process that helps under-represented minority students in higher education to make career choices on a path toward public health, health professions, biomedical research, and related careers. C1 [White, Wendy Brown; Srinivasan, Asoka; Fahmy, Nimr; Henderson, Frances] Tougaloo Coll, Div Nat Sci, Jackson Heart Study, 500 W Cty Line Rd, Tougaloo, MS 39174 USA. [Nelson, Cheryl] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP White, WB (reprint author), Tougaloo Coll, Div Nat Sci, Jackson Heart Study, 500 W Cty Line Rd, Tougaloo, MS 39174 USA. EM wwhite@tougaloo.msu.edu FU National Heart, Lung, and Blood Institute [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; National Institute on Minority Health and Health Disparities FX The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. The authors thank the students and support staff of the Jackson Heart Study Undergraduate Training and Education Center. NR 22 TC 1 Z9 1 U1 3 U2 4 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X EI 1945-0826 J9 ETHNIC DIS JI Ethn. Dis. PD SUM PY 2016 VL 26 IS 3 BP 399 EP 406 DI 10.18865/ed.26.3.399 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DS5DK UT WOS:000380800800020 PM 27440981 ER PT J AU Mensah, GA AF Mensah, George A. TI THE INAUGURAL ELIJAH B. SAUNDERS MEMORIAL LECTURE: THE GLOBAL CONSEQUENCES OF HYPERTENSION AND RELATED DISPARITIES SO ETHNICITY & DISEASE LA English DT Article DE Hypertension; Blood Pressure; Prevalence; Control Rate; Mortality; Disparities; Global; Low- and Middle-Income Countries ID UNITED-STATES; SYSTEMATIC ANALYSIS; EUROPEAN COUNTRIES; RISK-FACTORS; PREVALENCE; DISEASE; BURDEN; CANADA; EPIDEMIOLOGY; MORTALITY AB This inaugural memorial lecture provides an opportunity to celebrate the life of Elijah B. Saunders, MD, FACC and pays tribute to his pioneering spirit in the quest to advance health equity in the prevention and control of hypertension and cardiovascular diseases. It also enables an assessment of the state of the global burden of hypertension and related disparities. Despite the remarkable biomedical research progress made over the last half-century, hypertension remains the leading risk factor for global disease burden and the major preventable contributor to cardiovascular and all-cause mortality. Additionally, disparities in hypertension-related morbidity and mortality remain pervasive worldwide. National hypertension control rates showing progress often mask important suboptimal treatment and control in population groups defined by sex, race, ethnicity, geography, and social and environmental determinants. Within these groups, many hypertension-related disparities remain largely unchanged while other gaps have widened. In essence, current research has been relatively ineffective in guiding largescale, sustained elimination of hypertension-related disparities. An important explanation for these observations may be the significant advances made in observational epidemiological research, especially in improved surveillance and data collection that document the extent of disparities in marked contrast to the relative paucity of interventional disparities research. The paucity of these interventional research studies remains a continuing challenge. The time has come for renewed efforts in building strategic partnerships that leverage transdisciplinary, multi-sectoral expertise to provide global leadership in interventional implementation research for hypertension control and elimination of related disparities. Developing an appropriately skilled implementation research workforce will be crucial. The National Heart, Lung, and Blood Institute and its biomedical research funding partners remain committed to a strategic agenda of implementation research, training, and education for the prevention and control of hypertension and elimination of related disparities. C1 [Mensah, George A.] NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Mensah, GA (reprint author), Ctr Translat Res & Implementat Sci, Bldg 31,Room 5452,31 Ctr Dr MSC 2486, Bethesda, MD 20892 USA.; Mensah, GA (reprint author), Div Cardiovasc Sci, Bldg 31,Room 5452,31 Ctr Dr MSC 2486, Bethesda, MD 20892 USA. EM george.mensah@nih.gov OI Mensah, George/0000-0002-0387-5326 NR 32 TC 0 Z9 0 U1 5 U2 5 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X EI 1945-0826 J9 ETHNIC DIS JI Ethn. Dis. PD SUM PY 2016 VL 26 IS 3 BP 461 EP 468 DI 10.18865/ed.26.3.461 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DS5DK UT WOS:000380800800027 PM 27440988 ER PT J AU Wang, XQ Wei, YX Xiao, H Liu, XL Zhang, Y Han, GC Chen, GJ Hou, CM Ma, N Shen, BF Li, Y Egwuagu, CE Wang, RX AF Wang, Xiaoqian Wei, Yinxiang Xiao, He Liu, Xiaoling Zhang, Yu Han, Gencheng Chen, Guojiang Hou, Chunmei Ma, Ning Shen, Beifen Li, Yan Egwuagu, Charles E. Wang, Renxi TI A novel IL-23p19/Ebi3 (IL-39) cytokine mediates inflammation in Lupus-like mice SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Autoimmunity; IL-12; IL-23p19; IL-27/IL-35Ebi3; IL-39; Inflammation; Systemic lupus erythematosus ID IL-12 FAMILY CYTOKINES; REGULATORY B-CELLS; CD4(+) T-CELLS; AUTOIMMUNE INFLAMMATION; SLE PATHOGENESIS; DISEASE-ACTIVITY; ERYTHEMATOSUS; IL-23; INTERLEUKIN-23; EXPRESSION AB Interleukin-12 family cytokines have emerged as critical regulators of immunity with some members (IL-12, IL-23) associated with disease pathogenesis while others (IL-27, IL-35) mitigate autoimmune diseases. Each IL-12 family member is comprised of an alpha and a beta chain, and chain-sharing is a key feature. Although four bona fide members have thus far been described, promiscuous chain-pairing between alpha (IL-23p19, IL-27p28, IL-12/IL-35p35) and beta (IL-12/IL-23p40, IL-27/IL-35Ebi3) subunits, predicts six possible heterodimeric IL-12 family cytokines. Here, we describe a new IL-12member composed of IL-23p19 and Ebi3 heterodimer (IL-39) that is secreted by LPS-stimulated B cells and GL7(+) activated B cells of lupus-like mice. We further show that IL-39 mediates inflammatory responses through activation of STAT1/STAT3 in lupus-like mice. Taken together, our results show that IL-39 might contribute to immunopathogenic mechanisms of systemic lupus erythematosus, and could be used as a possible target for its treatment. C1 [Wang, Xiaoqian; Wei, Yinxiang; Xiao, He; Liu, Xiaoling; Zhang, Yu; Han, Gencheng; Chen, Guojiang; Hou, Chunmei; Shen, Beifen; Li, Yan; Wang, Renxi] Inst Basic Med Sci, Immunol Lab, POB 130 3,Taiping Rd 27, Beijing 100850, Peoples R China. [Egwuagu, Charles E.] NEI, Mol Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Wei, Yinxiang] Zhejiang Univ, Sch Med, Inst Immunol, Hangzhou, Zhejiang, Peoples R China. [Liu, Xiaoling] Chinese Peoples Liberat Army, Hosp 307, Dept Nephrol, Beijing, Peoples R China. [Zhang, Yu] Henan Univ, Coll Pharm, Kaifeng, Peoples R China. [Ma, Ning] Jilin Univ, Hosp 1, Dept Rheumatol, Changchun, Peoples R China. RP Wang, RX (reprint author), Inst Basic Med Sci, Immunol Lab, POB 130 3,Taiping Rd 27, Beijing 100850, Peoples R China.; Egwuagu, CE (reprint author), NEI, Mol Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. EM egwuaguc@nei.nih.gov; wang_renxi@yahoo.com FU National Basic Research Program 973 Grants [2013CB530506, 2015CB553704]; National Nature and Science Fund [81471529, 81401332, 81272320, 81471540, 81472647]; Beijing Natural Science Foundation [7141007]; Service Industry Scientific Research of National Health and Family Planning Commission of China [2015SQ00192]; Division of Intramural Research National Eye Institute, National Institutes of Health [EY000262-19, EY000372-14] FX This study was supported by National Basic Research Program 973 Grants (2013CB530506, 2015CB553704), National Nature and Science Fund (81471529, 81401332, 81272320, 81471540, and 81472647), the Key Program of the Beijing Natural Science Foundation (7141007), and Service Industry Scientific Research of National Health and Family Planning Commission of China (2015SQ00192). Charles E. Egwuagu was supported by the Division of Intramural Research National Eye Institute, National Institutes of Health (EY000262-19 & EY000372-14). NR 39 TC 5 Z9 5 U1 1 U2 1 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 JUN PY 2016 VL 46 IS 6 BP 1343 EP 1350 DI 10.1002/eji.201546095 PG 8 WC Immunology SC Immunology GA DS4LH UT WOS:000380752100006 PM 27019190 ER PT J AU Edwards, JP Hand, TW da Fonseca, DM Glass, DD Belkaid, Y Shevach, EM AF Edwards, Justin P. Hand, Timothy W. da Fonseca, Denise Morais Glass, Deborah D. Belkaid, Yasmine Shevach, Ethan M. TI The GARP/Latent TGF-beta 1 complex on Treg cells modulates the induction of peripherally derived Treg cells during oral tolerance SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Foxp3; GARP; TGF-beta; Tolerance; Treg cell ID REGULATORY T-CELLS; INFECTIOUS TRANSPLANTATION TOLERANCE; LATENT TGF-BETA; DENDRITIC CELLS; RETINOIC-ACID; CUTTING EDGE; EXPRESSION; DIFFERENTIATION; SUPPRESSION; GARP AB Treg cells can secrete latent TGF-beta 1 (LTGF-beta 1), but can also utilize an alternative pathway for transport and expression of LTGF-beta 1 on the cell surface in which LTGF-beta 1 is coupled to a distinct LTGF-beta binding protein termed glycoprotein A repetitions predominant (GARP)/LRRC32. The function of the GARP/LTGF-beta 1 complex has remained elusive. Here, we examine in vivo the roles of GARP and TGF-beta 1 in the induction of oral tolerance. When Foxp3(-) OT-II T cells were transferred to wild-type recipient mice followed by OVA feeding, the conversion of Foxp3(-) to Foxp3(+) OT-II cells was dependent on recipient Treg cells. Neutralization of IL-2 in the recipient mice also abrogated this conversion. The GARP/LTGF-beta 1 complex on recipient Treg cells, but not dendritic cell-derived TGF-beta 1, was required for efficient induction of Foxp3(+) T cells and for the suppression of delayed hypersensitivity. Expression of the integrin alpha v beta 8 by Treg cells (or T cells) in the recipients was dispensable for induction of Foxp3 expression. Transient depletion of the bacterial flora enhanced the development of oral tolerance by expanding Treg cells with enhanced expression of the GARP/LTGF-beta 1 complex. C1 [Edwards, Justin P.; Glass, Deborah D.; Shevach, Ethan M.] NIAID, Cellular Immunol Sect, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hand, Timothy W.; da Fonseca, Denise Morais; Belkaid, Yasmine] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, Cellular Immunol Sect, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ESHEVACH@niaid.nih.gov FU National Institutes of Health FX This work was supported by funds from the National Institutes of Health. The authors would like to thank Julie Edwards, Carol Henry, and Ke Weng from the NIAID Flow Cytometry Section for sorting their cells. J.P.E. designed and performed most experiments and prepared the manuscript; T.W.H, D.M.F., and Y.B. designed and performed the DTH experiments; D.D.G. assisted in performing several experiments; and E.M.S. supervised the studies and prepared the manuscript. NR 33 TC 1 Z9 1 U1 1 U2 1 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 JUN PY 2016 VL 46 IS 6 BP 1480 EP 1489 DI 10.1002/eji.201546204 PG 10 WC Immunology SC Immunology GA DS4LH UT WOS:000380752100019 PM 27062243 ER PT J AU Domingues, RG Lago-Baldaia, I Pereira-Castro, I Fachini, JM Oliveira, L Drpic, D Lopes, N Henriques, T Neilson, JR Carmo, AM Moreira, A AF Domingues, Rita G. Lago-Baldaia, Ines Pereira-Castro, Isabel Fachini, Joseph M. Oliveira, Liliana Drpic, Danica Lopes, Nair Henriques, Telmo Neilson, Joel R. Carmo, Alexandre M. Moreira, Alexandra TI CD5 expression is regulated during human T-cell activation by alternative polyadenylation, PTBP1, and miR-204 SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE CD5; Alternative polyadenylation; PTB/PTBP1; miR-204; T-lymphocyte activation ID PRE-MESSENGER-RNA; 3' UNTRANSLATED REGIONS; CANCER-CELLS; SIGNAL-TRANSDUCTION; PROTEIN; SELECTION; CLEAVAGE; MECHANISMS; EFFICIENCY; INHIBITION AB T lymphocytes stimulated through their antigen receptor (TCR) preferentially express mRNA isoforms with shorter 3' untranslated regions (3'-UTRs) derived from alternative pre-mRNA cleavage and polyadenylation (APA). However, the physiological relevance of APA programs remains poorly understood. CD5 is a T-cell surface glycoprotein that negatively regulates TCR signaling from the onset of T-cell activation. CD5 plays a pivotal role in mediating outcomes of cell survival or apoptosis, and may prevent both autoimmunity and cancer. In human primary T lymphocytes and Jurkat cells we found three distinct mRNA isoforms encoding CD5, each derived from distinct poly(A) signals (PASs). Upon T-cell activation, there is an overall increase in CD5 mRNAs with a specific increase in the relative expression of the shorter isoforms. 3'-UTRs derived from these shorter isoforms confer higher reporter expression in activated T cells relative to the longer isoform. We further show that polypyrimidine tract binding protein (PTB/PTBP1) directly binds to the proximal PAS and PTB siRNA depletion causes a decrease in mRNA derived from this PAS, suggesting an effect on stability or poly(A) site selection to circumvent targeting of the longer CD5 mRNA isoform by miR-204. These mechanisms fine-tune CD5 expression levels and thus ultimately T-cell responses. C1 [Domingues, Rita G.; Lago-Baldaia, Ines; Pereira-Castro, Isabel; Drpic, Danica; Lopes, Nair; Henriques, Telmo; Moreira, Alexandra] Univ Porto, Gene Regulat Grp, IBMC Inst Biol Mol & Celular, Rua Campo Alegre 823, P-4100 Oporto, Portugal. [Pereira-Castro, Isabel; Oliveira, Liliana; Drpic, Danica; Carmo, Alexandre M.; Moreira, Alexandra] Univ Porto, Inst Invest & Inovacao Saude, Rua Campo Alegre 823, P-4100 Oporto, Portugal. [Fachini, Joseph M.; Neilson, Joel R.] Baylor Coll Med, Dept Mol Physiol & Biophys, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Oliveira, Liliana; Carmo, Alexandre M.] Univ Porto, Cell Activat & Gene Express Grp, IBMC Inst Biol Mol & Celular, Rua Campo Alegre 823, P-4100 Oporto, Portugal. [Carmo, Alexandre M.; Moreira, Alexandra] Univ Porto, ICBAS Inst Ciencias Biomed Abel Salazar, Rua Campo Alegre 823, P-4100 Oporto, Portugal. [Domingues, Rita G.] Univ Lisbon, Fac Med, Inst Med Mol, Ave Prof Egas Moniz, P-1649028 Lisbon, Portugal. [Drpic, Danica] Univ Porto, Inst Biol Mol & Celular, Chromosome Instabil & Dynam Lab, Rua Campo Alegre 823, P-4100 Oporto, Portugal. [Henriques, Telmo] NIEHS, Lab Epigenet & Stem Cell Biol, POB 12233, Res Triangle Pk, NC 27709 USA. RP Moreira, A (reprint author), IBMC I3S, Gene Regulat Grp, Rua Alfredo Allen 208, P-4200135 Oporto, Portugal. EM alexandra.moreira@ibmc.up.pt RI Carmo, Alexandre/B-5191-2011; Pereira-Castro, Isabel/F-6487-2010 OI Carmo, Alexandre/0000-0002-2508-9799; Pereira-Castro, Isabel/0000-0003-4149-4310 FU FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operacional Programme for Competitiveness and Internationalisation (POCI) Portugal 2020; Portuguese funds through FCT - Fundacao para a Ciencia e a Tecnologia/Ministerio da Ciencia, Tecnologia e Inovacao in the framework of the project "Institute for Research and Innovation in Health Sciences" [POCI-01-0145-FEDER-007274]; Operational Competitiveness Programme - COMPETE [FCOMP-01-0124-FEDER-037277 (PEst-C/SAU/LA0002/2013), FCOMP-01-0124-FEDER-021201 (PTDC/SAU-GMG/116621/2010), FCOMP-01-0124-FEDER-028252 (PTDC/BEX-BCM/0468/2012)]; FCT [SFRH/BPD/107901/2015]; American-Portuguese Biomedical Research Fund; Nancy Chang Award for Research Excellence FX We thank Hospital Sao Joao, Servico de Imunohemoterapia for the buffy coats and Chris Smith, Simon Davis, Nicholas Proudfoot, Bin Tian, Elisa Izaurralde, Elisa Monzon-Casanova, Miguel Coelho and Margarida Gama-Carvalho for kindly providing reagents and helpful discussions. We are very grateful to Jaime Freitas for helping with model drawing, and all current and past members of the laboratories for helpful suggestions. This work was funded by FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operacional Programme for Competitiveness and Internationalisation (POCI) Portugal 2020, by Portuguese funds through FCT - Fundacao para a Ciencia e a Tecnologia/Ministerio da Ciencia, Tecnologia e Inovacao in the framework of the project "Institute for Research and Innovation in Health Sciences" (POCI-01-0145-FEDER-007274), and through the Operational Competitiveness Programme - COMPETE under projects FCOMP-01-0124-FEDER-037277 (PEst-C/SAU/LA0002/2013), FCOMP-01-0124-FEDER-021201 (PTDC/SAU-GMG/116621/2010) and FCOMP-01-0124-FEDER-028252 (PTDC/BEX-BCM/0468/2012). I.P.C. was funded by FCT through a post-doc fellowship with the reference SFRH/BPD/107901/2015. L.O. was partly funded by a fellowship from the American-Portuguese Biomedical Research Fund. J.M.F. was supported by the Nancy Chang Award for Research Excellence. NR 64 TC 1 Z9 1 U1 2 U2 3 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 JUN PY 2016 VL 46 IS 6 BP 1490 EP 1503 DI 10.1002/eji.201545663 PG 14 WC Immunology SC Immunology GA DS4LH UT WOS:000380752100020 PM 27005442 ER PT J AU Guardino, CM Schetter, CD Saxbe, DE Adam, EK Ramey, SL Shalowitz, MU AF Guardino, Christine M. Schetter, Christine Dunkel Saxbe, Darby E. Adam, Emma K. Ramey, Sharon Landesman Shalowitz, Madeleine U. CA Community Child Hlth Network TI Diurnal Salivary Cortisol Patterns Prior to Pregnancy Predict Infant Birth Weight SO HEALTH PSYCHOLOGY LA English DT Article DE pregnancy; cortisol; HPA axis; interpregnancy; birth ID CORTICOTROPIN-RELEASING HORMONE; MATERNAL CORTISOL; PSYCHOLOGICAL STRESS; PRECONCEPTION HEALTH; PSYCHOSOCIAL STRESS; PRENATAL EXPOSURE; UNITED-STATES; HPA AXIS; WOMEN; OUTCOMES AB Objective: Elevated maternal psychosocial stress during pregnancy and accompanying changes in stress hormones may contribute to risk of adverse birth outcomes such as low birth weight and preterm birth. Relatedly, research on fetal programming demonstrates intriguing associations between maternal stress processes during pregnancy and outcomes in offspring that extend into adulthood. The purpose of this study was to test whether hypothalamic-pituitary-adrenal (HPA) patterns in mothers during the period between 2 pregnancies (i.e., the interpregnancy interval) and during the subsequent pregnancy predict infant birth weight, a key birth outcome. Method: This study sampled salivary cortisol before and during pregnancy in a diverse community sample of 142 women enrolled in the Community Child Health Network study. Results: Using multilevel modeling, we found that flatter diurnal cortisol slopes in mothers during the interval between one birth and a subsequent pregnancy predicted lower infant birth weight of the subsequent child. This interpregnancy cortisol pattern in mothers also correlated with significantly shorter interpregnancy intervals, such that women with flatter cortisol slopes had more closely spaced pregnancies. After adding demographic covariates of household income, cohabitation with partner, and maternal race to the model, these results were unchanged. For participants who provided both interpregnancy and pregnancy cortisol data (n = 73), we found that interpregnancy cortisol slopes predicted infant birth weight independent of pregnancy cortisol slopes. Conclusions: These novel findings on interpregnancy HPA axis function and subsequent pregnancy outcomes strongly support life course health approaches and underscore the importance of maternal stress physiology between pregnancies. C1 [Guardino, Christine M.; Schetter, Christine Dunkel] Univ Calif Los Angeles, Dept Psychol, 1285A Franz Hall, Los Angeles, CA 90005 USA. [Saxbe, Darby E.] Univ Southern Calif, Dept Psychol, Los Angeles, CA USA. [Adam, Emma K.] Northwestern Univ, Sch Educ & Social Policy, Inst Policy Res, Evanston, IL 60208 USA. [Adam, Emma K.] Northwestern Univ, Cells Soc Ctr, Inst Policy Res, Evanston, IL 60208 USA. [Ramey, Sharon Landesman] Virginia Polytech Inst & State Univ, Virginia Tech, Caril Res Inst, Blacksburg, VA 24061 USA. [Shalowitz, Madeleine U.] NorthShore Univ Hlth Syst, Evanston, IL USA. [Shalowitz, Madeleine U.] Univ Chicago, Pritzker Sch Med, Dept Pediat, Chicago, IL 60637 USA. [Shalowitz, Madeleine U.] Eunice Kennedy Shriver Natl Inst Child & Hlth Dev, Community Child Hlth Network, Bethesda, MD USA. RP Guardino, CM (reprint author), Univ Calif Los Angeles, Dept Psychol, 1285A Franz Hall, Los Angeles, CA 90005 USA. EM crobbins@ucla.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U HD44207, U HD44219, U HD44226, U HD44245, HD44253, U HD54791, U HD54019, U HD44226-05S1, U HD44245-06S1, R03 HD59584]; National Institute for Nursing Research [U NR008929] FX This article is a product of the Child Community Health Research Network (CCHN). Accordingly, the last designated author is the network itself preceded by the names of those on the writing who directly prepared this article listed in the order the team judged best reflects their relative contributions. The CCHN was supported through cooperative agreements with the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U HD44207, U HD44219, U HD44226, U HD44245, HD44253, U HD54791, U HD54019, U HD44226-05S1, U HD44245-06S1, R03 HD59584) and the National Institute for Nursing Research (U NR008929). For more information on CCHN network sites, see https://www.nichd.nih.gov/research/supported/Pages/cchn.aspx. NR 65 TC 0 Z9 0 U1 5 U2 11 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 EI 1930-7810 J9 HEALTH PSYCHOL JI Health Psychol. PD JUN PY 2016 VL 35 IS 6 BP 625 EP 633 DI 10.1037/hea0000313 PG 9 WC Psychology, Clinical; Psychology SC Psychology GA DR9ZL UT WOS:000380254800011 PM 26844584 ER PT J AU Jin, XT Kruth, HS AF Jin, Xueting Kruth, Howard S. TI Culture of Macrophage Colony-stimulating Factor Differentiated Human Monocyte-derived Macrophages SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Immunology; Issue 112; Macrophage; cell culture; monocyte; macrophage colony-stimulating factor; granulocyte-macrophage colony-stimulating factor; differentiation; atherosclerosis ID CRYOPRESERVED HUMAN-MONOCYTES; DENSITY-LIPOPROTEIN UPTAKE; EXTRACELLULAR CHOLESTEROL; FUNCTIONAL-HETEROGENEITY; CSF; MICRODOMAINS; GENERATION AB A protocol is presented for cell culture of macrophage colony-stimulating factor (M-CSF) differentiated human monocyte-derived macrophages. For initiation of experiments, fresh or frozen monocytes are cultured in flasks for 1 week with M-CSF to induce their differentiation into macrophages. Then, the macrophages can be harvested and seeded into culture wells at required cell densities for carrying out experiments. The use of defined numbers of macrophages rather than defined numbers of monocytes to initiate macrophage cultures for experiments yields macrophage cultures in which the desired cell density can be more consistently attained. Use of cryopreserved monocytes reduces dependency on donor availability and produces more homogeneous macrophage cultures. C1 [Jin, Xueting; Kruth, Howard S.] NHLBI, Expt Atherosclerosis Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Kruth, HS (reprint author), NHLBI, Expt Atherosclerosis Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. EM kruthh@nhlbi.nih.gov FU Intramural Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health FX The Department of Transfusion Medicine, Clinical Center, National Institutes of Health, provided elutriated monocytes. This work was supported by the Intramural Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health. NR 22 TC 0 Z9 0 U1 1 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 JUN PY 2016 IS 112 AR e54244 DI 10.3791/54244 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS0CX UT WOS:000380264100089 ER PT J AU Peterson, SC Brownell, I Wong, SY AF Peterson, Shelby C. Brownell, Isaac Wong, Sunny Y. TI Cutaneous Surgical Denervation: A Method for Testing the Requirement for Nerves in Mouse Models of Skin Disease SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Medicine; Issue 112; Mouse models; skin; epidermis; hair follicle; touch dome; nerves; denervation; Cre recombinase; biopsy ID TOUCH DOME; IMPROVES ACANTHOSIS; HAIR FOLLICLE; STEM-CELLS; REGENERATION; INFLAMMATION; PSORIASIS; DEPENDENCE; DEFINES; FIBERS AB Cutaneous somatosensory nerves function to detect diverse stimuli that act upon the skin. In addition to their established sensory roles, recent studies have suggested that nerves may also modulate skin disorders including atopic dermatitis, psoriasis and cancer. Here, we describe protocols for testing the requirement for nerves in maintaining a cutaneous mechanosensory organ, the touch dome (TD). Specifically, we discuss methods for genetically labeling, harvesting and visualizing TDs by whole-mount staining, and for performing unilateral surgical denervation on mouse dorsal back skin. Together, these approaches can be used to directly compare TD morphology and gene expression in denervated as well as sham-operated skin from the same animal. These methods can also be readily adapted to examine the requirement for nerves in mouse models of skin pathology. Finally, the ability to repeatedly sample the skin provides an opportunity to monitor disease progression at different stages and times after initiation. C1 [Peterson, Shelby C.; Wong, Sunny Y.] Univ Michigan, Dermatol Cell & Dev Biol, Ann Arbor, MI 48109 USA. [Brownell, Isaac] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Wong, SY (reprint author), Univ Michigan, Dermatol Cell & Dev Biol, Ann Arbor, MI 48109 USA.; Brownell, I (reprint author), NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. EM isaac.brownell@nih.gov; sunnyw@umich.edu FU National Institute of Arthritis and Musculoskeletal and Skin Diseases [R00AR059796, R01AR065409]; University of Michigan Department of Dermatology; Biological Sciences Scholars Program; Center for Organogenesis; University of Michigan Comprehensive Cancer Center; John S. and Suzanne C. Munn Cancer Fund; National Institute of General Medical Sciences [T32 GM007315]; NIH Intramural Research Program, Center for Cancer Research, National Cancer Institute FX The authors would like to thank Autumn Peterson for assistance with mouse photography, Daniel Thoresen for assistance with mice, and Drs. Nicole Ward and Abdelmadjid Belkadi for assistance with surgical denervation. These studies were supported by funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grants R00AR059796 and R01AR065409); the University of Michigan Department of Dermatology; the Biological Sciences Scholars Program; the Center for Organogenesis; the University of Michigan Comprehensive Cancer Center; and the John S. and Suzanne C. Munn Cancer Fund. S.C.P. was supported by funding from the National Institute of General Medical Sciences (grant T32 GM007315). This work was also supported by the NIH Intramural Research Program, Center for Cancer Research, National Cancer Institute. NR 29 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 2016 IS 112 AR e54050 DI 10.3791/54050 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS0CX UT WOS:000380264100050 ER PT J AU Eder, AF AF Eder, Anne F. TI Knowns, unknowns, and perceptions in between SO TRANSFUSION LA English DT Editorial Material C1 [Eder, Anne F.] NIH, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Eder, AF (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM anne.eder@nih.gov NR 22 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD JUN PY 2016 VL 56 IS 6 SI SI BP 1491 EP 1495 DI 10.1111/trf.13668 PN 2 PG 5 WC Hematology SC Hematology GA DS1NC UT WOS:000380361600001 PM 27295023 ER PT J AU Custer, B Stramer, SL Glynn, S Williams, AE Anderson, SA AF Custer, Brian Stramer, Susan L. Glynn, Simone Williams, Alan E. Anderson, Steven A. TI Transfusion-transmissible infection monitoring system: a tool to monitor changes in blood safety SO TRANSFUSION LA English DT Editorial Material ID HIV; IMMUNODEFICIENCY; VIRUS C1 [Custer, Brian] UCSF, Blood Syst Res Inst, Epidemiol & Hlth Policy Res Lab Med, San Francisco, CA USA. [Stramer, Susan L.] Amer Red Cross, Sci Affairs, Gaithersburg, MD USA. [Glynn, Simone] NHLBI, Blood Epidemiol & Clin Therapeut Branch, Div Blood Dis & Resources, Bldg 10, Bethesda, MD 20892 USA. [Williams, Alan E.] US FDA, Off Blood Res & Review, CBER, Silver Spring, MD USA. [Anderson, Steven A.] US FDA, Off Biostat & Epidemiol, CBER, Silver Spring, MD USA. RP Custer, B (reprint author), UCSF, Blood Syst Res Inst, Epidemiol & Hlth Policy Res Lab Med, San Francisco, CA USA. EM bcuster@bloodsystems.org NR 13 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD JUN PY 2016 VL 56 IS 6 SI SI BP 1499 EP 1502 DI 10.1111/trf.13632 PN 2 PG 4 WC Hematology SC Hematology GA DS1NC UT WOS:000380361600003 PM 27295025 ER PT J AU Lowery-Gionta, E Wang, H Vendroscolo, L Thomas, L Morales, M Koob, GF AF Lowery-Gionta, E. Wang, H. Vendroscolo, L. Thomas, L. Morales, M. Koob, G. F. TI PROJECTIONS FROM THE CENTRAL NUCLEUS OF THE AMYGDALA AND THEIR ROLE IN ALCOHOL DEPENDENCE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Lowery-Gionta, E.; Wang, H.; Vendroscolo, L.; Thomas, L.; Morales, M.; Koob, G. F.] NIDA, Integrat Neurosci Branch, NIH, Baltimore, MD 21113 USA. RI koob, george/P-8791-2016 NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 051 BP 28A EP 28A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601051 ER PT J AU Spagnolo, PA Zhu, X Schwandt, M Kerich, M Yan, J Kwako, L Hillard, CJ Heilig, M Ramchandani, V AF Spagnolo, P. A. Zhu, X. Schwandt, M. Kerich, M. Yan, J. Kwako, L. Hillard, C. J. Heilig, M. Ramchandani, V. TI FAAH GENETIC VARIATION INCREASES FRONTO-AMYGDALA FUNCTION IN PATIENTS WITH POST-TRAUMATIC STRESS DISORDER AND COMORBID ALCOHOL DEPENDENCE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Spagnolo, P. A.; Zhu, X.; Schwandt, M.; Kerich, M.; Yan, J.; Kwako, L.; Hillard, C. J.; Heilig, M.; Ramchandani, V.] NIAAA, NIH, Bethesda, MD USA. RI Schwandt, Melanie/L-9866-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 103 BP 41A EP 41A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601103 ER PT J AU Goodyear, K Schwandt, ML Lee, MR Leggio, L AF Goodyear, K. Schwandt, M. L. Lee, M. R. Leggio, L. TI PRELIMINARY FINDINGS ON THE RELATIONSHIP BETWEEN METABOLIC FACTORS AND ALCOHOL DEPENDENCE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Goodyear, K.; Schwandt, M. L.; Lee, M. R.; Leggio, L.] NIDA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, NIAAA, Bethesda, MD 20892 USA. RI Leggio, Lorenzo/M-2972-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 132 BP 48A EP 48A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601132 ER PT J AU Saha, TD Grant, BF AF Saha, T. D. Grant, B. F. TI ASSOCIATION OF INTERNALIZING PSYCHOPATHOLOGY AND DSM-5 ALCOHOL USE DISORDER: RESULTS FROM THE NESARC III SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Saha, T. D.; Grant, B. F.] NIAAA, Div Intramural Clin & Biol Res, Lab Epidemiol & Biometry, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 134 BP 49A EP 49A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601134 ER PT J AU Priddy, BM Carmack, SA Thomas, LC Vendruscolo, JCM Koob, GF Vendruscolo, LF AF Priddy, B. M. Carmack, S. A. Thomas, L. C. Vendruscolo, J. C. M. Koob, G. F. Vendruscolo, L. F. TI SEX, STRAIN, AND HORMONAL INFLUENCES IN ALCOHOL DRINKING IN RATS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Priddy, B. M.; Carmack, S. A.; Thomas, L. C.; Vendruscolo, J. C. M.; Koob, G. F.; Vendruscolo, L. F.] NIDA, Neurobiol Addict Sect, NIH, Baltimore, MD 21224 USA. RI koob, george/P-8791-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 264 BP 81A EP 81A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601263 ER PT J AU Abrahao, KA Atwood, BK Lovinger, DM AF Abrahao, K. A. Atwood, B. K. Lovinger, D. M. TI SELF-INIATED OPERANT ETHANOL ADMINISTRATION IN C57BL/6J MICE IN THE ABSENCE OF TASTANT-FADING SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Abrahao, K. A.; Atwood, B. K.; Lovinger, D. M.] NIAAA, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 274 BP 84A EP 84A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601273 ER PT J AU Haass-Koffler, CL Giovenco, DE Lee, MR Swift, RM de la Monte, SM Zywiak, WH Kenna, GA Leggio, L AF Haass-Koffler, C. L. Giovenco, D. E. Lee, M. R. Swift, R. M. de la Monte, S. M. Zywiak, W. H. Kenna, G. A. Leggio, L. TI GHRELIN EFFECTS ON ENDOGENOUS SERUM INSULIN LEVELS IN ALCOHOL DEPENDENT INDIVIDUALS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Haass-Koffler, C. L.; Giovenco, D. E.; Lee, M. R.; Swift, R. M.; de la Monte, S. M.; Zywiak, W. H.; Kenna, G. A.; Leggio, L.] NIAA, Sect Clin Psychoneuroendocrinol Neuropsychopharma, NIDA, Bethesda, MD USA. [Haass-Koffler, C. L.; Giovenco, D. E.; Lee, M. R.; Swift, R. M.; de la Monte, S. M.; Zywiak, W. H.; Kenna, G. A.; Leggio, L.] Brown Univ, Ctr Alcohol Addict Studies Behav Social Sci, Providence, RI 02912 USA. RI Leggio, Lorenzo/M-2972-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 316 BP 94A EP 94A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601315 ER PT J AU Haass-Koffler, CL Giovenco, DE Zywiak, WH McGeary, JE Kenna, GA Leggio, L Swift, RM AF Haass-Koffler, C. L. Giovenco, D. E. Zywiak, W. H. McGeary, J. E. Kenna, G. A. Leggio, L. Swift, R. M. TI ROLE OF COMBINED TOPIRAMATE-ARIPIPRAZOLE ADMINISTRATION ON FREE-CHOICE ALCOHOL USE AND EXPLORATORY PHARMACOGENETICS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Haass-Koffler, C. L.; Giovenco, D. E.; Zywiak, W. H.; McGeary, J. E.; Kenna, G. A.; Leggio, L.; Swift, R. M.] NIAA, Sect Clin Psychoneuroendocrinol Neuropsychopharma, NIDA, Bethesda, MD USA. [Haass-Koffler, C. L.; Giovenco, D. E.; Zywiak, W. H.; McGeary, J. E.; Kenna, G. A.; Leggio, L.; Swift, R. M.] Brown Univ, Ctr Alcohol Addict Studies Behav Social Sci, Providence, RI 02912 USA. RI Leggio, Lorenzo/M-2972-2016 NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 320 BP 95A EP 95A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601319 ER PT J AU Bouhlal, S Temko, JE Farokhnia, M Lee, MR Leggio, L AF Bouhlal, S. Temko, J. E. Farokhnia, M. Lee, M. R. Leggio, L. TI THE ROLE OF THE GUT MICROBIOME IN PHENOTYPES ASSOCIATED WITH ALCOHOL AND OTHER ADDICTIVE DISORDERS: A SYSTEMATIC REVIEW SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Bouhlal, S.; Temko, J. E.; Farokhnia, M.; Lee, M. R.; Leggio, L.] NIDA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, NIAAA, Bethesda, MD 20892 USA. RI Leggio, Lorenzo/M-2972-2016 NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 345 BP 102A EP 102A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601344 ER PT J AU Brooks, AT Park, J Krumlauf, M Ramchandani, VA Wallen, GR AF Brooks, A. T. Park, J. Krumlauf, M. Ramchandani, V. A. Wallen, G. R. TI SLEEP DISTURBANCE IS NOT CREATED EQUAL: LATENT CLASS ANALYSIS IN INDIVIDUALS WHO ARE ALCOHOL DEPENDENT IN RECOVERY SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Brooks, A. T.; Park, J.; Krumlauf, M.; Ramchandani, V. A.; Wallen, G. R.] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 353 BP 104A EP 104A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601352 ER PT J AU Vaughan, CL Stangl, BL Sloan, ME Ramchandani, VA AF Vaughan, C. L. Stangl, B. L. Sloan, M. E. Ramchandani, V. A. TI THE RELATIONSHIP BETWEEN IMPULSIVITY AND CONTROL OVER DRINKING ON IV ALCOHOL SELF-ADMINISTRATION IN NON-DEPENDENT DRINKERS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Vaughan, C. L.; Stangl, B. L.; Sloan, M. E.; Ramchandani, V. A.] NIAAA, Sect Human Psychopharmacol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 396 BP 114A EP 114A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601394 ER PT J AU Haass-Koffler, CL Giovenco, DE Henry, AT Melkus, G Simms, JA Naemmuddin, N Nielsen, CK Schwandt, ML Lasek, AW Magill, M Momenam, R Hodgkinson, CA Bartlett, SE Swift, RM Bonci, A Leggio, L AF Haass-Koffler, C. L. Giovenco, D. E. Henry, A. T. Melkus, G. Simms, J. A. Naemmuddin, N. Nielsen, C. K. Schwandt, M. L. Lasek, A. W. Magill, M. Momenam, R. Hodgkinson, C. A. Bartlett, S. E. Swift, R. M. Bonci, A. Leggio, L. TI IN VITRO, IN VIVO AND HUMAN INVESTIGATION ON THE ROLE OF CORTICOTROPIN RELEASING FACTOR BINDING PROTEIN IN ALCOHOL CONSUMPTION SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Haass-Koffler, C. L.; Giovenco, D. E.; Henry, A. T.; Melkus, G.; Simms, J. A.; Naemmuddin, N.; Nielsen, C. K.; Schwandt, M. L.; Lasek, A. W.; Magill, M.; Momenam, R.; Hodgkinson, C. A.; Bartlett, S. E.; Swift, R. M.; Bonci, A.; Leggio, L.] NIDA, Sect Clin Psychoneuroendocrinol Neuropsychopharma, NIAA, Bethesda, MD 20892 USA. [Haass-Koffler, C. L.; Giovenco, D. E.; Henry, A. T.; Melkus, G.; Simms, J. A.; Naemmuddin, N.; Nielsen, C. K.; Schwandt, M. L.; Lasek, A. W.; Magill, M.; Momenam, R.; Hodgkinson, C. A.; Bartlett, S. E.; Swift, R. M.; Bonci, A.; Leggio, L.] Brown Univ, Ctr Alcohol Addict Studies Behav Social Sci, Providence, RI USA. RI Leggio, Lorenzo/M-2972-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 493 BP 139A EP 139A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601491 ER PT J AU Juczewski, K Lovinger, DM AF Juczewski, K. Lovinger, D. M. TI ETHANOL EFFECTS ON SYNAPTIC RESPONSES AND PLASTICITY IN THE DORSOMEDIAL STRIATUM SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Juczewski, K.; Lovinger, D. M.] NIAAA, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 519 BP 145A EP 145A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601517 ER PT J AU Johnson, KA Lovinger, DM AF Johnson, K. A. Lovinger, D. M. TI CHRONIC ALCOHOL EXPOSURE IMPAIRS METABOTROPIC GLUTAMATE RECEPTOR 2-MEDIATED LONG-TERM DEPRESSION OF EXCITATORY TRANSMISSION IN THE DORSAL STRIATUM SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Johnson, K. A.; Lovinger, D. M.] NIAAA, Div Intramural Clin & Biol Res, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 521 BP 146A EP 146A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601519 ER PT J AU Augier, E Damadzic, R Dulman, R Heilig, M AF Augier, E. Damadzic, R. Dulman, R. Heilig, M. TI THE GABAB POSITIVE ALLOSTERIC MODULATOR, ADX71441 DECREASES ALCOHOL SELF-ADMINISTRATION AND BLOCKS RELAPSE TO ALCOHOL SEEKING IN RATS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Augier, E.; Damadzic, R.; Dulman, R.; Heilig, M.] NIAAA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 527 BP 147A EP 147A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601525 ER PT J AU Tunstall, BJ Vendruscolo, JCM Lee, MR Koob, GF Vendruscolo, LF AF Tunstall, B. J. Vendruscolo, J. C. M. Lee, M. R. Koob, G. F. Vendruscolo, L. F. TI OXYTOCIN BLOCKS COMPULSIVE-LIKE ALCOHOL DRINKING IN RATS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Tunstall, B. J.; Vendruscolo, J. C. M.; Lee, M. R.; Koob, G. F.; Vendruscolo, L. F.] NIDA, NIH, Baltimore, MD 21224 USA. RI koob, george/P-8791-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 528 BP 147A EP 147A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601526 ER PT J AU N'Gouemo, P Cho, S Lovinger, DM AF N'Gouemo, P. Cho, S. Lovinger, D. M. TI PRENATAL ALCOHOL EXPOSURE INCREASES SUSCEPTIBILITY TO GENERALIZED TONIC-CLONIC SEIZURES IN DEVELOPING RATS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [N'Gouemo, P.; Cho, S.; Lovinger, D. M.] Georgetown Univ, Med Ctr, Pediat, Washington, DC 20057 USA. [N'Gouemo, P.; Cho, S.; Lovinger, D. M.] NIAAA, Lab Integrat Neurosci, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 556 BP 154A EP 154A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601554 ER PT J AU Schwandt, ML Cortes, CR Kwako, LE George, DT Momenan, R Sinha, R Leggio, L Heilig, M AF Schwandt, M. L. Cortes, C. R. Kwako, L. E. George, D. T. Momenan, R. Sinha, R. Leggio, L. Heilig, M. TI THE CORTICOTROPIN-RELEASING HORMONE RECEPTOR 1 (CRHR1) ANTAGONIST VERUCERFONT IN WOMEN WITH ANXIOUS ALCOHOL DEPENDENCE: A TRANSLATIONAL STUDY SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Schwandt, M. L.; Cortes, C. R.; Kwako, L. E.; George, D. T.; Momenan, R.; Sinha, R.; Leggio, L.; Heilig, M.] NIAAA, Bethesda, MD 20892 USA. RI Leggio, Lorenzo/M-2972-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 597 BP 165A EP 165A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601595 ER PT J AU Blau, LE Stangl, BL Kwako, LE Ramchandani, VA AF Blau, L. E. Stangl, B. L. Kwako, L. E. Ramchandani, V. A. TI THE RELATIONSHIP BETWEEN CHILDHOOD MALTREATMENT, IMPULSIVITY AND IMPAIRED CONTROL ON ALCOHOL USE IN NON-DEPENDENT DRINKERS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Blau, L. E.; Stangl, B. L.; Kwako, L. E.; Ramchandani, V. A.] NIAAA, Sect Human Psychopharmacol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 603 BP 166A EP 166A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601601 ER PT J AU Pava, MJ Lovinger, DM AF Pava, M. J. Lovinger, D. M. TI INSOMNIA AND SLEEP FRAGMENTATION DURING WITHDRAWAL IN ALCOHOL DEPENDENT MICE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Pava, M. J.; Lovinger, D. M.] NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, DICBR,NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 741 BP 201A EP 201A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601739 ER PT J AU Abrahao, KP Lovinger, DM AF Abrahao, K. P. Lovinger, D. M. TI ETHANOL-SENSITIVE PACEMAKER NEURONS IN THE MOUSE EXTERNAL GLOBUS PALLIDUS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Abrahao, K. P.; Lovinger, D. M.] NIAAA, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 745 BP 202A EP 202A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601743 ER PT J AU Ramirez, T Li, YM Yin, S Feng, D Xu, MJ Zang, MW Ding, WX Pacher, P Gao, B Wang, H AF Ramirez, T. Li, Y. M. Yin, S. Feng, D. Xu, M. J. Zang, M. W. Ding, W. X. Pacher, P. Gao, B. Wang, H. TI AGING AGGRAVATES ALCOHOLIC LIVER INJURY AND FIBROSIS IN MICE BY DOWN-REGULATING SIRT1 EXPRESSION IN HEPATOCYTE CELLS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Ramirez, T.; Li, Y. M.; Yin, S.; Feng, D.; Xu, M. J.; Zang, M. W.; Ding, W. X.; Pacher, P.; Gao, B.; Wang, H.] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 751 BP 203A EP 203A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601749 ER PT J AU Brietzke, S Grodin, EN Momenan, R AF Brietzke, S. Grodin, E. N. Momenan, R. TI NEURAL CORRELATES OF DELAYED REWARD DISCOUNTING AMONG ALCOHOL DEPENDENT SUBJECTS: AN FMRI STUDY SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Brietzke, S.; Grodin, E. N.; Momenan, R.] NIAAA, Sect Brain Electrophysiol & Imaging, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 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 JUN PY 2016 VL 40 SU 1 SI SI MA 806 BP 217A EP 217A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601804 ER PT J AU Shah, A Gowin, JL Vatsalya, V Schwandt, M Momenan, R Ramchandani, VA AF Shah, A. Gowin, J. L. Vatsalya, V. Schwandt, M. Momenan, R. Ramchandani, V. A. TI NEURAL RESPONSES TO REWARDING AND FEARFUL STIMULI INDEPENDENTLY PREDICT DRINKING OUTCOMES AND SELF-REPORTED EFFECTS OF ALCOHOL IN HEAVY DRINKERS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Shah, A.; Gowin, J. L.; Vatsalya, V.; Schwandt, M.; Momenan, R.; Ramchandani, V. A.] NIAAA, Sect Human Psychopharmacol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 807 BP 217A EP 217A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601805 ER PT J AU Sundby, K Zhu, X Mathur, K Grodin, E Momenan, R AF Sundby, K. Zhu, X. Mathur, K. Grodin, E. Momenan, R. TI NEURAL SUBSTRATES OF REWARD PREDICTION ERROR PROCESSING IN ALCOHOL DEPENDENCE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Sundby, K.; Zhu, X.; Mathur, K.; Grodin, E.; Momenan, R.] NIAAA, Brain Elect & Imaging, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 808 BP 217A EP 217A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601806 ER PT J AU Momenan, R Kwako, LE Zhu, X Voon, V Litten, RZ Koob, GF Goldman, D AF Momenan, R. Kwako, L. E. Zhu, X. Voon, V. Litten, R. Z. Koob, G. F. Goldman, D. TI ADDICTIONS NEUROCLINICAL ASSESSMENT: NEUROIMAGING FRAMEWORK SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Momenan, R.; Kwako, L. E.; Zhu, X.; Voon, V.; Litten, R. Z.; Koob, G. F.; Goldman, D.] NIAAA, Bethesda, MD 20892 USA. RI koob, george/P-8791-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 865 BP 232A EP 232A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601863 ER PT J AU Klitzner, M Thomas, S Schuler, J Hilton, M Mosher, J AF Klitzner, M. Thomas, S. Schuler, J. Hilton, M. Mosher, J. TI EXTENDING APIS - THE CANNABIS POLICY CLASSIFICATION SYSTEM: A TAXONOMY OF CANNABIS POLICY TOPICS FOR PUBLIC HEALTH RESEARCH SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Klitzner, M.; Thomas, S.; Schuler, J.; Hilton, M.; Mosher, J.] NIAAA, APIS, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 908 BP 242A EP 242A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814601905 ER PT J AU Song, BJ Choi, YS Abdelmegeed, MA Akbar, M AF Song, B. J. Choi, Y. S. Abdelmegeed, M. A. Akbar, M. TI PROTECTIVE MECHANISMS OF DIETARY WALNUTS OR POLYUNSATURATED FATTY ACIDS AGAINST ALCOHOLIC AND NONALCOHOLIC FATTY LIVER SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Song, B. J.; Choi, Y. S.; Abdelmegeed, M. A.; Akbar, M.] NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 003 BP 248A EP 248A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814602003 ER PT J AU Lovinger, DM AF Lovinger, D. M. TI ALCOHOL, HABIT FORMATION AND CORTICOSTRIATAL SYNAPTIC PLASTICITY SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Lovinger, D. M.] NIAAA, Lab Integrat Neurosci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 036 BP 256A EP 256A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814602036 ER PT J AU Zhou, Z Xu, MJ Cai, Y Wang, W Chang, B Gao, B AF Zhou, Z. Xu, M. J. Cai, Y. Wang, W. Chang, B. Gao, B. TI HEPATIC INFILTRATION OF NEUTROPHILS MEDIATES LIVER DAMAGE AND FIBROSIS IN A MOUSE MODEL OF HIGH-FAT-DIET-PLUS-BINGE ETHANOL FEEDING SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Zhou, Z.; Xu, M. J.; Cai, Y.; Wang, W.; Chang, B.; Gao, B.] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. RI Zhou, Zhou/R-7788-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 039 BP 257A EP 257A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814602039 ER PT J AU Gowin, JL Vatsalya, V Schwandt, ML Momenan, R Hommer, DW Bartlett, S Heilig, M Ramchandani, VA AF Gowin, J. L. Vatsalya, V. Schwandt, M. L. Momenan, R. Hommer, D. W. Bartlett, S. Heilig, M. Ramchandani, V. A. TI TOWARD THE DEVELOPMENT OF BIOMARKERS FOR EFFECTIVENESS OF MEDICATION USED TO TREAT ALCOHOL USE DISORDERS: AN FMRI STUDY OF VARENICLINE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Gowin, J. L.; Vatsalya, V.; Ramchandani, V. A.] NIAAA, Sect Human Psychopharmacol, Bethesda, MD USA. [Schwandt, M. L.; Momenan, R.; Hommer, D. W.] NIAAA, Bethesda, MD USA. [Bartlett, S.; Heilig, M.] Queensland Univ Technol, Translat Res Inst, Brisbane, Qld, Australia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 063 BP 263A EP 263A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814602063 ER PT J AU Grodin, EN Sundby, K Brennan, G Heilig, M Momenan, R AF Grodin, E. N. Sundby, K. Brennan, G. Heilig, M. Momenan, R. TI THE NEURAL CORRELATES OF AVERSION RESISTANT ALCOHOL ADDICTION SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Grodin, E. N.; Sundby, K.; Brennan, G.; Heilig, M.; Momenan, R.] NIAAA, Sect Brain Electrophysiol & Imaging, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 061 BP 263A EP 263A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814602061 ER PT J AU Hingson, RW Zha, W White, A AF Hingson, R. W. Zha, W. White, A. TI PREDICTORS, CONSEQUENCES, AND 10-YEAR CHANGES IN PREVALENCE OF BINGE, HEAVY BINGE, AND EXTREME BINGE DRINKING SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 NIAAA, Div Epidemiol & Prevent Res, 5635 Fishers Lane, Bethesda, MD 20892 USA. NIAAA, Off Director, 5635 Fishers Lane, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 101 BP 273A EP 273A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814602101 ER PT J AU White, A Hingson, R AF White, A. Hingson, R. TI BLACKOUTS AND ALCOHOL POISONING - BRAIN MECHANISMS, TRENDS AND IMPLICATIONS FOR PREVENTION SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [White, A.; Hingson, R.] NIAAA, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 102 BP 273A EP 273A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814602102 ER PT J AU Leggio, L AF Leggio, L. TI ROLE OF BACLOFEN IN THE TREATMENT OF ALCOHOL USE DISORDER: RECENT FINDINGS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Leggio, L.] NIAAA, CPN, Bethesda, MD 20892 USA. [Leggio, L.] NIDA, Bethesda, MD 20892 USA. RI Leggio, Lorenzo/M-2972-2016 NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 108 BP 275A EP 275A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814602108 ER PT J AU Salinas, AG Carlson, VCC Grant, KA Mateo, Y Lovinger, DM AF Salinas, A. G. Carlson, V. C. Cuzon Grant, K. A. Mateo, Y. Lovinger, D. M. TI DORSAL STRIATUM NEUROADAPTATIONS IN DOPAMINE SIGNALING ASSOCIATED WITH LONG-TERM ETHANOL EXPOSURE AND WITHDRAWAL SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Salinas, A. G.; Carlson, V. C. Cuzon; Grant, K. A.; Mateo, Y.; Lovinger, D. M.] NIAAA, Lab Integrat Neurosci, Div Clin & Biomed Res, NIH, Bethesday, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 161 BP 288A EP 288A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814602161 ER PT J AU Blair, RJR AF Blair, R. J. R. TI THE RELATIONSHIP BETWEEN ALCOHOL AND AGGRESSION FROM A COGNITIVE NEUROSCIENCE PERSPECTIVE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Blair, R. J. R.] NIMH, Sect Affect Cognit Neurosci, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 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 JUN PY 2016 VL 40 SU 1 SI SI MA 264 BP 314A EP 314A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814602264 ER PT J AU Stangl, BL Hendershot, CS Ramchandani, VA AF Stangl, B. L. Hendershot, C. S. Ramchandani, V. A. TI DETERMINANTS OF INTRAVENOUS SELF-ADMINISTRATION OF ALCOHOL IN HUMANS: IMPULSIVITY AND IMPAIRED CONTROL SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 39th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 25-29, 2016 CL New Orleans, LA SP Res Soc Alcoholism C1 [Stangl, B. L.; Hendershot, C. S.; Ramchandani, V. A.] NIAAA, NIH, Bethesda, MD 20892 USA. [Stangl, B. L.; Hendershot, C. S.; Ramchandani, V. A.] CAMH, Toronto, ON M6J 1H4, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2016 VL 40 SU 1 SI SI MA 266 BP 314A EP 314A PG 1 WC Substance Abuse SC Substance Abuse GA DR3PH UT WOS:000379814602266 ER PT J AU Doucet, ME Bloomhardt, HM Moroz, K Lindhurst, MJ Biesecker, LG AF Doucet, Meggie E. Bloomhardt, Hadley M. Moroz, Krzysztof Lindhurst, Marjorie J. Biesecker, Leslie G. TI Lack of Mutation-Histopathology Correlation in a Patient with Proteus Syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Proteus syndrome; AKT1 mutations; somatic mutation; histopathology ID MOSAICISM; SKIN; CHALLENGES; DIAGNOSIS; LESIONS AB Proteus syndrome (PS) is characterized by progressive, disproportionate, segmental overgrowth, and tumor susceptibility caused by a somatic mosaic AKT1 activating mutation. Each individual has unique manifestations making this disorder extremely heterogeneous. We correlated three variables in 38 tissue samples from a patient who died with PS: the gross affection status, the microscopic affection status, and the mutation level. The AKT1 mutation was measured using a PCR-based RFLP assay. Thirteen samples were grossly normal; six had detectable mutation (2-29%) although four of these six were histopathologically normal. Of the seven grossly normal samples that had no mutation, only four were histologically normal. The mutation level in the grossly abnormal samples was 3-35% and all but the right and left kidneys, skull, and left knee bone, with mutation levels of 19%, 15%, 26%, and 17%, respectively, had abnormal histopathology. The highest mutation level was in a toe bone sample whereas the lowest levels were in the soft tissue surrounding that toe, and an omental fat nodule. We also show here that PS overgrowth can be caused by cellular proliferation or by extracellular matrix expansion. Additionally, papillary thyroid carcinoma was identified, a tumor not previously associated with PS. We conclude that gross pathology and histopathology correlate poorly with mutation levels in PS, that overgrowth can be mediated by cellular proliferation or extracellular matrix expansion, and that papillary thyroid carcinoma is part of the tumor susceptibility of PS. New methods need to be developed to facilitate genotype-phenotype correlation in mosaic disorders. (C) 2016 Wiley Periodicals, Inc. C1 [Doucet, Meggie E.; Moroz, Krzysztof] Tulane Univ, Sch Med, Dept Pathol & Lab Med, 1430 Tulane Ave, New Orleans, LA 70112 USA. [Bloomhardt, Hadley M.; Lindhurst, Marjorie J.; Biesecker, Leslie G.] NHGRI, Med Genom & Metab Genet Branch, 49 Convent Dr Room 4A56, Bethesda, MD 20892 USA. [Bloomhardt, Hadley M.] Yale Sch Med, New Haven, CT USA. RP Biesecker, LG (reprint author), NHGRI, Med Genom & Metab Genet Branch, 49 Convent Dr Room 4A56, Bethesda, MD 20892 USA. EM lesb@mail.nih.gov FU National Human Genome Research Institute FX Grant sponsor: National Human Genome Research Institute. NR 13 TC 0 Z9 0 U1 2 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 JUN PY 2016 VL 170 IS 6 BP 1422 EP 1432 DI 10.1002/ajmg.a.37612 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA DR5ME UT WOS:000379946300005 PM 27112325 ER PT J AU Martin, S Wolters, PL Toledo-Tamula, MA Schmitt, SN Baldwin, A Starosta, A Gillespie, A Widemann, B AF Martin, Staci Wolters, Pamela L. Toledo-Tamula, Mary Anne Schmitt, Shawn Nelson Baldwin, Andrea Starosta, Amy Gillespie, Andrea Widemann, Brigitte TI Acceptance and Commitment Therapy in Youth with Neurofibromatosis Type 1 (NF1) and Chronic Pain and Their Parents: A Pilot Study of Feasibility and Preliminary Efficacy SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE acceptance; mindfulness; Neurofibromatosis 1; adolescents and young adults; parents ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; PHYSICAL-ACTIVITY; PEDIATRIC PAIN; MINDFULNESS; ADOLESCENTS; CANCER; CHILDREN; DISEASE; BRAIN AB Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder affecting about 1 in 3,500 individuals. Chronic pain is commonly reported among individuals with NF1 and plexiform neurofibroma tumors (PNs). Acceptance and Commitment Therapy (ACT), an empirically supported method for addressing chronic pain, helps individuals re-focus on valued relationships and activities. This pilot study investigated the feasibility and preliminary efficacy of a brief ACT workshop in the NF1 population. Eligible participants included adolescents and young adults (AYA; 12-21 years) with NF1 and chronic pain that interfered with daily functioning and their parents. Patients and parents completed baseline measures of pain interference, pain intensity, functional disability, pain acceptance, depression, and anxiety. Then, AYA and parents participated separately in a 2-day small-group ACT workshop. A telephone booster session occurred 1 month post-intervention. Three-month post-treatment measures were completed by mail. Ten adolescents (4 males; M age = 16.9 years) and seven parents provided baseline and 3-month data. Mean satisfaction with the study was moderate to high (3.9 for patients and 4.6 for parents on a 1-5 scales). Patients and parents reported significant declines in patients' pain interference at 3 months post-treatment. Patient-reported pain intensity significantly declined from baseline to 3 months. Parents reported marginally greater acceptance of their child's pain. No changes emerged in functional ability or mood. Preliminary findings suggest that a brief ACT group intervention is feasible and may help AYA with NF1 and PN scope with their chronic pain, although larger randomized studies are needed to confirm treatment efficacy. (C) 2016 Wiley Periodicals, Inc. C1 [Martin, Staci; Wolters, Pamela L.; Schmitt, Shawn Nelson; Baldwin, Andrea; Starosta, Amy; Gillespie, Andrea; Widemann, Brigitte] NCI, Pediat Oncol Branch, 9030 Old Georgetown Rd,107, Bethesda, MD 20892 USA. [Toledo-Tamula, Mary Anne] Leidos Biomedical Res Inc, Clin Res Directorate, CMRP, Natl Lab Canc Res, Frederick, MD USA. [Schmitt, Shawn Nelson] Uniformed Serv Univ Hlth Sci, Ettenhofer Lab Neurocognit Res, Bethesda, MD 20814 USA. [Starosta, Amy] SUNY Albany, Albany, NY 12222 USA. RP Martin, S (reprint author), NCI, Pediat Oncol Branch, 9030 Old Georgetown Rd,107, Bethesda, MD 20892 USA. EM martins@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute; NCI, NIH [HHSN261200800001E] FX The authors are thankful to the families who participated in this study. We also are grateful for the support of Katherine Burns, PhD and Ethan Eisen, MPhil, both of whom assisted with administering the intervention. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. In addition, this project was funded in part by the NCI, NIH, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 62 TC 4 Z9 4 U1 12 U2 16 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 JUN PY 2016 VL 170 IS 6 BP 1462 EP 1470 DI 10.1002/ajmg.a.37623 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA DR5ME UT WOS:000379946300010 PM 27021207 ER PT J AU Alter, BP Giri, N AF Alter, Blanche P. Giri, Neelam TI Thinking of VACTERL-H? Rule Out Fanconi Anemia According to PHENOS SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE VACTERL-H; fanconi anemia; VATER ID VATER ASSOCIATION; MUTATIONS; SPECTRUM AB VACTERL-H association includes three of eight features: vertebral anomalies, anal atresia, congenital heart disease, tracheo-esophageal fistula, esophageal atresia, renal, limb anomalies, and hydrocephalus. The VACTERL-H phenotype among cases with FA is considered to be about 5%; the frequency of FA among patients with VACTERL-H is unknown. We examined 54 patients with FA in the National Cancer Institute Inherited Bone Marrow Failure Syndrome Cohort for features of VACTERL-H, including imaging studies (radiology and ultrasound). Eighteen of the fifty-four patients had three or more VACTERL-H features. The presence of VACTERL-H association in 33% of those with FA is much higher than the previous estimate of 5% (P < 0.0001). We created the acronym PHENOS (Pigmentation, small Head, small Eyes, central Nervous system (not hydrocephalus), Otology, and Short stature) which includes all major phenotypic features of FA that are not in VACTERL-H; these findings were more frequent in the patients with FA who had VACTERL-H. Identification of any components of the VACTERL-H association should lead to imaging studies, and to consideration of the diagnosis of FA, particularly if the patient has radial ray and renal anomalies, as well as many features of PHENOS. There was no association of the presence or absence of VACTERL-H with development of cancer, stem cell transplant, or survival. Early diagnosis will lead to genetic counseling and early surveillance and management of complications of FA. (C) 2016 Wiley Periodicals, Inc. C1 [Alter, Blanche P.; Giri, Neelam] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E542,MSC 9772, Rockville, MD 20850 USA. RP Alter, BP (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E542,MSC 9772, Rockville, MD 20850 USA. EM alterb@mail.nih.gov FU Intramural Research Program; Westat [HHSN261201100018C] FX Grant sponsor: Intramural Research Program; Grant sponsor: Westat; Grant number: HHSN261201100018C. NR 14 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUN PY 2016 VL 170 IS 6 BP 1520 EP 1524 DI 10.1002/ajmg.a.37637 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA DR5ME UT WOS:000379946300017 PM 27028275 ER PT J AU Pipitone, A Raval, DB Duis, J Vernon, H Martin, R Hamosh, A Valle, D Gunay-Aygun, M AF Pipitone, Angela Raval, Donna B. Duis, Jessica Vernon, Hilary Martin, Regina Hamosh, Ada Valle, David Gunay-Aygun, Meral TI The Management of Pregnancy and Delivery in 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE 3-hydroxy-3-methylglutaric CoA lyase deficiency; HMG-CoA lyase deficiency; pregnancy ID SERIES AB 3-hydroxy-3-methylglutaric (HMG)-CoA lyase is required for ketogenesis and leucine degradation. Patients with HMG-CoA lyase deficiency typically present with hypoketotic hypoglycemia and metabolic acidosis, which can be fatal if untreated. The patient is a 28-year-old female with HMG-CoA lyase deficiency who presented at 4 weeks gestation for prenatal care. Protein intake as well as carnitine supplementation were gradually increased to support maternal and fetal demands up to 65 g per day for protein and 80 mg/kg/day for carnitine. Fetal growth was appropriate. At 36 5/7 weeks, she presented with spontaneous rupture of membranes. Twice maintenance 10% glucose-containing intravenous fluids were initiated. During labor, vomiting and metabolic acidosis developed. Delivery was by cesarean. Preeclampsia developed postpartum. The patient recovered well and was discharged home on postpartum day 5. Stress of pregnancy and labor and delivery can lead to metabolic decompensation in HMG-CoA lyase deficiency. Patients should be monitored closely by a biochemical geneticist, dietitian, and high-risk obstetrician at a tertiary care center during their pregnancy. Fasting should be avoided. Intravenous 10% glucose-containing fluids should be provided to prevent catabolism and metabolic decompensation during labor and delivery. (C) 2016 Wiley Periodicals, Inc. C1 [Pipitone, Angela; Duis, Jessica; Vernon, Hilary; Martin, Regina; Hamosh, Ada; Valle, David; Gunay-Aygun, Meral] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Raval, Donna B.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Raval, DB (reprint author), NHGRI, NIH, 9000 Rockville Pike,Bldg 10,3C-710, Bethesda, MD 20892 USA. EM donna.raval@nih.gov NR 3 TC 0 Z9 0 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 JUN PY 2016 VL 170 IS 6 BP 1600 EP 1602 DI 10.1002/ajmg.a.37620 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA DR5ME UT WOS:000379946300031 PM 26997609 ER PT J AU Guizzetti, M Davies, DL Egli, M Finn, DA Molina, P Regunathan, S Robinson, DL Sohrabji, F AF Guizzetti, Marina Davies, Daryl L. Egli, Mark Finn, Deborah A. Molina, Patricia Regunathan, Soundar Robinson, Donita L. Sohrabji, Farida TI Sex and the Lab: An Alcohol-Focused Commentary on the NIH Initiative to Balance Sex in Cell and Animal Studies SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Review DE Cell and Animal Studies; Ethanol; Gender; Policy; Preclinical Research ID SPRAGUE-DAWLEY RATS; NUCLEUS-ACCUMBENS; ESTROUS-CYCLE; ETHANOL-CONSUMPTION; C57BL/6 MICE; PROCEDURAL VARIABLES; GENDER-DIFFERENCES; VOLUNTARY ETHANOL; BINGE DRINKING; COMPLEX 1 AB In May 2014, Dr. Francis Collins, the director of U.S. National Institutes of Health (NIH), and Dr. Janine Clayton, the director of the U.S. National Institutes of Health Office of Research on Women's Health, published a commentary in the journal Nature announcing new policies to ensure that preclinical research funded by the NIH considers both males and females. While these policies are still developing, they have already generated great interest by the scientific community and triggered both criticism and applause. This review provides a description and interpretation of the NIH guidelines, and it traces the history that led to their implementation. As expected, this NIH initiative generated some anxiety in the scientific community. The use of female animals in the investigation of basic mechanisms is perceived to increase variability in the results, and the use of both sexes has been claimed to slow the pace of scientific discoveries and to increase the cost at a time characterized by declining research support. This review discusses issues related to the study of sex as a biological variable (SABV) in alcohol studies and provides examples of how researchers have successfully addressed some of them. A practical strategy is provided to include both sexes in biomedical research while maintaining control of the research direction. The inclusion of sex as an important biological variable in experimental design, analysis, and reporting of preclinical alcohol research is likely to lead to a better understanding of alcohol pharmacology and the development of alcohol use disorder, may promote drug discovery for new pharmacotherapies by increasing scientific rigor, and may provide clinical benefit to women's health. This review aims to promote the understanding of the NIH's SABV guidelines and to provide alcohol researchers with a theoretical and practical framework for working with both sexes in preclinical research. C1 [Guizzetti, Marina; Finn, Deborah A.] Oregon Hlth & Sci Univ, VA Portland Hlth Care Syst, Dept Behav Neurosci, Portland, OR 97201 USA. [Davies, Daryl L.] Univ Southern Calif, Dept Clin Pharm, Los Angeles, CA USA. [Egli, Mark; Regunathan, Soundar] NIAAA, Div Neurosci & Behav, NIH, Bethesda, MD USA. [Molina, Patricia] Louisiana State Univ, Dept Physiol, New Orleans, LA USA. [Molina, Patricia] Louisiana State Univ, Alcohol & Drug Abuse Ctr Excellence, New Orleans, LA USA. [Robinson, Donita L.] Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC USA. [Robinson, Donita L.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Sohrabji, Farida] Texas A&M, Dept Neurosci & Expt Therapeut, Bryan, TX USA. RP Guizzetti, M (reprint author), VA Portland Hlth Care Syst R&D39, 3710 SW Vet Hosp Rd, Portland, OR 97239 USA. EM guizzett@ohsu.edu RI Robinson, Donita/K-4416-2012; Davies, Daryl/P-1137-2016 OI Robinson, Donita/0000-0001-7540-3363; Davies, Daryl/0000-0003-2940-7739 FU Department of Veterans Affairs Merit Review Awards [BX001819, BX001070]; National Institutes of Health [R01AA021468, R21AA021876, R01AA022948, R01AA12439, P60AA011605, U24AA020024, P60 AA09803, R01 AA022448] FX This work was supported by Department of Veterans Affairs Merit Review Awards BX001819 (MG) and BX001070 (DAF) and by the National Institutes of Health R01AA021468 (MG), R21AA021876 (MG), R01AA022948 (MG), R01AA12439 (DAF), P60AA011605 (DLR), U24AA020024 (DLR), P60 AA09803 (PM), and R01 AA022448 (DLD). Additionally, this material is the result of work supported with resources and the use of facilities at the VA Portland Health Care System (MG and DAF). Contents do not necessarily represent the views of the U.S. Department of Veterans Affairs or of the United States Government. NR 68 TC 2 Z9 2 U1 3 U2 3 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 JUN PY 2016 VL 40 IS 6 BP 1182 EP 1191 DI 10.1111/acer.13072 PG 10 WC Substance Abuse SC Substance Abuse GA DR3OA UT WOS:000379811300003 PM 27154003 ER PT J AU Wang, SG Pacher, P De Lisle, RC Huang, HQ Ding, WX AF Wang, Shaogui Pacher, Pal De Lisle, Robert C. Huang, Heqing Ding, Wen-Xing TI A Mechanistic Review of Cell Death in Alcohol-Induced Liver Injury SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Review DE Alcohol; Apoptosis; Necroptosis; Autophagy; Liver Injury ID ENDOPLASMIC-RETICULUM STRESS; ACID ETHYL-ESTERS; MITOCHONDRIAL PERMEABILITY TRANSITION; ETHANOL ADMINISTRATION IMPAIRS; HEPATIC STELLATE CELLS; FACTOR-II RECEPTOR; PROTEIN-KINASE 3; RAT HEPATOCYTES; INDUCED APOPTOSIS; GROWTH-FACTOR AB Alcoholic liver disease (ALD) is a major health problem in the United States and worldwide without successful treatments. Chronic alcohol consumption can lead to ALD, which is characterized by steatosis, inflammation, fibrosis, cirrhosis, and even liver cancer. Recent studies suggest that alcohol induces both cell death and adaptive cell survival pathways in the liver, and the balance of cell death and cell survival ultimately decides the pathogenesis of ALD. This review summarizes the recent progress on the role and mechanisms of apoptosis, necroptosis, and autophagy in the pathogenesis of ALD. Understanding the complex regulation of apoptosis, necrosis, and autophagy may help to develop novel therapeutic strategies by targeting all 3 pathways simultaneously. C1 [Wang, Shaogui; Ding, Wen-Xing] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, MS 1018,3901 Rainbow Blvd, Kansas City, KS 66160 USA. [Wang, Shaogui; Huang, Heqing] Sun Yat Sen Univ, Lab Pharmacol & Toxicol, Sch Pharmaceut Sci, Guangzhou, Guangdong, Peoples R China. [Pacher, Pal] NIAAA, Lab Cardiovasc Physiol & Tissue Injury, NIH, Bethesda, MD USA. [De Lisle, Robert C.] Univ Kansas, Med Ctr, Dept Anat & Cell Biol, Kansas City, KS 66160 USA. RP Ding, WX (reprint author), Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, MS 1018,3901 Rainbow Blvd, Kansas City, KS 66160 USA. EM wxding@kumc.edu FU NIAAA [R01 AA020518, R01 DK102142]; National Center for Research Resources [P20RR021940]; National Institute of General Medical Sciences [P20 GM103549]; Cystic Fibrosis Foundation FX The research was supported in part by the NIAAA funds R01 AA020518, R01 DK102142, National Center for Research Resources P20RR021940, the National Institute of General Medical Sciences P20 GM103549, and the Cystic Fibrosis Foundation (RCD). All the authors have no conflict of interest to claim. NR 89 TC 2 Z9 2 U1 6 U2 11 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 JUN PY 2016 VL 40 IS 6 BP 1215 EP 1223 DI 10.1111/acer.13078 PG 9 WC Substance Abuse SC Substance Abuse GA DR3OA UT WOS:000379811300006 PM 27130888 ER PT J AU Decalf, J Tarbell, KV Casrouge, A Price, JD Linder, G Mottez, E Sultanik, P Mallet, V Pol, S Duffy, D Albert, ML AF Decalf, Jeremie Tarbell, Kristin V. Casrouge, Armanda Price, Jeffrey D. Linder, Grace Mottez, Estelle Sultanik, Philippe Mallet, Vincent Pol, Stanislas Duffy, Darragh Albert, Matthew L. TI Inhibition of DPP4 activity in humans establishes its invivo role in CXCL10 post-translational modification: prospective placebo-controlled clinical studies SO EMBO MOLECULAR MEDICINE LA English DT Article DE chemokines; clinical study; CXCL10; DPP4; post-translational modifications ID DIPEPTIDYL-PEPTIDASE-IV; CHEMOKINE ACTIVITY; HEPATITIS-C; LYMPHOCYTE; SITAGLIPTIN; CORRELATE; IMMUNITY; CXCR3; HCV AB Biochemical experiments, animal models, and observational studies in humans all support a role of dipeptidyl peptidase 4 (DPP4) in the N-terminal truncation of CXCL10, which results in the generation of an antagonist form of the chemokine that limits T-cell and NK cell migration. Motivated by the ability to regulate lymphocyte trafficking invivo, we conducted two prospective clinical trials to test the effects of DPP4 inhibition on CXCL10 processing in healthy donors and in chronic hepatitis C patients, a disease in which DPP4 levels are found to be elevated. Participants were treated daily with 100mg sitagliptin, a clinically approved DPP4 inhibitor. Plasma samples were analyzed using an ultrasensitive single-molecule assay (Simoa) to distinguish the full-length CXCL10(1-77) from the NH2-truncated CXCL10(3-77), as compared to the total CXCL10 levels. Sitagliptin treatment resulted in a significant decrease in CXCL10(3-77) concentration, a reciprocal increase in CXCL10(1-77), with only minimal effects on total levels of the chemokine. These data provide the first direct evidence that invivo DPP4 inhibition in humans can preserve the bioactive form of CXCL10, offering new therapeutic opportunities for DPP4 inhibitors. Synopsis The N-terminal truncation of CXCL10 by DPP4 results in the generation of an antagonist form of the chemokine that limits T-celland NK cell migration. This study shows for the first time that invivo DPP4 inhibition in humans can preserve the bioactive form of CXCL10. Sitagliptin, an FDA-approved DPP4 inhibitor for the treatment of type 2 diabetes, resulted in a decrease in the concentration of antagonist CXCL10 and a reciprocal increase in levels of the agonist form. Sitagliptin was effective in healthy subjects as well as in chronic HCV patients who have elevated levels of DPP4 and CXCL10. These results open new perspectives in the use of DPP4 inhibitors as therapeutic immune modulators. C1 [Decalf, Jeremie; Casrouge, Armanda; Duffy, Darragh; Albert, Matthew L.] Inst Pasteur, Lab Dendrit Cell Immunobiol, Paris, France. [Decalf, Jeremie; Casrouge, Armanda; Duffy, Darragh; Albert, Matthew L.] INSERM, U818, Paris, France. [Tarbell, Kristin V.; Price, Jeffrey D.; Linder, Grace] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Mottez, Estelle; Duffy, Darragh; Albert, Matthew L.] Inst Pasteur, Ctr Human Immunol, Paris, France. [Sultanik, Philippe; Mallet, Vincent; Pol, Stanislas] Univ Paris 05, Hop Cochin, AP HP, Dept Hepatol,INSERM,UMS20,Inst Pasteur, Paris, France. [Albert, Matthew L.] Genentech Inc, Dept Canc Immunotherapy, San Francisco, CA USA. RP Duffy, D; Albert, ML (reprint author), Inst Pasteur, Lab Dendrit Cell Immunobiol, Paris, France.; Duffy, D; Albert, ML (reprint author), INSERM, U818, Paris, France.; Duffy, D; Albert, ML (reprint author), Inst Pasteur, Ctr Human Immunol, Paris, France.; Albert, ML (reprint author), Genentech Inc, Dept Canc Immunotherapy, San Francisco, CA USA. EM darragh.duffy@pasteur.fr; albertm@pasteur.fr FU Agence nationale de recherches sur le sida et les hepatites virales (ANRS); Ligue nationale contre le cancer; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX This work was supported by the Agence nationale de recherches sur le sida et les hepatites virales (ANRS) and the Ligue nationale contre le cancer and by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). NR 20 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1757-4676 EI 1757-4684 J9 EMBO MOL MED JI EMBO Mol. Med. PD JUN PY 2016 VL 8 IS 6 BP 679 EP 683 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DR5SZ UT WOS:000379964000010 PM 27137491 ER PT J AU Psaila, B Barkas, N Iskander, D Roy, A Anderson, S Ashley, N Caputo, V Lichtenberg, J Loaiza, S Bodine, D Karadimitris, A Mead, A Irene, R AF Psaila, B. Barkas, N. Iskander, D. Roy, A. Anderson, S. Ashley, N. Caputo, V. Lichtenberg, J. Loaiza, S. Bodine, D. Karadimitris, A. Mead, A. Irene, R. TI SINGLE-CELL PROFILING OF HUMAN MEGAKARYOCYTE-ERYTHROID PROGENITORS IDENTIFIES DISTINCT MEGAKARYOCYTE AND ERYTHROID DIFFERENTIATION PATHWAYS SO HAEMATOLOGICA LA English DT Meeting Abstract CT 21st Congress of the European-Hematology-Association CY JUN 09-12, 2016 CL Copenhagen, DENMARK SP European Hematol Assoc C1 [Psaila, B.; Barkas, N.; Ashley, N.; Mead, A.; Irene, R.] Univ Oxford, Weatherall Inst Mol Med, MRC Mol Haematol Unit, Oxford, England. [Psaila, B.; Iskander, D.; Caputo, V.; Loaiza, S.; Karadimitris, A.; Irene, R.] Imperial Coll London, Dept Haematol, London, England. [Psaila, B.; Anderson, S.; Lichtenberg, J.; Bodine, D.] NHGRI, NIH, Bethesda, MD 20892 USA. [Roy, A.; Irene, R.] Univ Oxford, Weatherall Inst Mol Med, Dept Paediat, Oxford, England. NR 0 TC 0 Z9 0 U1 1 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD JUN PY 2016 VL 101 SU 1 MA S142 BP 21 EP 21 PG 1 WC Hematology SC Hematology GA DQ8TS UT WOS:000379484600044 ER PT J AU Tissino, E Caldana, C Benedetti, D Herman, SE ten Hacken, E Rossi, FM Dal Bo, M Bulian, P Bomben, R Zaja, F Chiarenza, A Sklar, LA Hartmann, TN Chigaev, A Burger, JA Del Poeta, G Wiestner, A Gattei, V Zucchetto, A AF Tissino, E. Caldana, C. Benedetti, D. Herman, S. E. ten Hacken, E. Rossi, F. M. Dal Bo, M. Bulian, P. Bomben, R. Zaja, F. Chiarenza, A. Sklar, L. A. Hartmann, T. N. Chigaev, A. Burger, J. A. Del Poeta, G. Wiestner, A. Gattei, V. Zucchetto, A. TI CD49D EXPRESSION IMPACTS ON THE IBRUTINIB-INDUCED LYMPHOCYTOSIS IN CHRONIC LYMPHOCYTIC LEUKEMIA: A ROLE OF BCR-MEDIATED INSIDE-OUT VLA-4 INTEGRIN ACTIVATION SO HAEMATOLOGICA LA English DT Meeting Abstract CT 21st Congress of the European-Hematology-Association CY JUN 09-12, 2016 CL Copenhagen, DENMARK SP European Hematol Assoc C1 [Tissino, E.; Caldana, C.; Benedetti, D.; Rossi, F. M.; Dal Bo, M.; Bulian, P.; Bomben, R.; Gattei, V.; Zucchetto, A.] Ctr Riferimento Oncol, Clin & Expt Oncohematol, Aviano, Italy. [Herman, S. E.; Wiestner, A.] NHLBI, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [ten Hacken, E.; Burger, J. A.] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Zaja, F.] Azienda Osped Univ S Maria Misericordia, Ctr Trapianti & Terapie Cellulari Carlo Melzi DIS, Clin Ematol, Udine, Italy. [Chiarenza, A.] Ferrarotto Hosp, Div Hematol, Catania, Italy. [Sklar, L. A.; Chigaev, A.] Univ New Mexico, Dept Pathol, Albuquerque, NM 87131 USA. [Sklar, L. A.; Chigaev, A.] Univ New Mexico, Ctr Canc, Albuquerque, NM 87131 USA. [Hartmann, T. N.] Paracelsus Med Univ Salzburg, Dept Hematol Med Oncol Hemostaseol Infect Dis & R, Ctr Oncol, Salzburg, Austria. [Del Poeta, G.] S Eugenio Hosp, Div Hematol, Rome, Italy. [Del Poeta, G.] Univ Tor Vergata, Rome, Italy. RI Chigaev, Alexandre/A-3103-2010 OI Chigaev, Alexandre/0000-0002-7726-638X NR 0 TC 0 Z9 0 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 JUN PY 2016 VL 101 SU 1 MA P206 BP 49 EP 50 PG 2 WC Hematology SC Hematology GA DQ8TS UT WOS:000379484600109 ER PT J AU Rognvaldsson, S Lund, SH Hultcrantz, M Eiriksdottir, G Harris, TB Gudnason, V Kristinsson, SY AF Rognvaldsson, S. Lund, S. H. Hultcrantz, M. Eiriksdottir, G. Harris, T. B. Gudnason, V. Kristinsson, S. Y. TI HIGH HEMOGLOBIN CONCENTRATIONS AND RISK OF THROMBOSIS: CAUSALITY OR CONFOUNDING? SO HAEMATOLOGICA LA English DT Meeting Abstract CT 21st Congress of the European-Hematology-Association CY JUN 09-12, 2016 CL Copenhagen, DENMARK SP European Hematol Assoc C1 [Rognvaldsson, S.; Lund, S. H.; Kristinsson, S. Y.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Hultcrantz, M.; Kristinsson, S. Y.] Karolinska Inst, Dept Hematol, Uppsala, Sweden. [Hultcrantz, M.] Mem Sloan Kettering Canc Ctr, Dept Med, Myeloma Serv, 1275 York Ave, New York, NY 10021 USA. [Eiriksdottir, G.; Gudnason, V.] Iceland Heart Assoc, Kopavogur, Iceland. [Harris, T. B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Kristinsson, S. Y.] Landspitali Univ Hosp, Dept Hematol, Reykjavik, Iceland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD JUN PY 2016 VL 101 SU 1 MA P412 BP 141 EP 142 PG 2 WC Hematology SC Hematology GA DQ8TS UT WOS:000379484600317 ER PT J AU Beekman, R Queiros, AC Vilarrasa-Blasi, R Merkel, A Raineri, E Castellano, G Bea, S Navarro, A Russinol, N Clot, G Kulis, M Duran-Ferrer, M Jares, P Enjuanes, A Calasanz, MJ Bergmann, A Vater, I Salaverria, I van Werken, HJG Wilson, WH Datta, A Flicek, P Martens, J Gine, E Lopez-Guillermo, A Stunnenberg, HG Klapper, W Pott, C Heath, S Gut, IG Siebert, R Campo, E Martin-Subero, JI AF Beekman, R. Queiros, A. C. Vilarrasa-Blasi, R. Merkel, A. Raineri, E. Castellano, G. Bea, S. Navarro, A. Russinol, N. Clot, G. Kulis, M. Duran-Ferrer, M. Jares, P. Enjuanes, A. Calasanz, M. J. Bergmann, A. Vater, I. Salaverria, I. van Werken, H. J. G. Wilson, W. H. Datta, A. Flicek, P. Martens, J. Gine, E. Lopez-Guillermo, A. Stunnenberg, H. G. Klapper, W. Pott, C. Heath, S. Gut, I. G. Siebert, R. Campo, E. Martin-Subero, J. I. TI DECODING THE ENTIRE DNA METHYLOME OF MANTLE CELL LYMPHOMA: NEW BIOLOGICAL AND CLINICAL INSIGHTS SO HAEMATOLOGICA LA English DT Meeting Abstract CT 21st Congress of the European-Hematology-Association CY JUN 09-12, 2016 CL Copenhagen, DENMARK SP European Hematol Assoc C1 [Beekman, R.; Castellano, G.; Bea, S.; Navarro, A.; Russinol, N.; Clot, G.; Jares, P.; Enjuanes, A.; Salaverria, I.] IDIBAPS, Barcelona, Spain. [Queiros, A. C.; Vilarrasa-Blasi, R.; Kulis, M.; Duran-Ferrer, M.; Martin-Subero, J. I.] Univ Barcelona, Dept Anat Patol, Barcelona, Spain. [Merkel, A.; Raineri, E.; Heath, S.; Gut, I. G.] Ctr Nacl Anal Genom, Barcelona, Spain. [Calasanz, M. J.] Univ Navarra, Dept Genet, Pamplona, Spain. [Bergmann, A.; Vater, I.; Klapper, W.; Siebert, R.] Univ Kiel, Kiel, Germany. [van Werken, H. J. G.] Erasmus MC, Rotterdam, Netherlands. [Wilson, W. H.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Datta, A.; Flicek, P.] European Bioinformat Inst EMBL EBI, Hinxton, England. [Martens, J.; Stunnenberg, H. G.] Radboud Univ Nijmegen, Nijmegen, Netherlands. [Gine, E.; Lopez-Guillermo, A.; Campo, E.] Hosp Clin Barcelona, Barcelona, Spain. [Pott, C.] Univ Hosp Schleswig Holstein, Kiel, Germany. RI Calasanz, MJ/R-5813-2016 OI Calasanz, MJ/0000-0002-0374-3008 NR 0 TC 0 Z9 0 U1 3 U2 9 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD JUN PY 2016 VL 101 SU 1 MA S488 BP 179 EP 179 PG 1 WC Hematology SC Hematology GA DQ8TS UT WOS:000379484600394 ER PT J AU Shirasugi, Y Sugimori, C Noji, H Shichishima, T Obara, N Chiba, S Ninomiya, H Nakamura, Y Ando, K Yonemura, Y Kawaguchi, T Hosokawa, K Ueda, Y Nishimura, J Kanakura, Y Nakao, S AF Shirasugi, Y. Sugimori, C. Noji, H. Shichishima, T. Obara, N. Chiba, S. Ninomiya, H. Nakamura, Y. Ando, K. Yonemura, Y. Kawaguchi, T. Hosokawa, K. Ueda, Y. Nishimura, Ji Kanakura, Y. Nakao, S. TI A CLINICAL SIGNIFICANCE AND TIME-DEPENDENT CHANGE OF PNH CLONE SIZE IN PATIENTS WITH BONE BARROW FAILURE SYNDROME: JAPANESE MULTI-CENTRE PROSPECTIVE STUDY SO HAEMATOLOGICA LA English DT Meeting Abstract CT 21st Congress of the European-Hematology-Association CY JUN 09-12, 2016 CL Copenhagen, DENMARK SP European Hematol Assoc C1 [Shirasugi, Y.; Nakamura, Y.; Ando, K.] Tokai Univ, Hematol & Oncol, Sch Med, Isehara, Kanagawa, Japan. [Shirasugi, Y.; Sugimori, C.; Noji, H.; Shichishima, T.; Obara, N.; Chiba, S.; Ninomiya, H.; Nakamura, Y.; Ando, K.; Yonemura, Y.; Kawaguchi, T.; Hosokawa, K.; Ueda, Y.; Nishimura, Ji; Kanakura, Y.; Nakao, S.] Japan PNH Study Grp, Tokyo, Japan. [Sugimori, C.] Ishikawa Prefectural Cent Hosp, Hematol, Kanazawa, Ishikawa, Japan. [Noji, H.; Shichishima, T.] Fukushima Med Univ, Cardiol & Hematol, Fukushima, Japan. [Shichishima, T.] Fukushima Res Inst Environm & Med, Fukushima, Japan. [Obara, N.; Chiba, S.] Univ Tsukuba, Hematol, Tsukuba, Ibaraki, Japan. [Ninomiya, H.] Univ Tsukuba, Med Sci, Tsukuba, Ibaraki, Japan. [Yonemura, Y.] Kumamoto Univ Hosp, Transfus Med & Cell Therapy, Kumamoto, Japan. [Kawaguchi, T.] Kumamoto Univ, Grad Sch Med Sci, Kumamoto, Japan. [Hosokawa, K.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Ueda, Y.; Nishimura, Ji; Kanakura, Y.] Osaka Univ, Grad Sch Med, Hematol & Oncol, Suita, Osaka, Japan. [Nakao, S.] Kanazawa Univ, Grad Sch Med Sci, Cellular Transplantat Biol, Kanazawa, Ishikawa, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD JUN PY 2016 VL 101 SU 1 MA P634 BP 248 EP 249 PG 2 WC Hematology SC Hematology GA DQ8TS UT WOS:000379484600542 ER PT J AU Kochenderfer, JN Somerville, RP Lu, T Shi, V Yang, JC Sherry, RM Klebanoff, CA Kamula, US Goff, SL Bot, A Rossi, J Sherman, M Perez, A Xue, A Feldman, T Friedberg, JW Roschewski, MJ Feldman, S McIntyre, L Toomey, MA Rosenberg, SA AF Kochenderfer, J. N. Somerville, R. P. Lu, T. Shi, V. Yang, J. C. Sherry, R. M. Klebanoff, C. A. Kamula, U. S. Goff, S. L. Bot, A. Rossi, J. Sherman, M. Perez, A. Xue, A. Feldman, T. Friedberg, J. W. Roschewski, M. J. Feldman, S. McIntyre, L. Toomey, M. A. Rosenberg, S. A. TI LOW-DOSE CHEMOTHERAPY FOLLOWED BY ANTI-CD19 CHIMERIC ANTIGEN RECEPTOR (CAR) T CELLS INDUCES REMISSIONS IN PATIENTS WITH ADVANCED LYMPHOMA SO HAEMATOLOGICA LA English DT Meeting Abstract CT 21st Congress of the European-Hematology-Association CY JUN 09-12, 2016 CL Copenhagen, DENMARK SP European Hematol Assoc C1 [Kochenderfer, J. N.; Shi, V.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Somerville, R. P.; Lu, T.; Yang, J. C.; Sherry, R. M.; Klebanoff, C. A.; Kamula, U. S.; Goff, S. L.; Feldman, S.; McIntyre, L.; Toomey, M. A.; Rosenberg, S. A.] NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Bot, A.; Rossi, J.; Sherman, M.; Perez, A.; Xue, A.] Kite Pharma Inc, Santa Monica, CA USA. [Feldman, T.] Hackensack Univ, Med Ctr, John Theurer Canc Ctr, Lyphoma Div, Hackensack, NJ USA. [Friedberg, J. W.] Univ Rochester, Sch Med, Rochester, NY 14627 USA. [Roschewski, M. J.] NCI, Lymphoid Malignancy Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD JUN PY 2016 VL 101 SU 1 MA S792 BP 318 EP 318 PG 1 WC Hematology SC Hematology GA DQ8TS UT WOS:000379484601154 ER PT J AU Ferrari, A Cimino, L Ilariucci, F Fama, A Alvarez, I Ruffini, A Chan, CC Luminari, S Merli, F AF Ferrari, A. Cimino, L. Ilariucci, F. Fama, A. Alvarez, I. Ruffini, A. Chan, C. C. Luminari, S. Merli, F. TI VITREORETINAL LYMPHOMA: A DESCRIPTIVE STUDY OF A VERY RARE OCCURRENCE FROM A SINGLE INSTITUTION IN ITALY SO HAEMATOLOGICA LA English DT Meeting Abstract CT 21st Congress of the European-Hematology-Association CY JUN 09-12, 2016 CL Copenhagen, DENMARK SP European Hematol Assoc C1 [Ferrari, A.; Ilariucci, F.; Fama, A.; Alvarez, I.; Ruffini, A.; Luminari, S.; Merli, F.] Arcispedale Santa Maria Nuova IRCCS, Dipartimento Oncol & Tecnol Avanzate, Ematol, Reggio Emilia, Italy. [Cimino, L.] Arcispedale Santa Maria Nuova IRCCS, Oculist Chirurg Gen & Specialist, Reggio Emilia, Italy. [Chan, C. C.] NEI, Sect Immunopathol, Immunol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD JUN PY 2016 VL 101 SU 1 MA E985 BP 404 EP 404 PG 1 WC Hematology SC Hematology GA DQ8TS UT WOS:000379484601357 ER PT J AU Thorsteinsdottir, S Lund, SH Lindqvist, E Sigurdsson, G Costello, R Burton, D Steingrimsdottir, H Launer, LJ Gudnason, V Eiriksdottir, G Siggeirsdottir, K Harris, TB Landgren, O Kristinsson, SY AF Thorsteinsdottir, S. Lund, S. H. Lindqvist, E. Sigurdsson, G. Costello, R. Burton, D. Steingrimsdottir, H. Launer, L. J. Gudnason, V. Eiriksdottir, G. Siggeirsdottir, K. Harris, T. B. Landgren, O. Kristinsson, S. Y. TI BONE DISEASE IN MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE: RESULTS FROM A SCREENED POPULATION-BASED STUDY SO HAEMATOLOGICA LA English DT Meeting Abstract CT 21st Congress of the European-Hematology-Association CY JUN 09-12, 2016 CL Copenhagen, DENMARK SP European Hematol Assoc C1 [Thorsteinsdottir, S.; Steingrimsdottir, H.; Kristinsson, S. Y.] Landspitali, Dept Internal Med, Reykjavik, Iceland. [Thorsteinsdottir, S.; Lund, S. H.; Gudnason, V.; Kristinsson, S. Y.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Lindqvist, E.] Karolinska Univ Hosp, Div Hematol, Dept Med, Stockholm, Sweden. [Lindqvist, E.] Karolinska Inst, Stockholm, Sweden. [Sigurdsson, G.; Gudnason, V.; Eiriksdottir, G.; Siggeirsdottir, K.] Iceland Heart Assoc, Kopavogur, Iceland. [Costello, R.; Burton, D.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Launer, L. J.; Harris, T. B.] NIA, NIH, Bethesda, MD 20892 USA. [Landgren, O.] Mem Sloan Kettering Canc Ctr, Div Hematol Oncol, Myeloma Serv, 1275 York Ave, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD JUN PY 2016 VL 101 SU 1 MA E1258 BP 518 EP 519 PG 2 WC Hematology SC Hematology GA DQ8TS UT WOS:000379484602047 ER PT J AU Thordardottir, M Lindqvist, E Lund, S Costello, R Torfadottir, J Burton, D Steingrimsdottir, L Korde, N Mailankody, S Eiriksdottir, G Launer, L Harris, T Landgren, O Gudnason, V Kristinsson, S AF Thordardottir, M. Lindqvist, E. Lund, S. Costello, R. Torfadottir, J. Burton, D. Steingrimsdottir, L. Korde, N. Mailankody, S. Eiriksdottir, G. Launer, L. Harris, T. Landgren, O. Gudnason, V. Kristinsson, S. TI DIETARY HABITS ACROSS THE LIFESPAN AND RISK OF MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE: A POPULATION BASED SCREENING STUDY SO HAEMATOLOGICA LA English DT Meeting Abstract CT 21st Congress of the European-Hematology-Association CY JUN 09-12, 2016 CL Copenhagen, DENMARK SP European Hematol Assoc C1 [Thordardottir, M.; Lund, S.; Kristinsson, S.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Lindqvist, E.; Kristinsson, S.] Karolinska Univ Hosp, Dept Med, Div Hematol, Stockholm, Sweden. [Lindqvist, E.; Kristinsson, S.] Karolinska Inst, Stockholm, Sweden. [Costello, R.; Burton, D.] NCI, Multiple Myeloma Sect, NIH, Bethesda, MD 20892 USA. [Torfadottir, J.; Steingrimsdottir, L.] Univ Iceland, Unit Nutr Res, Reykjavik, Iceland. [Korde, N.; Mailankody, S.; Landgren, O.] Mem Sloan Kettering Canc Ctr, Div Hematol Oncol, Myeloma Serv, 1275 York Ave, New York, NY 10021 USA. [Eiriksdottir, G.; Gudnason, V.] Icelandic Heart Assoc, Kopavogur, Iceland. [Launer, L.; Harris, T.] NIA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD JUN PY 2016 VL 101 SU 1 MA PB1940 BP 780 EP 781 PG 2 WC Hematology SC Hematology GA DQ8TS UT WOS:000379484603081 ER PT J AU Malinska, M Dauter, Z AF Malinska, Maura Dauter, Zbigniew TI Transferable aspherical atom model refinement of protein and DNA structures against ultrahigh-resolution X-ray data SO ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY LA English DT Article DE high-resolution X-ray crystal structures; spherical atom model; transferable aspherical atom model; interaction energy; electrostatic potential ID CHARGE-DENSITY ANALYSIS; ELECTROSTATIC INTERACTION ENERGY; HUMAN ALDOSE REDUCTASE; PSEUDOATOM DATA-BANK; CRYSTAL-STRUCTURE; SUBATOMIC RESOLUTION; DIFFRACTION DATA; MULTIPOLE-MODEL; PARAMETERS; MOLECULES AB In contrast to the independent-atom model (IAM), in which all atoms are assumed to be spherical and neutral, the transferable aspherical atom model (TAAM) takes into account the deformed valence charge density resulting from chemical bond formation and the presence of lone electron pairs. Both models can be used to refine small and large molecules, e.g. proteins and nucleic acids, against ultrahigh-resolution X-ray diffraction data. The University at Buffalo theoretical databank of aspherical pseudo-atoms has been used in the refinement of an oligopeptide, of Z-DNA hexamer and dodecamer duplexes, and of bovine trypsin. The application of the TAAM to these data improves the quality of the electron-density maps and the visibility of H atoms. It also lowers the conventional R factors and improves the atomic displacement parameters and the results of the Hirshfeld rigid-bond test. An additional advantage is that the transferred charge density allows the estimation of Coulombic interaction energy and electrostatic potential. C1 [Malinska, Maura; Dauter, Zbigniew] Argonne Natl Lab, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, NCI, 9700 S Cass Ave, Argonne, IL 60439 USA. [Malinska, Maura] Univ Warsaw, Fac Chem, PL-02093 Warsaw, Poland. RP Dauter, Z (reprint author), Argonne Natl Lab, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, NCI, 9700 S Cass Ave, Argonne, IL 60439 USA. EM dauter@anl.gov OI Malinska, Maura/0000-0002-7138-7041 FU Intramural Research Program of the National Cancer Institute, Center for Cancer Research; Polish Ministry of Science and Higher Education through 'Mobility Plus' program FX This work was supported in part by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research. MM acknowledges the Polish Ministry of Science and Higher Education for financial support through the 'Mobility Plus' program. NR 50 TC 1 Z9 1 U1 5 U2 6 PU INT UNION CRYSTALLOGRAPHY PI CHESTER PA 2 ABBEY SQ, CHESTER, CH1 2HU, ENGLAND SN 2059-7983 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Struct. Biol. PD JUN PY 2016 VL 72 BP 770 EP 779 DI 10.1107/S2059798316006355 PN 6 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA DR4ZD UT WOS:000379911500008 PM 27303797 ER PT J AU Siddharthan, T North, CM Attia, EF Christiani, DC Checkley, W West, TE AF Siddharthan, Trishul North, Crystal M. Attia, Engi F. Christiani, David C. Checkley, William West, T. Eoin TI Global Health Education in Pulmonary and Critical Care Medicine Fellowships SO ANNALS OF THE AMERICAN THORACIC SOCIETY LA English DT Article AB A growing number of pulmonary and critical care medicine fellowship programs in the United States offer global health training opportunities. Formal, integrated global health programs within pulmonary and critical care fellowships are relatively new but are built on principles and ideals of global health that focus on the mutually beneficial exchange of knowledge and social justice. Although core competencies consistent with these overarching themes in global health education have not been formalized for pulmonary and critical care trainees, relevant competency areas include clinical knowledge, international research training, cultural competency, and clinical and research capacity building. Existing global health education in U.S. pulmonary and critical care medicine training programs can generally be classified as one of three different models: integrated global health tracks, global health electives, and additional research years. Successful global health education programs foster partnerships and collaborations with international sites that emphasize bidirectional exchange. This bidirectional exchange includes ongoing, equitable commitments to mutual opportunities for training and professional development, including a focus on the particular knowledge and skill sets critical for addressing the unique priorities of individual countries. However, barriers related to the availability of mentorship, funding, and dedicated time exist to expanding global health education in pulmonary and critical care medicine. The implementation of global health training within pulmonary and critical care medicine programs requires continued optimization, but this training is essential to prepare the next generation of physicians to address the global aspects of respiratory disease and critical illness. C1 [Siddharthan, Trishul; Checkley, William] Johns Hopkins Univ, Johns Hopkins Sch Med, Dept Pulm & Crit Care Med, Baltimore, MD USA. [Siddharthan, Trishul; North, Crystal M.] Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Program Global Dis Epidemiol & Control, Baltimore, MD USA. [North, Crystal M.; Christiani, David C.] NIH, Fogarty Int Ctr, Fogarty Global Hlth Fellowship, Bethesda, MD USA. [North, Crystal M.; Christiani, David C.] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA USA. [Attia, Engi F.; West, T. Eoin] Harvard Univ, Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Checkley, William] Univ Washington, Div Pulm & Crit Care Med, Seattle, WA USA. [West, T. Eoin] Univ Washington, Dept Global Hlth, Seattle, WA USA. [West, T. Eoin] Univ Washington, Int Resp & Severe Illness Ctr, Seattle, WA USA. RP Siddharthan, T (reprint author), Dept Pulm & Crit Care Med, 1830 E Monument St,5th Floor, Baltimore, MD 21287 USA. EM tsiddha1@jhmi.edu OI Attia, Engi/0000-0002-5044-9602 FU Fogarty International Center [5R25TW009340, R25TW009337]; Harvard-National Institute of Environmental Health Sciences Center for Environmental Health [P30ES000002]; NHLBI/National Institutes of Health [K99HL096955]; Fogarty International Center/National Cancer Institute/National Institute of Environmental Health Sciences [U01TW010107] FX Supported by Fogarty International Center grants 5R25TW009340 and R25TW009337 (T.S., C.M.N.), the Harvard-National Institute of Environmental Health Sciences Center for Environmental Health grant P30ES000002 (C.M.N., D.C.C.), the NHLBI/National Institutes of Health grant K99HL096955 (W.C.), and Fogarty International Center/National Cancer Institute/National Institute of Environmental Health Sciences grant U01TW010107 (W.C.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the respective institutions or governmental organizations. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1546-3222 EI 2325-6621 J9 ANN AM THORAC SOC JI Ann. Am. Thoracic Society PD JUN PY 2016 VL 13 IS 6 BP 779 EP 783 DI 10.1513/AnnalsATS.201601-028PS PG 5 WC Respiratory System SC Respiratory System GA DR7WD UT WOS:000380109500009 PM 26974557 ER PT J AU Klemm, BP Wu, N Chen, Y Liu, X Kaitany, KJ Howard, MJ Fierke, CA AF Klemm, Bradley P. Wu, Nancy Chen, Yu Liu, Xin Kaitany, Kipchumba J. Howard, Michael J. Fierke, Carol A. TI The Diversity of Ribonuclease P: Protein and RNA Catalysts with Analogous Biological Functions SO BIOMOLECULES LA English DT Review DE RNase P; ribozyme; PRORP; endonuclease; tRNA maturation; tRNA recognition ID PRE-TRANSFER-RNA; PRECURSOR-TRANSFER-RNA; PHENYLALANINE TRANSFER-RNA; PYROCOCCUS-HORIKOSHII OT3; METAL-ION BINDING; ESCHERICHIA-COLI RIBONUCLEASE; HUMAN MITOCHONDRIAL TRNA(LYS); CLEAVAGE-SITE SELECTION; 4.5 S-RNA; BACILLUS-SUBTILIS AB Ribonuclease P (RNase P) is an essential endonuclease responsible for catalyzing 5' end maturation in precursor transfer RNAs. Since its discovery in the 1970s, RNase P enzymes have been identified and studied throughout the three domains of life. Interestingly, RNase P is either RNA-based, with a catalytic RNA subunit, or a protein-only (PRORP) enzyme with differential evolutionary distribution. The available structural data, including the active site data, provides insight into catalysis and substrate recognition. The hydrolytic and kinetic mechanisms of the two forms of RNase P enzymes are similar, yet features unique to the RNA-based and PRORP enzymes are consistent with different evolutionary origins. The various RNase P enzymes, in addition to their primary role in tRNA 5' maturation, catalyze cleavage of a variety of alternative substrates, indicating a diversification of RNase P function in vivo. The review concludes with a discussion of recent advances and interesting research directions in the field. C1 [Klemm, Bradley P.; Kaitany, Kipchumba J.; Howard, Michael J.; Fierke, Carol A.] Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48109 USA. [Wu, Nancy; Fierke, Carol A.] Univ Michigan, Program Chem Biol, Ann Arbor, MI 48109 USA. [Chen, Yu; Liu, Xin; Fierke, Carol A.] Univ Michigan, Dept Chem, Ann Arbor, MI 48103 USA. [Liu, Xin] Stanford Univ, Dept Chem, Palo Alto, CA 94305 USA. [Howard, Michael J.] NIEHS, Durham, NC 27713 USA. RP Fierke, CA (reprint author), Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48109 USA.; Fierke, CA (reprint author), Univ Michigan, Program Chem Biol, Ann Arbor, MI 48109 USA.; Fierke, CA (reprint author), Univ Michigan, Dept Chem, Ann Arbor, MI 48103 USA. EM klemmbp@umich.edu; nancywu@umich.edu; yyuchen@umich.edu; chemxliu@umich.edu; kaitanyk@umich.edu; mhowa@umich.edu; fierke@umich.edu RI Liu, Xin/O-8285-2014 OI Howard, Michael/0000-0001-9990-930X; Liu, Xin/0000-0002-9622-672X NR 216 TC 1 Z9 1 U1 0 U2 2 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2218-273X J9 BIOMOLECULES JI Biomolecules PD JUN PY 2016 VL 6 IS 2 AR 27 DI 10.3390/biom6020027 PG 29 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DR3WY UT WOS:000379834600012 ER PT J AU Zhang, JW Ferre-DAmare, AR AF Zhang, Jinwei Ferre-DAmare, Adrian R. TI Trying on tRNA for Size: RNase P and the T-box Riboswitch as Molecular Rulers SO BIOMOLECULES LA English DT Review DE RNA structure; molecular rulers; tRNA; RNase P; T-box; riboswitch; tRNA elbow; interdigitated T-loops; noncoding RNA; noncanonical base pairs ID PHENYLALANINE TRANSFER-RNA; BACTERIAL RIBONUCLEASE-P; DOUBLE-STRANDED-RNA; CCA-ADDING ENZYME; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; IN-VITRO; TRANSCRIPTION ANTITERMINATION; RIBONUCLEOPROTEIN ENZYME; FUNCTIONAL IMPLICATIONS AB Length determination is a fundamental problem in biology and chemistry. Numerous proteins measure distances on linear biopolymers to exert effects with remarkable spatial precision. Recently, ruler-like devices made of noncoding RNAs have been structurally and biochemically characterized. Two prominent examples are the RNase P ribozyme and the T-box riboswitch. Both act as molecular calipers. The two RNAs clamp onto the elbow of tRNA (or pre-tRNA) and make distance measurements orthogonal to each other. Here, we compare and contrast the molecular ruler characteristics of these RNAs. RNase P appears pre-configured to measure a fixed distance on pre-tRNA to ensure the fidelity of its maturation. RNase P is a multiple-turnover ribozyme, and its rigid structure efficiently selects pre-tRNAs, cleaves, and releases them. In contrast, the T-box is flexible and segmented, an architecture that adapts to the intrinsically flexible tRNA. The tripartite T-box inspects the overall shape, anticodon sequence, and aminoacylation status of an incoming tRNA while it folds co-transcriptionally, leading to a singular, conditional genetic switching event. The elucidation of the structures and mechanisms of action of these two RNA molecular rulers may augur the discovery of new RNA measuring devices in noncoding and viral transcriptomes, and inform the design of artificial RNA rulers. C1 [Zhang, Jinwei] NIDDK, Mol Biol Lab, 50 South Dr, Bethesda, MD 20892 USA. [Ferre-DAmare, Adrian R.] NHLBI, Lab RNA Biophys & Cellular Physiol, 50 South Dr, Bethesda, MD 20892 USA. RP Zhang, JW (reprint author), NIDDK, Mol Biol Lab, 50 South Dr, Bethesda, MD 20892 USA.; Ferre-DAmare, AR (reprint author), NHLBI, Lab RNA Biophys & Cellular Physiol, 50 South Dr, Bethesda, MD 20892 USA. EM jinwei.zhang@nih.gov; adrian.ferre@nih.gov OI Zhang, Jinwei/0000-0002-2114-173X NR 77 TC 0 Z9 0 U1 8 U2 9 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2218-273X J9 BIOMOLECULES JI Biomolecules PD JUN PY 2016 VL 6 IS 2 AR 18 DI 10.3390/biom6020018 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DR3WY UT WOS:000379834600003 ER PT J AU Roloff, GW Yang, ZM Wood, LV Neychev, VK AF Roloff, Gregory W. Yang, Zhiming Wood, Lauren V. Neychev, Vladimir K. TI Colon cancer metastasis to the thyroid gland: report of a case with unique molecular profile SO CLINICAL CASE REPORTS LA English DT Article DE Colorectal cancer; HER2/neu; metastasis; molecular characteristics; thyroid ID BREAST-CANCER; EXPRESSION; CARCINOMA; PROGNOSIS; NEOPLASMS; MARKER AB A high index of suspicion is needed when a patient presents with thyroid mass in the settings of an advanced CRC. Secondary thyroid malignancy should be considered unless proven otherwise. reatment should be determined considering extent of CRC metastasis, patient's general condition, and presence of local symptoms. C1 [Roloff, Gregory W.; Wood, Lauren V.] NCI, Vaccine Branch, Ctr Canc Res, Bethesda, MD USA. [Yang, Zhiming] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD USA. [Neychev, Vladimir K.] NCI, Endocrine Oncol Branch, Ctr Canc Res, Bethesda, MD USA. [Neychev, Vladimir K.] Med Univ Sofia, Dept Surg, Alexandrovska Hosp, Sofia, Bulgaria. RP Neychev, VK (reprint author), NCI, NIH, 10 Ctr Dr,CRC 3-5840, Bethesda, MD 20892 USA. EM vladimir.neychev@nih.gov NR 14 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2050-0904 J9 CLIN CASE REP JI Clin. Case Rep. PD JUN PY 2016 VL 4 IS 6 BP 549 EP 553 DI 10.1002/ccr3.497 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA DR4BB UT WOS:000379845300003 PM 27398194 ER PT J AU Reis, JP Selvin, E Pankow, JS Michos, ED Rebholz, CM Lutsey, PL AF Reis, J. P. Selvin, E. Pankow, J. S. Michos, E. D. Rebholz, C. M. Lutsey, P. L. TI Parathyroid hormone is associated with incident diabetes in white, but not black adults: The Atherosclerosis Risk in Communities (ARIC) Study SO DIABETES & METABOLISM LA English DT Article DE Diabetes; Parathyroid hormone; Prospective study; Race ID NUTRITION EXAMINATION SURVEY; BETA-CELL FUNCTION; VITAMIN-D; PRIMARY HYPERPARATHYROIDISM; INSULIN SENSITIVITY; 25-HYDROXYVITAMIN D; NATIONAL-HEALTH; METABOLIC SYNDROME; RACIAL-DIFFERENCES; OLDER-ADULTS AB Objective. - Accumulating evidence has linked elevated parathyroid hormone (PTH) with insulin resistance, beta cell dysfunction and dysglycaemia, however, its role in the development of diabetes is largely unclear, particularly among non-whites. We sought to examine the association of PTH with the incidence of diabetes. Methods. We studied 8066 white and 2034 black adults aged 46-70 years at baseline (1990-92) from the ARIC Study with follow-up for incident diabetes ascertained during study visits conducted in 1993-95 and 1996-98. Hazard ratios (HR) and their 95% CIs for diabetes adjusted for demographics, lifestyle, and 25-hydroxyvitamin D were estimated according to PTH measured at baseline. Results. PTH was higher among blacks than whites (median [IQR], 43.8 [35.0-55.8] vs. 37.9 [30.4-17.3] pg/mL; P < 0.001). During a median follow-up of 6 years, 498 white and 167 black participants developed diabetes. The association of PTH with diabetes varied significantly by race (P-interaction 0.02). PTH was not associated with risk for diabetes among black adults. Among whites, HRs according to quintiles of PTH were 1 (referent), 0.95 (0.71, 1.29), 0.95 (0.70, 1.28), 1.12 (0.84, 1.51), and 1.31 (0.98, 1.76) (P-trend 0.03). When a clinical cut-point for PTH was applied (>= 65 pg/mL; 5.7% of whites), the HR for diabetes among whites was 1.38 (1.01, 1.88). Results were similar when restricted to participants with normal baseline kidney function. Conclusion. In this large, population-based study, elevated PTH was independently associated with risk for diabetes among white, but not black adults. Further studies are needed to elucidate the mechanisms that may underlie this differential association of PTH with diabetes across race groups. Published by Elsevier Masson SAS. C1 [Reis, J. P.] NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Suite 10186, Bethesda, MD 20892 USA. [Selvin, E.; Michos, E. D.; Rebholz, C. M.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Pankow, J. S.; Lutsey, P. L.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Michos, E. D.] Johns Hopkins Sch Med, Div Cardiol, Baltimore, MD USA. RP Reis, JP (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Suite 10186, Bethesda, MD 20892 USA. EM reisjp@mail.nih.gov FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268-201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; NHLBI [R01 HL103706]; NIH Office of Dietary Supplements; National Institute of Neurological Disorders and Stroke [R01NS072243]; National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK089174] FX The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268-201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Further support was obtained by grant R01 HL103706 from the NHLBI with a supplement from the NIH Office of Dietary Supplements (to Dr. Lutsey), the National Institute of Neurological Disorders and Stroke (R01NS072243 to Dr. Michos), as well as the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK089174 to Dr. Selvin). NR 34 TC 1 Z9 1 U1 0 U2 0 PU MASSON EDITEUR PI MOULINEAUX CEDEX 9 PA 21 STREET CAMILLE DESMOULINS, ISSY, 92789 MOULINEAUX CEDEX 9, FRANCE SN 1262-3636 EI 1878-1780 J9 DIABETES METAB JI Diabetes Metab. PD JUN PY 2016 VL 42 IS 3 BP 162 EP 169 DI 10.1016/j.diabet.2015.12.004 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DR3HY UT WOS:000379795500004 PM 26782010 ER PT J AU Rasooly, R Bruck, HA Balsam, J Prickril, B Ossandon, M Rasooly, A AF Rasooly, Reuven Bruck, Hugh Alan Balsam, Joshua Prickril, Ben Ossandon, Miguel Rasooly, Avraham TI Improving the Sensitivity and Functionality of Mobile Webcam-Based Fluorescence Detectors for Point-of-Care Diagnostics in Global Health SO DIAGNOSTICS LA English DT Review DE webcams; CCD cameras; mobile phones; fluorescence imaging; flow cytometry; rare cells; resource-poor settings; image enhancement; background subtraction; pixel binning; global health ID STAPHYLOCOCCAL-ENTEROTOXIN-B; LINKED IMMUNOSORBENT ASSAYS; IMAGING FLOW CYTOMETER; ARRAY BIOSENSOR; CELL-PHONE; CHEMILUMINESCENCE DETECTION; ISOTHERMAL AMPLIFICATION; COLORIMETRIC DETECTION; MOLECULAR DIAGNOSTICS; MICROFLUIDIC DEVICE AB Resource-poor countries and regions require effective, low-cost diagnostic devices for accurate identification and diagnosis of health conditions. Optical detection technologies used for many types of biological and clinical analysis can play a significant role in addressing this need, but must be sufficiently affordable and portable for use in global health settings. Most current clinical optical imaging technologies are accurate and sensitive, but also expensive and difficult to adapt for use in these settings. These challenges can be mitigated by taking advantage of affordable consumer electronics mobile devices such as webcams, mobile phones, charge-coupled device (CCD) cameras, lasers, and LEDs. Low-cost, portable multi-wavelength fluorescence plate readers have been developed for many applications including detection of microbial toxins such as C. Botulinum A neurotoxin, Shiga toxin, and S. aureus enterotoxin B (SEB), and flow cytometry has been used to detect very low cell concentrations. However, the relatively low sensitivities of these devices limit their clinical utility. We have developed several approaches to improve their sensitivity presented here for webcam based fluorescence detectors, including (1) image stacking to improve signal-to-noise ratios; (2) lasers to enable fluorescence excitation for flow cytometry; and (3) streak imaging to capture the trajectory of a single cell, enabling imaging sensors with high noise levels to detect rare cell events. These approaches can also help to overcome some of the limitations of other low-cost optical detection technologies such as CCD or phone-based detectors (like high noise levels or low sensitivities), and provide for their use in low-cost medical diagnostics in resource-poor settings. C1 [Rasooly, Reuven] USDA, Western Reg Res Ctr, Agr Res Serv, Albany, CA 94706 USA. [Bruck, Hugh Alan] UMCP, Dept Mech Engn, College Pk, MD 20742 USA. [Balsam, Joshua] FDA, Div Chem & Toxicol Devices, Off Vitro Diagnost & Radiol Hlth, Silver Spring, MD 20993 USA. [Prickril, Ben; Ossandon, Miguel; Rasooly, Avraham] NCI, Rockville, MD 20850 USA. RP Rasooly, A (reprint author), NCI, Rockville, MD 20850 USA. EM reuven.rasooly@ars.usda.gov; bruck@umd.edu; joshua.balsam@fda.hhs.gov; ben.prickril@nih.gov; ossandom@mail.nih.gov; rasoolya@mail.nih.gov NR 151 TC 0 Z9 0 U1 11 U2 17 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2075-4418 J9 DIAGNOSTICS JI Diagnostics PD JUN PY 2016 VL 6 IS 2 AR 19 DI 10.3390/diagnostics6020019 PG 21 WC Medicine, General & Internal SC General & Internal Medicine GA DR6VL UT WOS:000380039300006 ER PT J AU Khoshnoodi, MA Truelove, S Burakgazi, A Hoke, A Mammen, AL Polydefkis, M AF Khoshnoodi, Mohammad A. Truelove, Shaun Burakgazi, Ahmet Hoke, Ahmet Mammen, Andrew L. Polydefkis, Michael TI Longitudinal Assessment of Small Fiber Neuropathy Evidence of a Non-Length-Dependent Distal Axonopathy SO JAMA NEUROLOGY LA English DT Article ID HUMAN DIABETIC-NEUROPATHY; EPIDERMAL NERVE-FIBERS; SKIN BIOPSY; CONFOCAL MICROSCOPY; NORMATIVE-REFERENCE; AXONAL SWELLINGS; TRANSPORT; DENSITY; DISEASE; POLYNEUROPATHY AB IMPORTANCE Few data are available on the natural history of small fiber neuropathy (SNF). Peripheral neuropathy typically follows a length-dependent pattern, leading us to hypothesize that patients with SFN would lose intraepidermal nerve fibers at the distal leg more quickly than at more proximal thigh sites. OBJECTIVE To compare the longitudinal rate and pattern of intraepidermal nerve fiber density (IENFD) change in idiopathic SFN (iSFN), impaired glucose tolerance-associated SFN (IGT-SFN), and diabetes mellitus-associated SFN (DM-SFN). DESIGN, SETTING, AND PARTICIPANTS In this longitudinal, case-control study, patients diagnosed as having SFN from January 1, 2002, through December 31, 2010, and age-and sex-matched controls underwent additional evaluation at tertiary outpatient neurology clinics. Participants and healthy controls were evaluated twice separated by at least 2 years. Participants underwent standardized examinations, nerve conduction, and skin biopsy at 3 sites along the leg. A linear mixed-effects model was used to compare rates of IENFD decrease between cause and biopsy site. MAIN OUTCOMES AND MEASURES We compared the rate of IENFD loss over time in subjects with iSFN, IGT-SFN and DM-SFN as well as the spatiotemporal pattern of IENF loss at different rostal-caudal sites along the leg. RESULTS Fifty-two participants (25 with iSFN, 13 with IGT-SFN, and 14 with DM-SFN) and 10 healthy controls were evaluated. Mean (SD) ages were 50.9 (12.9), 63.1 (10.4), and 61.6 (11.6) years for the iSFN, IGT-SFN, and DM-SFN groups, respectively. There were 12, 7, and 8 female patients and 13, 6, and 6 male patients in the iSFN, IGT-SFN, and DM-SFN groups, respectively. The mean follow-up time was 24.2, 26.7, and 38.8 months for those with iSFN, IGT-SFN, and DM-SFN, respectively, and 32 months for healthy controls. At baseline, mean (SE) for distal leg IENFD (6.48 [1.06]) was lower than distal thigh (13.32 [1.08]) and proximal thigh IENFD (19.98 [1.07]) (P = .001). In addition, IENFD was significantly lower in patients with DM-SFN and IGT-SFN compared with iSFN at all biopsy sites (P = .001). All 3 neuropathy groups had significant IENFD decrease at follow-up at all 3 sites (P =.002), whereas there was no change in the control group. The mean yearly rates of IENFD change over time at the distal leg, distal thigh, and proximal thigh irrespective of cause are -1.42, -1.59, and -2.8 fibers per millimeter, respectively. The mean slopes of IENFD change over time by cause regardless of biopsy site are -0.179, -0.164, and -0.198 for iSFN, IGT-SFN, and DM-SFN, respectively. No difference was found between SFN groups in the rate of decrease. The rate of IENFD decrease was similar at all 3 biopsy sites. CONCLUSIONS AND RELEVANCE Similar rates of IENFD decrease irrespective of cause were observed. Epidermal nerve fibers were lost at similar rates in proximal and distal sites, suggesting that SFN is a non-length-dependent terminal axonopathy. C1 [Khoshnoodi, Mohammad A.; Hoke, Ahmet; Mammen, Andrew L.; Polydefkis, Michael] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Truelove, Shaun] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Burakgazi, Ahmet] Virginia Tech, Carilion Sch Med, Dept Med, Neurosci Sect, Roanoke, VA USA. [Mammen, Andrew L.] NIAMSD, Muscle Dis Unit, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Polydefkis, M (reprint author), Johns Hopkins Univ, Dept Neurol, Cutaneous Nerve Lab, 855 North Wolfe St,Rangos Bldg,Room 435, Baltimore, MD 21205 USA. EM mpolyde@jhmi.edu FU Mark Rubenstein, MEng FX The study was supported by a philanthropic gift from Mark Rubenstein, MEng. NR 37 TC 2 Z9 2 U1 2 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD JUN PY 2016 VL 73 IS 6 BP 684 EP 690 DI 10.1001/jamaneurol.2016.0057 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA DQ7WL UT WOS:000379418600018 PM 27065313 ER PT J AU Alqahtani, SA Leigh, R AF Alqahtani, Saeed A. Leigh, Richard TI Imaging Active Intracerebral Hemorrhage After Attempted Endovascular Thrombectomy SO JAMA NEUROLOGY LA English DT Editorial Material ID ACUTE ISCHEMIC-STROKE C1 [Alqahtani, Saeed A.; Leigh, Richard] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Alqahtani, SA (reprint author), 10 Ctr Dr,Room B1D733,MSC 1063, Bethesda, MD 20892 USA. EM saeedqanea@hotmail.com NR 2 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 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD JUN PY 2016 VL 73 IS 6 BP 754 EP 754 DI 10.1001/jamaneurol.2016.0570 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA DQ7WL UT WOS:000379418600027 PM 27088250 ER PT J AU Szekely, E Pappa, I Wilson, JD Bhamidi, S Jaddoe, VW Verhulst, FC Tiemeier, H Shaw, P AF Szekely, Eszter Pappa, Irene Wilson, James D. Bhamidi, Shankar Jaddoe, Vincent W. Verhulst, Frank C. Tiemeier, Henning Shaw, Philip TI Childhood peer network characteristics: genetic influences and links with early mental health trajectories SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE Heritability; peer networks; externalizing; internalizing; preschoolers ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; INTERNALIZING PROBLEMS; FRIENDSHIP NETWORKS; ELEMENTARY-SCHOOL; BEHAVIOR PROBLEMS; SOCIAL NETWORKS; GENERATION R; CHILDREN; PRESCHOOL; PSYCHOPATHOLOGY AB Background: Peer relationships are important for children's mental health, yet little is known of their etiological underpinnings. Here, we explore the genetic influences on childhood peer network characteristics in three different networks defined by rejection, acceptance, and prosocial behavior. We further examine the impact of early externalizing and internalizing trajectories on these same peer network characteristics. Methods: Participants were 1,288 children from the Dutch 'Generation R' birth cohort. At age 7, we mapped out children's classroom peer networks for peer rejection, acceptance, and prosocial behavior using mutual peer nominations. In each network, genetic influences were estimated for children's degree centrality, closeness centrality and link reciprocity from DNA using Genome-wide Complex Trait Analysis. Preschool externalizing and internalizing trajectories were computed using parental ratings at ages 1.5, 3, and 5 years. Results: Of the three network properties examined, closeness centrality emerged as significantly heritable across all networks. Preschool externalizing problems predicted unfavorable positions within peer rejection networks and having fewer mutual friendships. In contrast, children with preschool-internalizing problems were not actively rejected by their peers, but were less well-connected within their social support network. Conclusions: Our finding of significant heritability for closeness centrality should be taken as preliminary evidence that requires replication. Nevertheless, it can orient us to the role of genes in shaping a child's position within peer networks. Additionally, social network perspectives offer rich insights into how early life mental health trajectories impact a child's later functioning within peer networks. C1 [Szekely, Eszter; Shaw, Philip] NHGRI, Sect Neurobehav Clin Res, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Pappa, Irene] Erasmus Univ, Sch Pedag & Educ Sci, Rotterdam, Netherlands. [Pappa, Irene; Jaddoe, Vincent W.; Tiemeier, Henning] Erasmus Univ, Med Ctr, Generat R Study Grp, Rotterdam, Netherlands. [Wilson, James D.] Univ San Francisco, Dept Math & Stat, San Francisco, CA 94117 USA. [Bhamidi, Shankar] Univ N Carolina, Dept Stat & Operat Res, Chapel Hill, NC USA. [Jaddoe, Vincent W.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Verhulst, Frank C.; Tiemeier, Henning] Erasmus Univ, Med Ctr, Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands. RP Szekely, E (reprint author), 31 Ctr Dr,Room B1B37, Bethesda, MD 20892 USA. EM eszter.szekely@nih.gov FU Erasmus Medical Center, Rotterdam; Erasmus University Rotterdam; Netherlands Organization for Health Research and Development (ZonMw) FX F.C.V. is a contributing editor of the Achenbach System of Empirically Based Assessment, from which he receives remuneration. The rest of the authors declare that they have no competing or potential conflicts of interest. The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the Erasmus University Rotterdam, School of Law and Faculty of Social Sciences, the Municipal Health Service Rotterdam area, the Rotterdam Homecare Foundation, and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR). The authors would like to gratefully acknowledge the contribution of general practitioners, hospitals, midwives, and pharmacies in Rotterdam. The first phase of the Generation R Study is made possible by financial support from: Erasmus Medical Center, Rotterdam; Erasmus University Rotterdam; and the Netherlands Organization for Health Research and Development (ZonMw). NR 47 TC 0 Z9 0 U1 6 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9630 EI 1469-7610 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD JUN PY 2016 VL 57 IS 6 BP 687 EP 694 DI 10.1111/jcpp.12493 PG 8 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA DR5HV UT WOS:000379935000007 PM 26689862 ER PT J AU Cardone, A Brady, M Sriram, R Pant, HC Hassan, SA AF Cardone, A. Brady, M. Sriram, R. Pant, H. C. Hassan, S. A. TI Computational study of the inhibitory mechanism of the kinase CDK5 hyperactivity by peptide p5 and derivation of a pharmacophore SO JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN LA English DT Article DE CDK5; p5; p25; p35; TFP5; Alzheimer's disease; Beta amyloid; Hyperphosphorylation; Protein-protein association; Computer simulation; Molecular dynamics ID CYCLIN-DEPENDENT KINASE-5; ALZHEIMERS-DISEASE; TAU HYPERPHOSPHORYLATION; NEURONAL ACTIVATOR; MOUSE MODEL; P35; BINDING; P25; ASSOCIATION; SIMULATIONS AB The hyperactivity of the cyclic dependent kinase 5 (CDK5) induced by the activator protein p25 has been linked to a number of pathologies of the brain. The CDK5-p25 complex has thus emerged as a major therapeutic target for Alzheimer's disease (AD) and other neurodegenerative conditions. Experiments have shown that the peptide p5 reduces the CDK5-p25 activity without affecting the endogenous CDK5-p35 activity, whereas the peptide TFP5, obtained from p5, elicits similar inhibition, crosses the blood-brain barrier, and exhibits behavioral rescue of AD mice models with no toxic side effects. The molecular basis of the kinase inhibition is not currently known, and is here investigated by computer simulations. It is shown that p5 binds the kinase at the same CDK5/p25 and CDK5/p35 interfaces, and is thus a non-selective competitor of both activators, in agreement with available experimental data in vitro. Binding of p5 is enthalpically driven with an affinity estimated in the low A mu M range. A quantitative description of the binding site and pharmacophore is presented, and options are discussed to increase the binding affinity and selectivity in the design of drug-like compounds against AD. C1 [Cardone, A.; Brady, M.; Sriram, R.] NIST, Software & Syst Div, Gaithersburg, MD 20899 USA. [Cardone, A.] Univ Maryland, Inst Adv Comp Studies, College Pk, MD 20742 USA. [Pant, H. C.] NINDS, Lab Neurochem, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Hassan, S. A.] NIH, Ctr Mol Modeling, Div Computat Biosci, CIT, Bldg 10, Bethesda, MD 20892 USA. RP Cardone, A (reprint author), NIST, Software & Syst Div, Gaithersburg, MD 20899 USA.; Cardone, A (reprint author), Univ Maryland, Inst Adv Comp Studies, College Pk, MD 20742 USA. EM antonio.cardone@nist.gov FU NIH Intramural Research Program through the CIT; NINDS; NIST Research Fund FX This study utilized the high-performance computer capabilities of the Biowulf PC/Linux cluster at the NIH. This work was supported by the NIH Intramural Research Program through the CIT and NINDS, and an internal NIST Research Fund. NR 39 TC 1 Z9 1 U1 1 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-654X EI 1573-4951 J9 J COMPUT AID MOL DES JI J. Comput.-Aided Mol. Des. PD JUN PY 2016 VL 30 IS 6 BP 513 EP 521 DI 10.1007/s10822-016-9922-3 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Biophysics; Computer Science GA DR6BP UT WOS:000379986400005 PM 27387995 ER PT J AU Alter, BP Rosenberg, PS AF Alter, Blanche P. Rosenberg, Philip S. TI In Reference to Natural History and Management of Fanconi Anemia Patients With Head and Neck Cancer: A 10-Year Follow-up SO LARYNGOSCOPE LA English DT Letter ID SQUAMOUS-CELL CARCINOMAS; HUMAN-PAPILLOMAVIRUS C1 [Alter, Blanche P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Rosenberg, Philip S.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Alter, BP (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CA999999] NR 8 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD JUN PY 2016 VL 126 IS 6 BP E229 EP E229 DI 10.1002/lary.25874 PG 1 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA DR5ZF UT WOS:000379980200006 PM 26801202 ER PT J AU Hwang, E Billups, C Onar-Thomas, A Warren, K Beaty, O Gururangan, S Packer, R Fouladi, M Gajjar, A AF Hwang, Eugene Billups, Catherine Onar-Thomas, Arzu Warren, Katherine Beaty, Oren, III Gururangan, Sridharan Packer, Roger Fouladi, Maryam Gajjar, Amar TI OUTCOMES FOR PATIENTS WITH RECURRENT MEDULLOBLASTOMA OR EPENDYMOMA ENROLLED ON PHASE II CLINICAL TRIALS: AN ANALYSIS OF CONTEMPORARY CHILDREN'S ONCOLOGY GROUP (COG) AND PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) TRIALS SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 12-15, 2016 CL Liverpool, ENGLAND C1 [Hwang, Eugene; Packer, Roger] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Billups, Catherine; Onar-Thomas, Arzu; Gajjar, Amar] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [Warren, Katherine] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Gururangan, Sridharan] Univ Florida, Gainesvile, FL USA. [Fouladi, Maryam] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 SU 3 MA EPT-06 BP 25 EP 25 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DR2QM UT WOS:000379749000095 ER PT J AU Jackson, S Piotrowski, A Weingart, J Abd, T George, R Hays, A Ye, XB Anders, N Rudek, M Grossman, S AF Jackson, Sadhana Piotrowski, Anna Weingart, Jon Abd, Thura George, Richard Hays, Allison Ye, Xiaobu Anders, Nicole Rudek, Michelle Grossman, Stuart TI THE POTENTIAL ROLE OF REGADENOSON TO TRANSIENTLY DISRUPT THE BLOOD-BRAIN BARRIER AND IMPROVE TEMOZOLOMIDE DELIVERY TO BRAIN TUMORS SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 12-15, 2016 CL Liverpool, ENGLAND C1 [Jackson, Sadhana] NIH, Bldg 10, Bethesda, MD 20892 USA. [Jackson, Sadhana; Piotrowski, Anna; Weingart, Jon; Abd, Thura; George, Richard; Hays, Allison; Ye, Xiaobu; Anders, Nicole; Rudek, Michelle; Grossman, Stuart] Johns Hopkins Univ, Baltimore, MD USA. NR 0 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 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 SU 3 MA EPT-11 BP 26 EP 26 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DR2QM UT WOS:000379749000100 ER PT J AU Hipp, S Goldman, S Kaushal, A Glod, J Shih, J Garvin, J Karajannis, M Atlas, M Camphausen, K Packer, R Warren, K AF Hipp, Sean Goldman, Stewart Kaushal, Aradhana Glod, John Shih, Joanna Garvin, James Karajannis, Matthias Atlas, Mark Camphausen, Kevin Packer, Roger Warren, Kathy TI A PHASE 1 TRIAL OF LENALIDOMIDE PLUS RADIOTHERAPY IN CHILDREN WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMAS OR HIGH-GRADE GLIOMAS SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 12-15, 2016 CL Liverpool, ENGLAND C1 [Hipp, Sean] San Antonio Mil Med Ctr, Houston, TX USA. [Goldman, Stewart] Ann & Robert Lurie Childrens Hosp Chicago, Chicago, IL USA. [Kaushal, Aradhana; Glod, John; Shih, Joanna; Camphausen, Kevin; Warren, Kathy] NCI, Bethesda, MD 20892 USA. [Garvin, James] Columbia Univ, Med Ctr, New York, NY USA. [Karajannis, Matthias] NYU, Langone Med Ctr, New York, NY USA. [Atlas, Mark] Steven & Alexandra Cohen Childrens Med Ctr, New Hyde Pk, NY USA. [Packer, Roger] Childrens Natl Med Ctr, Washington, DC 20010 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 SU 3 MA EPT-16 BP 27 EP 27 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DR2QM UT WOS:000379749000105 ER PT J AU Maachani, UB Shankavaram, U Schweitzer, M Wu, YL Camphausen, K Souweidane, M AF Maachani, Uday Bhanu Shankavaram, Uma Schweitzer, Melanie Wu, Yue Linda Camphausen, Kevin Souweidane, Mark TI DIFFERENTIAL EXPRESSION OF PARP1/2 AS A BIOMARKER OF DIPG MALIGNANT PROGRESSION: RELATIONSHIP TO TGF-beta/BMP SIGNALING AND EZH2 GLOBAL METHYLATION SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 12-15, 2016 CL Liverpool, ENGLAND C1 [Maachani, Uday Bhanu; Schweitzer, Melanie; Wu, Yue Linda; Souweidane, Mark] Weill Cornell Med, New York, NY USA. [Shankavaram, Uma; Camphausen, Kevin] NCI, NIH, Bethesda, MD 20892 USA. NR 0 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 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 SU 3 MA HG-05 BP 48 EP 48 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DR2QM UT WOS:000379749000183 ER PT J AU Rodgers, L McCully, CL Peer, C Cruz, R Figg, W AF Rodgers, Louis McCully, Cynthia Lester Peer, Cody Cruz, Rafael Figg, William TI PLASMA AND CEREBROSPINAL FLUID (CSF) PHARMACOKINETICS OF PANOBINOSTAT FOLLOWING ORAL ADMINISTRATION TO NONHUMAN PRIMATES SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 12-15, 2016 CL Liverpool, ENGLAND C1 [Rodgers, Louis; McCully, Cynthia Lester; Peer, Cody; Cruz, Rafael; Figg, William] NCI, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 SU 3 MA HG-36 BP 55 EP 55 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DR2QM UT WOS:000379749000212 ER PT J AU Hwang, E Billups, C Onar-Thomas, A Gururangan, S Warren, K Beaty, O Warwick, A Macdonald, T Packer, R Gajjar, A Fouladi, M AF Hwang, Eugene Billups, Catherine Onar-Thomas, Arzu Gururangan, Sridharan Warren, Katherine Beaty, Oren, III Warwick, Anne Macdonald, Tobey Packer, Roger Gajjar, Amar Fouladi, Maryam TI OUTCOMES FOR PATIENTS WITH RECURRENT MALIGNANT GLIOMA ENROLLED ON PHASE II CLINICAL TRIALS: AN ANALYSIS OF CONTEMPORARY CHILDREN'S ONCOLOGY GROUP (COG) AND PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) TRIALS SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 12-15, 2016 CL Liverpool, ENGLAND C1 [Hwang, Eugene; Packer, Roger] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Billups, Catherine; Onar-Thomas, Arzu; Gajjar, Amar] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [Warren, Katherine] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Warwick, Anne] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. [Gururangan, Sridharan] Univ Florida, Gainesvile, FL USA. [Macdonald, Tobey] Childrens Healthcare Atlanta, Atlanta, GA USA. [Fouladi, Maryam] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 SU 3 MA HG-41 BP 56 EP 56 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DR2QM UT WOS:000379749000217 ER PT J AU Stampar, M Saratsis, A Brown, K Yadavilli, S Raabe, E Warren, K Kambhampati, M Giri, M Gupta, N Packer, R Nazarian, J AF Stampar, Mojca Saratsis, Amanda Brown, Kristy Yadavilli, Sridevi Raabe, Eric Warren, Kathy Kambhampati, Madhuri Giri, Mamta Gupta, Nalin Packer, Roger Nazarian, Javad TI MOLECULAR CHARACTERIZATION OF IN VIVO AND IN VITRO MODELS OF DIPG SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 12-15, 2016 CL Liverpool, ENGLAND C1 [Stampar, Mojca; Brown, Kristy; Yadavilli, Sridevi; Kambhampati, Madhuri; Giri, Mamta; Packer, Roger; Nazarian, Javad] Childrens Natl Hlth Syst, Washington, DC USA. [Saratsis, Amanda] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. [Saratsis, Amanda] Northwestern Univ Feinberg Sch Med, Chicago, IL USA. [Brown, Kristy; Nazarian, Javad] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA. [Raabe, Eric] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Warren, Kathy] NIH, Bldg 10, Bethesda, MD 20892 USA. [Gupta, Nalin] Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 SU 3 MA HG-61 BP 61 EP 62 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DR2QM UT WOS:000379749000236 ER PT J AU Hoffman, LM van Zanten, SEMV Colditz, N Baugh, J Chaney, B Lane, A Fuller, C Miles, L Hawkins, C Bartels, U Bouffet, E Goldman, S Leary, S Foreman, NK Packer, R Warren, KE Broniscer, A Kieran, MW Minturn, J Comito, M Broxon, E Shih, CS Khatua, S Chintagumpala, M Carret, AS Hassall, T Ziegler, D Gottardo, N Dholaria, H Lerme, B Kirkendall, J Doughman, R Hoffmann, M Wollman, M O'Keefe, R Benesch, M Gerber, N Bailey, S Solanki, G Massimino, M Biassoni, V Cvrlje, FJ Hulleman, E Drissi, R Nazarian, J Jabado, N von Bueren, AO Pietsch, T Gielen, GH Sturm, D Jones, DT Pfister, S Jones, C Hargrave, D Sanchez, E Bison, B Warmuth-Metz, M Leach, J Jones, B van Vuurden, DG Kramm, CM Fouladi, M AF Hoffman, Lindsey M. van Zanten, Sophie E. M. Veldhuijzen Colditz, Niclas Baugh, Joshua Chaney, Brooklyn Lane, Adam Fuller, Christine Miles, Lili Hawkins, Cynthia Bartels, Ute Bouffet, Eric Goldman, Stewart Leary, Sarah Foreman, Nicholas K. Packer, Roger Warren, Katherine E. Broniscer, Alberto Kieran, Mark W. Minturn, Jane Comito, Melanie Broxon, Emmett Shih, Chie-Schin Khatua, Soumen Chintagumpala, Murali Carret, Anne-Sophie Hassall, Timothy Ziegler, David Gottardo, Nick Dholaria, Hetal Lerme, Brianna Kirkendall, Jenavieve Doughman, Renee Hoffmann, Marion Wollman, Matthew O'Keefe, Rachel Benesch, Martin Gerber, Nicolas Bailey, Simon Solanki, Guirish Massimino, Maura Biassoni, Veronica Cvrlje, Filip Jadrijevic Hulleman, Esther Drissi, Rachid Nazarian, Javad Jabado, Nada von Bueren, Andre Oscar Pietsch, Torsten Gielen, Gerrit H. Sturm, Dominik Jones, David T. Pfister, Stefan Jones, Chris Hargrave, Darren Sanchez, Esther Bison, Brigitte Warmuth-Metz, Monika Leach, James Jones, Blaise van Vuurden, Dannis G. Kramm, Christof M. Fouladi, Maryam TI CLINICAL, RADIOLOGICAL, AND HISTO-GENETIC CHARACTERISTICS OF LONG-TERM SURVIVORS OF DIFFUSE INTRINSIC PONTINE GLIOMA: A COLLABORATIVE REPORT FROM THE INTERNATIONAL AND SIOP-E DIPG REGISTRIES SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 12-15, 2016 CL Liverpool, ENGLAND C1 [Hoffman, Lindsey M.; Baugh, Joshua; Chaney, Brooklyn; Lane, Adam; Fuller, Christine; Miles, Lili; Lerme, Brianna; Kirkendall, Jenavieve; Doughman, Renee; Wollman, Matthew; O'Keefe, Rachel; Drissi, Rachid; Leach, James; Jones, Blaise; Fouladi, Maryam] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [van Zanten, Sophie E. M. Veldhuijzen; Hulleman, Esther; Sanchez, Esther; van Vuurden, Dannis G.] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. [Colditz, Niclas; Hoffmann, Marion; von Bueren, Andre Oscar; Pietsch, Torsten; Gielen, Gerrit H.; Sturm, Dominik; Jones, David T.; Pfister, Stefan; Bison, Brigitte; Warmuth-Metz, Monika; Kramm, Christof M.] Univ Med Ctr Goettingen, Gottingen, Germany. [Hawkins, Cynthia; Bartels, Ute; Bouffet, Eric] Hosp Sick Children, Toronto, ON, Canada. [Goldman, Stewart] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. [Leary, Sarah] Seattle Childrens Hosp, Seattle, WA USA. [Foreman, Nicholas K.] Childrens Hosp Colorado, Aurora, CO USA. [Packer, Roger; Nazarian, Javad] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Warren, Katherine E.] NCI, NIH, Bethesda, MD 20892 USA. [Broniscer, Alberto] St Jude Childrens Res Hosp, Memphis, TN USA. [Kieran, Mark W.] Boston Childrens Hosp, Dana Farber Canc Inst, Boston, MA USA. [Minturn, Jane] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Comito, Melanie] Penn State Hershey Childrens Hosp, Hummelstown, PA USA. [Broxon, Emmett] Dayton Childrens Hosp, Dayton, OH USA. [Shih, Chie-Schin] Riley Childrens Hosp, Indianapolis, IN USA. [Khatua, Soumen] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Chintagumpala, Murali] Texas Childrens Hosp, Houston, TX 77030 USA. [Carret, Anne-Sophie] CHU St Justine, Montreal, PQ, Canada. [Hassall, Timothy] Lady Cilento Chidlrens Hosp, Brisbane, Qld, Australia. [Ziegler, David] Sydney Childrens Hosp, Sydney, NSW, Australia. [Gottardo, Nick; Dholaria, Hetal] Telethon Kids Inst, Perth, Australia. [Benesch, Martin] Med Univ Graz, Graz, Austria. [Gerber, Nicolas; von Bueren, Andre Oscar] Univ Hosp Geneva, Geneva, Switzerland. [Bailey, Simon] Great North Childrens Hosp, New Castle, England. [Solanki, Guirish] Univ Birmingham, Birmingham, W Midlands, England. [Massimino, Maura; Biassoni, Veronica] Fdn IRCCS Inst Nazl Tumori, Milan, Italy. [Cvrlje, Filip Jadrijevic] Childrens Hosp Zagreb, Zagreb, Croatia. [Jabado, Nada] Montreal Childrens Hosp, Montreal, PQ H3H 1P3, Canada. [Jones, Chris] Inst Canc Res, Sutton, Surrey, England. [Hargrave, Darren] Great Ormond St Hosp Sick Children, London, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 SU 3 MA HG-75 BP 65 EP 66 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DR2QM UT WOS:000379749000250 ER PT J AU Panditharatna, E Nikbakht, H Mikael, L Li, R Gayden, T Osmand, M Ho, CY Kambhampati, M Hwang, EI Faury, D Siu, A Papillon-Cavanagh, S Bechet, D Ligon, KL Ellezam, B Ingram, WJ Stinson, C Moore, AS Warren, KE Karamchandani, J Packer, RJ Jabado, N Majewski, J Nazarian, J AF Panditharatna, Eshini Nikbakht, Hamid Mikael, Leonie Li, Rui Gayden, Tenzin Osmand, Matthew Ho, Cheng-Ying Kambhampati, Madhuri Hwang, Eugene I. Faury, Damien Siu, Alan Papillon-Cavanagh, Simon Bechet, Denise Ligon, Keith L. Ellezam, Benjamin Ingram, Wendy J. Stinson, Caedyn Moore, Andrew S. Warren, Katherine E. Karamchandani, Jason Packer, Roger J. Jabado, Nada Majewski, Jacek Nazarian, Javad TI SPATIAL AND TEMPORAL HOMOGENEITY OF DRIVER MUTATIONS IN DIFFUSE INTRINSIC PONTINE GLIOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 12-15, 2016 CL Liverpool, ENGLAND C1 [Panditharatna, Eshini; Ho, Cheng-Ying; Kambhampati, Madhuri; Hwang, Eugene I.; Packer, Roger J.; Nazarian, Javad] Childrens Natl Hlth Syst, Washington, DC USA. [Panditharatna, Eshini; Ho, Cheng-Ying; Kambhampati, Madhuri; Siu, Alan; Packer, Roger J.; Nazarian, Javad] George Washington Univ, Washington, DC USA. [Nikbakht, Hamid; Mikael, Leonie; Li, Rui; Gayden, Tenzin; Osmand, Matthew; Faury, Damien; Papillon-Cavanagh, Simon; Bechet, Denise; Karamchandani, Jason; Jabado, Nada; Majewski, Jacek] McGill Univ, Montreal, PQ, Canada. [Ligon, Keith L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ellezam, Benjamin] Univ Montreal, Montreal, PQ, Canada. [Ingram, Wendy J.; Stinson, Caedyn; Moore, Andrew S.] Univ Queensland, Brisbane, Qld, Australia. [Warren, Katherine E.] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 SU 3 MA HG-76 BP 66 EP 66 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DR2QM UT WOS:000379749000251 ER PT J AU Cooney, T League-Pascual, J Lane, A Hoffman, L Bartels, U Bouffet, E Goldman, S Leary, S Foreman, N Packer, R Broniscer, A Kieran, M Minturn, J Comito, M Broxon, E Shih, CS Khatua, S Chintagumpala, M Carret, A Hassall, T Gottardo, N Baugh, J Chaney, B Doughman, R Leach, J Jones, B Fouladi, M Monje, M Warren, K AF Cooney, Tabitha League-Pascual, James Lane, Adam Hoffman, Lindsey Bartels, Ute Bouffet, Eric Goldman, Stewart Leary, Sarah Foreman, Nicholas Packer, Roger Broniscer, Alberto Kieran, Mark Minturn, Jane Comito, Melanie Broxon, Emmett Shih, Chie-Schin Khatua, Soumen Chintagumpala, Murali Carret, Anne Hassall, Tim Gottardo, Nick Baugh, Joshua Chaney, Brooklyn Doughman, Renee Leach, James Jones, Blaise Fouladi, Maryam Monje, Michelle Warren, Kathy TI CONTEMPORARY SURVIVAL ENDPOINTS: AN INTERNATIONAL DIFFUSE INTRINSIC PONTINE GLIOMA REGISTRY STUDY SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 12-15, 2016 CL Liverpool, ENGLAND C1 [Cooney, Tabitha; Monje, Michelle] Stanford Univ, Palo Alto, CA 94304 USA. [League-Pascual, James; Warren, Kathy] NCI, Bethesda, MD 20892 USA. [Lane, Adam; Hoffman, Lindsey; Baugh, Joshua; Chaney, Brooklyn; Doughman, Renee; Leach, James; Jones, Blaise; Fouladi, Maryam] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Bartels, Ute; Bouffet, Eric] Hosp Sick Children, Toronto, ON, Canada. [Goldman, Stewart] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. [Chintagumpala, Murali] Texas Childrens Hosp, Houston, TX 77030 USA. [Khatua, Soumen] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Shih, Chie-Schin] Riley Hosp Children, Indianapolis, IN USA. [Packer, Roger] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Broniscer, Alberto] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [Comito, Melanie] Penn State Childrens Hosp, Hershey, PA USA. [Minturn, Jane] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Kieran, Mark] Dana Farber Canc Inst, Boston, MA 02115 USA. [Foreman, Nicholas] Childrens Hosp Colorado, Denver, CO USA. [Leary, Sarah] Seattle Childrens, Seattle, WA USA. [Broxon, Emmett] Dayton Childrens Hosp, Dayton, OH USA. [Carret, Anne] CHU St Justine, Montreal, PQ, Canada. [Hassall, Tim] Lady Cilento Childrens Hosp, South Brisbane, Qld, Australia. [Gottardo, Nick] Telethon Kids Inst, Perth, Australia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 SU 3 MA HG-109 BP 73 EP 74 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DR2QM UT WOS:000379749000284 ER PT J AU Dalvi, N Kleinerman, R Huse, J Abramson, D Dunkel, I AF Dalvi, Nagma Kleinerman, Ruth Huse, Jason Abramson, David Dunkel, Ira TI LOW GRADE ASTROCYTOMA: A RARE SECOND TUMOR IN RETINOBLASTOMA SURVIVORS SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 12-15, 2016 CL Liverpool, ENGLAND C1 [Dalvi, Nagma; Huse, Jason; Abramson, David; Dunkel, Ira] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Kleinerman, Ruth] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 SU 3 MA LG-36 BP 86 EP 86 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DR2QM UT WOS:000379749000339 ER PT J AU Nellan, A Rota, C Warren, K Lee, D AF Nellan, Anandani Rota, Christopher Warren, Katherine Lee, Daniel TI OPTIMIZATION OF CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY FOR MEDULLOBLASTOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 12-15, 2016 CL Liverpool, ENGLAND C1 [Nellan, Anandani; Rota, Christopher; Warren, Katherine; Lee, Daniel] NCI, NIH, Bethesda, MD 20892 USA. [Nellan, Anandani] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 SU 3 MA MB-42 BP 106 EP 106 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DR2QM UT WOS:000379749000420 ER PT J AU Warren, K Harreld, J Chamberlain, M Vezina, G Warmuth-Metz, M von Hoff, K Packer, R Brandes, A Reiss, M Goldman, S Fisher, M Poussaint, T Pollack, I Prados, M Wen, P Chang, S Dufour, C Zurakowski, D Kortmann, RD Kieran, M AF Warren, Kathy Harreld, Julie Chamberlain, Marc Vezina, Gilbert Warmuth-Metz, Monika von Hoff, Katja Packer, Roger Brandes, Alba Reiss, Moshe Goldman, Stewart Fisher, Michael Poussaint, Tina Pollack, Ian Prados, Michael Wen, Patrick Chang, Susan Dufour, Christelle Zurakowski, David Kortmann, Rolf-Dieter Kieran, Mark TI RESPONSE ASSESSMENT IN PEDIATRIC NEURO-ONCOLOGY (RAPNO) COMMITTEE GUIDELINES FOR RESPONSE ASSESSMENT IN MEDULLOBLASTOMA AND OTHER LEPTOMENINGEAL SEEDING TUMORS SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 12-15, 2016 CL Liverpool, ENGLAND C1 [Warren, Kathy; Kieran, Mark] NCI, Bethesda, MD 20892 USA. [Harreld, Julie] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [Chamberlain, Marc] Seattle Canc Care Alliance, Seattle, WA USA. [Vezina, Gilbert; Packer, Roger] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Warmuth-Metz, Monika] Univ Wurzburg, Wurzburg, Germany. [von Hoff, Katja] Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany. [Brandes, Alba] Azienda USL IRCCS Sci Neurol, Bologna, Italy. [Reiss, Moshe] Maria Fareri Childrens Hosp, Valhalla, NY USA. [Goldman, Stewart] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. [Fisher, Michael] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Poussaint, Tina; Zurakowski, David] Boston Childrens Hosp, Boston, MA USA. [Pollack, Ian] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Prados, Michael; Chang, Susan] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Wen, Patrick] Dana Farber Canc Inst, Boston, MA 02115 USA. [Dufour, Christelle] Inst Gustave Roussy, Villejuif, France. [Kortmann, Rolf-Dieter] Univ Leipzig, Leipzig, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 SU 3 MA MB-52 BP 109 EP 109 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DR2QM UT WOS:000379749000430 ER PT J AU McCully, CML Rodgers, L Cruz, R Peer, C Figg, WD Warren, KE AF McCully, Cynthia M. Lester Rodgers, Louis Cruz, Rafael Peer, Cody Figg, William D., Sr. Warren, Katherine E. TI PLASMA AND CEREBROSPINAL FLUID PHARMACOKINETICS OF 5-AZACYTIDINE FOLLOWING INTRAVENOUS, INTRANASAL, AND INTRATHECAL ADMINISTRATION IN A NON-HUMAN PRIMATE MODEL SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 12-15, 2016 CL Liverpool, ENGLAND C1 [McCully, Cynthia M. Lester; Rodgers, Louis; Cruz, Rafael; Peer, Cody; Figg, William D., Sr.; Warren, Katherine E.] NCI, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 SU 3 MA PCM-10 BP 141 EP 141 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DR2QM UT WOS:000379749000566 ER PT J AU Hwang, E Hardy, K Armstrong, T Acquaye, A Gioia, A Gilbert, M Mendoza, T AF Hwang, Eugene Hardy, Kristina Armstrong, Terri Acquaye, Alvina Gioia, Anthony Gilbert, Mark Mendoza, Tito TI THE ASSOCIATION OF SOCIODEMOGRAPHIC AND MEDICAL FACTORS WITH CLINICAL OUTCOMES ASSESSMENTS (COAS) IN CHILDREN WITH EPENDYMOMA: RESULTS OF THE PEDIATRIC EPENDYMOMA OUTCOMES (PEO) PROJECT SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 12-15, 2016 CL Liverpool, ENGLAND C1 [Hwang, Eugene; Hardy, Kristina; Gioia, Anthony] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Gilbert, Mark] NIH, Neurooncol Branch, Bldg 10, Bethesda, MD 20892 USA. [Armstrong, Terri; Acquaye, Alvina; Mendoza, Tito] UT Hlth Sci Ctr Houston, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 SU 3 MA QOS-12 BP 147 EP 147 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DR2QM UT WOS:000379749000590 ER PT J AU Zhang, H Wheeler, W Hyland, PL Yang, YF Shi, JX Chatterjee, N Yu, K AF Zhang, Han Wheeler, William Hyland, Paula L. Yang, Yifan Shi, Jianxin Chatterjee, Nilanjan Yu, Kai TI A Powerful Procedure for Pathway-Based Meta-analysis Using Summary Statistics Identifies 43 Pathways Associated with Type II Diabetes in European Populations SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; GENETIC ARCHITECTURE; RARE VARIANTS; SNP SELECTION; INDIVIDUALS; IMPUTATION; COVERAGE; DESIGN; TRAITS; LOCI AB Meta-analysis of multiple genome-wide association studies (GWAS) has become an effective approach for detecting single nucleotide polymorphism (SNP) associations with complex traits. However, it is difficult to integrate the readily accessible SNP-level summary statistics from a meta-analysis into more powerful multi-marker testing procedures, which generally require individual-level genetic data. We developed a general procedure called Summary based Adaptive Rank Truncated Product (sARTP) for conducting gene and pathway meta-analysis that uses only SNP-level summary statistics in combination with genotype correlation estimated from a panel of individual-level genetic data. We demonstrated the validity and power advantage of sARTP through empirical and simulated data. We conducted a comprehensive pathway-based meta-analysis with sARTP on type 2 diabetes (T2D) by integrating SNP-level summary statistics from two large studies consisting of 19,809 T2D cases and 111,181 controls with European ancestry. Among 4,713 candidate pathways from which genes in neighborhoods of 170 GWAS established T2D loci were excluded, we detected 43 T2D globally significant pathways (with Bonferroni corrected p-values < 0.05), which included the insulin signaling pathway and T2D pathway defined by KEGG, as well as the pathways defined according to specific gene expression patterns on pancreatic adenocarcinoma, hepatocellular carcinoma, and bladder carcinoma. Using summary data from 8 eastern Asian T2D GWAS with 6,952 cases and 11,865 controls, we showed 7 out of the 43 pathways identified in European populations remained to be significant in eastern Asians at the false discovery rate of 0.1. We created an R package and a web-based tool for sARTP with the capability to analyze pathways with thousands of genes and tens of thousands of SNPs. C1 [Zhang, Han; Hyland, Paula L.; Shi, Jianxin; Yu, Kai] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wheeler, William] Informat Management Serv Inc, Calverton, MD USA. [Yang, Yifan] Univ Kentucky, Dept Stat, Lexington, KY USA. [Chatterjee, Nilanjan] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Chatterjee, Nilanjan] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. RP Chatterjee, N (reprint author), Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA.; Chatterjee, N (reprint author), Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. EM nchatte2@jhu.edu; yuka@mail.nih.gov RI Zhang, Han/K-2118-2016 OI Zhang, Han/0000-0001-7977-9616 FU Intramural Program of the National Institutes of Health; National Cancer Institute FX The work of HZ, JS, and KY were supported by the Intramural Program of the National Institutes of Health and the National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 0 Z9 0 U1 5 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUN PY 2016 VL 12 IS 6 AR e1006122 DI 10.1371/journal.pgen.1006122 PG 28 WC Genetics & Heredity SC Genetics & Heredity GA DQ6WS UT WOS:000379347100037 PM 27362418 ER PT J AU Denis, RGP Joly-Amado, A Castel, J Cansell, C Webber, E Padilla, S Delbes, AS Martinez, S Schaeffer, M Langlet, F Dehouck, B Lacombe, A Rouch, C Kassis, N Fehrentz, JA Martinez, J Verdie, P Hnasko, TS Palmiter, RD Magnan, C Krashes, M Guler, AD Luquet, S AF Denis, Raphael G. P. Joly-Amado, Aurelie Castel, Julien Cansell, Celine Webber, Emily Padilla, Stephanie Delbes, Anne-Sophie Martinez, Sarah Schaeffer, Marie Langlet, Fanny Dehouck, Benedicte Lacombe, Amelie Rouch, Claude Kassis, Nadim Fehrentz, Jean-Alain Martinez, Jean Verdie, Pascal Hnasko, Thomas S. Palmiter, Richard D. Magnan, Christophe Krashes, Michael Guler, Ali D. Luquet, Serge TI Food palatability and neuronal circuit SO ACTA PHYSIOLOGICA LA English DT Meeting Abstract C1 [Denis, Raphael G. P.; Joly-Amado, Aurelie; Castel, Julien; Cansell, Celine; Delbes, Anne-Sophie; Martinez, Sarah; Lacombe, Amelie; Rouch, Claude; Kassis, Nadim; Magnan, Christophe; Luquet, Serge] CNRS, UMR 8251, Unite Biol Fonct & Adaptat, Paris, France. [Denis, Raphael G. P.; Joly-Amado, Aurelie] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France. [Webber, Emily; Krashes, Michael] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Webber, Emily; Krashes, Michael] NIDA, Baltimore, MD USA. [Padilla, Stephanie; Palmiter, Richard D.; Guler, Ali D.] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. [Padilla, Stephanie; Palmiter, Richard D.; Guler, Ali D.] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Schaeffer, Marie] CNRS, UMR 5203, Inst Genom Fonct, Montpellier, France. [Schaeffer, Marie] INSERM, U661, Montpellier, France. [Schaeffer, Marie] Univ Montpellier I, UMR 5203, Montpellier, France. [Schaeffer, Marie] Univ Montpellier 2, UMR 5203, Montpellier, France. [Langlet, Fanny; Dehouck, Benedicte] INSERM, Jean Pierre Aubert Res Ctr, U837, Lille, France. [Langlet, Fanny; Dehouck, Benedicte] Univ Droit & Sante Lille, Fac Med, Lille, France. [Fehrentz, Jean-Alain; Martinez, Jean; Verdie, Pascal] Univ Montpellier I, CNRS, UMR 5247, Inst Biomol Max Mousseron, Montpellier, France. [Fehrentz, Jean-Alain; Martinez, Jean; Verdie, Pascal] Univ Montpellier 2, CNRS, UMR 5247, Inst Biomol Max Mousseron, Montpellier, France. [Hnasko, Thomas S.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Guler, Ali D.] Univ Virginia, Dept Biol, Charlottesville, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 JUN PY 2016 VL 217 SU 708 SI SI MA SYM.023 BP 10 EP 10 PG 1 WC Physiology SC Physiology GA DQ9EU UT WOS:000379514000017 ER PT J AU Baek, JS Kim, BS Puri, A Kumar, K Cho, CW AF Baek, Jong-Suep Kim, Bo-Sik Puri, Anu Kumar, K. Cho, Cheong-Weon TI Stability of paclitaxel-loaded solid lipid nanoparticles in the presence of 2-hydoxypropyl-beta-cyclodextrin SO ARCHIVES OF PHARMACAL RESEARCH LA English DT Article DE Paclitaxel; Hydroxypropyl-beta-cyclodextrin; Solid lipid nanoparticle; Stability ID ANTIBACTERIAL ACTIVITY; ADSORPTION-KINETICS; DELIVERY-SYSTEM; PLASMA-PROTEINS; CELLULAR UPTAKE; DRUG-DELIVERY; CANCER-CELLS; SLN; CYTOTOXICITY AB Paclitaxel (PTX)-loaded solid lipid nanoparticles without hydroxyl-beta-cyclodextrin (PS) or with hydroxypropyl-beta-cyclodextrin (PSC) were prepared by hot-melted sonication. Biocompatible and biodegradable stearic acid was used to produce the solid matrix. The stability of PS and PSC was assessed at different temperatures. Drug stability, as assessed by encapsulation efficiency (EE; %), particle size, and the polydispersity index (PDI), was examined and in vitro release of PTX from PS or PSC for up to 180 days was assessed. After 180 days of storage at 25 A degrees C, no significant change in particle size, PDI, or EE of PS or PSC was observed. PS and PSC displayed similar sustained PTX release patterns. The particle size, PDI, EE, PTX release profile, and cytotoxicity of PS changed significantly with increasing incubation time, whereas those of PSC showed no significant change, when samples were stored at 40 +/- 2 A degrees C. PSC was more stable than PS in plasma with regard to particle size and PDI. These results demonstrate that PSC could be a promising formulation to increase drug stability. C1 [Baek, Jong-Suep; Kim, Bo-Sik; Cho, Cheong-Weon] Chungnam Natl Univ, Coll Pharm, Daejeon 305764, South Korea. [Baek, Jong-Suep; Kim, Bo-Sik; Cho, Cheong-Weon] Chungnam Natl Univ, Inst Drug Res & Dev, Daejeon 305764, South Korea. [Puri, Anu] NCI Frederick, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res, NIH, POB B,Bldg 469,Rm 216A, Frederick, MD 21702 USA. [Kumar, K.] Howard Univ, Coll Pharm, 2400 Sixth St NW, Washington, DC 20059 USA. RP Cho, CW (reprint author), Chungnam Natl Univ, Coll Pharm, Daejeon 305764, South Korea.; Cho, CW (reprint author), Chungnam Natl Univ, Inst Drug Res & Dev, Daejeon 305764, South Korea. EM chocw@cnu.ac.kr FU Priority Research Centers Program through National Research Foundation of Korea [2009-0093815]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Priority Research Centers Program (2009-0093815) through the National Research Foundation of Korea. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 39 TC 0 Z9 0 U1 8 U2 10 PU PHARMACEUTICAL SOC KOREA PI SEOUL PA 1489-3 SUHCHO-DONG, SUHCHO-KU, SEOUL 137-071, SOUTH KOREA SN 0253-6269 EI 1976-3786 J9 ARCH PHARM RES JI Arch. Pharm. Res. PD JUN PY 2016 VL 39 IS 6 BP 785 EP 793 DI 10.1007/s12272-016-0753-5 PG 9 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DQ2CH UT WOS:000379008100007 PM 27146520 ER PT J AU Ward, MM Deodhar, A Reveille, JD Caplan, L AF Ward, Michael M. Deodhar, Atul Reveille, John D. Caplan, Liron TI Treatment of patients with nonradiographic axial spondyloarthritis who have negative magnetic resonance imaging results and normal C-reactive protein levels at baseline: comment on the article by Ward et al Reply SO ARTHRITIS CARE & RESEARCH LA English DT Letter ID PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; EFFICACY; SACROILIITIS; ADALIMUMAB C1 [Ward, Michael M.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Deodhar, Atul] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Reveille, John D.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Caplan, Liron] Denver Vet Affairs Med Ctr, Aurora, CO USA. [Caplan, Liron] Univ Colorado, Aurora, CO USA. RP Ward, MM (reprint author), NIAMSD, NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 AR041153-04] NR 8 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 2016 VL 68 IS 6 BP 886 EP 887 DI 10.1002/acr.22878 PG 3 WC Rheumatology SC Rheumatology GA DR1ON UT WOS:000379674900023 PM 26990665 ER PT J AU Devarakonda, K Nguyen, KP Kravitz, AV AF Devarakonda, Kavya Nguyen, Katrina P. Kravitz, Alexxai V. TI ROBucket: A low cost operant chamber based on the Arduino microcontroller SO BEHAVIOR RESEARCH METHODS LA English DT Article DE Operant chamber; Operant conditioning; Open source; Arduino; Instrumental conditioning AB The operant conditioning chamber is a cornerstone of animal behavioral research. Operant boxes are used to assess learning and motivational behavior in animals, particularly for food and drug reinforcers. However, commercial operant chambers cost several thousands of dollars. We have constructed the Rodent Operant Bucket (ROBucket), an inexpensive and easily assembled open-source operant chamber based on the Arduino microcontroller platform, which can be used to train mice to respond for sucrose solution or other liquid reinforcers. The apparatus contains two nose pokes, a drinking well, and a solenoid-controlled liquid delivery system. ROBucket can run fixed ratio and progressive ratio training schedules, and can be programmed to run more complicated behavioral paradigms. Additional features such as motion sensing and video tracking can be added to the operant chamber through the array of widely available Arduino-compatible sensors. The design files and programming code are open source and available online for others to use. C1 [Devarakonda, Kavya; Nguyen, Katrina P.; Kravitz, Alexxai V.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bldg 10-CRC,Room 5-5932,10 Ctr Dr, Bethesda, MD 20892 USA. RP Kravitz, AV (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bldg 10-CRC,Room 5-5932,10 Ctr Dr, Bethesda, MD 20892 USA. EM lex.kravitz@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program FX This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program. Thanks to Daniel Serven and Verma Walker for their assistance with designing and printing the 3D printed housing, the members of the Kravitz laboratory for input on the design and use of the ROBuckets, and Michael J. Krashes for inspirational discussions. 3D printing services were provided by the National Institutes of Health Technology Sandbox and the National Institutes of Health Library. NR 7 TC 3 Z9 3 U1 6 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1554-351X EI 1554-3528 J9 BEHAV RES METHODS JI Behav. Res. Methods PD JUN PY 2016 VL 48 IS 2 BP 503 EP 509 DI 10.3758/s13428-015-0603-2 PG 7 WC Psychology, Mathematical; Psychology, Experimental SC Psychology GA DR2ZO UT WOS:000379772600007 PM 26019006 ER PT J AU Furcron, AE Romero, R Mial, TN Balancio, A Panaitescu, B Hassan, SS Sahi, A Nord, C Gomez-Lopez, N AF Furcron, Amy-Eunice Romero, Roberto Mial, Tara N. Balancio, Amapola Panaitescu, Bogdan Hassan, Sonia S. Sahi, Aashna Nord, Claire Gomez-Lopez, Nardhy TI Human Chorionic Gonadotropin Has Anti-Inflammatory Effects at the Maternal-Fetal Interface and Prevents Endotoxin-Induced Preterm Birth, but Causes Dystocia and Fetal Compromise in Mice SO BIOLOGY OF REPRODUCTION LA English DT Article DE decidua; estradiol; hCG; interleukin-1 beta; M1 macrophages; M2 macrophages; mouse; neutrophils; parturition; pregnancy; preterm labor; progesterone; regulatory T cells; Th17 cells ID REGULATORY T-CELLS; EARLY HUMAN-PREGNANCY; LUTEINIZING-HORMONE RECEPTORS; MIGRATION INHIBITORY FACTOR; DENDRITIC CELLS; ALTERNATIVE ACTIVATION; MACROPHAGE PLASTICITY; HUMAN TROPHOBLASTS; HUMAN ENDOMETRIAL; HUMAN PLACENTA AB Human chorionic gonadotropin (hCG) is implicated in the maintenance of uterine quiescence by down-regulating myometrial gap junctions during pregnancy, and it was considered as a strategy to prevent preterm birth after the occurrence of preterm labor. However, the effect of hCG on innate and adaptive immune cells implicated in parturition is poorly understood. Herein, we investigated the immune effects of hCG at the maternal-fetal interface during late gestation, and whether this hormone can safely prevent endotoxin-induced preterm birth. Using immunophenotyping, we demonstrated that hCG has immune effects at the maternal-fetal interface (decidual tissues) by: 1) increasing the proportion of regulatory T cells; 2) reducing the proportion of macrophages and neutrophils; 3) inducing an M1 -> M2 macrophage polarization; and 4) increasing the proportion of T helper 17 cells. Next, ELISAs were used to determine whether the local immune changes were associated with systemic concentrations of progesterone, estradiol, and/or cytokines (IFNgamma, IL1beta, IL2, IL4, IL5, IL6, IL10, IL12p70, KC/GRO, and TNFalpha). Plasma concentrations of IL1beta, but not progesterone, estradiol, or any other cytokine, were increased following hCG administration. Pre-treatment with hCG prevented endotoxin-induced preterm birth by 44%, proving the effectiveness of this hormone as an anti-inflammatory agent. However, hCG administration alone caused dystocia and fetal compromise, as proven by Doppler ultrasound. These results provide insight into the mechanisms whereby hCG induces an anti-inflammatory microenvironment at the maternal-fetal interface during late gestation, and demonstrate its effectiveness in preventing preterm labor/birth. However, the deleterious effects of this hormone on mothers and fetuses warrant caution. C1 [Furcron, Amy-Eunice; Romero, Roberto; Mial, Tara N.; Balancio, Amapola; Panaitescu, Bogdan; Hassan, Sonia S.; Nord, Claire; Gomez-Lopez, Nardhy] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH,US Dept HHS, Bethesda, MD USA. [Furcron, Amy-Eunice; Romero, Roberto; Mial, Tara N.; Balancio, Amapola; Panaitescu, Bogdan; Hassan, Sonia S.; Nord, Claire; Gomez-Lopez, Nardhy] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH,US Dept HHS, Detroit, MI USA. [Furcron, Amy-Eunice; Mial, Tara N.; Hassan, Sonia S.; Sahi, Aashna; Gomez-Lopez, Nardhy] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, 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 Obstet & Genet, Detroit, MI USA. [Gomez-Lopez, Nardhy] Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Detroit, MI 48201 USA. RP Gomez-Lopez, N (reprint author), Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA.; Gomez-Lopez, N (reprint author), NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI 48201 USA. EM nardhy.gomez-lopez@wayne.edu 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, U.S. Department of Health and Human Services; Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health FX This research was supported by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, and by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health. This study was partially presented at the 34th Annual Meeting of the American Society for Reproductive Immunology, Long Beach, New York, 2-5 June, 2014, and the 62nd Annual Scientific Meeting of the Society for Reproductive Investigation, San Francisco, California, 25-28 March, 2015. NR 133 TC 3 Z9 3 U1 1 U2 2 PU SOC STUDY REPRODUCTION PI MADISON PA 1691 MONROE ST,SUITE # 3, MADISON, WI 53711-2021 USA SN 0006-3363 EI 1529-7268 J9 BIOL REPROD JI Biol. Reprod. PD JUN 1 PY 2016 VL 94 IS 6 AR 136 DI 10.1095/biolreprod.116.139345 PG 13 WC Reproductive Biology SC Reproductive Biology GA DR0BK UT WOS:000379572800012 PM 27146032 ER PT J AU Ballard, ED Vande Voort, JL Luckenbaugh, DA Machado-Vieira, R Tohen, M Zarate, CA AF Ballard, Elizabeth D. Vande Voort, Jennifer L. Luckenbaugh, David A. Machado-Vieira, Rodrigo Tohen, Mauricio Zarate, Carlos A. TI Acute risk factors for suicide attempts and death: prospective findings from the STEP-BD study SO BIPOLAR DISORDERS LA English DT Article DE anhedonia; anxiety; bipolar disorder; suicidal ideation; suicide ID TREATMENT ENHANCEMENT PROGRAM; BIPOLAR DISORDER; WARNING SIGNS; TASK-FORCE; FOLLOW-UP; IDEATION; SAMPLE; ADULTS; OUTPATIENTS; PREDICTORS AB ObjectivesSuicide is unfortunately common in psychiatric practice, but difficult to predict. The present study sought to assess which clinical symptoms increase in the months before suicidal behavior in a sample of psychiatric outpatients with bipolar disorder. MethodsData from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) trial were used. A total of 103 participants who attempted suicide or died by suicide during the trial were included; a 15% random sample of the remaining participants (n = 427) was used as a comparison sample. Linear mixed models in the six months before suicidal behavior were conducted for each of five proposed acute risk factors for suicidal behavior. Participants were assessed using the Clinical Monitoring Form (CMF) at each visit for the following potential acute risk factors for suicidal behavior: suicidal ideation, loss of interest, anxiety, psychomotor agitation, and high-risk behavior. ResultsEach of the five symptoms was elevated overall in individuals who engaged in suicidal behavior (p < 0.05). The severity of both suicidal ideation and loss of interest significantly increased in the months before suicidal behavior (p < 0.001). Anxiety demonstrated comparable effect sizes across multiple models. Psychomotor agitation and high-risk behavior were not significantly elevated before suicidal behavior. ConclusionsSuicidal ideation, loss of interest and, to a lesser extent, anxiety may represent acute suicide risk factors up to four months before suicidal behavior in outpatients with bipolar disorder. Further investigation of these potential acute risk factors in prospective analyses is warranted. C1 [Ballard, Elizabeth D.; Vande Voort, Jennifer L.; Luckenbaugh, David A.; Machado-Vieira, Rodrigo; Zarate, Carlos A.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bldg 10,CRC Room 7-5541,10 Ctr Dr,MSC 1282, Bethesda, MD 20892 USA. [Vande Voort, Jennifer L.] Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA. [Tohen, Mauricio] Univ New Mexico, Hlth Sci Ctr, Dept Psychiat & Behav Sci, Albuquerque, NM 87131 USA. RP Ballard, ED (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bldg 10,CRC Room 7-5541,10 Ctr Dr,MSC 1282, Bethesda, MD 20892 USA. EM elizabeth.ballard@nih.gov RI MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU National Institute of Health; National Institute of Mental Health (NIMH) [N01MH80001]; University of Pittsburgh; Intramural Research Program at the NIMH, National Institutes of Health (IRP-NIMH-NIH) [ZIA MH002927]; NARSAD Independent Investigator Award; Brain and Behavior Mood Disorders Research Award FX Data used in the preparation of this article were obtained from the limited access datasets distributed from the National Institute of Health-supported Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study. This multisite clinical trial studies current treatments for bipolar disorder, including medications and psychosocial therapies. The study was supported by National Institute of Mental Health (NIMH) Contract No. N01MH80001 to Massachusetts General Hospital and the University of Pittsburgh. The ClinicalTrials.gov identifier is NCT00012558. The opinions, interpretations, conclusions, and recommendations reported here are those of the authors and are not necessarily endorsed by the STEP-BD study investigators or the federal government. Funding for this work was supported by the Intramural Research Program at the NIMH, National Institutes of Health (IRP-NIMH-NIH; ZIA MH002927) by a NARSAD Independent Investigator Award to CAZ, and by a Brain and Behavior Mood Disorders Research Award to CAZ. EDB had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Ioline Henter (NIMH) provided invaluable editorial assistance. NR 39 TC 0 Z9 0 U1 4 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2016 VL 18 IS 4 BP 363 EP 372 DI 10.1111/bdi.12397 PG 10 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DR1XI UT WOS:000379697800006 PM 27233466 ER PT J AU Akinyemiju, T Moore, JX Ojesina, AI Waterbor, JW Altekruse, SF AF Akinyemiju, Tomi Moore, Justin Xavier Ojesina, Akinyemi I. Waterbor, John W. Altekruse, Sean F. TI Racial disparities in individual breast cancer outcomes by hormone-receptor subtype, area-level socio-economic status and healthcare resources SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer outcomes; Hormone-receptor subtype; Racial disparities; Healthcare access; Socio-economic status ID AFRICAN-AMERICAN WOMEN; OVARIAN-CANCER; TREATMENT GUIDELINES; GEOCODING PROJECT; WHITE WOMEN; MORTALITY; SURVIVAL; RACE/ETHNICITY; ADHERENCE; RACE AB The aim of the study is to determine the influence of area-level socio-economic status and healthcare access in addition to tumor hormone-receptor subtype on individual breast cancer stage, treatment, and mortality among Non-Hispanic (NH)-Black, NH-White, and Hispanic US adults. Analysis was based on 456,217 breast cancer patients in the SEER database from 2000 to 2010. Multilevel and multivariable-adjusted logistic and Cox proportional hazards regression analysis was conducted to account for clustering by SEER registry of diagnosis. NH-Black women had greater area-level access to healthcare resources compared with women of other races. For instance, the average numbers of oncology hospitals per million population in counties with NH-Black, NH-White, and Hispanic women were 8.1, 7.7, and 5.0 respectively; average numbers of medical doctors per million in counties with NH-Black, NH-White, and Hispanic women were 100.7, 854.0, and 866.3 respectively; and average number of Ob/Gyn in counties with NH-Black, NH-White, and Hispanic women was 155.6, 127.4, and 127.3, respectively (all p values <0.001). Regardless, NH-Black women (HR 1.39, 95 % CI 1.36-1.43) and Hispanic women (HR 1.05, 95 % CI 1.03-1.08) had significantly higher breast cancer mortality compared with NH-White women even after adjusting for hormone-receptor subtype, area-level socioeconomic status, and area-level healthcare access. In addition, lower county-level socio-economic status and healthcare access measures were significantly and independently associated with stage at presentation, surgery, and radiation treatment as well as mortality after adjusting for age, race/ethnicity, and HR subtype. Although breast cancer HR subtype is a strong, important, and consistent predictor of breast cancer outcomes, we still observed significant and independent influences of area-level SES and HCA on breast cancer outcomes that deserve further study and may be critical to eliminating breast cancer outcome disparities. C1 [Akinyemiju, Tomi; Moore, Justin Xavier; Ojesina, Akinyemi I.; Waterbor, John W.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Akinyemiju, Tomi; Moore, Justin Xavier; Ojesina, Akinyemi I.; Waterbor, John W.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Ojesina, Akinyemi I.] HudsonAlpha Inst Biotechnol, Huntsville, AL USA. [Altekruse, Sean F.] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Akinyemiju, T (reprint author), Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA.; Akinyemiju, T (reprint author), Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. EM tomiakin@uab.edu FU NIH [U54 CA118948]; National Cancer Institute [R25 CA47888] FX Dr. Akinyemiju was supported by Grant U54 CA118948 from the NIH. Mr. Moore was supported by Grant R25 CA47888 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. 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 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUN PY 2016 VL 157 IS 3 BP 575 EP 586 DI 10.1007/s10549-016-3840-x PG 12 WC Oncology SC Oncology GA DQ8XQ UT WOS:000379495400017 PM 27255533 ER PT J AU Vitale, C Ahn, IE Sivina, M Ferrajoli, A Wierda, WG Estrov, Z Konoplev, SN Jain, N O'Brien, S Farooqui, M Keating, MJ Wiestner, A Burger, JA AF Vitale, Candida Ahn, Inhye E. Sivina, Mariela Ferrajoli, Alessandra Wierda, William G. Estrov, Zeev Konoplev, Sergej N. Jain, Nitin O'Brien, Susan Farooqui, Mohammed Keating, Michael J. Wiestner, Adrian Burger, Jan A. TI Autoimmune cytopenias in patients with chronic lymphocytic leukemia treated with ibrutinib SO HAEMATOLOGICA LA English DT Letter DE autoimmune cytopenia; chronic lymphochytic leukemia; ibrutinib ID HEMOLYTIC-ANEMIA C1 [Vitale, Candida; Sivina, Mariela; Ferrajoli, Alessandra; Wierda, William G.; Estrov, Zeev; Jain, Nitin; Keating, Michael J.; Burger, Jan A.] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Ahn, Inhye E.; Farooqui, Mohammed; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Konoplev, Sergej N.] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA. [O'Brien, Susan] Univ Calif Irvine, Chao Family Comprehens Canc Ctr, Orange, CA 92668 USA. RP Burger, JA (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. EM jaburger@mdanderson.org FU NCI NIH HHS [P30 CA016672] NR 15 TC 3 Z9 3 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD JUN PY 2016 VL 101 IS 6 BP E254 EP E258 DI 10.3324/haematol.2015.138289 PG 5 WC Hematology SC Hematology GA DQ8OV UT WOS:000379471900010 PM 27013651 ER PT J AU Park, K Park, J Kwon, YD Kang, Y Noh, JW AF Park, Kisoo Park, Jumin Kwon, Young Dae Kang, Yoonjeong Noh, Jin-Won TI Public satisfaction with the healthcare system performance in South Korea: Universal healthcare system SO HEALTH POLICY LA English DT Article DE Healthcare system; Satisfaction; South Korea; Universal healthcare system ID PATIENT SATISFACTION; COUNTRIES; QUALITY; SERVICE; ISSUES; REFORM; VISIT AB Background: An awareness of the public's level of satisfaction with health professionals is becoming more important as steps are being taken to improve quality, reduce costs, and implement reform. The purpose of this study is to assess public satisfaction with the healthcare system and to examine the relationship between satisfaction and socio-demographic factors in the context of the health care environment in the Republic of Korea. Methods: The data were obtained from 1573 adults aged 20-69 in three major areas Seoul, Gyeonggi, and Busan by the Ministry of Health and Welfare during June and July 2011 in South Korea. Satisfaction with the healthcare system was evaluated by using 13 items in three sections: access to care, cost of care, and quality of care. A confirmatory factor analysis (CFA) was conducted to examine the validity of satisfaction with a healthcare system performance questionnaire. A structural equation model (SEM) was estimated to assess the relative impact of demographic and socio-economic variables on satisfaction. Results: The study proposed a comprehensive three-factor model of healthcare system performance satisfaction. Among the three factors, the quality of care had the largest impact on satisfaction with the healthcare system, suggesting that is the most important determinant of consumers' satisfaction with their healthcare system. Regarding the relationships between public satisfaction and demographic and socio-economic variables, residence and marital status were significant predictors of the satisfaction level. Conclusions: It is important to be aware of the potential significance of background variables in determining satisfaction with the healthcare system. An understanding of the characteristics of the sample enables healthcare managers and/or policymakers to inform targeted follow-up actions. (C) 2016 Published by Elsevier Ireland Ltd. C1 [Park, Kisoo] Korea Univ, Dept Healthcare Management, Seoul, South Korea. [Park, Jumin] NIH, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Kwon, Young Dae] Catholic Univ Korea, Dept Humanities & Social Med, Coll Med, Seoul, South Korea. [Kwon, Young Dae] Catholic Univ Korea, Catholic Inst Healthcare Management, Seoul, South Korea. [Kang, Yoonjeong] Amer Inst Res, Washington, DC USA. [Noh, Jin-Won] Eulji Univ, Dept Healthcare Management, Songnam, South Korea. [Noh, Jin-Won] Eulji Univ, Inst Global Healthcare Res, Songnam, South Korea. RP Noh, JW (reprint author), 212 Yangji Dong, Songnam 461713, Gyeonggi Do, South Korea. EM jinwon.noh@gmail.com OI Noh, Jin-Won/0000-0001-5172-4023; Kwon, Young Dae/0000-0002-8781-6832 NR 32 TC 1 Z9 1 U1 1 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0168-8510 EI 1872-6054 J9 HEALTH POLICY JI Health Policy PD JUN PY 2016 VL 120 IS 6 BP 621 EP 629 DI 10.1016/j.healthpol.2016.01.017 PG 9 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA DR0YB UT WOS:000379631700007 PM 26831040 ER PT J AU Lerner, ZF Damiano, DL Bulea, TC AF Lerner, Zachary F. Damiano, Diane L. Bulea, Thomas C. TI Estimating the Mechanical Behavior of the Knee Joint During Crouch Gait: Implications for Real-Time Motor Control of Robotic Knee Orthoses SO IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING LA English DT Article DE Cerebral palsy (CP); control of wearable robotic devices; crouch gait; kinematic-kinetic joint coupling; knee joint moment; rehabilitation robotics ID CEREBRAL-PALSY; MUSCLE CONTRIBUTIONS; LOWER-EXTREMITY; WALKING; CHILDREN; MODEL; REHABILITATION; EXOSKELETON; PROGRESSION; MOMENTS AB Individuals with cerebral palsy frequently exhibit crouch gait, a pathological walking pattern characterized by excessive knee flexion. Knowledge of the knee joint moment during crouch gait is necessary for the design and control of assistive devices used for treatment. Our goal was to 1) develop statistical models to estimate knee joint moment extrema and dynamic stiffness during crouch gait, and 2) use the models to estimate the instantaneous joint moment during weight-acceptance. We retrospectively computed knee moments from 10 children with crouch gait and used stepwise linear regression to develop statistical models describing the knee moment features. The models explained at least 90% of the response value variability: peak moment in early (99%) and late (90%) stance, and dynamic stiffness of weight-acceptance flexion (94%) and extension (98%). We estimated knee extensor moment profiles from the predicted dynamic stiffness and instantaneous knee angle. This approach captured the timing and shape of the computed moment (root-mean-squared error: 2.64 Nm); including the predicted early-stance peak moment as a correction factor improved model performance (root-mean-squared error: 1.37 Nm). Our strategy provides a practical, accurate method to estimate the knee moment during crouch gait, and could be used for real-time, adaptive control of robotic orthoses. C1 [Lerner, Zachary F.; Damiano, Diane L.; Bulea, Thomas C.] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Lerner, ZF (reprint author), NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. EM zachary.lerner@nih.gov; damianod@cc.nih.gov; thomas.bulea@nih.gov OI Lerner, Zachary/0000-0002-7359-436X FU Intramural Research Program at the National Institutes of Health [13-CC-0210] FX This work was supported by the Intramural Research Program at the National Institutes of Health (protocol 13-CC-0210). NR 23 TC 0 Z9 0 U1 8 U2 10 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1534-4320 EI 1558-0210 J9 IEEE T NEUR SYS REH JI IEEE Trans. Neural Syst. Rehabil. Eng. PD JUN PY 2016 VL 24 IS 6 BP 621 EP 629 DI 10.1109/TNSRE.2016.2550860 PG 9 WC Engineering, Biomedical; Rehabilitation SC Engineering; Rehabilitation GA DR2SI UT WOS:000379753800001 PM 27101612 ER PT J AU Bitar, C Farooqui, MZH Valdez, J Saba, NS Soto, S Bray, A Marti, G Wiestner, A Cowen, EW AF Bitar, Carole Farooqui, Mohammed Z. H. Valdez, Janet Saba, Nakhle S. Soto, Susan Bray, Amanda Marti, Gerald Wiestner, Adrian Cowen, Edward W. TI Hair and Nail Changes During Long-term Therapy With Ibrutinib for Chronic Lymphocytic Leukemia SO JAMA DERMATOLOGY LA English DT Article ID TARGETING BTK; INHIBITORS AB IMPORTANCE Ibrutinib, a Bruton tyrosine kinase inhibitor, is a new targeted agent approved by the US Food and Drug Administration for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and Waldenstrom macroglobulinemia. Ibrutinib is overall well tolerated but long-term treatment is required until disease progression or intolerable toxic effects occur. Little is known regarding its cutaneous adverse effects. OBJECTIVE To describe the hair and nail manifestations associated with the long-term use of ibrutinib for the treatment of CLL. DESIGN, SETTING, AND PARTICIPANTS Prospective study of 66 patients with CLL enrolled in a single-arm phase 2 clinical trial of ibrutinib for CLL between March 2014 and October 2015 at the National Institutes of Health. MAIN OUTCOMES AND MEASURES The primary outcome, nail and hair changes associated with ibrutinib therapy, was assessed by an 11-question survey. In addition, the severity of nail changes was determined from a 0 to 3 rating scale for both onychoschizia and onychorrhexis. RESULTS Among 66 patients (43 men and 23 women with ages ranging from 55 to 85 years), 44 (67%) reported brittle fingernails at a median of 6.5 (95% CI, 6-12) months after starting ibrutinib therapy. Fifteen patients (23%) developed brittle toenails after a median of 9 (95% CI, 6-15) months of ibrutinib therapy. Textural hair changes were reported in 17 patients (26%), at a median of 9 (95% CI, 6-12) months of ibrutinib treatment. CONCLUSIONS AND RELEVANCE Hair and nail abnormalities are commonly associated with ibrutinib and appear several months after initiating therapy. Ibrutinib inhibits Bruton tyrosine kinase by covalently binding to cysteine 481. Whether ibrutinib affects the hair and nails by binding and altering cysteine-rich proteins of hair and nails or by means of another mechanism remains unknown. C1 [Bitar, Carole] Tulane Univ, Dept Med, New Orleans, LA 70118 USA. [Bitar, Carole; Farooqui, Mohammed Z. H.; Valdez, Janet; Saba, Nakhle S.; Soto, Susan; Bray, Amanda; Marti, Gerald; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Saba, Nakhle S.] Tulane Univ, Dept Med, Sect Hematol & Med Oncol, New Orleans, LA 70118 USA. [Cowen, Edward W.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH10 Ctr Dr,Bldg 10, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, the National, Heart, Lung, and Blood Institute (NHLBI); Pharmacyclics FX This study was supported in part by the Intramural Research Program of the National Institutes of Health, the National, Heart, Lung, and Blood Institute (NHLBI), and by Pharmacyclics, which provided ibrutinib, research support, and comments on the manuscript. NR 15 TC 3 Z9 3 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6068 EI 2168-6084 J9 JAMA DERMATOL JI JAMA Dermatol. PD JUN PY 2016 VL 152 IS 6 BP 698 EP 701 DI 10.1001/jamadermatol.2016.0225 PG 4 WC Dermatology SC Dermatology GA DR0HM UT WOS:000379588600021 PM 26982511 ER PT J AU Hariri, AH Zhang, HY Ho, A Francis, P Weleber, RG Birch, DG Ferris, FL Sadda, SR AF Hariri, Amir H. Zhang, Hong Yang Ho, Alexander Francis, Peter Weleber, Richard G. Birch, David G. Ferris, Frederick L., III Sadda, SriniVas R. CA Trial Oral Valproic Acid Retinitis TI Quantification of Ellipsoid Zone Changes in Retinitis Pigmentosa Using en Face Spectral Domain-Optical Coherence Tomography SO JAMA OPHTHALMOLOGY LA English DT Article ID VISUAL-FIELD SENSITIVITY; GEOGRAPHIC ATROPHY; NATURAL-HISTORY; CLINICAL-TRIALS; THICKNESS; RECEPTOR; RATES AB IMPORTANCE New methods are needed to quantify the change in the outer retinal structures in retinitis pigmentosa (RP). OBJECTIVE To implement an alternate method for tracking ellipsoid zone (EZ) changes in RP by quantifying the EZ area on en face spectral domain-optical coherence tomographic (SD-OCT) images. DESIGN, SETTING, AND PARTICIPANTS Data for this observational case study were collected at the Department of Ophthalmology, University of California, Los Angeles, from May 1 to July 30, 2015, and included SD-OCT images of a subset of patients from the Trial of Oral Valproic Acid for Retinitis Pigmentosa. To be eligible for the en face OCT subanalysis, the preserved EZ area was required to be limited to the SD-OCT scanning field. Cases in which the EZ band extended to the margins of any B-scan or the most superior or inferior B-scan were excluded. The SD-OCT images of all included cases were imported into the manufacturer's software to generate en face images at the level of the EZ. Two certified SD-OCT graders independently delineated the boundaries of the preserved EZ on the en face images. MAIN OUTCOMES AND MEASURES Comparison of the 2 masked gradings of the generated en face images of patients with RP for agreement between the graders and the validity of the method. RESULTS Of the 43 available patients with volume SD-OCT data, 45 eyes of 24 patients met the eligibility criteria and were included in this subanalysis. Every patient had 2 visits that were 1 year apart, which included a total of 90 en face OCT images that were graded. The mean (SD) absolute difference and percentage difference between the 2 independent graders for each visit were 0.08 (0.10) mm(2) and 4.5%(5.9%), respectively. The EZ area determined by the 2 graders showed excellent agreement with an intraclass correlation coefficient of 0.996 (95% CI, 0.995-0.997; P < .001). CONCLUSIONS AND RELEVANCE Quantification of the preserved EZ area on en face SD-OCT images of patients with RP is a valid and reproducible method. En face SD-OCT quantification may be a useful tool for monitoring the EZ changes of patients with advanced RP and a useful outcome measurement variable in therapeutic trials. C1 [Hariri, Amir H.; Zhang, Hong Yang; Ho, Alexander; Sadda, SriniVas R.] Doheny Eye Inst, 1355 San Pablo St,Ste 119, Los Angeles, CA 90033 USA. [Hariri, Amir H.; Zhang, Hong Yang; Sadda, SriniVas R.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Ophthalmol, Los Angeles, CA USA. [Francis, Peter] Pacific Ophthalmol Consulting, Portland, OR USA. [Weleber, Richard G.] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. [Birch, David G.] Retina Fdn Southwest, Dallas, TX USA. [Ferris, Frederick L., III] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Sadda, SR (reprint author), Doheny Eye Inst, 1355 San Pablo St,Ste 119, Los Angeles, CA 90033 USA. EM ssadda@doheny.org FU Foundation Fighting Blindness Clinical Research Institute FX The Trial for Oral Valproic Acid for Retinitis Pigmentosa was supported by the Foundation Fighting Blindness Clinical Research Institute, which also sponsored the ellipsoid zone area analysis described in this report. NR 18 TC 2 Z9 2 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD JUN PY 2016 VL 134 IS 6 BP 628 EP 635 DI 10.1001/jamaophthalmol.2016.0502 PG 8 WC Ophthalmology SC Ophthalmology GA DR0KL UT WOS:000379596300004 PM 27031504 ER PT J AU Saha, TD Kerridge, BT Goldstein, RB Chou, SP Zhang, HT Jung, J Pickering, RP Ruan, WJ Smith, SM Huang, B Hasin, DS Grant, BF AF Saha, Tulshi D. Kerridge, Bradley T. Goldstein, Rise B. Chou, S. Patricia Zhang, Haitao Jung, Jeesun Pickering, Roger P. Ruan, W. June Smith, Sharon M. Huang, Boji Hasin, Deborah S. Grant, Bridget F. TI Nonmedical Prescription Opioid Use and DSM-5 Nonmedical Prescription Opioid Use Disorder in the United States SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article DE Substance-Related Disorders ID NATIONAL EPIDEMIOLOGIC SURVEY; ALCOHOL-USE DISORDER; SUBSTANCE USE DISORDERS; DRUG-USE DISORDERS; MEDICATION-ASSISTED TREATMENT; INTERVIEW SCHEDULE AUDADIS; GENERAL-POPULATION SAMPLE; CHRONIC NONCANCER PAIN; BORDERLINE PERSONALITY-DISORDER; CHRONIC BACK-PAIN AB Objective: The authors present 12-month and lifetime prevalence, correlates, psychiatric comorbidity, and treatment of nonmedical prescription opioid use (NMPOU) and DSM-5 NMPOU disorder (NMPOUD). Methods: Data were derived from the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III) (N = 36,309). Results: Prevalences of 12-month and lifetime NMPOU were 4.1% and 11.3%, exceeding rates in the 2001-2002 NESARC (1.8%, 4.7%). Twelve-month and lifetime rates of DSM-5 NMPOUD were 0.9% and 2.1%. NESARC-III DSM-IV NMPOUD rates (0.8%, 2.9%) were greater than those observed in the 2001-2002 NESARC (0.4% and 1.4%). Rates of NMPOU were greater among men, but no sex differential was observed for NMPOUD. Prevalences of NMPOU and NMPOUD were generally greater among 18- to 64-year-old individuals, whites, and Native Americans, and individuals with lower socioeconomic status. Associations were observed between 12-month and lifetime NMPOU and NMPOUD and other drug use disorders, posttraumatic stress disorder, and borderline, schizotypal, and antisocial personality disorders; persistent depression and major depressive disorder (for NMPOU); and bipolar I disorder (for NMPOUD). Only 5.5% and 17.7% of individuals with 12-month NMPOU and NMPOUD were ever treated. Conclusions: NMPOU and NMPOUD have considerably increased over the past decade, are associated with a broad array of risk factors and comorbidities, and largely go untreated in the United States. More information on the determinants, characteristics, and outcomes of NMPOU and NMPOUD is needed to support evidence-based interventions and prevention. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Saha, Tulshi D.; Goldstein, Rise B.; Chou, S. Patricia; Zhang, Haitao; Jung, Jeesun; Pickering, Roger P.; Ruan, W. June; Smith, Sharon M.; Huang, Boji; Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, 5635 Fishers Ln,Room 3083, Rockville, MD 20852 USA. [Kerridge, Bradley T.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Hasin, Deborah S.] Columbia Univ, Mailman Sch Publ Hlth, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Hasin, Deborah S.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. RP Saha, TD (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, 5635 Fishers Ln,Room 3083, Rockville, MD 20852 USA. EM sahatd@mail.nih.gov OI Goldstein, Rise/0000-0002-9603-9473 FU National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institute on Drug Abuse; National Institute on Drug Abuse [R01DA034244-01, F32DA0364431]; New York State Psychiatric Institute; NIAAA, National Institutes of Health FX The 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 Institute on Drug Abuse R01DA034244-01 and New York State Psychiatric Institute (Dr Hasin), National Institute on Drug Abuse F32DA0364431 (Dr Kerridge), and from the intramural program, NIAAA, National Institutes of Health. NR 105 TC 3 Z9 3 U1 7 U2 12 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JUN PY 2016 VL 77 IS 6 BP 772 EP 780 DI 10.4088/JCP.15m10386 PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DQ6GM UT WOS:000379302500014 PM 27337416 ER PT J AU Tohen, M Khalsa, HMK Salvatore, P Zarate, CA Strakowski, SM Sanchez-Toledo, JP Baldessarini, RJ AF Tohen, Mauricio Khalsa, Hari-Mandir K. Salvatore, Paola Zarate, Carlos A., Jr. Strakowski, Stephen M. Sanchez-Toledo, Jesus Perez Baldessarini, Ross J. TI The McLean-Harvard First-Episode Project: Early Course in 114 Cases of First-Episode Nonaffective Psychoses SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article DE Diagnosis/Diagnosec Tools; Psychoec Disorders ID DIAGNOSTIC STABILITY; FOLLOW-UP; BIPOLAR DISORDER; SCHIZOPHRENIFORM DISORDER; CYCLOID PSYCHOSES; 2-YEAR STABILITY; CAVAN-MONAGHAN; RECOVERY; PSYCHOPATHOLOGY; HOSPITALIZATION AB Background: Early course in contemporary, clinically treated, nonaffective psychotic disorders other than schizophrenia remains incompletely defined. Methods: We prospectively, repeatedly, and systematically assessed 114 patients hospitalized for a first episode of DSM-IV-TR nonaffective psychotic illness for >= 2 years (1989-1996) using structured (Structured Clinical Interview for DSM-III-R, Patient Edition; Clinical Global Impressions scale; Scale for the Assessment of Negative Symptoms; Scale for the Assessment of Positive Symptoms; and the expanded version of the Brief Psychiatric Rating Scale) and unstructured (best-estimate procedure, life charting) naturalistic follow-up procedures and survival analysis. Results: Duration of untreated psychosis (22 +/- 38 months) was longest with schizophrenia. Within 2 years, syndromal remission sustained for >= 8 weeks (recovery) was attained by 75 subjects (65.8%); median latency to syndromal recovery was 9.4 (95% CI, 5.7-13.3) weeks and was shorter with cycloid features, initial diagnosis of brief psychosis or schizophreniform disorder, and shorter initial hospitalization. Functional recovery within 2 years was achieved by 28 of 68 subjects (41.2%), more often without initial mood-psychomotor instability or homicidal ideation. New episodes occurred in 52 of 114 subjects (45.6%) and were more likely with less affective flattening, younger age, and white race. Median time to new episodes (43.7 [27.9-70.6] weeks) was earlier with initial first-rank auditory hallucinations, substance abuse, and functional nonrecovery. Diagnosis changed to other nonaffective, schizoaffective, or affective disorders within 2 years in 62 of 108 cases (57.4%). Conclusions: Three-quarters of patients presenting in first lifetime, nonaffective psychotic episodes achieved recovery within 2 years, but only 41% returned to baseline functioning, and nearly half experienced new episodes. Patients with schizophrenia had the longest duration of untreated psychosis. A majority changed diagnosis, indicating instability of some DSM psychotic-disorder diagnoses. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Tohen, Mauricio] Univ New Mexico, Hlth Sci Ctr, Dept Psychiat, 2400 Tucker Ave, Albuquerque, NM 87131 USA. [Tohen, Mauricio; Khalsa, Hari-Mandir K.; Salvatore, Paola; Baldessarini, Ross J.] McLean Hosp, Int Consortium Bipolar & Psychot Disorders Res, Boston, MA USA. [Tohen, Mauricio; Khalsa, Hari-Mandir K.; Salvatore, Paola; Baldessarini, Ross J.] Harvard Med Sch, Boston, MA USA. [Tohen, Mauricio; Salvatore, Paola; Baldessarini, Ross J.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Salvatore, Paola] Univ Parma, Sch Med, Dept Neurosci, Psychiat Sect, Parma, Italy. [Zarate, Carlos A., Jr.] NIMH, Bethesda, MD 20892 USA. [Strakowski, Stephen M.] Univ Cincinnati, Dept Psychiat, Cincinnati, OH USA. [Sanchez-Toledo, Jesus Perez] Univ Cambridge, Dept Psychiat, Cambridge, England. [Strakowski, Stephen M.] Univ Texas Austin, Dell Med Sch, Dept Psychiat, Austin, TX 78712 USA. RP Tohen, M (reprint author), Univ New Mexico, Hlth Sci Ctr, Dept Psychiat, 2400 Tucker Ave, Albuquerque, NM 87131 USA. EM mtohen@salud.unm.edu FU National Institute of Mental Health [MH-04844, MH-10948]; Atlas Foundation grants; National Alliance for Research on Schizophrenia and Depression; National Institutes of Health [MH-47370, MH-073049]; Bruce J. Anderson Foundation; McLean Private Donors Research Fund FX Supported by National Institute of Mental Health (MH-04844, MH-10948) and Atlas Foundation grants (Dr Tohen), National Alliance for Research on Schizophrenia and Depression (Dr Salvatore), National Institutes of Health grants (MH-47370, MH-073049), and a grant from the Bruce J. Anderson Foundation and by the McLean Private Donors Research Fund (Dr Baldessarini). NR 46 TC 0 Z9 0 U1 3 U2 3 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JUN PY 2016 VL 77 IS 6 BP 781 EP 788 DI 10.4088/JCP.14m09414 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DQ6GM UT WOS:000379302500015 PM 27232651 ER PT J AU Han, B Compton, WM Eisenberg, D Milazzo-Sayre, L McKeon, R Hughes, A AF Han, Beth Compton, Wilson M. Eisenberg, Daniel Milazzo-Sayre, Laura McKeon, Richard Hughes, Art TI Prevalence and Mental Health Treatment of Suicidal Ideation and Behavior Among College Students Aged 18-25 Years and Their Non-College-Attending Peers in the United States SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article DE Suicide ID COMORBIDITY-SURVEY-REPLICATION; MAJOR DEPRESSIVE DISORDER; SUBSTANCE USE DISORDERS; COMMON OUTCOMES; PREVENTION PROGRAM; RELATIVE RISK; CARE; ADULTS; POPULATION; PREDICTORS AB Objective: College students have been the focus of many studies on suicidal ideation with or without suicidal behavior. Little attention has been given to their non-collegeattending peers on these issues. We examined the 12-month prevalence and mental health treatment of suicidal ideation with or without suicidal behavior among college students aged 18-25 years and their non-college-attending peers in the United States. Methods: We assessed data from 135,300 persons aged 18-25 years who participated in the 2008-2013 National Surveys on Drug Use and Health. Descriptive analyses and multivariate logistic regression models were applied. Results: Compared with full-time college students, high school students, those not enrolled in a school or college, and part-time college students were more likely to attempt suicide with a plan (model-adjusted prevalence = 0.67% vs 1.09%, 1.06%, and 1.07%, respectively). The mental health treatment rate among full-time college students with suicidal ideation with or without suicidal behavior was similar to the rates among the other 3 counterparts. The effects of race/ethnicity and serious mental illness on receipt of mental health treatment were significantly larger among those who did not perceive unmet treatment need than among those who perceived unmet treatment need (P = .019 and P = .001, respectively). Conclusions: Compared to full-time college students, non-college-attending young adults and part-time college students were at higher risk for attempting suicide with a plan. Suicide prevention and intervention strategies should emphasize increasing access to mental health treatment among both college students with suicidal ideation with or without suicidal behavior and their non-college-attending peers (particularly among minorities and those who seem to be at low risk because they are without serious mental illness and report no need for mental health treatment). (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Han, Beth; Milazzo-Sayre, Laura; McKeon, Richard; Hughes, Art] Subst Abuse & Mental Hlth Serv Adm, Rockville, MD USA. [Compton, Wilson M.] NIDA, NIH, Bethesda, MD 20892 USA. [Eisenberg, Daniel] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. RP Han, B (reprint author), 5600 Fishers Lane,15E85C, Rockville, MD 20857 USA. EM Beth.Han@SAMHSA.HHS.GOV NR 51 TC 1 Z9 1 U1 8 U2 10 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JUN PY 2016 VL 77 IS 6 BP 815 EP 824 DI 10.4088/JCP.15m09929 PG 10 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DQ6GM UT WOS:000379302500020 PM 27232194 ER PT J AU Ballard, ED Voort, JLV Bernert, RA Luckenbaugh, DA Richards, EM Niciu, MJ Furey, ML Duncan, WC Zarate, CA AF Ballard, Elizabeth D. Voort, Jennifer L. Vande Bernert, Rebecca A. Luckenbaugh, David A. Richards, Erica M. Niciu, Mark J. Furey, Maura L. Duncan, Wallace C., Jr. Zarate, Carlos A., Jr. TI Nocturnal Wakefulness Is Associated With Next-Day Suicidal Ideation in Major Depressive Disorder and Bipolar Disorder SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article DE Bipolar Disorder; Depression; Sleep Disorders; Suicide ID SLEEP-DEPRIVATION; SCALE; BEHAVIOR; RHYTHMS; HEALTH; ADULTS AB Objective: Self-reported sleep disturbances may confer elevated risk for suicidal ideation, suicide attempts, and death. However, limited research has evaluated polysomnographically determined sleep disturbance as an acute physiologic risk factor for suicidal thoughts. This study sought to investigate the relationship between nocturnal wakefulness in association with next-day suicidal ideation using overnight polysomnography assessment from data collected between 2006 and 2013. Methods: Sixty-five participants with DSM-IV-diagnosed major depressive disorder or bipolar depression underwent overnight polysomnography monitoring in a sleep laboratory. The Hamilton Depression Rating Scale (HDRS) was administered the morning after polysomnography recording to assess next-day suicidal ideation, severity of depressive symptoms, and subjective sleep disturbances. Results: Using a generalized linear mixed model, a significant time-by-ideation interaction was found indicating greater nocturnal wakefulness at 4:00 am among participants with suicidal ideation (F-4,F-136 = 3.65, P = .007). Increased time awake during the 4:00 am hour (4:00 to 4:59) was significantly associated with elevated suicidal thoughts the next day (standardized beta = 0.31, P = .008). This relationship persisted after controlling for age, gender, diagnosis, and severity of depressive symptoms. Conclusions: Greater nocturnal wakefulness, particularly in the early morning hours, was significantly associated with next-day suicidal thoughts. Polysomnographically documented sleep disruption at specific times of night may represent an acute risk factor of suicidal ideation that warrants additional research. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Ballard, Elizabeth D.; Voort, Jennifer L. Vande; Luckenbaugh, David A.; Richards, Erica M.; Niciu, Mark J.; Furey, Maura L.; Duncan, Wallace C., Jr.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Bernert, Rebecca A.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Suicide Prevent Res Lab,Stanford Mood Disorders C, Stanford, CA 94305 USA. [Furey, Maura L.] Janssen Pharmaceut, Neurosci Res & Dev, La Jolla, CA USA. RP Ballard, ED (reprint author), Bldg 10,CRC Room 7-5345,10 Ctr Dr,MSC 1282, Bethesda, MD 20892 USA. EM Elizabeth.Ballard@nih.gov RI Niciu, Mark/J-1766-2014 OI Niciu, Mark/0000-0002-5612-3021 FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) [NCT00024635, 04-M-0222]; NARSAD Independent Investigator Grant; Brain & Behavior Mood Disorders Research Award; National Institutes of Health [K23MH093490] FX Funding for this work was provided in part by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) (NCT00024635; 04-M-0222), by a NARSAD Independent Investigator Grant to Dr Zarate, by a Brain & Behavior Mood Disorders Research Award to Dr Zarate, and by grants from the National Institutes of Health (K23MH093490) to Dr Bernert. NR 33 TC 1 Z9 1 U1 0 U2 0 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JUN PY 2016 VL 77 IS 6 BP 825 EP 831 DI 10.4088/JCP.15m09943 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DQ6GM UT WOS:000379302500021 PM 27337418 ER PT J AU Fost, N AF Fost, Norman TI Informed Consent Should Be a Required Element for Newborn Screening, Even for Disorders with High Benefit-Risk Ratios SO JOURNAL OF LAW MEDICINE & ETHICS LA English DT Article ID SODIUM-BICARBONATE; MATERNAL PHENYLKETONURIA; INTRACRANIAL HEMORRHAGE; BILIRUBIN LEVELS; OUTCOMES; INFANTS; PHENYLALANINE; MEDICINE; CHILDREN; THERAPY AB Over-enthusiastic newborn screening has often caused substantial harm and has been imposed on the public without adequate information on benefits and risks and without parental consent. This problem will become worse when genomic screening is implemented. For the past 40 years, there has been broad agreement about the criteria for ethically responsible screening, but the criteria have been systematically ignored by policy makers and practitioners. Claims of high benefit and low risk are common, but they require precise definition and documentation, which has often not occurred, undermining claims that involuntary testing is justified. Even when the benefits and risks are well established, it does not automatically follow that involuntary testing is justified, a position supported by the widespread tolerance for parental refusal of immunizations and newborn screening. C1 [Fost, Norman] Univ Wisconsin, Pediat, Madison, WI 53706 USA. [Fost, Norman] Univ Wisconsin, Bioeth Program, Madison, WI USA. [Fost, Norman] Univ Wisconsin, Child Protect Team, Madison, WI USA. [Fost, Norman] Hosp Eth Comm, Chapel Hill, NC USA. [Fost, Norman] Hlth Sci Inst Review Board, Chapel Hill, NC USA. [Fost, Norman] US FDA, Pediat Advisory Comm, Rockville, MD 20857 USA. [Fost, Norman] NIH, Recombinant DNA Advisory Comm, Bldg 10, Bethesda, MD 20892 USA. RP Fost, N (reprint author), Univ Wisconsin, Pediat, Madison, WI 53706 USA. NR 62 TC 3 Z9 3 U1 4 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-1105 EI 1748-720X J9 J LAW MED ETHICS JI J. Law Med. Ethics PD JUN PY 2016 VL 44 IS 2 BP 241 EP 255 DI 10.1177/1073110516654118 PG 15 WC Ethics; Law; Medical Ethics; Medicine, Legal SC Social Sciences - Other Topics; Government & Law; Medical Ethics; Legal Medicine GA DR0QI UT WOS:000379611600004 PM 27338600 ER PT J AU Smith, GH AF Smith, Gilbert H. TI Binuclear Cells in the Lactating Mammary Gland: New Insights on an Old Concept? SO JOURNAL OF MAMMARY GLAND BIOLOGY AND NEOPLASIA LA English DT Review DE Mammary; Differentiation; Lactation; Deoxyribonucleic acid (DNA) synthesis ID FUNCTIONAL-DIFFERENTIATION; DNA-SYNTHESIS; EPITHELIAL-CELLS; VIRGIN; MICE; PREGNANCY AB In a recent paper (Rios et al. Nat Commun. 7:11400, 2016), it was reported that polyploid cells are frequent in lactating mammary tissues. This phenomenon was observed in mammary tissue sampled from five separate mammalian species. According to that report, these binucleated cells occur late in pregnancy and early in lactation. Unfortunately, this paper did not mention a number of earlier observations and findings that remain pertinent to this day (Banerjee et al. Life sciences Pt 2: Biochemistry, general and molecular biology. 10(15):867-77, 1971; Banerjee MR, Wagner JE. Biochem. Biophys. Res. Commun. 49(2):480-7, 1972). In these classical experiments, the authors demonstrated in vivo that DNA synthesis continued without commensurate cell division during late pregnancy and lactation, and that this DNA synthesis was imperative for functional differentiation of the mammary epithelium. Later studies showed that DNA synthesis was indispensable to the induction of milk protein production in explant cultures of mammary tissue from unprimed, nulliparous mice. This dependence on DNA synthesis in mammary explant cultures stimulated by lactogenic hormones was found to be dispensable following a single pregnancy. The absolute requirement for DNA synthesis in nulliparous mouse mammary explants stimulated to synthesize milk protein in vitro has remained unexplained, as has the need for DNA synthesis prior to the onset of lactation. From a historical perspective, it is more likely that binuclear secretory cells in the lactating mammary gland are a consequence of the DNA synthesis requirement for lactation, rather than an essential element. C1 [Smith, Gilbert H.] NCI, Basic Res Lab, Ctr Canc Res, NIH, Bldg 37,Rm 1122A,37 Convent Dr, Bethesda, MD 20892 USA. RP Smith, GH (reprint author), NCI, Basic Res Lab, Ctr Canc Res, NIH, Bldg 37,Rm 1122A,37 Convent Dr, Bethesda, MD 20892 USA. EM gs4d@nih.gov NR 12 TC 0 Z9 0 U1 1 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1083-3021 EI 1573-7039 J9 J MAMMARY GLAND BIOL JI J. Mammary Gland Biol. Neoplasia PD JUN PY 2016 VL 21 IS 1-2 BP 21 EP 23 DI 10.1007/s10911-016-9356-5 PG 3 WC Oncology; Endocrinology & Metabolism; Physiology SC Oncology; Endocrinology & Metabolism; Physiology GA DQ6PJ UT WOS:000379327000004 PM 27255141 ER PT J AU Rozas, P Lazcano, P Pina, R Cho, A Terse, A Pertusa, M Madrid, R Gonzalez-Billault, C Kulkarni, AB Utreras, E AF Rozas, Pablo Lazcano, Pablo Pina, Ricardo Cho, Andrew Terse, Anita Pertusa, Maria Madrid, Rodolfo Gonzalez-Billault, Christian Kulkarni, Ashok B. Utreras, Elias TI Targeted overexpression of tumor necrosis factor-alpha increases cyclin-dependent kinase 5 activity and TRPV1-dependent Ca2+ influx in trigeminal neurons SO PAIN LA English DT Article DE Orofacial pain; Inflammation; Cdk5; TNF-alpha; TRPV1 ID D-ASPARTATE RECEPTOR; DORSAL-ROOT GANGLIA; NEUROPATHIC PAIN; TNF-ALPHA; SPINAL-CORD; CDK5 ACTIVITY; CENTRAL MECHANISMS; INFLAMMATORY PAIN; PATHOLOGICAL PAIN; ACTIVATION AB We reported earlier that TNF-alpha, a proinflammatory cytokine implicated in many inflammatory disorders causing orofacial pain, increases the activity of Cdk5, a key kinase involved in brain development and function and recently found to be involved in pain signaling. To investigate a potential mechanism underlying inflammatory pain in trigeminal ganglia (TGs), we engineered a transgenic mouse model (TNFglo) that can conditionally overexpresses TNF-alpha upon genomic recombination by Cre recombinase. TNFglo mice were bred with Nav1.8-Cre mouse line that expresses the Cre recombinase in sensory neurons to obtain TNF-alpha: Nav1.8-Cre (TNF-alpha cTg) mice. Although TNF-alpha cTg mice appeared normal without any gross phenotype, they displayed a significant increase in TNF-alpha levels after activation of NFkB signaling in the TG. IL-6 and MCP-1 levels were also increased along with intense immunostaining for Iba1 and GFAP in TG, indicating the presence of infiltrating macrophages and the activation of satellite glial cells. TNF-alpha cTg mice displayed increased trigeminal Cdk5 activity, and this increase was associated with elevated levels of phospho-T407-TRPV1 and capsaicin-evocated Ca2+ influx in cultured trigeminal neurons. Remarkably, this effect was prevented by roscovitine, an inhibitor of Cdk5, which suggests that TNF-alpha overexpression induced sensitization of the TRPV1 channel. Furthermore, TNF-alpha cTg mice displayed more aversive behavior to noxious thermal stimulation (45 degrees C) of the face in an operant pain assessment device as compared with control mice. In summary, TNF-alpha overexpression in the sensory neurons of TNF-alpha cTg mice results in inflammatory sensitization and increased Cdk5 activity; therefore, this mouse model would be valuable for investigating the mechanism of TNF-alpha involved in orofacial pain. C1 [Rozas, Pablo; Lazcano, Pablo; Utreras, Elias] Univ Chile, Fac Sci, Dept Biol, Lab Mol & Cellular Mech Pain, Santiago, Chile. [Rozas, Pablo; Lazcano, Pablo; Gonzalez-Billault, Christian] Univ Chile, Fac Sci, Dept Biol, Lab Cellular & Neuronal Dynam, Santiago, Chile. [Pina, Ricardo; Pertusa, Maria; Madrid, Rodolfo] Univ Santiago Chile, Fac Chem & Biol, Dept Biol, Santiago, Chile. [Cho, Andrew; Terse, Anita; Kulkarni, Ashok B.] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. RP Utreras, E (reprint author), Univ Chile, Fac Sci, Dept Biol, Las Palmeras 3425, Santiago 7800024, Chile. EM elias.utreras@uchile.cl FU FONDECYT [11110136, 1151043, PAI-79100009, 1140325, ACT-1114, 1131064, ACT-1113, 11130144]; Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health FX This work was supported by FONDECYT 11110136 and 1151043, and PAI-79100009 (to E.U.), and FONDECYT 1140325 and ACT-1114 (to C.G.-B.); FONDECYT 1131064 (to R.M.) and ACT-1113 (to R.M. and M.P.); FONDECYT 11130144 (to M.P.); and the Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health. NR 71 TC 0 Z9 0 U1 6 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD JUN PY 2016 VL 157 IS 6 BP 1346 EP 1362 DI 10.1097/j.pain.0000000000000527 PG 17 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA DQ0GG UT WOS:000378876300022 PM 26894912 ER PT J AU Vamvaka, E Arcalis, E Ramessar, K Evans, A O'Keefe, BR Shattock, RJ Medina, V Stoger, E Christou, P Capell, T AF Vamvaka, Evangelia Arcalis, Elsa Ramessar, Koreen Evans, Abbey O'Keefe, Barry R. Shattock, Robin J. Medina, Vicente Stoger, Eva Christou, Paul Capell, Teresa TI Rice endosperm is cost-effective for the production of recombinant griffithsin with potent activity against HIV SO PLANT BIOTECHNOLOGY JOURNAL LA English DT Article DE griffithsin; rice; endosperm; lectin; HIV; microbicides ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIVIRAL PROTEIN GRIFFITHSIN; ENTRY INHIBITOR GRIFFITHSIN; SEED-DERIVED EXPLANTS; VAGINAL MICROBICIDE; PARTICLE BOMBARDMENT; GENITAL HERPES; ANTIBODY 2G12; BINDING; TYPE-1 AB Protein microbicides containing neutralizing antibodies and antiviral lectins may help to reduce the rate of infection with human immunodeficiency virus (HIV) if it is possible to manufacture the components in large quantities at a cost affordable in HIV-endemic regions such as sub-Saharan Africa. We expressed the antiviral lectin griffithsin (GRFT), which shows potent neutralizing activity against HIV, in the endosperm of transgenic rice plants (Oryza sativa), to determine whether rice can be used to produce inexpensive GRFT as a microbicide ingredient. The yield of (OS)GRFT in the best-performing plants was 223 mu g/g dry seed weight. We also established a one-step purification protocol, achieving a recovery of 74% and a purity of 80%, which potentially could be developed into a larger-scale process to facilitate inexpensive downstream processing. (OS)GRFT bound to HIV glycans with similar efficiency to GRFT produced in Escherichia coli. Whole-cell assays using purified (OS)GRFT and infectivity assays using crude extracts of transgenic rice endosperm confirmed that both crude and pure (OS)GRFT showed potent activity against HIV and the crude extracts were not toxic towards human cell lines, suggesting they could be administered as a microbicide with only minimal processing. A freedom-to-operate analysis confirmed that GRFT produced in rice is suitable for commercial development, and an economic evaluation suggested that 1.8 kg/ha of pure GRFT could be produced from rice seeds. Our data therefore indicate that rice could be developed as an inexpensive production platform for GRFT as a microbicide component. C1 [Vamvaka, Evangelia; Medina, Vicente; Christou, Paul; Capell, Teresa] Univ Lleida, Sch Agrifood & Forestry Sci & Engn ETSEA, Dept Plant Prod & Forestry Sci, Agrotecnio Ctr, Lleida, Spain. [Arcalis, Elsa; Stoger, Eva] Univ Nat Resources & Life Sci, Dept Appl Genet & Cell Biol, Mol Plant Physiol & Crop Biotechnol, Vienna, Austria. [Ramessar, Koreen; O'Keefe, Barry R.] NCI, Mol Targets Lab, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Evans, Abbey; Shattock, Robin J.] Univ London Imperial Coll Sci Technol & Med, Dept Med, Norfolk Pl, London, England. [O'Keefe, Barry R.] NCI, Nat Prod Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21701 USA. [Christou, Paul] Catalan Inst Res & Adv Studies ICREA, Barcelona, Spain. RP Capell, T (reprint author), Univ Lleida, Sch Agrifood & Forestry Sci & Engn ETSEA, Dept Plant Prod & Forestry Sci, Agrotecnio Ctr, Lleida, Spain. EM teresa.capell@pvcf.udl.cat OI VAMVAKA, EVANGELIA/0000-0002-9818-4404; Arcalis, Elsa/0000-0001-9883-465X FU Ministerio de Ciencia e Innovacion, Spain [BIO2012-35359]; Centre CONSOLIDER on Agrigenomics - MICINN, Spain; COST Action [FA0804]; National Cancer Institute, National Institutes of Health [HHSN26120080001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX The authors are grateful to Dr. Maite Sabalza Gallues for cloning the GRFT gene in the pgZ63 plasmid, Ms. Jennifer Wilson for technical assistance with live-virus anti-HIV assays and Ms. Lauren Krumpe for graphical assistance. In addition, the authors would like to acknowledge funding from the Ministerio de Ciencia e Innovacion, Spain (BIO2012-35359), the Centre CONSOLIDER on Agrigenomics funded by MICINN, Spain, and COST Action FA0804 (Molecular farming: plants as a production platform for high value proteins). The authors report no conflicts of interest. This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E, and supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations that imply endorsement by the U.S. Government. NR 69 TC 1 Z9 1 U1 4 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1467-7644 EI 1467-7652 J9 PLANT BIOTECHNOL J JI Plant Biotechnol. J. PD JUN PY 2016 VL 14 IS 6 BP 1427 EP 1437 DI 10.1111/pbi.12507 PG 11 WC Biotechnology & Applied Microbiology; Plant Sciences SC Biotechnology & Applied Microbiology; Plant Sciences GA DP8HY UT WOS:000378740200010 PM 26800650 ER PT J AU Liu, J Nussinov, R AF Liu, Jin Nussinov, Ruth TI Allostery: An Overview of Its History, Concepts, Methods, and Applications SO PLOS COMPUTATIONAL BIOLOGY LA English DT Editorial Material ID FOLDING FUNNELS; CONFORMATIONAL-CHANGE; PLAUSIBLE MODEL; PROTEINS; TRANSITIONS; HEMOGLOBIN AB The concept of allostery has evolved in the past century. In this Editorial, we briefly overview the history of allostery, from the pre-allostery nomenclature era starting with the Bohr effect (1904) to the birth of allostery by Monod and Jacob (1961). We describe the evolution of the allostery concept, from a conformational change in a two-state model (1965, 1966) to dynamic allostery in the ensemble model (1999); from multi-subunit (1965) proteins to all proteins (2004). We highlight the current available methods to study allostery and their applications in studies of conformational mechanisms, disease, and allosteric drug discovery. We outline the challenges and future directions that we foresee. Altogether, this Editorial narrates the history of this fundamental concept in the life sciences, its significance, methodologies to detect and predict it, and its application in a broad range of living systems. C1 [Liu, Jin] Univ North Texas Hlth Sci Ctr, Dept Pharmaceut Sci, Univ North Texas Syst Coll Pharm, Ft Worth, TX USA. [Liu, Jin] Southern Methodist Univ, Dept Chem, CD4, Ctr Sci Computat, Dallas, TX USA. [Nussinov, Ruth] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Inst Mol Med, Dept Human Genet & Mol Med, Sackler Sch Med, Tel Aviv, Israel. RP Liu, J (reprint author), Univ North Texas Hlth Sci Ctr, Dept Pharmaceut Sci, Univ North Texas Syst Coll Pharm, Ft Worth, TX USA.; Liu, J (reprint author), Southern Methodist Univ, Dept Chem, CD4, Ctr Sci Computat, Dallas, TX USA.; Nussinov, R (reprint author), NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA.; Nussinov, R (reprint author), Tel Aviv Univ, Sackler Inst Mol Med, Dept Human Genet & Mol Med, Sackler Sch Med, Tel Aviv, Israel. EM jin.liu@unthsc.edu; NussinoR@helix.nih.gov NR 27 TC 3 Z9 3 U1 7 U2 13 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 JUN PY 2016 VL 12 IS 6 AR e1004966 DI 10.1371/journal.pcbi.1004966 PG 5 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA DQ6XN UT WOS:000379349700040 PM 27253437 ER PT J AU Matias, WR Falkard, B Charles, RC Mayo-Smith, LM Teng, JE Xu, P Kovac, P Ryan, ET Qadri, F Franke, MF Ivers, LC Harris, JB AF Matias, Wilfredo R. Falkard, Brie Charles, Richelle C. Mayo-Smith, Leslie M. Teng, Jessica E. Xu, Peng Kovac, Pavol Ryan, Edward T. Qadri, Firdausi Franke, Molly F. Ivers, Louise C. Harris, Jason B. TI Antibody Secreting Cell Responses following Vaccination with Bivalent Oral Cholera Vaccine among Haitian Adults SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID MEMORY B-CELL; O-SPECIFIC POLYSACCHARIDE; VIBRIO-CHOLERAE; IMMUNE-RESPONSES; WHOLE-CELL; KILLED CHOLERA; INFECTION; CHILDREN; BANGLADESH; LIPOPOLYSACCHARIDE AB Background The bivalent whole-cell (BivWC) oral cholera vaccine (Shanchol) is effective in preventing cholera. However, evaluations of immune responses following vaccination with BivWC have been limited. To determine whether BivWC induces significant mucosal immune responses, we measured V. cholerae O1 antigen-specific antibody secreting cell (ASC) responses following vaccination. Methodology/Principal Findings We enrolled 24 Haitian adults in this study, and administered doses of oral BivWC vaccine 14 days apart (day 0 and day 14). We drew blood at baseline, and 7 days following each vaccine dose (day 7 and 21). Peripheral blood mononuclear cells (PBMCs) were isolated, and ASCs were enumerated using an ELISPOT assay. Significant increases in Ogawa (6.9 cells per million PBMCs) and Inaba (9.5 cells per million PBMCs) OSP-specific IgA ASCs were detected 7 days following the first dose (P < 0.001), but not the second dose. The magnitude of V. cholerae-specific ASC responses did not appear to be associated with recent exposure to cholera. ASC responses measured against the whole lipolysaccharide (LPS) antigen and the OSP moiety of LPS were equivalent, suggesting that all or nearly all of the LPS response targets the OSP moiety. Conclusions/Significance Immunization with the BivWC oral cholera vaccine induced ASC responses among a cohort of healthy adults in Haiti after a single dose. The second dose of vaccine resulted in minimal ASC responses over baseline, suggesting that the current dosing schedule may not be optimal for boosting mucosal immune responses to V. cholerae antigens for adults in a choleraendemic area. C1 [Matias, Wilfredo R.; Franke, Molly F.; Ivers, Louise C.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA USA. [Matias, Wilfredo R.; Ivers, Louise C.] Partners In Hlth, Boston, MA USA. [Falkard, Brie; Charles, Richelle C.; Mayo-Smith, Leslie M.; Ryan, Edward T.; Harris, Jason B.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Charles, Richelle C.] Harvard Univ, Sch Med, Boston, MA USA. [Teng, Jessica E.; Ivers, Louise C.] Brigham & Womens Hosp, Div Global Hlth Equ, 75 Francis St, Boston, MA 02115 USA. [Xu, Peng; Kovac, Pavol] NIDDK, LBC, NIH, Bethesda, MD 20892 USA. [Qadri, Firdausi] Icddr B, Dhaka, Bangladesh. [Harris, Jason B.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Harris, JB (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA.; Harris, JB (reprint author), Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. EM jbharris@mgh.harvard.edu RI Xu, Peng/K-7036-2012 FU Doris Duke Charitable Foundation; Doris Duke Charitable Foundation - National Institutes of Health; National Institute of Allergy and Infectious Diseases [AI099243, AI103055, AI106878, K08 AI089721]; Intramural Research Program of the NIH; NIDDK; Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program; Abundance foundation FX This research was supported by core grants to the icddr,b, the Doris Duke Charitable Foundation through a grant supporting the Doris Duke International Clinical Research Fellows Program at Harvard Medical School (WRM), through programs funded by the National Institutes of Health, including the National Institute of Allergy and Infectious Diseases (AI099243 [JBH and LCI], AI103055 [JBH], AI106878 [ETR and FQ], and K08 AI089721 [RCC]), and the Intramural Research Program of the NIH and NIDDK (PX and PK), the Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program [RCC], the Abundance foundation [LCI]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 1 Z9 1 U1 2 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JUN PY 2016 VL 10 IS 6 AR e0004753 DI 10.1371/journal.pntd.0004753 PG 14 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DQ6WL UT WOS:000379346200021 PM 27308825 ER PT J AU Tacher, V Duran, R Lin, MD Sohn, JH Sharma, KV Wang, ZJ Chapiro, J Johnson, CG Bhagat, N Dreher, MR Schafer, D Woods, DL Lewis, AL Tang, YQ Grass, M Wood, BJ Geschwind, JF AF Tacher, Vania Duran, Rafael Lin, MingDe Sohn, Jae Ho Sharma, Karun V. Wang, Zhijun Chapiro, Julius Johnson, Carmen Gacchina Bhagat, Nikhil Dreher, Matthew R. Schaefer, Dirk Woods, David L. Lewis, Andrew L. Tang, Yiqing Grass, Michael Wood, Bradford J. Geschwind, Jean-Francois TI Multimodality Imaging of Ethiodized Oil-loaded Radiopaque Microspheres during Transarterial Embolization of Rabbits with VX2 Liver Tumors SO RADIOLOGY LA English DT Article ID DRUG-ELUTING BEADS; UNRESECTABLE HEPATOCELLULAR-CARCINOMA; TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION; ENDOVASCULAR EMBOLIZATION; SPHERICAL-PARTICLES; COMPUTED-TOMOGRAPHY; PORCINE MODEL; DOXORUBICIN; TACE; HYDROGELS AB Purpose: To assess the visibility of radiopaque microspheres during transarterial embolization (TAE) in the VX2 rabbit liver tumor model by using multimodality imaging, including single-snapshot radiography, cone-beam computed tomography (CT), multidetector CT, and micro-CT. Materials and Methods: The study was approved by the institutional animal care and use committee. Fifteen VX2-tumor-bearing rabbits were assigned to three groups depending on the type of embolic agent injected: 70-150-mu m radiopaque microspheres in saline (radiopaque microsphere group), 70-150-mu m radiopaque microspheres in contrast material (radiopaque microsphere plus contrast material group), and 70-150-mu m radiolucent microspheres in contrast material (nonradiopaque microsphere plus contrast material group). Rabbits were imaged with single-snapshot radiography, cone-beam CT, and multidetector CT. Three to 5 weeks after sacrifice, excised livers were imaged with micro-CT and histologic analysis was performed. The visibility of the embolic agent was assessed with all modalities before and after embolization by using a qualitative three-point scale score reading study and a quantitative assessment of the signal-to-noise ratio (SNR) change in various regions of interest, including the tumor and its feeding arteries. The Kruskal-Wallis test was used to compare the rabbit characteristics across groups, and the Wilcoxon signed rank test was used to compare SNR measurements before and after embolization. Results: Radiopaque microspheres were qualitatively visualized within tumor feeding arteries and targeted tissue with all imaging modalities (P<.05), and their presence was confirmed with histologic examination. SNRs of radiopaque microsphere deposition increased after TAE on multidetector CT, cone-beam CT, and micro-CT images (P<.05). Similar results were obtained when contrast material was added to radiopaque microspheres, except for additional image attenuation due to tumor enhancement. For the group with nonradiopaque microspheres and contrast material, retained tumoral contrast remained qualitatively visible with all modalities except for micro-CT, which demonstrated soluble contrast material washout over time. Conclusion: Radiopaque microspheres were visible with all imaging modalities and helped increase conspicuity of the tumor as well as its feeding arteries after TAE in a rabbit VX2 liver tumor model. (C) RSNA, 2015 C1 [Tacher, Vania; Duran, Rafael; Sohn, Jae Ho; Wang, Zhijun; Chapiro, Julius; Bhagat, Nikhil; Geschwind, Jean-Francois] Johns Hopkins Univ Hosp, Russell H Morgan Dept Radiol & Radiol Sci, Div Vasc & Intervent Radiol, Baltimore, MD 21287 USA. [Duran, Rafael; Sohn, Jae Ho; Chapiro, Julius; Geschwind, Jean-Francois] Yale Univ, Sch Med, Dept Radiol, 330 Cedar St,TE 2-230, New Haven, CT 06520 USA. [Lin, MingDe] Philips Res North Amer, US Imaging & Intervent UII, Cambridge, MA USA. [Sharma, Karun V.; Johnson, Carmen Gacchina; Dreher, Matthew R.; Woods, David L.; Wood, Bradford J.] NIH, Ctr Intervent Oncol, Intervent Radiol Sect, Bethesda, MD USA. [Dreher, Matthew R.; Lewis, Andrew L.; Tang, Yiqing] Biocompatibles UK Ltd, Surrey, England. [Schaefer, Dirk; Grass, Michael] Philips Res Hamburg, Hamburg, Germany. RP Geschwind, JF (reprint author), Johns Hopkins Univ Hosp, Russell H Morgan Dept Radiol & Radiol Sci, Div Vasc & Intervent Radiol, Baltimore, MD 21287 USA.; Geschwind, JF (reprint author), Yale Univ, Sch Med, Dept Radiol, 330 Cedar St,TE 2-230, New Haven, CT 06520 USA. EM jeff.geschwind@yale.edu OI Lewis, Andrew/0000-0001-5779-5631 FU French Society of Radiology; Philips Research North America; Biocompatibles UK Ltd.; National Institutes of Health [R01 CA160771] FX Supported by the French Society of Radiology, Philips Research North America, and Biocompatibles UK Ltd. This research was supported by the National Institutes of Health (grant R01 CA160771). NR 33 TC 2 Z9 2 U1 5 U2 8 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUN PY 2016 VL 279 IS 3 BP 741 EP 753 DI 10.1148/radiol.2015141624 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DP8AG UT WOS:000378719700010 PM 26678453 ER PT J AU Mortensen, NP Mercier, KA McRitchie, S Cavallo, TB Pathmasiri, W Stewart, D Sumner, SJ AF Mortensen, Ninell P. Mercier, Kelly A. McRitchie, Susan Cavallo, Tammy B. Pathmasiri, Wimal Stewart, Delisha Sumner, Susan J. TI Microfluidics meets metabolomics to reveal the impact of Campylobacter jejuni infection on biochemical pathways SO BIOMEDICAL MICRODEVICES LA English DT Article DE Microfluidic; Metabolomics; Campylobacter jejuni; Caco-2 cells; Host-pathogen interaction; Infectious disease model ID ON-A-CHIP; HUMAN INTESTINAL-CELLS; REACTIVE ARTHRITIS; MASS-SPECTROMETRY; INVASION; CULTURE; METABOLISM; COCULTURE; EXPOSURE; LIVER AB Microfluidic devices that are currently being used in pharmaceutical research also have a significant potential for utilization in investigating exposure to infectious agents. We have established a microfluidic device cultured with Caco-2 cells, and utilized metabolomics to investigate the biochemical responses to the bacterial pathogen Campylobacter jejuni. In the microfluidic devices, Caco-2 cells polarize at day 5, are uniform, have defined brush borders and tight junctions, and form a mucus layer. Metabolomics analysis of cell culture media collected from both Caco-2 cell culture systems demonstrated a more metabolic homogenous biochemical profile in the media collected from microfluidic devices, compared with media collected from transwells. GeneGo pathway mapping indicated that aminoacyl-tRNA biosynthesis was perturbed by fluid flow, suggesting that fluid dynamics and shear stress impacts the cells translational quality control. Both microfluidic device and transwell culturing systems were used to investigate the impact of Campylobacter jejuni infection on biochemical processes. Caco-2 cells cultured in either system were infected at day 5 with C. jejuni 81-176 for 48 h. Metabolomics analysis clearly differentiated C. jejuni 81-176 infected and non-infected medias collected from the microfluidic devices, and demonstrated that C. jejuni 81-176 infection in microfluidic devices impacts branched-chain amino acid metabolism, glycolysis, and gluconeogenesis. In contrast, no distinction was seen in the biochemical profiles of infected versus non-infected media collected from cells cultured in transwells. Microfluidic culturing conditions demonstrated a more metabolically homogenous cell population, and present the opportunity for studying host-pathogen interactions for extended periods of time. C1 [Mortensen, Ninell P.; Mercier, Kelly A.; McRitchie, Susan; Cavallo, Tammy B.; Pathmasiri, Wimal; Stewart, Delisha; Sumner, Susan J.] RTI Int, Syst & Translat Sci Discovery Sci Technol, 3040 Cornwallis Dr, Res Triangle Pk, NC 27709 USA. [Mercier, Kelly A.; McRitchie, Susan; Cavallo, Tammy B.; Pathmasiri, Wimal; Stewart, Delisha; Sumner, Susan J.] RTI Int, NIH Eastern Reg Comprehens Metabol Resource Core, Syst & Translat Sci, 3040 East Cornwallis Rd, Res Triangle Pk, NC 27709 USA. RP Mortensen, NP; Sumner, SJ (reprint author), RTI Int, Syst & Translat Sci Discovery Sci Technol, 3040 Cornwallis Dr, Res Triangle Pk, NC 27709 USA.; Sumner, SJ (reprint author), RTI Int, NIH Eastern Reg Comprehens Metabol Resource Core, Syst & Translat Sci, 3040 East Cornwallis Rd, Res Triangle Pk, NC 27709 USA. EM nmortensen@rti.org; ssumner@rti.org FU RTI International internal research; National Institute of Diabetes and Digestive and Kidney Diseases [1U24DK097193-01] FX This study was supported by RTI International internal research funding and National Institute of Diabetes and Digestive and Kidney Diseases (1U24DK097193-01, Dr. Susan Sumner, PI). The authors are grateful to Andrew Novokhatny and Zachery Acuff for providing analytical and statistical assistance with the metabolomics data analysis. The metabolomics data are available at the NIH Common Fund Metabolomics Data Repository and Coordinating Center at the University of California at San Diego (Dr. Shankar Subramaniam, PI) under studies ST000124 and ST000125. NR 65 TC 0 Z9 0 U1 8 U2 11 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1387-2176 EI 1572-8781 J9 BIOMED MICRODEVICES JI Biomed. Microdevices PD JUN PY 2016 VL 18 IS 3 AR 51 DI 10.1007/s10544-016-0076-9 PG 11 WC Engineering, Biomedical; Nanoscience & Nanotechnology SC Engineering; Science & Technology - Other Topics GA DP7PK UT WOS:000378691100011 PM 27231016 ER PT J AU Gaur, S Mandelbaum, M Herold, M Majumdar, HD Neilson, KM Maynard, TM Mood, K Daar, IO Moody, SA AF Gaur, Shailly Mandelbaum, Max Herold, Mona Majumdar, Himani Datta Neilson, Karen M. Maynard, Thomas M. Mood, Kathy Daar, Ira O. Moody, Sally A. TI Neural transcription factors bias cleavage stage blastomeres to give rise to neural ectoderm SO GENESIS LA English DT Article DE Foxd5; Foxd4; Foxd4l1; 1; Foxd4l1; geminin; Sox11; Zic2; Sox2; Zic1; neural induction ID GERM-LAYER SPECIFICATION; CELL MASS-SPECTROMETRY; XENOPUS-LAEVIS; SPEMANNS-ORGANIZER; GENE-EXPRESSION; MIDBLASTULA TRANSITION; CORTICAL ROTATION; PATTERN-FORMATION; BMP ANTAGONISTS; 32-CELL EMBRYO AB The decision by embryonic ectoderm to give rise to epidermal versus neural derivatives is the result of signaling events during blastula and gastrula stages. However, there also is evidence in Xenopus that cleavage stage blastomeres contain maternally derived molecules that bias them toward a neural fate. We used a blastomere explant culture assay to test whether maternally deposited transcription factors bias 16-cell blastomere precursors of epidermal or neural ectoderm to express early zygotic neural genes in the absence of gastrulation interactions or exogenously supplied signaling factors. We found that Foxd4l1, Zic2, Gmnn, and Sox11 each induced explants made from ventral, epidermis-producing blastomeres to express early neural genes, and that at least some of the Foxd4l1 and Zic2 activities are required at cleavage stages. Similarly, providing extra Foxd4l1 or Zic2 to explants made from dorsal, neural plate-producing blastomeres significantly increased the expression of early neural genes, whereas knocking down either significantly reduced them. These results show that maternally delivered transcription factors bias cleavage stage blastomeres to a neural fate. We demonstrate that mouse and human homologs of Foxd4l1 have similar functional domains compared to the frog protein, as well as conserved transcriptional activities when expressed in Xenopus embryos and blastomere explants. genesis 54:334-349, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Gaur, Shailly; Mandelbaum, Max; Herold, Mona; Majumdar, Himani Datta; Neilson, Karen M.; Moody, Sally A.] George Washington Univ, Sch Med & Hlth Sci, Dept Anat & Regenerat Biol, 2300 1 St NW, Washington, DC 20037 USA. [Maynard, Thomas M.; Moody, Sally A.] George Washington Univ, Inst Neurosci, Washington, DC 20037 USA. [Mood, Kathy; Daar, Ira O.] NCI, Lab Cell & Dev Signaling, NIH, Frederick, MD 21701 USA. RP Moody, SA (reprint author), George Washington Univ, Sch Med & Hlth Sci, Dept Anat & Regenerat Biol, 2300 1 St NW, Washington, DC 20037 USA. EM samoody@gwu.edu RI Maynard, Thomas/I-9039-2012; OI Maynard, Thomas/0000-0001-6976-3936; Daar, Ira/0000-0003-2657-526X; Moody, Sally/0000-0003-4192-1087 FU NSF [MCB-1121711]; GWU Luther Rice Undergraduate Research Fellowships; GWU School of Medicine and Health Sciences (GWIN); NCI [ZIA BC010006 20] FX NSF grant MCB-1121711 (SAM), GWU Luther Rice Undergraduate Research Fellowships (SG, MM, and MH), and GWU School of Medicine and Health Sciences (GWIN Biomarker Discovery Facility; TEM), NCI ZIA BC010006 20 (IOD). NR 95 TC 1 Z9 1 U1 10 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1526-954X EI 1526-968X J9 GENESIS JI Genesis PD JUN PY 2016 VL 54 IS 6 BP 334 EP 349 DI 10.1002/dvg.22943 PG 16 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA DQ4HR UT WOS:000379165300003 PM 27092474 ER PT J AU Hoy, MA Waterhouse, RM Wu, K Estep, AS Ioannidis, P Palmer, WJ Pomerantz, AF Simao, FA Thomas, J Jiggins, FM Murphy, TD Pritham, EJ Robertson, HM Zdobnov, EM Gibbs, RA Richards, S AF Hoy, Marjorie A. Waterhouse, Robert M. Wu, Ke Estep, Alden S. Ioannidis, Panagiotis Palmer, William J. Pomerantz, Aaron F. Simao, Felipe A. Thomas, Jainy Jiggins, Francis M. Murphy, Terence D. Pritham, Ellen J. Robertson, Hugh M. Zdobnov, Evgeny M. Gibbs, Richard A. Richards, Stephen TI Genome Sequencing of the Phytoseiid Predatory Mite Metaseiulus occidentalis Reveals Completely Atomized Hox Genes and Superdynamic Intron Evolution SO GENOME BIOLOGY AND EVOLUTION LA English DT Article DE Metaseiulus Typhlodromus Galendromus occidentalis; western orchard predatory mite; genome assembly; Helitron rolling-circle transposons parahaploid sex determination; Dicer-2 gene duplication ID MESOBUTHUS-MARTENSII REVEALS; DOUBLE-STRANDED-RNA; ACARI PHYTOSEIIDAE; DROSOPHILA-MELANOGASTER; HIERARCHICAL CATALOG; TETRANYCHUS-URTICAE; ORAL DELIVERY; DRAFT GENOME; MITE; TRANSCRIPTOME AB Metaselulus occidentalis is an eyeless phytoseiid predatory mite employed for the biological control of agricultural pests including spider mites. Despite appearances, these predator and prey mites are separated by some 400 Myr of evolution and radically different lifestyles. We present a 152-Mb draft assembly of the M. occidentalis genome: Larger than that of its favored prey, Tetranychus urticae, but considerably smaller than those of many other chelicerates, enabling an extremely contiguous and complete assembly to be built the best arachnid to date. Aided by transcriptome data, genome annotation cataloged 18,338 protein-coding genes and identified large numbers of Helitron transposable elements. Comparisons with other arthropods revealed a particularly dynamic and turbulent genomic evolutionary history. Its genes exhibit elevated molecular evolution, with strikingly high numbers of intron gains and losses, in stark contrast to the deer tick Ixodes scapularis. Uniquely among examined arthropods, this predatory mite's Hox genes are completely atomized, dispersed across the genome, and it encodes five copies of the normally single-copy RNA processing Dicer-2 gene. Examining gene families linked to characteristic biological traits of this tiny predator provides initial insights into processes of sex determination, development, immune defense, and how it detects, disables, and digests its prey. As the first reference genome for the Phytoseiidae, and for any species with the rare sex determination system of parahaploidy, the genome of the western orchard predatory mite improves genomic sampling of chelicerates and provides invaluable new resources for functional genomic analyses of this family of agriculturally important mites. C1 [Hoy, Marjorie A.; Wu, Ke; Estep, Alden S.; Pomerantz, Aaron F.] Univ Florida, Dept Entomol & Nematol, Gainesville, FL 32611 USA. [Waterhouse, Robert M.; Ioannidis, Panagiotis; Simao, Felipe A.; Zdobnov, Evgeny M.] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva 4, Switzerland. [Waterhouse, Robert M.; Ioannidis, Panagiotis; Simao, Felipe A.; Zdobnov, Evgeny M.] Swiss Inst Bioinformat, Geneva, Switzerland. [Waterhouse, Robert M.] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Waterhouse, Robert M.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Palmer, William J.; Jiggins, Francis M.] Univ Cambridge, Dept Genet, Cambridge CB2 1TN, England. [Thomas, Jainy; Pritham, Ellen J.] Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA. [Murphy, Terence D.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Robertson, Hugh M.] Univ Illinois, Dept Entomol, Champaign, IL USA. [Gibbs, Richard A.; Richards, Stephen] Baylor Coll Med, Human Genome Sequencing Ctr, Dept Mol & Human Genet, Houston, TX 77030 USA. RP Hoy, MA (reprint author), Univ Florida, Dept Entomol & Nematol, Gainesville, FL 32611 USA.; Waterhouse, RM (reprint author), Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva 4, Switzerland.; Waterhouse, RM (reprint author), Swiss Inst Bioinformat, Geneva, Switzerland.; Waterhouse, RM (reprint author), MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA.; Waterhouse, RM (reprint author), Broad Inst MIT & Harvard, Cambridge, MA USA.; Richards, S (reprint author), Baylor Coll Med, Human Genome Sequencing Ctr, Dept Mol & Human Genet, Houston, TX 77030 USA. EM mahoy@ufl.edu; robert.waterhouse@unige.ch; stephenr@bcm.edu RI Waterhouse, Robert/A-1858-2010; Zdobnov, Evgeny/K-1133-2012 OI Waterhouse, Robert/0000-0003-4199-9052; FU Davies, Fischer and Eckes endowment in biological control; Marie Curie International Outgoing Fellowship [PIOF-GA-2011-303312]; Swiss National Science Foundation [31003A-125350, 31003A-143936]; National Human Genome Research Institute [U54 HG003272] FX The authors thank the anonymous reviewers for their constructive comments. This work was supported by the Davies, Fischer and Eckes endowment in biological control to M.A.H.; Marie Curie International Outgoing Fellowship (PIOF-GA-2011-303312 to R.M.W.); the Swiss National Science Foundation (31003A-125350, 31003A-143936 to E.M.Z.); and the National Human Genome Research Institute (U54 HG003272 to R.A.G.). NR 73 TC 7 Z9 7 U1 15 U2 19 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 JUN PY 2016 VL 8 IS 6 BP 1762 EP 1775 DI 10.1093/gbe/evw048 PG 14 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA DP6UG UT WOS:000378633900011 PM 26951779 ER PT J AU Michael, A Michael, D Rothrock, JF AF Michael, A. Michael, D. Rothrock, J. F. TI Predictors of Early Positive Response to Treatment of Chronic Migraine With OnabotulinumtoxinA SO HEADACHE LA English DT Meeting Abstract CT 58th Annual Scientific Meeting of the American-Headache-Society CY JUN 09-12, 2016 CL San Diego, CA SP Amer Headache Soc C1 [Michael, A.; Rothrock, J. F.] George Washington Univ, Sch Med, Washington, DC USA. [Michael, D.] NIH, Natl Genome Res Inst, Washington, DC USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-8748 EI 1526-4610 J9 HEADACHE JI Headache PD JUN PY 2016 VL 56 SU 1 SI SI MA PF34 BP 30 EP 31 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA DQ4ER UT WOS:000379157200056 ER PT J AU Choi, J Michael, A Michael, D Rothrock, JF AF Choi, J. Michael, A. Michael, D. Rothrock, J. F. TI A Regional Comparison of Headache Clinic Populations: Demography, Diagnoses and Frequencies/Types of Symptomatic Medication Overuse SO HEADACHE LA English DT Meeting Abstract CT 58th Annual Scientific Meeting of the American-Headache-Society CY JUN 09-12, 2016 CL San Diego, CA SP Amer Headache Soc C1 [Choi, J.; Michael, A.; Rothrock, J. F.] George Washington Univ, Sch Med, Washington, DC USA. [Michael, D.] Natl Genome Res Inst, NIH, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-8748 EI 1526-4610 J9 HEADACHE JI Headache PD JUN PY 2016 VL 56 SU 1 SI SI MA PF64 BP 45 EP 46 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA DQ4ER UT WOS:000379157200083 ER PT J AU Perino, J Fried, N Oshinsky, M Daugherty, B Lederman, S Elliott, MB AF Perino, J. Fried, N. Oshinsky, M. Daugherty, B. Lederman, S. Elliott, M. B. TI The (R)-isomer of isometheptene decreases trigeminal sensitivity in a rat model of primary headache. SO HEADACHE LA English DT Meeting Abstract CT 58th Annual Scientific Meeting of the American-Headache-Society CY JUN 09-12, 2016 CL San Diego, CA SP Amer Headache Soc C1 [Perino, J.; Fried, N.; Elliott, M. B.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Fried, N.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Daugherty, B.; Lederman, S.] Tonix Pharmaceut Inc, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-8748 EI 1526-4610 J9 HEADACHE JI Headache PD JUN PY 2016 VL 56 SU 1 SI SI MA PS62 BP 79 EP 79 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA DQ4ER UT WOS:000379157200144 ER PT J AU Rudra, M Chatterjee, B Bahadur, M AF Rudra, Mahua Chatterjee, Bishwanath Bahadur, Min TI Phylogenetic relationship and time of divergence of Mus terricolor with reference to other Mus species SO JOURNAL OF GENETICS LA English DT Article DE mitochondrial DNA; phylogenetic relationship; sequence divergence; Mus terricolor; Mus spretus; Mus caroli ID NEIGHBOR-JOINING METHOD; DNA SEQUENCE VARIATION; INDIAN PYGMY MOUSE; MITOCHONDRIAL-DNA; HOUSE MICE; GENUS MUS; SUBGENUS MUS; CONSTITUTIVE HETEROCHROMATIN; EVOLUTIONARY DIVERGENCE; MUSCULUS AB Mitochondrial DNA control region of Mus terricolor, three aboriginal species M. spretus, M. macedonicus, M. spicilegus; the Asian lineage M. caroli, M. cervicolor, M. cookii; and the two house mice, M. musculus domesticus and M. m. castaneus were analysed to estimate the substitution rate, phylogenetic relationship and the probable time of divergence. Results showed that M. spretus, M. caroli and M. terricolor are highly diverged from each other (caroli/terricolor = 0.146, caroli/spretus = 0.147 and terricolor/spretus = 0.122), whereas M. spretus showed less divergence with two house mice species (0.070 and 0.071). Sequence divergence between M. terricolor and the Palearctic group were found to be ranging from 0.121 to 0.134. Phylogenetic analysis by minimum evolution, neighbour-joining, unweighed pair group method with arithmetic mean and maximum parsimony showed almost similar topology. Two major clusters were found, one included the Asian lineage, M. caroli, M. cookii and M. cervicolor and the other included the house mice M. m. domesticus, M. m. castaneus and the aboriginal mice M. macedonicus and M. spicilegus along with M. spretus, forming the Palearctic clade. M. terricolor was positioned between the Palearctic and Asian clades. Results showed that Palearctic-terricolor and the Asian lineages diverged 5.47 million years ago (Mya), while M. terricolor had split around 4.63 Mya from their ancestor. M. cervicolor, M. cookii and M. caroli diverged between 4.70 and 3.36 Mya, which indicates that M. terricolor and the Asian lineages evolved simultaneously. M. spretus is expected to have diverged nearly 2.9 Mya from their most recent common ancestor. C1 [Rudra, Mahua; Bahadur, Min] Univ North Bengal, Dept Zool, Genet & Mol Biol Lab, Siliguri 734013, India. [Chatterjee, Bishwanath] NHLBI, Lab Dev Biol, NIH, Bethesda, MD 20892 USA. RP Bahadur, M (reprint author), Univ North Bengal, Dept Zool, Genet & Mol Biol Lab, Siliguri 734013, India. EM bahadurmin@rediffmail.com FU University of North Bengal, Rajarammohunpur, Siliguri, West Bengal, India FX The financial support received from the University of North Bengal, Rajarammohunpur, Siliguri 734013, West Bengal, India, routed through the Department of Zoology is sincerely acknowledged. The DNA of M. caroli and M. spretus received from the Jackson Laboratory is gratefully acknowledged. The authors gratefully acknowledge Prof Ananda Mukhopadhyay, Department of Zoology, University of North Bengal for editing the manuscript with valuable suggestions on language. NR 70 TC 0 Z9 0 U1 1 U2 5 PU INDIAN ACAD SCIENCES PI BANGALORE PA C V RAMAN AVENUE, SADASHIVANAGAR, P B #8005, BANGALORE 560 080, INDIA SN 0022-1333 EI 0973-7731 J9 J GENET JI J. Genet. PD JUN PY 2016 VL 95 IS 2 BP 399 EP 409 DI 10.1007/s12041-016-0654-x PG 11 WC Genetics & Heredity SC Genetics & Heredity GA DQ2LN UT WOS:000379033900024 PM 27350685 ER PT J AU Ambudkar, IS AF Ambudkar, Indu S. TI Calcium signalling in salivary gland physiology and dysfunction SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Review ID PRIMARY SJOGRENS-SYNDROME; STROMAL INTERACTION MOLECULE-1; CA2+ STORE DEPLETION; TRPC CHANNELS; ACINAR-CELLS; FLUID SECRETION; PLASMA-MEMBRANE; EXOCRINE SECRETION; ELECTROLYTE SECRETION; MUSCARINIC RECEPTORS AB Studies over the past four decades have established that Ca2+ is a critical factor in control of salivary gland function and have led to identification of the critical components of this process. The major ion transport mechanisms and ion channels that are involved in fluid secretion have also been established. The key event in activation of fluid secretion is an increase in [Ca2+](i) triggered by inositol 1,4,5-trisphosphate (IP3)-induced release of Ca2+ from ER via the IP3 receptor (IP3R). IP3Rs determine the site of initiation and the pattern of the [Ca2+](i) signal in the cell. However, Ca2+ entry into the cell is required to sustain the elevation of [Ca2+](i) and fluid secretion and is mediated by the store-operated Ca2+ entry (SOCE) mechanism. Orai1, TRPC1, TRPC3 and STIM1 have been identified as critical components of SOCE in these cells. Cells finely tune the generation and amplification of [Ca2+](i) signals for regulation of cell function. An important emerging area is the concept that unregulated [Ca2+](i) signals in cells can directly cause cell damage, dysfunction and disease. Alternatively, aberrant [Ca2+](i) signals can also amplify and increase the rates of cell damage. Such defects in Ca2+ signalling have been described in salivary glands in conjunction with radiation-induced loss of salivary gland function as well as in the salivary defects associated with the autoimmune exocrinopathy Sjogren's syndrome. Such defects have been associated with altered function or expression of key Ca2+ signalling components, such as STIM proteins and TRP channels. These studies offer new avenues for examining the mechanisms underlying the disease and development of novel clinical targets and therapeutic strategies. C1 [Ambudkar, Indu S.] NIDR, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Ambudkar, IS (reprint author), NIH, Bldg 10,Room 1N-113, Bethesda, MD 20892 USA. EM indu.ambudkar@nih.gov FU NIDCR-DIR [Z01-DE00438-31] FX I.A. is funded by NIDCR-DIR (Z01-DE00438-31). NR 95 TC 4 Z9 4 U1 5 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD JUN 1 PY 2016 VL 594 IS 11 BP 2813 EP 2824 DI 10.1113/JP271143 PG 12 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA DQ4QM UT WOS:000379188400009 PM 26592972 ER PT J AU Son, MJ Kim, JC Kim, SW Chidipi, B Muniyandi, J Singh, TD So, I Subedi, KP Woo, H AF Son, Min-Jeong Kim, Joon-Chul Kim, Sung Woo Chidipi, Bojjibabu Muniyandi, Jeyaraj Singh, Thoudam Debraj So, Insuk Subedi, Krishna P. Woo, Sun-Hee TI Shear stress activates monovalent cation channel transient receptor potential melastatin subfamily 4 in rat atrial myocytes via type 2 inositol 1,4,5-trisphosphate receptors and Ca2+ release SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID 2-AMINOETHOXYDIPHENYL BORATE 2-APB; CARDIAC MYOCYTES; VENTRICULAR MYOCYTES; POTASSIUM CHANNELS; CALCIUM SPARKS; MUSCLE-CELLS; TRPM4; MECHANISMS; EXCITATION; CURRENTS AB Atrial myocytes are subjected to shear stress during the cardiac cycle under physiological or pathological conditions. The ionic currents regulated by shear stress remain poorly understood. We report the characteristics, molecular identity and activation mechanism of the shear stress-sensitive current (I-shear) in rat atrial myocytes. A shear stress of similar to 16 dyn cm(-2) was applied to single myocytes using a pressurized microflow system, and the current was measured by whole-cell patch clamp. In symmetrical CsCl solutions with minimal concentrations of internal EGTA, I-shear showed an outwardly rectifying current-voltage relationship (reversal at -2 mV). The current was conducted primarily (similar to 80%) by monovalent cations but not Ca2+. It was suppressed by intracellular Ca2+ buffering at a fixed physiological level, inhibitors of transient receptor potential melastatin subfamily 4 (TRPM4), intracellular introduction of TRPM4 antibodies or knockdown of TRPM4 expression, suggesting that TRPM4 carries most of this current. A notable reduction in I-shear occurred upon inhibition of Ca2+ release through the ryanodine receptors or inositol 1,4,5-trisphosphate receptors (IP3R) and upon depletion of sarcoplasmic reticulum Ca2+. In type 2 IP3R (IP(3)R2) knockout atrial myocytes, I-shear was 10-20% of that in wild-type myocytes. Immunocytochemistry and proximity ligation assays revealed that TRPM4 and IP(3)R2 were expressed at peripheral sites with co-localization, although they are not localized within 40 nm. Peripheral localization of TRPM4 was intact in IP(3)R2 knockout cells. The data obtained in the present study suggest that shear stress activates TRPM4 current by triggering Ca2+ release from the IP(3)R2 in the peripheral domains of atrial myocytes. C1 [Son, Min-Jeong; Kim, Joon-Chul; Kim, Sung Woo; Chidipi, Bojjibabu; Muniyandi, Jeyaraj; Singh, Thoudam Debraj; Subedi, Krishna P.; Woo, Sun-Hee] Chungnam Natl Univ, Coll Pharm, Lab Physiol, 99 Daehak Ro, Daejeon 305764, South Korea. [So, Insuk] Seoul Natl Univ, Dept Physiol, Coll Med, Seoul, South Korea. [Subedi, Krishna P.] Natl Inst Dent & Craniofacial Res, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. RP Woo, H (reprint author), Chungnam Natl Univ, Coll Pharm, Lab Physiol, 99 Daehak Ro, Daejeon 305764, South Korea. EM shwoo@cnu.ac.kr FU National Research Foundation of Korea (NRF) - Korea Government (MEST) [2012-0005369, 2015R1A2A2A01002625, 2012-0006681] FX The work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea Government (MEST) (2012-0005369, 2015R1A2A2A01002625, 2012-0006681). NR 57 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD JUN 1 PY 2016 VL 594 IS 11 BP 2985 EP 3004 DI 10.1113/JP270887 PG 20 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA DQ4QM UT WOS:000379188400022 PM 26751048 ER PT J AU La Rosa, AM Harrison, LJ Taiwo, B Wallis, CL Zheng, L Kim, P Kumarasamy, N Hosseinipour, MC Jarocki, B Mellors, JW Collier, AC AF La Rosa, Alberto M. Harrison, Linda J. Taiwo, Babafemi Wallis, Carole L. Zheng, Lu Kim, Peter Kumarasamy, Nagalingeswaran Hosseinipour, Mina C. Jarocki, Bernadette Mellors, John W. Collier, Ann C. CA ACTG A5273 Study Grp TI Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-inferiority study SO LANCET HIV LA English DT Article ID HIV-1 REVERSE-TRANSCRIPTASE; INFECTED PATIENTS; CLINICAL-TRIALS; RESISTANCE; INHIBITORS; ADHERENCE; MUTATIONS; FAILURE; K65R AB Background For second-line antiretroviral therapy, WHO recommends a boosted protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs). However, concerns about toxicity and cross-resistance motivated a search for regimens that do not contain NRTIs. We aimed to assess whether boosted lopinavir plus raltegravir would be non-inferior to boosted lopinavir plus NRTIs for virological suppression in resource-limited settings. Methods A5273 was a randomised, open-label, phase 3, non-inferiority study at 15 AIDS Clinical Trials Group (ACTG) research sites in nine resource-limited countries (three sites each in India and South Africa, two each in Malawi and Peru, and one each in Brazil, Kenya, Tanzania, Thailand, and Zimbabwe). Adults with plasma HIV-1 RNA concentrations of at least 1000 copies per mL after at least 24 weeks on a regimen based on a non-NRTI inhibitor were randomly assigned (1:1) to receive oral ritonavir-boosted lopinavir (100 mg ritonavir, 400 mg lopinavir) plus 400 mg raltegravir twice a day (raltegravir group) or to ritonavir-boosted lopinavir plus two or three NRTIs selected from an algorithm (eg, zidovudine after failure with tenofovir and vice versa; NRTI group). Randomised group assignment was done with a computer algorithm concealed to site personnel, and stratified by HIV-1 RNA viral load, CD4 cell count, and intention to use zidovudine, with the groups balanced by each site. The primary endpoint was time to confirmed virological failure (two measurements of HIV-1 RNA viral load >400 copies per mL) at or after week 24 in the intention-to-treat population. Non-inferiority (10% margin) was assessed by comparing the cumulative probability of virological failure by 48 weeks. This trial was registered with ClinicalTrials.gov, NCT01352715. Findings Between March 13, 2012, and Oct 2, 2013, we randomly assigned 515 participants:260 to the raltegravir group and 255 to the NRTI group; two participants in the raltegravir group and one in the NRTI group were excluded from analyses because of ineligibility. By the end of follow-up (October, 2014), 96 participants had virological failure (46 in the raltegravir group and 50 in the NRTI group). By 48 weeks, the cumulative probability of virological failure was 10.3% (95% CI 6.5-14.0) in the raltegravir group and 12.4% (8.3-16.5) in the NRTI group, with a weighted difference of -3.4% (-8.4 to 1.5), indicating that raltegravir was non-inferior, but not superior, to NRTIs. 62 (24%) participants in the raltegravir group and 81 (32%) in the NRTI group had grade 3 or higher adverse events; 19 (7%) and 29 (11%), respectively, had serious adverse events. Three participants in each group died, all from HIV-related causes. Interpretation In settings with extensive NRTI resistance but no available resistance testing, our data support WHO's recommendation for ritonavir-boosted lopinavir plus NRTI for second-line antiretroviral therapy. Ritonavir-boosted lopinavir plus raltegravir is an appropriate alternative, especially if NRTI use is limited by toxicity. C1 [La Rosa, Alberto M.] Asociac Civil Impacta Salud & Educ, Lima, Peru. [Harrison, Linda J.; Zheng, Lu] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Taiwo, Babafemi] Northwestern Univ, Chicago, IL 60611 USA. [Wallis, Carole L.] BARC SA & Lancet Labs, Johannesburg, South Africa. [Kim, Peter] NIAID, Div AIDS, Bethesda, MD 20892 USA. [Kumarasamy, Nagalingeswaran] YRG CARE, Madras, Tamil Nadu, India. [Hosseinipour, Mina C.] Univ N Carolina, Chapel Hill, NC USA. [Hosseinipour, Mina C.] UNC Project, Lilongwe, Malawi. [Jarocki, Bernadette] Frontier Sci & Technol Res Fdn Inc, Buffalo, NY USA. [Mellors, John W.] Univ Pittsburgh, Pittsburgh, PA USA. [Collier, Ann C.] Univ Washington, Seattle, WA 98195 USA. RP Collier, AC (reprint author), Harborview Med Ctr, Seattle, WA 98104 USA. EM acollier@u.washington.edu FU National Institutes of Health FX National Institutes of Health. NR 27 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 2352-3018 J9 LANCET HIV JI Lancet HIV PD JUN PY 2016 VL 3 IS 6 BP E247 EP E258 DI 10.1016/S2352-3018(16)30011-X PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DQ1GS UT WOS:000378950100006 PM 27240787 ER PT J AU Rosenthal, LS Drake, D Alcalay, RN Babcock, D Bowman, FD Chen-Plotkin, A Dawson, TM Dewey, RB German, DC Huang, XM Landin, B McAuliffe, M Petyuk, VA Scherzer, CR Hillaire-Clarke, CS Sieber, BA Sutherland, M Tarn, C West, A Vaillancourt, D Zhang, J Gwinn, K AF Rosenthal, Liana S. Drake, Daniel Alcalay, Roy N. Babcock, Debra Bowman, F. DuBois Chen-Plotkin, Alice Dawson, Ted M. Dewey, Richard B., Jr. German, Dwight C. Huang, Xuemei Landin, Barry McAuliffe, Matthew Petyuk, Vladislav A. Scherzer, Clemens R. Hillaire-Clarke, Coryse St. Sieber, Beth-Anne Sutherland, Margaret Tarn, Chi West, Andrew Vaillancourt, David Zhang, Jing Gwinn, Katrina CA PDBP Consortium TI The NINDS Parkinson's Disease Biomarkers Program SO MOVEMENT DISORDERS LA English DT Article; Proceedings Paper CT International Workshop on Biomarkers in Parkinson's Disease (PD) CY MAY, 2015 CL Assisi, ITALY DE Parkinsonism; disease-modifying strategies; biofluids; data management ID GENOME-WIDE ASSOCIATION; RISK AB Background: Neuroprotection for Parkinson's disease (PD) remains elusive. Biomarkers hold the promise of removing roadblocks to therapy development. The National Institute of Neurological Disorders and Stroke has therefore established the Parkinson's Disease Biomarkers Program to promote discovery of PD biomarkers for use in phase II and III clinical trials. Methods: Using a novel consortium design, the Parkinson's Disease Biomarker Program is focused on the development of clinical and laboratory-based biomarkers for PD diagnosis, progression, and prognosis. Standardized operating procedures and pooled reference samples were created to allow cross-project comparisons and assessment of batch effects. A web-based Data Management Resource facilitates rapid sharing of data and biosamples across the research community for additional biomarker projects. Results: Eleven consortium projects are ongoing, seven of which recruit participants and obtain biosamples. As of October 2014, 1,082 participants have enrolled (620 PD, 101 with other causes of parkinsonism, 23 essential tremor, and 338 controls), 1,040 of whom have at least one biosample. Six thousand eight hundred ninety-eight total biosamples are available from baseline, 6-, 12-, and 18-month visits: 1,006 DNA, 1,661 RNA, 1,419 whole blood, 1,382 plasma, 1,200 serum, and 230 cerebrospinal fluid (CSF). Quality control analysis of plasma, serum, and CSF samples indicates that almost all samples are high quality (24 of 2,812 samples exceed acceptable hemoglobin levels). Conclusions: By making samples and data widely available, using stringent operating procedures based on existing standards, hypothesis testing for biomarker discovery, and providing a resource that complements existing programs, the Parkinson's Disease Biomarker Program will accelerate the pace of PD biomarker research. (C) 2015 International Parkinson and Movement Disorder Society C1 [Rosenthal, Liana S.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Drake, Daniel; Bowman, F. DuBois] Columbia Univ, Dept Biostat, New York, NY USA. [Alcalay, Roy N.] Columbia Univ, Dept Neurol, New York, NY USA. [Babcock, Debra; Hillaire-Clarke, Coryse St.; Sieber, Beth-Anne; Sutherland, Margaret; Gwinn, Katrina] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Chen-Plotkin, Alice] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Dawson, Ted M.] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci Pharmacol & Mol Sc, Inst Cell Engn,Neuroregenerat Program, Baltimore, MD USA. [Dawson, Ted M.] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci Pharmacol & Mol Sc, Inst Cell Engn,Stem Cell Program, Baltimore, MD USA. [Dewey, Richard B., Jr.] Univ Texas Southwestern Med Ctr, Dept Neurol & Neurotherapeut, Dallas, TX USA. [German, Dwight C.] Univ Texas Southwestern Med Ctr, Dept Psychiat, Dallas, TX USA. [Huang, Xuemei] Penn State Hershey Med Ctr, Dept Neurol, Hershey, PA USA. [Landin, Barry; McAuliffe, Matthew] NIH, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. [Petyuk, Vladislav A.] Pacific Northwest Natl Lab, Div Biol Sci, Richland, WA USA. [Scherzer, Clemens R.] Harvard Med Sch, Brigham & Womens Hosp, Dept Neurol, Cambridge, MA USA. [Tarn, Chi] Coriell Inst Med Res, Camden, NJ USA. [West, Andrew] Univ Alabama Birmingham, Dept Neurol, Birmingham, AL USA. [Vaillancourt, David] Univ Florida, Dept Appl Physiol & Kinesiol, Gainesville, FL USA. [Zhang, Jing] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. RP Rosenthal, LS (reprint author), 10751 Falls Rd,Suite 250, Lutherville Timonium, MD 21093 USA. EM liana.rosenthal@jhmi.edu OI Gwinn, Katrina/0000-0002-8277-651X FU CIT NIH HHS [ZIH CT000272]; NCRR NIH HHS [UL1 RR033184]; NINDS NIH HHS [K02 NS080915, P50 NS038377, R01 NS075012, U01 NS082133, U01 NS082134, U01 NS082137, U01 NS082148, U01 NS082151, U01 NS082157, U18 NS082132, U18 NS082140, U18 NS082143] NR 16 TC 6 Z9 6 U1 0 U2 0 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 JUN PY 2016 VL 31 IS 6 BP 915 EP 923 DI 10.1002/mds.26438 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DQ4KL UT WOS:000379172600015 PM 26442452 ER PT J AU Kang, UJ Goldman, JG Alcalay, RN Xie, T Tuite, P Henchcliffe, C Hogarth, P Amara, AW Frank, S Rudolph, A Casaceli, C Andrews, H Gwinn, K Sutherland, M Kopil, C Vincent, L Frasier, M AF Kang, Un Jung Goldman, Jennifer G. Alcalay, Roy N. Xie, Tao Tuite, Paul Henchcliffe, Claire Hogarth, Penelope Amara, Amy W. Frank, Samuel Rudolph, Alice Casaceli, Cynthia Andrews, Howard Gwinn, Katrina Sutherland, Margaret Kopil, Catherine Vincent, Lona Frasier, Mark TI The BioFIND Study: Characteristics of a Clinically Typical Parkinson's Disease Biomarker Cohort SO MOVEMENT DISORDERS LA English DT Article; Proceedings Paper CT International Workshop on Biomarkers in Parkinson's Disease (PD) CY MAY, 2015 CL Assisi, ITALY DE biomarkers; cerebrospinal fluid; DNA; plasma; RNA; saliva; urine ID MILD COGNITIVE IMPAIRMENT; RATING-SCALE; CEREBROSPINAL-FLUID; INITIATIVE PPMI; ALPHA-SYNUCLEIN; ACCURACY; PROGRESSION; DIAGNOSIS; MUTATIONS; LEVODOPA AB Background: Identifying PD-specific biomarkers in biofluids will greatly aid in diagnosis, monitoring progression, and therapeutic interventions. PD biomarkers have been limited by poor discriminatory power, partly driven by heterogeneity of the disease, variability of collection protocols, and focus on de novo, unmedicated patients. Thus, a platform for biomarker discovery and validation in well-characterized, clinically typical, moderate to advanced PD cohorts is critically needed. Methods: BioFIND (Fox Investigation for New Discovery of Biomarkers in Parkinson's Disease) is a cross-sectional, multicenter biomarker study that established a repository of clinical data, blood, DNA, RNA, CSF, saliva, and urine samples from 118 moderate to advanced PD and 88 healthy control subjects. Inclusion criteria were designed to maximize diagnostic specificity by selecting participants with clinically typical PD symptoms, and clinical data and biospecimen collection utilized standardized procedures to minimize variability across sites. Results: We present the study methodology and data on the cohort's clinical characteristics. Motor scores and biospecimen samples including plasma are available for practically defined off and on states and thus enable testing the effects of PD medications on biomarkers. Other biospecimens are available from off state PD assessments and from controls. Conclusion: Our cohort provides a valuable resource for biomarker discovery and validation in PD. Clinical data and biospecimens, available through The Michael J. Fox Foundation for Parkinson's Research and the National Institute of Neurological Disorders and Stroke, can serve as a platform for discovering biomarkers in clinically typical PD and comparisons across PD's broad and heterogeneous spectrum. (C) 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society C1 [Kang, Un Jung; Alcalay, Roy N.; Andrews, Howard] Columbia Univ, Dept Neurol, Med Ctr, Div Movement Disorders, New York, NY USA. [Goldman, Jennifer G.] Rush Univ, Med Ctr, Dept Neurol Sci, Sect Parkinson Dis & Movement Disorders, Chicago, IL 60612 USA. [Xie, Tao] Univ Chicago, Dept Neurol, Parkinson Dis & Movement Disorder Program, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Tuite, Paul] Univ Minnesota, Dept Neurol, Minneapolis, MN 55455 USA. [Henchcliffe, Claire] Weill Cornell Med Coll, Dept Neurol, New York, NY USA. [Hogarth, Penelope] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA. [Amara, Amy W.] Univ Alabama Birmingham, Dept Neurol, Birmingham, AL USA. [Frank, Samuel] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Rudolph, Alice; Casaceli, Cynthia] Univ Rochester, Clin Trials Coordinat Ctr, Ctr Human Expt Therapeut, Rochester, NY USA. [Gwinn, Katrina; Sutherland, Margaret] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Kopil, Catherine; Vincent, Lona; Frasier, Mark] Michael J Fox Fdn Parkinsons Res, New York, NY USA. RP Kang, UJ (reprint author), Columbia Univ, Med Ctr, Dept Neurol, 650 West 168th St,BB302, New York, NY 10032 USA. EM ujk2101@columbia.edu OI Amara, Amy/0000-0003-0762-9656; Gwinn, Katrina/0000-0002-8277-651X FU NCRR NIH HHS [KL2 RR024157] NR 46 TC 2 Z9 2 U1 1 U2 1 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 JUN PY 2016 VL 31 IS 6 BP 924 EP 932 DI 10.1002/mds.26613 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DQ4KL UT WOS:000379172600016 PM 27113479 ER PT J AU Rieff, HI Drugan, JK Cheever, TR Van't Veer, A Nuckolls, GH Katz, SI AF Rieff, Heather I. Drugan, Jonelle K. Cheever, Thomas R. Van't Veer, Ashlee Nuckolls, Glen H. Katz, Stephen I. TI THE MUSCULAR DYSTROPHY COORDINATING COMMITTEE ACTION PLAN FOR THE MUSCULAR DYSTROPHIES SO MUSCLE & NERVE LA English DT Editorial Material C1 [Rieff, Heather I.; Van't Veer, Ashlee; Nuckolls, Glen H.] NINDS, NIH, Neurosci Ctr, 6001 Execut Blvd,Room 2203, Bethesda, MD 20892 USA. [Drugan, Jonelle K.; Cheever, Thomas R.; Katz, Stephen I.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Nuckolls, GH (reprint author), NINDS, NIH, Neurosci Ctr, 6001 Execut Blvd,Room 2203, Bethesda, MD 20892 USA. EM glen.nuckolls@nih.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0148-639X EI 1097-4598 J9 MUSCLE NERVE JI Muscle Nerve PD JUN PY 2016 VL 53 IS 6 BP 839 EP 841 DI 10.1002/mus.25111 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DQ2HK UT WOS:000379023200001 PM 26999713 ER PT J AU Evrard, SM Lecce, L Michelis, KC Nomura-Kitabayashi, A Pandey, G Purushothaman, KR d'Escamard, V Li, JR Hadri, L Fujitani, K Moreno, PR Benard, L Rimmele, P Cohain, A Mecham, B Randolph, GJ Nabel, EG Hajjar, R Fuster, V Boehm, M Kovacic, JC AF Evrard, Solene M. Lecce, Laura Michelis, Katherine C. Nomura-Kitabayashi, Aya Pandey, Gaurav Purushothaman, K-Raman d'Escamard, Valentina Li, Jennifer R. Hadri, Lahouaria Fujitani, Kenji Moreno, Pedro R. Benard, Ludovic Rimmele, Pauline Cohain, Ariella Mecham, Brigham Randolph, Gwendalyn J. Nabel, Elizabeth G. Hajjar, Roger Fuster, Valentin Boehm, Manfred Kovacic, Jason C. TI Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability SO NATURE COMMUNICATIONS LA English DT Article ID FIBROBLAST ACTIVATION PROTEIN; AMERICAN-HEART-ASSOCIATION; MARROW-DERIVED CELLS; SMOOTH-MUSCLE-CELLS; IN-VIVO; PULMONARY-HYPERTENSION; CARDIAC FIBROSIS; RENAL FIBROSIS; EXPRESSION; MICE AB Endothelial to mesenchymal transition (EndMT) plays a major role during development, and also contributes to several adult cardiovascular diseases. Importantly, mesenchymal cells including fibroblasts are prominent in atherosclerosis, with key functions including regulation of: inflammation, matrix and collagen production, and plaque structural integrity. However, little is known about the origins of atherosclerosis-associated fibroblasts. Here we show using endothelial-specific lineage-tracking that EndMT-derived fibroblast-like cells are common in atherosclerotic lesions, with EndMT-derived cells expressing a range of fibroblast-specific markers. In vitro modelling confirms that EndMT is driven by TGF-beta signalling, oxidative stress and hypoxia; all hallmarks of atherosclerosis. 'Transitioning' cells are readily detected in human plaques co-expressing endothelial and fibroblast/mesenchymal proteins, indicative of EndMT. The extent of EndMT correlates with an unstable plaque phenotype, which appears driven by altered collagen-MMP production in EndMT-derived cells. We conclude that EndMT contributes to atherosclerotic patho-biology and is associated with complex plaques that may be related to clinical events. C1 [Evrard, Solene M.; Lecce, Laura; Michelis, Katherine C.; Nomura-Kitabayashi, Aya; Purushothaman, K-Raman; d'Escamard, Valentina; Li, Jennifer R.; Hadri, Lahouaria; Fujitani, Kenji; Moreno, Pedro R.; Benard, Ludovic; Rimmele, Pauline; Hajjar, Roger; Fuster, Valentin; Kovacic, Jason C.] Icahn Sch Med Mt Sinai, Zena & Michael A Wiener Cardiovasc Inst, New York, NY 10029 USA. [Pandey, Gaurav; Cohain, Ariella] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Pandey, Gaurav; Cohain, Ariella] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Mecham, Brigham] Trialomics LLC, Seattle, WA 98115 USA. [Randolph, Gwendalyn J.] Washington Univ, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Nabel, Elizabeth G.] Brigham & Womens Hlth Care, Boston, MA 02115 USA. [Fuster, Valentin] Icahn Sch Med Mt Sinai, Marie Josee & Henry R Kravis Cardiovasc Hlth Ctr, New York, NY 10029 USA. [Fuster, Valentin] Ctr Nacl Invest Cardiovasc CNIC, Madrid 28029, Spain. [Boehm, Manfred] NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Kovacic, JC (reprint author), Icahn Sch Med Mt Sinai, Zena & Michael A Wiener Cardiovasc Inst, New York, NY 10029 USA. EM jason.kovacic@mountsinai.org RI Fuster, Valentin/H-4319-2015; OI Fuster, Valentin/0000-0002-9043-9986; Pandey, Gaurav/0000-0003-1939-679X FU National Institutes of Health (NIH) [K08HL111330]; NIH [R01HL130423, T32HL007824, K01HL103176, R01GM114434, P30ES023515, U01HL107388, U2CES026561, U2CES026555, R01HL117505, HL119046, HL129814, 128072, P50HL112324]; Fondation Leducq (Transatlantic Network of Excellence Award); AstraZeneca; IBM faculty award FX J.C.K. and this project were directly supported by National Institutes of Health (NIH) Grant K08HL111330. J.C.K. also acknowledges support from NIH R01HL130423, Fondation Leducq (Transatlantic Network of Excellence Award) and receives research support from AstraZeneca. K.C.M. and V.d'E. are supported by NIH T32HL007824. L.H. is supported by NIH K01HL103176. G.P. is supported by NIH R01GM114434, P30ES023515, U01HL107388, U2CES026561, U2CES026555 and an IBM faculty award. R.H. is supported by NIH R01HL117505, HL119046, HL129814, 128072, P50HL112324 and the Fondation Leducq (Transatlantic Network of Excellence Award). We acknowledge the assistance and technical expertise of the Microscopy, Genomics and Multiscale Biology, and Flow Cytometry Core Facilities and the Center for Comparative Medicine and Surgery of the Icahn School of Medicine at Mount Sinai. NR 62 TC 4 Z9 4 U1 8 U2 12 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 JUN PY 2016 VL 7 AR 11853 DI 10.1038/ncomms11853 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ3AW UT WOS:000379076100001 PM 27340017 ER PT J AU Scott, LJ Erdos, MR Huyghe, JR Welch, RP Beck, AT Wolford, BN Chines, PS Didion, JP Narisu, N Stringham, HM Taylor, DL Jackson, AU Vadlamudi, S Bonnycastle, LL Kinnunen, L Saramies, J Sundvall, J Albanus, RD Kiseleva, A Hensley, J Crawford, GE Jiang, H Wen, XQ Watanabe, RM Lakka, TA Mohlke, KL Laakso, M Tuomilehto, J Koistinen, HA Boehnke, M Collins, FS Parker, SCJ AF Scott, Laura J. Erdos, Michael R. Huyghe, Jeroen R. Welch, Ryan P. Beck, Andrew T. Wolford, Brooke N. Chines, Peter S. Didion, John P. Narisu, Narisu Stringham, Heather M. Taylor, D. Leland Jackson, Anne U. Vadlamudi, Swarooparani Bonnycastle, Lori L. Kinnunen, Leena Saramies, Jouko Sundvall, Jouko Albanus, Ricardo D'Oliveira Kiseleva, Anna Hensley, John Crawford, Gregory E. Jiang, Hui Wen, Xiaoquan Watanabe, Richard M. Lakka, Timo A. Mohlke, Karen L. Laakso, Markku Tuomilehto, Jaakko Koistinen, Heikki A. Boehnke, Michael Collins, Francis S. Parker, Stephen C. J. TI The genetic regulatory signature of type 2 diabetes in human skeletal muscle SO NATURE COMMUNICATIONS LA English DT Article ID RNA-SEQ EXPERIMENTS; SMALL ANKYRIN 1; SUPER-ENHANCERS; SARCOPLASMIC-RETICULUM; TRANSCRIPTION FACTORS; INSULIN SENSITIVITY; GENOTYPE IMPUTATION; CELL IDENTITY; BINDING; VARIANTS AB Type 2 diabetes (T2D) results from the combined effects of genetic and environmental factors on multiple tissues over time. Of the 4100 variants associated with T2D and related traits in genome-wide association studies (GWAS), >90% occur in non-coding regions, suggesting a strong regulatory component to T2D risk. Here to understand how T2D status, metabolic traits and genetic variation influence gene expression, we analyse skeletal muscle biopsies from 271 well-phenotyped Finnish participants with glucose tolerance ranging from normal to newly diagnosed T2D. We perform high-depth strand-specific mRNA-sequencing and dense genotyping. Computational integration of these data with epigenome data, including ATAC-seq on skeletal muscle, and transcriptome data across diverse tissues reveals that the tissue-specific genetic regulatory architecture of skeletal muscle is highly enriched in muscle stretch/super enhancers, including some that overlap T2D GWAS variants. In one such example, T2D risk alleles residing in a muscle stretch/super enhancer are linked to increased expression and alternative splicing of muscle-specific isoforms of ANK1. C1 [Scott, Laura J.; Huyghe, Jeroen R.; Welch, Ryan P.; Beck, Andrew T.; Stringham, Heather M.; Jackson, Anne U.; Jiang, Hui; Wen, Xiaoquan; Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Scott, Laura J.; Huyghe, Jeroen R.; Welch, Ryan P.; Beck, Andrew T.; Stringham, Heather M.; Jackson, Anne U.; Jiang, Hui; Wen, Xiaoquan; Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Erdos, Michael R.; Wolford, Brooke N.; Chines, Peter S.; Didion, John P.; Narisu, Narisu; Taylor, D. Leland; Bonnycastle, Lori L.; Collins, Francis S.] Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. [Taylor, D. Leland] European Mol Biol Lab, European Bioinformat Inst, Wellcome Trust Genome Campus, Hinxton CB10 1SD, Cambs, England. [Vadlamudi, Swarooparani; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Kinnunen, Leena; Sundvall, Jouko; Koistinen, Heikki A.] Natl Inst Hlth & Welf, Dept Hlth, POB 30, FI-00271 Helsinki, Finland. [Saramies, Jouko] South Karelia Cent Hosp, Lappeenranta 53130, Finland. [Albanus, Ricardo D'Oliveira; Kiseleva, Anna; Hensley, John; Parker, Stephen C. J.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Crawford, Gregory E.] Duke Univ, Ctr Genom & Computat Biol, Durham, NC 27708 USA. [Crawford, Gregory E.] Duke Univ, Med Ctr, Dept Pediat, Div Med Genet, Durham, NC 27708 USA. [Watanabe, Richard M.] USC, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. [Watanabe, Richard M.] USC, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90089 USA. [Lakka, Timo A.] Univ Eastern Finland, Inst Biomed Physiol, FI-00100 Kuopio, Finland. [Lakka, Timo A.] Kuopio Res Inst Exercise Med, FI-00100 Kuopio, Finland. [Lakka, Timo A.] Univ Eastern Finland, Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, FI-00100 Kuopio, Finland. [Laakso, Markku] Univ Eastern Finland, Dept Med, FI-00100 Kuopio, Finland. [Laakso, Markku] Kuopio Univ Hosp, FI-00100 Kuopio, Finland. [Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Chron Dis Prevent Unit, POB 30, FI-00271 Helsinki, Finland. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, A-3500 Krems, Austria. [Tuomilehto, Jaakko] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21589, Saudi Arabia. [Tuomilehto, Jaakko] Dasman Diabet Inst, Dasman 15461, Kuwait. [Koistinen, Heikki A.] Univ Helsinki, Dept Med & Abdominal Ctr Endocrinol, POB 340,Haartmaninkatu 4, FI-00029 Helsinki, Finland. [Koistinen, Heikki A.] Univ Helsinki, Cent Hosp, POB 340,Haartmaninkatu 4, FI-00029 Helsinki, Finland. [Koistinen, Heikki A.] Minerva Fdn, Biomedicum 2U, Tukholmankatu 8, FI-00029 Helsinki, Finland. [Parker, Stephen C. J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. RP Collins, FS (reprint author), Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA.; Parker, SCJ (reprint author), Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA.; Parker, SCJ (reprint author), Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. EM Francis.Collins3@nih.gov; scjp@umich.edu RI kinnunen, leena/B-7059-2012; Taylor, D. Leland/L-7160-2013; OI Wen, Xiaoquan/0000-0001-8990-2737; kinnunen, leena/0000-0001-8739-4812; Taylor, D. Leland/0000-0001-6498-6970; Wolford, Brooke/0000-0003-3153-1552; Didion, John/0000-0002-8111-6261; Koistinen, Heikki/0000-0001-7870-070X FU US National Institutes of Health grants [1-ZIA-HG000024, U01DK062370, R00DK099240, R01DK072193, U01DK089256]; American Diabetes Association Pathway [1-14-INI-07]; Academy of Finland Grants [271961, 272741, 258753] FX This research was supported in part by US National Institutes of Health grants 1-ZIA-HG000024 (to F.S.C.), U01DK062370 (to M.B.), R00DK099240 (to S.C.J.P.), R01DK072193 and U01DK089256 (to K.L.M.), the American Diabetes Association Pathway to Stop Diabetes Grant 1-14-INI-07 (to S.C.J.P.), and Academy of Finland Grants 271961 and 272741 (to M.L.) and 258753 (to H.A.K.). We thank Yun Li for helpful discussions about RNA-seq analyses, James Douglas Engel for the TR4 antibody, Jacob Kitzman for Tn5 transposase preparation, Roger Pique-Regi for assistance with CENTIPEDE, Darryl Leja for artwork in Fig. 1a, all the subjects for participation and the study personnel for excellent technical assistance. NR 71 TC 2 Z9 2 U1 6 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 JUN PY 2016 VL 7 AR 11764 DI 10.1038/ncomms11764 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ3NB UT WOS:000379107900001 PM 27353450 ER PT J AU Shi, LL Guo, YF Dong, CL Huddleston, J Yang, H Han, XL Fu, AS Li, Q Li, N Gong, SY Lintner, KE Ding, Q Wang, Z Hu, J Wang, DP Wang, F Wang, L Lyon, GJ Guan, YT Shen, YF Evgrafov, OV Knowles, JA Thibaud-Nissen, F Schneider, V Yu, CY Zhou, LB Eichler, EE So, KF Wang, K AF Shi, Lingling Guo, Yunfei Dong, Chengliang Huddleston, John Yang, Hui Han, Xiaolu Fu, Aisi Li, Quan Li, Na Gong, Siyi Lintner, Katherine E. Ding, Qiong Wang, Zou Hu, Jiang Wang, Depeng Wang, Feng Wang, Lin Lyon, Gholson J. Guan, Yongtao Shen, Yufeng Evgrafov, Oleg V. Knowles, James A. Thibaud-Nissen, Francoise Schneider, Valerie Yu, Chack-Yung Zhou, Libing Eichler, Evan E. So, Kwok-Fai Wang, Kai TI Long-read sequencing and de novo assembly of a Chinese genome SO NATURE COMMUNICATIONS LA English DT Article ID GENETIC-VARIATION; STRUCTURAL VARIATION; ALIGNMENT; HAPLOTYPE; FRAMEWORK; RNA; MAP AB Short-read sequencing has enabled the de novo assembly of several individual human genomes, but with inherent limitations in characterizing repeat elements. Here we sequence a Chinese individual HX1 by single-molecule real-time (SMRT) long-read sequencing, construct a physical map by NanoChannel arrays and generate a de novo assembly of 2.93 Gb (contig N50: 8.3 Mb, scaffold N50: 22.0 Mb, including 39.3Mb N-bases), together with 206Mb of alternative haplotypes. The assembly fully or partially fills 274 (28.4%) N-gaps in the reference genome GRCh38. Comparison to GRCh38 reveals 12.8Mb of HX1-specific sequences, including 4.1Mb that are not present in previously reported Asian genomes. Furthermore, long-read sequencing of the transcriptome reveals novel spliced genes that are not annotated in GENCODE and are missed by short-read RNA-Seq. Our results imply that improved characterization of genome functional variation may require the use of a range of genomic technologies on diverse human populations. C1 [Shi, Lingling; Li, Na; Gong, Siyi; Zhou, Libing; So, Kwok-Fai] Jinan Univ, Guangdong Hongkong Macau Inst CNS Regenerat, Guangzhou 510632, Guangdong, Peoples R China. [Shi, Lingling; Zhou, Libing; So, Kwok-Fai] Jinan Univ, Minist Educ, Joint Int Res Lab CNS Regenerat, Guangzhou 510632, Guangdong, Peoples R China. [Shi, Lingling; Zhou, Libing; So, Kwok-Fai] Nantong Univ, Coinnovat Ctr Neuroregenerat, Nantong 226001, Peoples R China. [Guo, Yunfei; Dong, Chengliang; Yang, Hui; Li, Quan; Evgrafov, Oleg V.; Knowles, James A.; Wang, Kai] Univ Southern Calif, Zilkha Neurogenet Inst, Los Angeles, CA 90089 USA. [Huddleston, John; Eichler, Evan E.] Univ Washington, Howard Hughes Med Inst, Dept Genome Sci, Seattle, WA 98195 USA. [Han, Xiaolu] Univ Southern Calif, Keck Sch Med, Genet Mol & Cellular Biol Program, Los Angeles, CA 90089 USA. [Fu, Aisi; Ding, Qiong; Wang, Zou] Wuhan Inst Biotechnol, Wuhan 430000, Peoples R China. [Lintner, Katherine E.; Yu, Chack-Yung] Ohio State Univ, Dept Pediat, Columbus, OH 43205 USA. [Lintner, Katherine E.; Yu, Chack-Yung] Nationwide Childrens Hosp, Res Inst, Columbus, OH 43205 USA. [Hu, Jiang; Wang, Depeng] Next Biosci, Wuhan 430000, Peoples R China. [Wang, Feng] Wuhan Inst Technol, Sch Chem Engn & Pharm, Wuhan 430000, Peoples R China. [Wang, Lin] Huazhong Univ Sci & Technol, Union Hosp, Ctr Tissue Engn & Regenerat Med, Wuhan 430022, Peoples R China. [Lyon, Gholson J.] Cold Spring Harbor Lab, Stanley Inst Cognit Genom, New York, NY 11797 USA. [Guan, Yongtao] USDA ARS, Childrens Nutr Res Ctr, Dept Pediat, Dept Mol & Human Genet,Baylor Coll Med, Houston, TX 77030 USA. [Shen, Yufeng] Columbia Univ, Dept Syst Biol, New York, NY 10032 USA. [Shen, Yufeng] Columbia Univ, Dept Biomed Informat, New York, NY 10032 USA. [Evgrafov, Oleg V.; Knowles, James A.; Wang, Kai] Univ Southern Calif, Keck Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA. [Thibaud-Nissen, Francoise; Schneider, Valerie] US Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [So, Kwok-Fai] Univ Hong Kong, Dept Ophthalmol, Hong Kong, Hong Kong, Peoples R China. [So, Kwok-Fai] Univ Hong Kong, State Key Lab Brain & Cognit Sci, Hong Kong, Hong Kong, Peoples R China. RP Zhou, LB; So, KF (reprint author), Jinan Univ, Guangdong Hongkong Macau Inst CNS Regenerat, Guangzhou 510632, Guangdong, Peoples R China.; Zhou, LB; So, KF (reprint author), Jinan Univ, Minist Educ, Joint Int Res Lab CNS Regenerat, Guangzhou 510632, Guangdong, Peoples R China.; Zhou, LB; So, KF (reprint author), Nantong Univ, Coinnovat Ctr Neuroregenerat, Nantong 226001, Peoples R China.; Wang, K (reprint author), Univ Southern Calif, Zilkha Neurogenet Inst, Los Angeles, CA 90089 USA.; Wang, K (reprint author), Univ Southern Calif, Keck Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA.; So, KF (reprint author), Univ Hong Kong, Dept Ophthalmol, Hong Kong, Hong Kong, Peoples R China.; So, KF (reprint author), Univ Hong Kong, State Key Lab Brain & Cognit Sci, Hong Kong, Hong Kong, Peoples R China. EM libingzh@gmail.com; hrmaskf@hku.hk; kaiwang@usc.edu FU NIH [HG006465, MH108728, HG007635, HG002385]; National Natural Science Foundation of China [31400922]; Program of Introducing Talents of Discipline to Universities [B14036]; Leading Talents of Guangdong FX We thank the staff members of the Wuhan Institute of Biotechnology for generating the long-read DNA sequencing data, and thank Pacific Biosciences for generating the long-read RNA sequencing data. We thank Ahmed Naguib from BioNano Genomics for providing technical assistance. This project is supported by NIH grant HG006465 and MH108728 (K.W.), HG007635 and HG002385 (E.E.E.), the National Natural Science Foundation of China 31400922 (L.S.), the Program of Introducing Talents of Discipline to Universities B14036 (L.S. and S.K.F.) and Leading Talents of Guangdong 2013 (S.K.F.). E.E.E. is an investigator of the Howard Hughes Medical Institute. NR 41 TC 7 Z9 7 U1 13 U2 17 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 JUN PY 2016 VL 7 AR 12065 DI 10.1038/ncomms12065 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ3OO UT WOS:000379111800001 PM 27356984 ER PT J AU Tang, XH Zhu, YP Baker, SL Bowler, MW Chen, BJM Chen, C Hogg, JR Goff, SP Song, HW AF Tang, Xuhua Zhu, Yiping Baker, Stacey L. Bowler, Matthew W. Chen, Benjamin Jieming Chen, Chen Hogg, J. Robert Goff, Stephen P. Song, Haiwei TI Structural basis of suppression of host translation termination by Moloney Murine Leukemia Virus SO NATURE COMMUNICATIONS LA English DT Article ID RETROVIRAL REVERSE-TRANSCRIPTASE; STOP CODON RECOGNITION; MESSENGER-RNA DECAY; POL FUSION PROTEIN; CRYSTAL-STRUCTURE; GENE-EXPRESSION; READ-THROUGH; COMPLEX; SYSTEM; UPF1 AB Retroviral reverse transcriptase (RT) of Moloney murine leukemia virus (MoMLV) is expressed in the form of a large Gag-Pol precursor protein by suppression of translational termination in which the maximal efficiency of stop codon read-through depends on the interaction between MoMLV RT and peptidyl release factor 1 (eRF1). Here, we report the crystal structure of MoMLV RT in complex with eRF1. The MoMLV RT interacts with the C-terminal domain of eRF1 via its RNase H domain to sterically occlude the binding of peptidyl release factor 3 (eRF3) to eRF1. Promotion of read-through by MoMLV RNase H prevents nonsense-mediated mRNA decay (NMD) of mRNAs. Comparison of our structure with that of HIV RT explains why HIV RT cannot interact with eRF1. Our results provide a mechanistic view of how MoMLV manipulates the host translation termination machinery for the synthesis of its own proteins. C1 [Tang, Xuhua; Chen, Benjamin Jieming; Chen, Chen; Song, Haiwei] Proteos, Inst Mol & Cell Biol, 61 Biopolis Dr, Singapore 138673, Singapore. [Zhu, Yiping; Goff, Stephen P.] Columbia Univ, Dept Biochem & Mol Biophys, HHSC 1310C,701 West 168th St, New York, NY 10032 USA. [Zhu, Yiping; Goff, Stephen P.] Columbia Univ, Howard Hughes Med Inst, HHSC 1310C,701 West 168th St, New York, NY 10032 USA. [Baker, Stacey L.; Hogg, J. Robert] NHLBI, Biochem & Biophys Ctr, NIH, 50 South Dr, Bethesda, MD 20892 USA. [Bowler, Matthew W.] European Mol Biol Lab, Grenoble Outstn, CS 90181, 71 Ave Martyrs, F-38042 Grenoble, France. [Bowler, Matthew W.] Univ Grenoble Alpes, EMBL, CNRS, Unit Virus Host Cell Interact,CS 90181, 71 Ave Martyrs, F-38042 Grenoble, France. [Song, Haiwei] Zhejiang Univ, Inst Life Sci, 388 Yuhangtang Rd, Hangzhou 310058, Zhejiang, Peoples R China. [Song, Haiwei] Natl Univ Singapore, Dept Biochem, 14 Sci Dr, Singapore 117543, Singapore. RP Song, HW (reprint author), Proteos, Inst Mol & Cell Biol, 61 Biopolis Dr, Singapore 138673, Singapore.; Goff, SP (reprint author), Columbia Univ, Dept Biochem & Mol Biophys, HHSC 1310C,701 West 168th St, New York, NY 10032 USA.; Goff, SP (reprint author), Columbia Univ, Howard Hughes Med Inst, HHSC 1310C,701 West 168th St, New York, NY 10032 USA.; Hogg, JR (reprint author), NHLBI, Biochem & Biophys Ctr, NIH, 50 South Dr, Bethesda, MD 20892 USA.; Song, HW (reprint author), Zhejiang Univ, Inst Life Sci, 388 Yuhangtang Rd, Hangzhou 310058, Zhejiang, Peoples R China.; Song, HW (reprint author), Natl Univ Singapore, Dept Biochem, 14 Sci Dr, Singapore 117543, Singapore. EM j.hogg@nih.gov; spg1@cumc.columbia.edu; haiwei@imcb.a-star.edu.sg OI Bowler, Matthew/0000-0003-0465-3351; Hogg, J. Robert/0000-0001-5729-5135 FU Agency for Science, Technology and Research in Singapore; Intramural Research Program of the NIH, NHLBI; NCI Grant from the National Cancer Institute [R01 CA 30488] FX We thank the beamline scientists at ID-23-1 (ESRF, Grenoble, France), beamline PX-I (SLS, PSI, Switzerland), BL13B1 (NSRRC, Taiwan) and beamline I02 (DLS, UK) for assistance and access to synchrotron radiation facilities. We thank Dr Stephen Hughes for generously providing plasmid of HIV RT. This work was supported by the Agency for Science, Technology and Research in Singapore (H.S.), in part by the Intramural Research Program of the NIH, NHLBI (J.R.H.) and by the NCI Grant R01 CA 30488 from the National Cancer Institute (S.P.G.). S.P.G. is an investigator of the Howard Hughes Medical Institute. NR 42 TC 1 Z9 1 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUN PY 2016 VL 7 AR 12070 DI 10.1038/ncomms12070 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ3HA UT WOS:000379092200001 PM 27329342 ER PT J AU Woodford, MR Dunn, DM Blanden, AR Capriotti, D Loiselle, D Prodromou, C Panaretou, B Hughes, PF Smith, A Ackerman, W Haystead, TA Loh, SN Bourboulia, D Schmidt, LS Linehan, WM Bratslavsky, G Mollapour, M AF Woodford, Mark R. Dunn, Diana M. Blanden, Adam R. Capriotti, Dante Loiselle, David Prodromou, Chrisostomos Panaretou, Barry Hughes, Philip F. Smith, Aaron Ackerman, Wendi Haystead, Timothy A. Loh, Stewart N. Bourboulia, Dimitra Schmidt, Laura S. Linehan, W. Marston Bratslavsky, Gennady Mollapour, Mehdi TI The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding SO NATURE COMMUNICATIONS LA English DT Article ID HOGG-DUBE-SYNDROME; COCHAPERONE AHA1; CYSTIC-FIBROSIS; INHIBITORS; PROTEIN; PHOSPHORYLATION; SENSITIVITY; MUTATIONS; PRODUCT; ROLES AB Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability. FNIPs compete with the activating co-chaperone Aha1 for binding to Hsp90, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins. Lastly, downregulation of FNIPs desensitizes cancer cells to Hsp90 inhibitors, whereas FNIPs overexpression in renal tumours compared with adjacent normal tissues correlates with enhanced binding of Hsp90 to its inhibitors. Our findings suggest that FNIPs expression can potentially serve as a predictive indicator of tumour response to Hsp90 inhibitors. C1 [Woodford, Mark R.; Dunn, Diana M.; Capriotti, Dante; Bourboulia, Dimitra; Bratslavsky, Gennady; Mollapour, Mehdi] SUNY Upstate Med Univ, Dept Urol, 750 East Adams St, Syracuse, NY 13210 USA. [Woodford, Mark R.; Dunn, Diana M.; Blanden, Adam R.; Capriotti, Dante; Loh, Stewart N.; Bourboulia, Dimitra; Bratslavsky, Gennady; Mollapour, Mehdi] SUNY Upstate Med Univ, Canc Res Inst, 750 East Adams St, Syracuse, NY 13210 USA. [Dunn, Diana M.; Blanden, Adam R.; Loh, Stewart N.; Bourboulia, Dimitra; Mollapour, Mehdi] SUNY Upstate Med Univ, Dept Biochem & Mol Biol, 750 East Adams St, Syracuse, NY 13210 USA. [Loiselle, David; Hughes, Philip F.; Smith, Aaron; Haystead, Timothy A.] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. [Prodromou, Chrisostomos] Univ Sussex, Genome Damage & Stabil Ctr, Brighton BN1 9RQ, E Sussex, England. [Panaretou, Barry] Kings Coll London, Inst Pharmaceut Sci, London SE1 9NH, England. [Ackerman, Wendi] SUNY Upstate Med Univ, Hlth Sci Lib, 750 East Adams St, Syracuse, NY 13210 USA. [Schmidt, Laura S.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Basic Sci Program, Frederick, MD 21702 USA. [Schmidt, Laura S.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Mollapour, M (reprint author), SUNY Upstate Med Univ, Dept Urol, 750 East Adams St, Syracuse, NY 13210 USA.; Mollapour, M (reprint author), SUNY Upstate Med Univ, Canc Res Inst, 750 East Adams St, Syracuse, NY 13210 USA.; Mollapour, M (reprint author), SUNY Upstate Med Univ, Dept Biochem & Mol Biol, 750 East Adams St, Syracuse, NY 13210 USA. EM mollapom@upstate.edu FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; NIH [HHSN261200800001E]; DoD [W81XWH-15-1-0072]; Wellcome Trust [095605/Z11/Z]; SUNY Upstate Medical University; Upstate Foundation; One Square Mile of Hope Foundation; Carol M. Baldwin Breast Cancer Fund; Frederick National Laboratory for Cancer Research FX We thank Dr Len Neckers (NCI), Dr Jane B. Trepel (NCI) and Dr Masaya Baba (Kumamoto University) for their constructive comments. We are grateful to Dr J.L. Brodsky (University of Pittsburgh) for CFTR plasmid, Dr Weiwen Ying (Synta Pharmaceuticals) for GB, Dr Gabriela Chiosis (Memorial Sloan Kettering Cancer Center) for PU-H71 and Dr Jason Gestwicki for JG-98 (University of California San Francisco). This work was partly supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Frederick National Laboratory for Cancer Research, NIH, under contract HHSN261200800001E, DoD W81XWH-15-1-0072 and Wellcome Trust 095605/Z11/Z. This research was fully supported with funds from the SUNY Upstate Medical University, Upstate Foundation, One Square Mile of Hope Foundation and Carol M. Baldwin Breast Cancer Fund. NR 31 TC 1 Z9 1 U1 4 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 JUN PY 2016 VL 7 AR 12037 DI 10.1038/ncomms12037 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ3OC UT WOS:000379110600001 PM 27353360 ER PT J AU Zhang, XL Cheng, XP Yu, L Yang, JS Calvo, R Patnaik, S Hu, X Gao, Q Yang, MM Lawas, M Delling, M Marugan, J Ferrer, M Xu, HX AF Zhang, Xiaoli Cheng, Xiping Yu, Lu Yang, Junsheng Calvo, Raul Patnaik, Samarjit Hu, Xin Gao, Qiong Yang, Meimei Lawas, Maria Delling, Markus Marugan, Juan Ferrer, Marc Xu, Haoxing TI MCOLN1 is a ROS sensor in lysosomes that regulates autophagy SO NATURE COMMUNICATIONS LA English DT Article ID OXIDATIVE STRESS; QUALITY-CONTROL; ION CHANNELS; TFEB; CALCIUM; BIOGENESIS; DISEASE; MITOCHONDRIA; TRAFFICKING; SENSITIZE AB Cellular stresses trigger autophagy to remove damaged macromolecules and organelles. Lysosomes 'host' multiple stress-sensing mechanisms that trigger the coordinated biogenesis of autophagosomes and lysosomes. For example, transcription factor (TF)EB, which regulates autophagy and lysosome biogenesis, is activated following the inhibition of mTOR, a lysosome-localized nutrient sensor. Here we show that reactive oxygen species (ROS) activate TFEB via a lysosomal Ca2+-dependent mechanism independent of mTOR. Exogenous oxidants or increasing mitochondrial ROS levels directly and specifically activate lysosomal TRPML1 channels, inducing lysosomal Ca2+ release. This activation triggers calcineurin-dependent TFEB-nuclear translocation, autophagy induction and lysosome biogenesis. When TRPML1 is genetically inactivated or pharmacologically inhibited, clearance of damaged mitochondria and removal of excess ROS are blocked. Furthermore, TRPML1's ROS sensitivity is specifically required for lysosome adaptation to mitochondrial damage. Hence, TRPML1 is a ROS sensor localized on the lysosomal membrane that orchestrates an autophagy-dependent negative-feedback programme to mitigate oxidative stress in the cell. C1 [Zhang, Xiaoli; Cheng, Xiping; Yu, Lu; Yang, Junsheng; Gao, Qiong; Yang, Meimei; Lawas, Maria; Xu, Haoxing] Univ Michigan, Dept Mol Cellular & Dev Biol, 3089 Nat Sci Bldg Kraus,830 North Univ, Ann Arbor, MI 48109 USA. [Yang, Junsheng] Zhejiang Univ Technol, Coll Pharmaceut Sci, Collaborat Innovat Ctr Yangtze River Delta Reg Gr, Hangzhou 310014, Zhejiang, Peoples R China. [Calvo, Raul; Patnaik, Samarjit; Hu, Xin; Marugan, Juan; Ferrer, Marc] NIH, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA. [Delling, Markus] Childrens Hosp Boston, Dept Cardiol, Enders 1350,320 Longwood Ave, Boston, MA 02115 USA. RP Xu, HX (reprint author), Univ Michigan, Dept Mol Cellular & Dev Biol, 3089 Nat Sci Bldg Kraus,830 North Univ, Ann Arbor, MI 48109 USA. EM haoxingx@umich.edu FU NIH grants [NS062792, MH096595, NS091928, AR060837] FX This work was supported by NIH grants (NS062792, MH096595, NS091928 and AR060837 to H.X.). We are grateful to Dr David Rubinsztein for GFP-mRFP-LC3 stable cell line, Dr Shawn M. Ferguson for GFP-TFEB stable cell line and Dr Susan Slaugenhaupt (Harvard Medical School) for the TRPML1 KO mice. we also thank Dr Xinran Li and Mr Stephen Ireland for generating Gcamp7-TRPML1 construct. We appreciate the encouragement and helpful comments provided by other Xu lab members, especially Dr Nirakar Sahoo. NR 44 TC 4 Z9 4 U1 5 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUN PY 2016 VL 7 AR 12109 DI 10.1038/ncomms12109 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ3PK UT WOS:000379114000001 PM 27357649 ER PT J AU Arrode-Bruses, G Goode, D Kleinbeck, K Wilk, J Frank, I Byrareddy, S Arthos, J Grasperge, B Blanchard, J Zydowsky, T Gettie, A Martinelli, E AF Arrode-Bruses, Geraldine Goode, Diana Kleinbeck, Kyle Wilk, Jolanta Frank, Ines Byrareddy, Siddappa Arthos, James Grasperge, Brooke Blanchard, James Zydowsky, Thomas Gettie, Agegnehu Martinelli, Elena TI A Small Molecule, Which Competes with MAdCAM-1, Activates Integrin alpha(4)beta(7) and Fails to Prevent Mucosal Transmission of SHIV-SF162P3 SO PLOS PATHOGENS LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; ACUTE SIV INFECTION; CD4(+) T-CELLS; HIV-1 INFECTION; RHESUS MACAQUES; ALPHA-4-BETA-7; ADHESION; EXPRESSION; RECEPTOR; SUSCEPTIBILITY AB Mucosal HIV-1 transmission is inefficient. However, certain viral and host characteristics may play a role in facilitating HIV acquisition and systemic expansion. Cells expressing high levels of integrin alpha(4)beta(7) have been implicated in favoring the transmission process and the infusion of an anti-alpha(4)beta(7) mAb (RM-Act-1) prior to, and during a repeated low-dose vaginal challenge (RLDC) regimen with SIVmac251 reduced SIV acquisition and protected the gut-associated lymphoid tissues (GALT) in the macaques that acquired SIV. alpha(4)beta(7) expression is required for lymphocyte trafficking to the gut lamina propria and gut inductive sites. Several therapeutic strategies that target alpha(4)beta(7) have been shown to be effective in treating inflammatory conditions of the intestine, such as inflammatory bowel disease (IBD). To determine if blocking alpha(4)beta(7) with ELN, an orally available anti-alpha(4) small molecule, would inhibit SHIV-SF162P3 acquisition, we tested its ability to block MAdCAM-1 (alpha(4)beta(7) natural ligand) and HIV-gp120 binding in vitro. We studied the pharmacokinetic profile of ELN after oral and vaginal delivery in macaques. Twenty-six macaques were divided into 3 groups: 9 animals were treated with ELN orally, 9 orally and vaginally and 8 were used as controls. All animals were challenged intra-vaginally with SHIV-SF162P3 using the RLDC regimen. We found that ELN did not protect macaques from SHIV acquisition although it reduced the SHIV-induced inflammatory status during the acute phase of infection. Notably, integrins can exist in different activation states and, comparing the effect of ELN and the anti-alpha(4)beta(7) mAb RM-Act-1 that reduced susceptibility to SIV infection, we determined that ELN induces the active conformation of alpha(4)beta(7), while RM-Act-1 inhibits its activation through an allosteric mechanism. These results suggest that inhibition of alpha(4)beta(7) activation may be necessary to reduce susceptibility to SIV/SHIV infection and highlight the complexity of anti-integrins therapeutic approach in HIV as well as in IBD and other autoimmune diseases. C1 [Arrode-Bruses, Geraldine; Goode, Diana; Kleinbeck, Kyle; Wilk, Jolanta; Frank, Ines; Zydowsky, Thomas; Martinelli, Elena] Populat Council, Ctr Biomed Res, 1230 York Ave, New York, NY 10021 USA. [Byrareddy, Siddappa] Univ Nebraska, Med Ctr, Omaha, NE USA. [Arthos, James] NIAID, Immunoregulat Lab, Bldg 10, Bethesda, MD 20892 USA. [Grasperge, Brooke; Blanchard, James] Tulane Univ, Tulane Natl Primate Res Ctr, Covington, LA USA. [Gettie, Agegnehu] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, 1230 York Ave, New York, NY 10021 USA. RP Martinelli, E (reprint author), Populat Council, Ctr Biomed Res, 1230 York Ave, New York, NY 10021 USA. EM emartinelli@popcouncil.org FU NIAID [R01AI098546]; NIH [U42OD010568] FX This work was funded by NIAID grant R01AI098546 and partially supported by NIH grant U42OD010568. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JUN PY 2016 VL 12 IS 6 AR e1005720 DI 10.1371/journal.ppat.1005720 PG 27 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DQ6WD UT WOS:000379345300052 PM 27348748 ER PT J AU Mukhopadhyay, R Roy, S Venkatadri, R Su, YP Ye, WJ Barnaeva, E Griner, LM Southall, N Hu, X Wang, AQ Xu, X Dulcey, AE Marugan, JJ Ferrer, M Arav-Boger, R AF Mukhopadhyay, Rupkatha Roy, Sujayita Venkatadri, Rajkumar Su, Yu-Pin Ye, Wenjuan Barnaeva, Elena Griner, Lesley Mathews Southall, Noel Hu, Xin Wang, Amy Q. Xu, Xin Dulcey, Andres E. Marugan, Juan J. Ferrer, Marc Arav-Boger, Ravit TI Efficacy and Mechanism of Action of Low Dose Emetine against Human Cytomegalovirus SO PLOS PATHOGENS LA English DT Article ID CONGENITAL CYTOMEGALOVIRUS; PROTEIN-SYNTHESIS; IN-VITRO; TRANSPLANT RECIPIENTS; COMPOUND AIC246; IE2-86 PROTEIN; MESSENGER-RNA; PHASE-I; P53; INFECTION AB Infection with human cytomegalovirus (HCMV) is a threat for pregnant women and immunocompromised hosts. Although limited drugs are available, development of new agents against HCMV is desired. Through screening of the LOPAC library, we identified emetine as HCMV inhibitor. Additional studies confirmed its anti-HCMV activities in human foreskin fibroblasts: EC50-40+/-1.72 nM, CC50-8+/-0.56 mu M, and selectivity index of 200. HCMV inhibition occurred after virus entry, but before DNA replication, and resulted in decreased expression of viral proteins. Synergistic virus inhibition was achieved when emetine was combined with ganciclovir. In a mouse CMV (MCMV) model, emetine was well-tolerated, displayed long half-life, preferential distribution to tissues over plasma, and effectively suppressed MCMV. Since the in vitro anti-HCMV activity of emetine decreased significantly in low-density cells, a mechanism involving cell cycle regulation was suspected. HCMV inhibition by emetine depended on ribosomal processing S14 (RPS14) binding to MDM2, leading to disruption of HCMV-induced MDM2-p53 and MDM2-IE2 interactions. Irrespective of cell density, emetine induced RPS14 translocation into the nucleus during infection. In infected high-density cells, MDM2 was available for interaction with RPS14, resulting in disruption of MDM2-p53 interaction. However, in low-density cells the pre-existing interaction of MDM2-p53 could not be disrupted, and RPS14 could not interact with MDM2. In high-density cells the interaction of MDM2-RPS14 resulted in ubiquitination and degradation of RPS14, which was not observed in low-density cells. In infected-only or in non-infected emetine-treated cells, RPS14 failed to translocate into the nucleus, hence could not interact with MDM2, and was not ubiquitinated. HCMV replicated similarly in RPS14 knockdown or control cells, but emetine did not inhibit virus replication in the former cell line. The interaction of MDM2-p53 was maintained in infected RPS14 knockdown cells despite emetine treatment, confirming a unique mechanism by which emetine exploits RPS14 to disrupt MDM2-p53 interaction. Summarized, emetine may represent a promising candidate for HCMV therapy alone or in combination with ganciclovir through a novel host-dependent mechanism. C1 [Mukhopadhyay, Rupkatha; Roy, Sujayita; Venkatadri, Rajkumar; Su, Yu-Pin; Arav-Boger, Ravit] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Infect Dis, Baltimore, MD 21205 USA. [Ye, Wenjuan; Barnaeva, Elena; Griner, Lesley Mathews; Southall, Noel; Hu, Xin; Wang, Amy Q.; Xu, Xin; Dulcey, Andres E.; Marugan, Juan J.; Ferrer, Marc] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. RP Arav-Boger, R (reprint author), Johns Hopkins Univ, Sch Med, Dept Pediat, Div Infect Dis, Baltimore, MD 21205 USA. EM boger@jhmi.edu FU National Institutes of Health [R01DC013550] FX This work was supported by the National Institutes of Health grant R01DC013550 (to RAB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 1 Z9 1 U1 4 U2 4 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 JUN PY 2016 VL 12 IS 6 AR e1005717 DI 10.1371/journal.ppat.1005717 PG 26 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DQ6WD UT WOS:000379345300049 PM 27336364 ER PT J AU Wang, YY Jenkins, SA Gu, CF Shree, A Martinez-Moczygemba, M Herold, J Botto, M Wetsel, RA Xu, Y AF Wang, Yanyu Jenkins, Sarah A. Gu, Chunfang Shree, Ankita Martinez-Moczygemba, Margarita Herold, Jennifer Botto, Marina Wetsel, Rick A. Xu, Yi TI Bacillus anthracis Spore Surface Protein BclA Mediates Complement Factor H Binding to Spores and Promotes Spore Persistence SO PLOS PATHOGENS LA English DT Article ID PSEUDOMONAS-AERUGINOSA BIOFILMS; UROPATHOGENIC ESCHERICHIA-COLI; IMMUNE EVASION STRATEGIES; AEROSOL CHALLENGE MODEL; SEROGROUP-B VACCINE; T-CELL IMMUNITY; NEISSERIA-MENINGITIDIS; STAPHYLOCOCCUS-AUREUS; CYSTIC-FIBROSIS; MYCOBACTERIUM-TUBERCULOSIS AB Spores of Bacillus anthracis, the causative agent of anthrax, are known to persist in the host lungs for prolonged periods of time, however the underlying mechanism is poorly understood. In this study, we demonstrated that BclA, a major surface protein of B. anthracis spores, mediated direct binding of complement factor H (CFH) to spores. The surface bound CFH retained its regulatory cofactor activity resulting in C3 degradation and inhibition of downstream complement activation. By comparing results from wild type C57BL/6 mice and complement deficient mice, we further showed that BclA significantly contributed to spore persistence in the mouse lungs and dampened antibody responses to spores in a complement C3-dependent manner. In addition, prior exposure to BclA deletion spores (Delta bclA) provided significant protection against lethal challenges by B. anthracis, whereas the isogenic parent spores did not, indicating that BclA may also impair protective immunity. These results describe for the first time an immune inhibition mechanism of B. anthracis mediated by BclA and CFH that promotes spore persistence in vivo. The findings also suggested an important role of complement in persistent infections and thus have broad implications. C1 [Wang, Yanyu; Jenkins, Sarah A.; Gu, Chunfang; Shree, Ankita; Martinez-Moczygemba, Margarita; Herold, Jennifer; Xu, Yi] Texas A&M Hlth Sci Ctr, Inst Biosci & Technol, Ctr Infect & Inflammatory Dis, Houston, TX 77030 USA. [Martinez-Moczygemba, Margarita; Xu, Yi] Texas A&M Hlth Sci Ctr, Dept Microbial Pathogenesis & Immunol, College Stn, TX 77845 USA. [Botto, Marina] Imperial Coll London, Dept Med, London, England. [Wetsel, Rick A.] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med Prevent Human Dis, Houston, TX 77030 USA. [Jenkins, Sarah A.] Naval Med Ctr Portsmouth, 620 John Paul Jones Circle, Portsmouth, VA USA. [Gu, Chunfang] NIEHS, Lab Signal Transduct, NIH, 101 TW Alexander Dr, Res Triangle Pk, NC USA. RP Xu, Y (reprint author), Texas A&M Hlth Sci Ctr, Inst Biosci & Technol, Ctr Infect & Inflammatory Dis, Houston, TX 77030 USA.; Xu, Y (reprint author), Texas A&M Hlth Sci Ctr, Dept Microbial Pathogenesis & Immunol, College Stn, TX 77845 USA. EM yxu@ibt.tamhsc.edu FU National Insititutes of Health (NIH) [AI0952293] FX The study is funded by National Insititutes of Health (NIH) with grant number AI0952293. The funding was received by YX (https://grants.nih.gov/grants/oer.htm). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 89 TC 0 Z9 0 U1 6 U2 9 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 JUN PY 2016 VL 12 IS 6 AR e1005678 DI 10.1371/journal.ppat.1005678 PG 25 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DQ6WD UT WOS:000379345300028 PM 27304426 ER PT J AU Wolff-Hughes, DL Troiano, RP Boyer, WR Fitzhugh, EC McClain, JJ AF Wolff-Hughes, Dana L. Troiano, Richard P. Boyer, William R. Fitzhugh, Eugene C. McClain, James J. TI Use of population-referenced total activity counts percentiles to assess and classify physical activity of population groups SO PREVENTIVE MEDICINE LA English DT Article DE Actigraphy; Epidemiologic measurements; Health promotion; Motor activity; New York City ID PUBLIC-HEALTH; ACCELEROMETER; INACTIVITY; ADULTS AB Objectives. Population-referenced total activity counts per day (TAC/d) percentiles provide public health practitioners a standardized measure of physical activity (PA) volume obtained from an accelerometer that can be compared across populations. The purpose of this study was to describe the application of TAC/d population-referenced percentiles to characterize the PA levels of population groups relative to US estimates. Methods. A total of 679 adults participating in the 2011 NYC Physical Activity Transit survey wore an ActiGraph accelerometer on their hip for seven consecutive days. Accelerometer-derived TAC/dwas classified into age-and gender-specific quartiles of US population-referenced TAC/d to compare differences in the distributions by borough (N = 5). Results. Males in Brooklyn, Manhattan, and Staten Island had significantly greater TAC/d than US males. Females in Brooklyn and Queens had significantly greater levels of TAC/d compared to US females. The proportion of males in each population-referenced TAC/d quartile varied significantly by borough (chi(2)(12) = 2.63, p = 0.002), with disproportionately more men in Manhattan and the Bronx found to be in the highest and lowest US population-referenced TAC/d quartiles, respectively. For females, there was no significant difference in US population-reference TAC/d quartile by borough (chi(2)(12) = 1.09, p = 0.36). Conclusions. These results demonstrate the utility of population-referenced TAC/d percentiles in public health monitoring and surveillance. These findings also provide insights into the PA levels of NYC residents relative to the broader US population, which can be used to guide health promotion efforts. Published by Elsevier Inc. C1 [Wolff-Hughes, Dana L.; Troiano, Richard P.; McClain, James J.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Boyer, William R.; Fitzhugh, Eugene C.] Univ Tennessee, Dept Kinesiol Recreat & Sports Studies, Knoxville, TN USA. RP Wolff-Hughes, DL (reprint author), NCI, Sci Res & Technol Branch, Behav Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,3E544,MSC 9762, Bethesda, MD 20850 USA. EM dana.wolff@nih.gov FU National Cancer Institute FX This work was supported by the National Cancer Institute. NR 25 TC 1 Z9 1 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD JUN PY 2016 VL 87 BP 35 EP 40 DI 10.1016/j.ypmed.2016.02.019 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DQ2HX UT WOS:000379024500006 PM 26876630 ER PT J AU Li, KG Haynie, D Palla, H Lipsky, L Iannotti, RJ Simons-Morton, B AF Li, Kaigang Haynie, Denise Palla, Hira Lipsky, Leah Iannotti, Ronald J. Simons-Morton, Bruce TI Assessment of adolescent weight status: Similarities and differences between CDC, IOTF, and WHO references SO PREVENTIVE MEDICINE LA English DT Article DE Adolescents; Body weight; Body mass index; Growth charts ID BODY-MASS INDEX; SELF-RATED HEALTH; YOUNG-ADULTS; OVERWEIGHT; OBESITY; CHILDREN; LIFE; IMAGE AB Objective. The research sought to determine the reliability of assessing adolescents' weight status based on three standard criteria, Centers for Disease Control and Prevention (CDC) growth charts, International Obesity Task Force (IOTF) standards, and the World Health Organization (WHO) growth references. Methods. Data from the NEXT Generation Health Study US 10th grade cohort (n = 2323, mean age = 16.19 years) starting in 2009 were used. Kappa statistics assessed agreement of assignment to weight categories. Associations of weight status with perceived body image, weight control intention, and general health were examined using linear regressions accounting for complex survey design. Results. Kappas across weight status criteria were >=.89 and agreement exceeded 90% in all analyses. For all three criteria, overweight and obese participants, compared to normal weight, were significantly more likely to indicate fatter body image, higher weight control intention, and poorer general health; small differences in the regression coefficients by classification method were observed. Conclusion. The three criteria of weight status classifications substantially agreed. Associations of weight status with selected health correlates were similar regardless of the methods. Thus, the three classifications can be considered comparable for most research and practice purposes. (C) 2016 Elsevier Inc. All rights reserved. C1 [Li, Kaigang] Colorado State Univ, Dept Hlth & Exercise Sci, B 215E Moby Complex, Ft Collins, CO 80523 USA. [Haynie, Denise; Palla, Hira; Lipsky, Leah; Simons-Morton, Bruce] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD USA. [Iannotti, Ronald J.] CDM Grp Inc, 7500 Old Georgetown Rd, 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; Haynie, Denise/0000-0002-8270-6079; Lipsky, Leah/0000-0003-2645-4388 FU 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 the Health Resources and Services Administration (HRSA); National Institute on Drug Abuse (NIDA) FX This project (contract number HHSN275201200001I) was supported in part by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Heart, Lung and Blood Institute (NHLBI), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA), with supplemental support from the National Institute on Drug Abuse (NIDA). NR 15 TC 1 Z9 1 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 JUN PY 2016 VL 87 BP 151 EP 154 DI 10.1016/j.ypmed.2016.02.035 PG 4 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DQ2HX UT WOS:000379024500023 PM 26921658 ER PT J AU Xiao, L He, B Koster, A Caserotti, P Lange-Maia, B Glynn, NW Harris, TB Crainiceanu, CM AF Xiao, Luo He, Bing Koster, Annemarie Caserotti, Paolo Lange-Maia, Brittney Glynn, Nancy W. Harris, Tamara B. Crainiceanu, Ciprian M. TI Movement prediction using accelerometers in a human population SO BIOMETRICS LA English DT Article DE Accelerometer; Activity type; Movelets; Prediction ID PHYSICAL-ACTIVITY; ENERGY-EXPENDITURE; MOVELETS; BEHAVIOR; WRIST AB We introduce statistical methods for predicting the types of human activity at sub-second resolution using triaxial accelerometry data. The major innovation is that we use labeled activity data from some subjects to predict the activity labels of other subjects. To achieve this, we normalize the data across subjects by matching the standing up and lying down portions of triaxial accelerometry data. This is necessary to account for differences between the variability in the position of the device relative to gravity, which are induced by body shape and size as well as by the ambiguous definition of device placement. We also normalize the data at the device level to ensure that the magnitude of the signal at rest is similar across devices. After normalization we use overlapping movelets (segments of triaxial accelerometry time series) extracted from some of the subjects to predict the movement type of the other subjects. The problem was motivated by and is applied to a laboratory study of 20 older participants who performed different activities while wearing accelerometers at the hip. Prediction results based on other people's labeled dictionaries of activity performed almost as well as those obtained using their own labeled dictionaries. These findings indicate that prediction of activity types for data collected during natural activities of daily living may actually be possible. C1 [Xiao, Luo] N Carolina State Univ, Raleigh, NC 27695 USA. [He, Bing; Crainiceanu, Ciprian M.] Johns Hopkins Univ, Baltimore, MD USA. [Koster, Annemarie] Maastricht Univ, NL-6200 MD Maastricht, Netherlands. [Caserotti, Paolo] Univ Southern Denmark, Odense, Denmark. [Lange-Maia, Brittney; Glynn, Nancy W.] Univ Pittsburgh, Pittsburgh, PA USA. [Harris, Tamara B.] NIA, Bethesda, MD 20892 USA. RP Xiao, L (reprint author), N Carolina State Univ, Raleigh, NC 27695 USA. EM xiaoyuesixi@gmail.com RI Koster, Annemarie/E-7438-2010; OI Glynn, Nancy/0000-0003-2265-0162 FU Intramural Research Program of the National Institute on Aging; National Institute of Neurological Disorders and Stroke [R01NS060910]; National Institute of Health [RC2AG036594]; Pittsburgh Claude D. Pepper Older American's Independence Center Research Registry (NIH) [P30 AG024826]; National Institute on Aging Professional Services [HHSN271201100605P]; University of Pittsburgh Department of Epidemiology Small Grant; National Institute on Aging Training Grant [T32AG000181] FX This research was funded in part by the Intramural Research Program of the National Institute on Aging. Xiao, He, and Crainiceanu were supported by Grant Number R01NS060910 from the National Institute of Neurological Disorders and Stroke. This work was supported by the National Institute of Health through the funded Study of Energy and Aging Pilot (RC2AG036594), Pittsburgh Claude D. Pepper Older American's Independence Center Research Registry (NIH P30 AG024826), a National Institute on Aging Professional Services Contract (HHSN271201100605P), a University of Pittsburgh Department of Epidemiology Small Grant, and the National Institute on Aging Training Grant (T32AG000181). The work are the opinions of the researchers and not necessarily that of the granting organizations. NR 26 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD JUN PY 2016 VL 72 IS 2 BP 513 EP 524 DI 10.1111/biom.12382 PG 12 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA DP5HW UT WOS:000378527900021 PM 26288278 ER PT J AU Li, Y Panagiotou, OA Black, A Liao, DD Wacholder, S AF Li, Yan Panagiotou, Orestis A. Black, Amanda Liao, Dandan Wacholder, Sholom TI Multivariate piecewise exponential survival modeling SO BIOMETRICS LA English DT Article DE Absolute risks; Complex sampling designs; Marginal prediction; PLCO; Poisson regression; Probability proportional to a measure of size (PPS) ID COHORT AB In this article, we develop a piecewise Poisson regression method to analyze survival data from complex sample surveys involving cluster-correlated, differential selection probabilities, and longitudinal responses, to conveniently draw inference on absolute risks in time intervals that are prespecified by investigators. Extensive simulations evaluate the developed methods with extensions to multiple covariates under various complex sample designs, including stratified sampling, sampling with selection probability proportional to a measure of size (PPS), and a multi-stage cluster sampling. We applied our methods to a study of mortality in men diagnosed with prostate cancer in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial to investigate whether a biomarker available from biospecimens collected near time of diagnosis stratifies subsequent risk of death. Poisson regression coefficients and absolute risks of mortality (and the corresponding 95% confidence intervals) for prespecified age intervals by biomarker levels are estimated. We conclude with a brief discussion of the motivation, methods, and findings of the study. C1 [Li, Yan] Univ Maryland, Joint Program Survey Methodol, College Pk, MD 20742 USA. [Panagiotou, Orestis A.; Black, Amanda; Wacholder, Sholom] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Liao, Dandan] Univ Maryland, Coll Educ, Measurement Stat & Evaluat, College Pk, MD 20742 USA. RP Li, Y (reprint author), Univ Maryland, Joint Program Survey Methodol, College Pk, MD 20742 USA. EM yli6@umd.edu RI Panagiotou, Orestis/I-5934-2015 OI Panagiotou, Orestis/0000-0001-9604-8380 FU Intramural NIH HHS [Z99 CA999999] NR 14 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD JUN PY 2016 VL 72 IS 2 BP 546 EP 553 DI 10.1111/biom.12435 PG 8 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA DP5HW UT WOS:000378527900024 PM 26583951 ER PT J AU Satagopan, JM Sen, A Zhou, Q Lan, Q Rothman, N Langseth, H Engel, LS AF Satagopan, Jaya M. Sen, Ananda Zhou, Qin Lan, Qing Rothman, Nathaniel Langseth, Hilde Engel, Lawrence S. TI Bayes and empirical Bayes methods for reduced rank regression models in matched case-control studies SO BIOMETRICS LA English DT Article DE Bayesian lasso; Bayesian ridge; Empirical Bayes; Hierarchical Bayes; Non-Hodgkin's lymphoma; Two-stage lasso ID LIMITING RISK; ESTIMATORS; SHRINKAGE; SELECTION; EXPOSURES; LASSO AB Matched case-control studies are popular designs used in epidemiology for assessing the effects of exposures on binary traits. Modern studies increasingly enjoy the ability to examine a large number of exposures in a comprehensive manner. However, several risk factors often tend to be related in a nontrivial way, undermining efforts to identify the risk factors using standard analytic methods due to inflated type-I errors and possible masking of effects. Epidemiologists often use data reduction techniques by grouping the prognostic factors using a thematic approach, with themes deriving from biological considerations. We propose shrinkage-type estimators based on Bayesian penalization methods to estimate the effects of the risk factors using these themes. The properties of the estimators are examined using extensive simulations. The methodology is illustrated using data from a matched case-control study of polychlorinated biphenyls in relation to the etiology of non-Hodgkin's lymphoma. C1 [Satagopan, Jaya M.; Zhou, Qin] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10017 USA. [Sen, Ananda] Univ Michigan, Dept Family Med, Ann Arbor, MI 48104 USA. [Sen, Ananda] Univ Michigan, Dept Biostat, Ann Arbor, MI 48104 USA. [Lan, Qing; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. [Langseth, Hilde] Canc Registry Norway, Inst Populat Based Canc Res, N-0304 Oslo, Norway. [Engel, Lawrence S.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. RP Satagopan, JM (reprint author), Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10017 USA. EM satagopj@mskcc.org; anandas@umich.edu FU National Cancer Institute [R01CA137420, P30CA008748]; Clinical and Translational Science Center at Weill Cornell Medical College, New York [UL1RR024996]; GI SPORE grant from the National Cancer Institute [P50CA130810] FX The first two authors contributed equally to this work. The first author's work was supported in part by research grant R01CA137420, Cancer Center Support Grant P30CA008748 from the National Cancer Institute, and grant UL1RR024996 from the Clinical and Translational Science Center at Weill Cornell Medical College, New York. The second author's work was supported in part by the GI SPORE grant P50CA130810 from the National Cancer Institute. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health. NR 26 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD JUN PY 2016 VL 72 IS 2 BP 584 EP 595 DI 10.1111/biom.12444 PG 12 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA DP5HW UT WOS:000378527900028 PM 26575519 ER PT J AU Scott, BH Mishkin, M AF Scott, Brian H. Mishkin, Mortimer TI Auditory short-term memory in the primate auditory cortex SO BRAIN RESEARCH LA English DT Review DE Working memory; Short-term memory; Macaque; Cortex; Hearing ID INFERIOR TEMPORAL CORTEX; STIMULUS-SPECIFIC ADAPTATION; MONKEYS MACACA-FASCICULARIS; VISUAL WORKING-MEMORY; MATCHING-TO-SAMPLE; PREFRONTAL CORTEX; RECOGNITION MEMORY; LONG-TERM; REPETITION ENHANCEMENT; PROACTIVE-INTERFERENCE AB Sounds are fleeting, and assembling the sequence of inputs at the ear into a coherent percept requires auditory memory across various time scales. Auditory short-term memory comprises at least two components: an active 'working memory' bolstered by rehearsal, and a sensory trace that may be passively retained. Working memory relies on representations recalled from long-term memory, and their rehearsal may require phonological mechanisms unique to humans. The sensory component, passive short-term memory (pSTM), is tractable to study in nonhuman primates, whose brain architecture and behavioral repertoire are comparable to our own. This review discusses recent advances in the behavioral and neurophysiological study of auditory memory with a focus on single-unit recordings from macaque monkeys performing delayed-match-to-sample (DMS) tasks. Monkeys appear to employ pSTM to solve these tasks, as evidenced by the impact of interfering stimuli on memory performance. In several regards, pSTM in monkeys resembles pitch memory in humans, and may engage similar neural mechanisms. Neural correlates of DMS performance have been observed throughout the auditory and prefrontal cortex, defining a network of areas supporting auditory STM with parallels to that supporting visual STM. These correlates include persistent neural firing, or a suppression of firing, during the delay period of the memory task, as well as suppression or (less commonly) enhancement of sensory responses when a sound is repeated as a 'match' stimulus. Auditory STM is supported by a distributed temporo-frontal network in which sensitivity to stimulus history is an intrinsic feature of auditory processing. This article is part of a Special Issue entitled SI: Auditory working memory. Published by Elsevier B.V. C1 [Scott, Brian H.; Mishkin, Mortimer] NIMH, Neuropsychol Lab, NIH, Bldg 9, Bethesda, MD 20892 USA. RP Scott, BH (reprint author), NIMH, Neuropsychol Lab, 49 Convent Dr,Room 1B80, Bethesda, MD 20892 USA. EM brianscott@mail.nih.gov; mishkinm@mail.nih.gov FU Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services [ZIAMH00110123] FX The authors would like to acknowledge Pingbo Yin for establishing the auditory serial DMS paradigm while at the Laboratory of Neuropsychology. We thank Corrie Camalier and John Wittig, Jr. for comments on the manuscript. This work was supported by the Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services Project ZIAMH00110123. NR 156 TC 2 Z9 2 U1 4 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD JUN 1 PY 2016 VL 1640 SI SI BP 264 EP 277 DI 10.1016/j.brainres.2015.10.048 PN B PG 14 WC Neurosciences SC Neurosciences & Neurology GA DP4DZ UT WOS:000378447700009 PM 26541581 ER PT J AU Fritz, JB Malloy, M Mishkin, M Saunders, RC AF Fritz, Jonathan B. Malloy, Megan Mishkin, Mortimer Saunders, Richard C. TI Monkey's short-term auditory memory nearly abolished by combined removal of the rostral superior temporal gyrus and rhinal cortices SO BRAIN RESEARCH LA English DT Review DE Auditory; Cortex; Monkey; Recognition; Memory; Echoic ID MEDIAL PREFRONTAL NETWORKS; RECOGNITION MEMORY; PERIRHINAL CORTEX; MACAQUE MONKEYS; RHESUS-MONKEYS; CEBUS-APELLA; PARAHIPPOCAMPAL CORTICES; DIFFERENTIAL CONNECTIONS; VISUAL RECOGNITION; ENTORHINAL CORTEX AB While monkeys easily acquire the rules for performing visual and tactile delayed matching-to-sample, a method for testing recognition memory, they have extraordinary difficulty acquiring a similar rule in audition. Another striking difference between the modalities is that whereas bilateral ablation of the rhinal cortex (RhC) leads to profound impairment in visual and tactile recognition, the same lesion has no detectable effect on auditory recognition memory (Fritz et al., 2005). In our previous study, a mild impairment in auditory memory was obtained following bilateral ablation of the entire medial temporal lobe (MTL), including the RhC, and an equally mild effect was observed after bilateral ablation of the auditory cortical areas in the rostral superior temporal gyms (rSTG). In order to test the hypothesis that each of these mild impairments was due to partial disconnection of acoustic input to a common target (e.g., the ventromedial prefrontal cortex), in the current study we examined the effects of a more complete auditory disconnection of this common target by combining the removals of both the rSTG and the MTL. We found that the combined lesion led to forgetting thresholds (performance at 75% accuracy) that fell precipitously from the normal retention duration of similar to 30 to 40 s to a duration of similar to 1 to 2 s, thus nearly abolishing auditory recognition memory, and leaving behind only a residual echoic memory. This article is part of a Special Issue entitled SI: Auditory working memory. Published by Elsevier B.V. This is an open access article under the CC BY license C1 [Fritz, Jonathan B.] Univ Maryland, Syst Res Inst, Ctr Acoust & Auditory Res, Neural Syst Lab, College Pk, MD 20742 USA. [Malloy, Megan; Mishkin, Mortimer; Saunders, Richard C.] NIMH, Neuropsychol Lab, NIH, Bldg 9, Bethesda, MD 20892 USA. RP Saunders, RC (reprint author), NIMH, Neuropsychol Lab, Bldg 49,Rm 1B80, Bethesda, MD 20892 USA. EM ripple@isr.umd.edu; meganmalloy@mail.nih.gov; mishkinm@mail.nih.gov; richardsaunders@mail.nih.gov FU NIH FX Funded by NIH Intramural Program. NR 62 TC 0 Z9 0 U1 4 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD JUN 1 PY 2016 VL 1640 SI SI BP 289 EP 298 DI 10.1016/j.brainres.2015.12.012 PN B PG 10 WC Neurosciences SC Neurosciences & Neurology GA DP4DZ UT WOS:000378447700011 PM 26707975 ER PT J AU Barta, SK Joshi, J Mounier, N Xue, XN Wang, D Ribera, JM Navarro, JT Hoffmann, C Dunleavy, K Little, RF Wilson, WH Spina, M Galicier, L Noy, A Sparano, JA AF Barta, Stefan K. Joshi, Jitesh Mounier, Nicolas Xue, Xiaonan Wang, Dan Ribera, Josep-Maria Navarro, Jose-Tomas Hoffmann, Christian Dunleavy, Kieron Little, Richard F. Wilson, Wyndham H. Spina, Michele Galicier, Lionel Noy, Ariela Sparano, Joseph A. TI Central nervous system involvement in AIDS-related lymphomas SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE acquired immunodeficiency syndrome; lymphoma; central nervous system relapse; non-Hodgkin lymphoma; AIDS-related lymphoma ID B-CELL LYMPHOMA; NON-HODGKINS-LYMPHOMA; CHEMOTHERAPY INCLUDING RITUXIMAB; ACTIVE ANTIRETROVIRAL THERAPY; OCCULT LEPTOMENINGEAL DISEASE; STUDY-GROUP DSHNHL; PHASE-II TRIAL; RISK-FACTORS; INTENSIVE CHEMOTHERAPY; BURKITT LYMPHOMA/LEUKEMIA AB Central nervous system (CNS) involvement is reportedly more common in acquired immunodeficiency syndrome (AIDS)-related lymphomas (ARL). We describe factors and outcomes associated with CNS involvement at baseline (CNSB) and relapse (CNSR) in 886 patients with newly diagnosed ARL. Of 886 patients, 800 received either intrathecal (IT) therapy for CNSB or IT prophylaxis. CNSB was found in 13%. CNSB was not associated with reduced overall survival (OS). There was no difference in the prevalence of CNSB between the pre-combination antiretroviral therapy (cART) and cART eras. 53% of patients experienced CNSR at a median of 42months after diagnosis (12% if CNSB; 4% if not). Median OS after CNSR was 16months. On multivariate analysis, only CNSB [hazard ratio (HR) 368, P=0005] and complete response to initial therapy (HR 014, P<00001) were significantly associated with CNSR. When restricted to patients without CNSB, IT CNS prophylaxis with 3 vs. 1 agent did not significantly impact the risk of CNSR. Despite IT CNS prophylaxis, 5% of patients experienced CNSR. Our data confirms that CNSR in ARL occurs early and has a poor outcome. Complete response to initial therapy was associated with a reduced frequency of CNSR. Although CNSB conferred an increased risk for CNSR, it did not impact OS. C1 [Barta, Stefan K.] Fox Chase Canc Ctr, 333 Cottman Ave, Philadelphia, PA 19111 USA. [Joshi, Jitesh; Xue, Xiaonan; Wang, Dan; Sparano, Joseph A.] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. [Mounier, Nicolas] Ctr Hosp Univ Archet, Nice, France. [Ribera, Josep-Maria; Navarro, Jose-Tomas] Hosp Badalona Germans Trias & Pujol, Josep Carreras Res Inst Badalona, Badalona, Spain. [Hoffmann, Christian] IPM Study Ctr, Hamburg, Germany. [Hoffmann, Christian] Univ Schleswig Holstein, Kiel, Germany. [Dunleavy, Kieron; Little, Richard F.; Wilson, Wyndham H.] NCI, NIH, Bethesda, MD 20892 USA. [Spina, Michele] NCI, Div Med Oncol A, Aviano, Italy. [Galicier, Lionel] Hop St Louis, AP HP, Dept Clin Immunol, Paris, France. [Galicier, Lionel] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France. [Noy, Ariela] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Noy, Ariela] Weill Cornell New York, New York, NY USA. RP Barta, SK (reprint author), Fox Chase Canc Ctr, 333 Cottman Ave, Philadelphia, PA 19111 USA. EM Stefan.Barta@fccc.edu FU AMC [UO1 CA121947]; Paul Calabresi Career Development Award for Clinical Oncology [K12CA132783-03]; ASCO Cancer Foundation Young Investigator Award; Red Tematica de Investigacion Cooperativa en Cancer (RTICC) [RD12/0036/0029]; Instituto de Salud Carlos III, Spain; CTSA from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [UL1 RR025750, KL2 RR025749, TL1 RR025748]; NIH roadmap for Medical Research FX The authors would like to thank the National Cancer Institute, as well as the AIDS Malignancy Consortium (AMC) and other group investigators for enrolling patients on the included clinical trials. This work was supported in parts by the AMC (grant UO1 CA121947), the Paul Calabresi Career Development Award for Clinical Oncology (K12CA132783-03 Grant), The ASCO Cancer Foundation 2010 Young Investigator Award, grant RD12/0036/0029 from Red Tematica de Investigacion Cooperativa en Cancer (RTICC), Instituto de Salud Carlos III, Spain, and by the CTSA Grants UL1 RR025750 and KL2 RR025749 and TL1 RR025748 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH roadmap for Medical Research. NR 42 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JUN PY 2016 VL 173 IS 6 BP 857 EP 866 DI 10.1111/bjh.13998 PG 10 WC Hematology SC Hematology GA DP6XW UT WOS:000378644100004 PM 27062389 ER PT J AU Korde, N Zhang, Y Loeliger, K Poon, A Simakova, O Zingone, A Costello, R Childs, R Noel, P Silver, S Kwok, M Mo, C Young, N Landgren, O Sloand, E Maric, I AF Korde, Neha Zhang, Yong Loeliger, Kelsey Poon, Andrea Simakova, Olga Zingone, Adriana Costello, Rene Childs, Richard Noel, Pierre Silver, Samuel Kwok, Mary Mo, Clifton Young, Neal Landgren, Ola Sloand, Elaine Maric, Irina TI Monoclonal gammopathy-associated pure red cell aplasia SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE anaemia; monoclonal gammopathy of undetermined significance; myeloma; plasmacytosis; pure red cell aplasia ID MULTIPLE-MYELOMA; CYCLOSPORINE-A; ANEMIA; ERYTHROPOIETIN; INHIBITOR; HEPCIDIN; PATIENT; DISEASE; JAPAN AB Pure red cell aplasia (PRCA) is a rare disorder characterized by inhibition of erythroid precursors in the bone marrow and normochromic, normocytic anaemia with reticulocytopenia. Among 51 PRCA patients, we identified 12 (24%) patients having monoclonal gammopathy, monoclonal gammopathy of undetermined significance or smouldering multiple myeloma, with presence of monoclonal protein or abnormal serum free light chains and atypical bone marrow features of clonal plasmacytosis, hypercellularity and fibrosis. Thus far, three patients treated with anti-myeloma based therapeutics have responded with reticulocyte recovery and clinical transfusion independence, suggesting plasma cells play a key role in the pathogenesis of this specific monoclonal gammopathy-associated PRCA. C1 [Korde, Neha; Landgren, Ola] Mem Sloan Kettering Canc Ctr, Myeloma Serv, 1275 York Ave, New York, NY 10065 USA. [Korde, Neha; Zhang, Yong; Zingone, Adriana; Costello, Rene; Landgren, Ola] NCI, Multiple Myeloma Sect, Metab Branch, Silver Spring, MD USA. [Loeliger, Kelsey; Poon, Andrea; Childs, Richard; Young, Neal; Sloand, Elaine] NHLBI, Hematol Branch, Silver Spring, MD 20892 USA. [Simakova, Olga] US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Noel, Pierre; Maric, Irina] NIH, Dept Lab Med, Ctr Clin, Ann Arbor, MI USA. [Silver, Samuel] Univ Michigan, Sch Med, Internal Med Hematol Oncol, Ann Arbor, MI USA. [Kwok, Mary; Mo, Clifton] Walter Reed Natl Mil Med Ctr, Murtha Canc Ctr, Bethesda, MD USA. RP Korde, N (reprint author), Mem Sloan Kettering Canc Ctr, Myeloma Serv, 1275 York Ave, New York, NY 10065 USA. EM korden@mskcc.org NR 23 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JUN PY 2016 VL 173 IS 6 BP 876 EP 883 DI 10.1111/bjh.14012 PG 8 WC Hematology SC Hematology GA DP6XW UT WOS:000378644100006 PM 26999424 ER PT J AU Land, SR Warren, GW Crafts, JL Hatsukami, DK Ostroff, JS Willis, GB Chollette, VY Mitchell, SA Folz, JNM Gulley, JL Szabo, E Brandon, TH Duffy, SA Toll, BA AF Land, Stephanie R. Warren, Graham W. Crafts, Jennifer L. Hatsukami, Dorothy K. Ostroff, Jamie S. Willis, Gordon B. Chollette, Veronica Y. Mitchell, Sandra A. Folz, Jasmine N. M. Gulley, James L. Szabo, Eva Brandon, Thomas H. Duffy, Sonia A. Toll, Benjamin A. TI Cognitive Testing of Tobacco Use Items for Administration to Patients with Cancer and Cancer Survivors in Clinical Research SO CANCER LA English DT Article DE behavior; clinical trials as topic; questionnaire design; smoking; surveys and questionnaires; tobacco ID MAJOR PULMONARY MORBIDITY; OUTCOMES PRO INSTRUMENTS; QUALITY-OF-LIFE; SMOKING-CESSATION; REPORTED OUTCOMES; CIGARETTE-SMOKING; LUNG-CANCER; NECK-CANCER; DIAGNOSIS; TRIALS AB BACKGROUND: To the authors' knowledge, there are currently no standardized measures of tobacco use and secondhand smoke exposure in patients diagnosed with cancer, and this gap hinders the conduct of studies examining the impact of tobacco on cancer treatment outcomes. The objective of the current study was to evaluate and refine questionnaire items proposed by an expert task force to assess tobacco use. METHODS: Trained interviewers conducted cognitive testing with cancer patients aged >= 21 years with a history of tobacco use and a cancer diagnosis of any stage and organ site who were recruited at the National Institutes of Health Clinical Center in Bethesda, Maryland. Iterative rounds of testing and item modification were conducted to identify and resolve cognitive issues (comprehension, memory retrieval, decision/judgment, and response mapping) and instrument navigation issues until no items warranted further significant modification. RESULTS: Thirty participants (6 current cigarette smokers, 1 current cigar smoker, and 23 former cigarette smokers) were enrolled from September 2014 to February 2015. The majority of items functioned well. However, qualitative testing identified wording ambiguities related to cancer diagnosis and treatment trajectory, such as "treatment" and "surgery"; difficulties with lifetime recall; errors in estimating quantities; and difficulties with instrument navigation. Revisions to item wording, format, order, response options, and instructions resulted in a questionnaire that demonstrated navigational ease as well as good question comprehension and response accuracy. CONCLUSIONS: The Cancer Patient Tobacco Use Questionnaire (C-TUQ) can be used as a standardized item set to accelerate the investigation of tobacco use in the cancer setting. (C) 2016 American Cancer Society. C1 [Land, Stephanie R.] NCI, Tobacco Control Res Branch, Behav Res Program, 9609 Med Ctr Dr, Rockville, MD 20892 USA. [Land, Stephanie R.; Willis, Gordon B.; Chollette, Veronica Y.; Mitchell, Sandra A.] NCI, Div Canc Control & Populat Sci, Rockville, MD 20892 USA. [Warren, Graham W.] Med Univ S Carolina, Dept Radiat Oncol, Charleston, SC 29425 USA. [Warren, Graham W.] Med Univ S Carolina, Dept Cell & Mol Pharmacol, Charleston, SC 29425 USA. [Crafts, Jennifer L.; Folz, Jasmine N. M.] Westat Corp, Rockville, MD USA. [Hatsukami, Dorothy K.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA. [Ostroff, Jamie S.] Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, 1275 York Ave, New York, NY 10021 USA. [Gulley, James L.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Szabo, Eva] NCI, Canc Prevent Div, Rockville, MD 20892 USA. [Brandon, Thomas H.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Hlth Outcomes & Behav, Tampa, FL 33682 USA. [Duffy, Sonia A.] Ohio State Univ, Coll Nursing, Columbus, OH 43210 USA. [Toll, Benjamin A.] Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA. RP Land, SR (reprint author), NCI, Tobacco Control Res Branch, Behav Res Program, 9609 Med Ctr Dr, Rockville, MD 20892 USA.; Land, SR (reprint author), NCI, Div Canc Control & Populat Sci, Rockville, MD 20892 USA. EM Stephanie.land@nih.gov RI Gulley, James/K-4139-2016; OI Gulley, James/0000-0002-6569-2912; Folz, Jasmine/0000-0002-9609-2469 FU National Cancer Institute of the National Institutes of Health FX Funding for this study was provided by the National Cancer Institute of the National Institutes of Health. NR 37 TC 0 Z9 0 U1 2 U2 2 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 JUN 1 PY 2016 VL 122 IS 11 BP 1728 EP 1734 DI 10.1002/cncr.29964 PG 7 WC Oncology SC Oncology GA DP3NY UT WOS:000378402900015 PM 27019325 ER PT J AU Makarova-Rusher, OV Altekruse, SF McNeel, TS Ulahannan, S Duffy, AG Graubard, BI Greten, TF McGlynn, KA AF Makarova-Rusher, Oxana V. Altekruse, Sean F. McNeel, Tim S. Ulahannan, Susanna Duffy, Austin G. Graubard, Barry I. Greten, Tim F. McGlynn, Katherine A. TI Population Attributable Fractions of Risk Factors for Hepatocellular Carcinoma in the United States SO CANCER LA English DT Article DE attributable fractions; hepatitis B virus; hepatitis C virus; hepatocellular carcinoma; metabolic disorders; population ID METABOLIC SYNDROME; DIABETES-MELLITUS; CHRONIC HEPATITIS; EUROPEAN COHORT; VIRUS-INFECTION; DISEASE BURDEN; LIVER-DISEASE; CANCER-RISK; PREVALENCE; TRENDS AB BACKGROUND: Hepatocellular carcinoma (HCC) incidence has been increasing in the United States for several decades; and, as the incidence of hepatitis C virus (HCV) infection declines and the prevalence of metabolic disorders rises, the proportion of HCC attributable to various risk factors may be changing. METHODS: Data from the Surveillance, Epidemiology, and End Results-Medicare linkage were used to calculate population attributable fractions (PAFs) for each risk factor over time. Patients with HCC (n = 10,708) who were diagnosed during the years 2000 through 2011 were compared with a 5% random sample of cancer-free controls (n 5 332,107) residing in the Surveillance, Epidemiology, and End Results areas. Adjusted odds ratios (ORs) and PAFs were calculated for HCV, hepatitis B virus (HBV), metabolic disorders, alcohol-related disorders, smoking, and genetic disorders. RESULTS: Overall, the PAF was greatest for metabolic disorders (32%), followed by HCV (20.5%), alcohol (13.4%), smoking (9%), HBV (4.3%), and genetic disorders (1.5%). The PAF for all factors combined was 59.5%. PAFs differed by race/ethnicity and sex. Metabolic disorders had the largest PAF among Hispanics (PAF, 39.3%; 95% confidence interval [CI], 31.9%-46.7%) and whites (PAF, 34.8%; 95% CI, 33.1%-36.5%), whereas HCV had the largest PAF among blacks (PAF, 36.1%; 95% CI, 31.8%-40.4%) and Asians (PAF, 29.7%; 95% CI, 25.9%-33.4%). Between 2000 and 2011, the PAF of metabolic disorders increased from 25.8% (95% CI, 22.8%-28.9%) to 36% (95% CI, 33.6%-38.5%). In contrast, the PAFs of alcohol-related disorders and HCV remained stable. CONCLUSIONS: Among US Medicare recipients, metabolic disorders contribute more to the burden of HCC than any other risk factor, and the fraction of HCC caused by metabolic disorders has increased in the last decade. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. C1 [Makarova-Rusher, Oxana V.; Ulahannan, Susanna; Duffy, Austin G.; Greten, Tim F.] NCI, Gastrointestinal Malignancy Sect, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Altekruse, Sean F.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [McNeel, Tim S.] Informat Management Serv Inc, Calverton, MD USA. [Graubard, Barry I.; McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Room 7E-104, Bethesda, MD 20892 USA. RP McGlynn, KA (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Room 7E-104, Bethesda, MD 20892 USA. EM mcglynnk@mail.nih.gov RI Ulahannan, Susanna/H-6525-2016 OI Ulahannan, Susanna/0000-0002-7234-2283 FU National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 48 TC 4 Z9 4 U1 1 U2 3 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 JUN 1 PY 2016 VL 122 IS 11 BP 1757 EP 1765 DI 10.1002/cncr.29971 PG 9 WC Oncology SC Oncology GA DP3NY UT WOS:000378402900018 PM 26998818 ER PT J AU Liu, WL Rodgers, GP AF Liu, Wenli Rodgers, Griffin P. TI Olfactomedin 4 expression and functions in innate immunity, inflammation, and cancer SO CANCER AND METASTASIS REVIEWS LA English DT Review DE Olfactomedin 4; NF-kappa B; Bacterial infection; Inflammation; Cancer ID OPEN-ANGLE GLAUCOMA; GASTRIC-CANCER; STEM-CELLS; UP-REGULATION; STAPHYLOCOCCUS-AUREUS; TRANSCRIPTION FACTOR; HELICOBACTER-PYLORI; COLORECTAL-CANCER; OLFM4 EXPRESSION; PROSTATE-CANCER AB Olfactomedin 4 (OLFM4) is an olfactomedin domain-containing glycoprotein. Multiple signaling pathways and factors, including NF-kappa B, Wnt, Notch, PU.1, retinoic acids, estrogen receptor, and miR-486, regulate its expression. OLFM4 interacts with several other proteins, such as gene associated with retinoic-interferon-induced mortality 19 (GRIM-19), cadherins, lectins, nucleotide oligomerization domain-1 (NOD1) and nucleotide oligomerization domain-2 (NOD2), and cathepsins C and D, known to regulate important cellular functions. Recent investigations using Olfm4-deficient mouse models have provided important clues about its in vivo biological functions. Olfm4 inhibited Helicobacter pylori-induced NF-kappa B pathway activity and inflammation and facilitated H. pylori colonization in the mouse stomach. Olfm4-deficient mice exhibited enhanced immunity against Escherichia coli and Staphylococcus aureus infection. Olfm4 deletion in a chronic granulomatous disease mouse model rescued them from S. aureus infection. Olfm4 deletion in mice treated with azoxymethane/dextran sodium sulfate led to robust intestinal inflammation and intestinal crypt hyperplasia. Olfm4 deletion in Apc (Min/+) mice promoted intestinal polyp formation as well as adenocarcinoma development in the distal colon. Further, Olfm4-deficient mice spontaneously developed prostatic epithelial lesions as they age. OLFM4 expression is correlated with cancer differentiation, stage, metastasis, and prognosis in a variety of cancers, suggesting its potential clinical value as an early-stage cancer marker or a therapeutic target. Collectively, these data suggest that OLFM4 plays important roles in innate immunity against bacterial infection, gastrointestinal inflammation, and cancer. In this review, we have summarized OLFM4's initial characterization, expression, regulation, protein interactions, and biological functions. C1 [Liu, Wenli; Rodgers, Griffin P.] NHLBI, Mol & Clin Hematol Branch, NIH, Bldg 10,Room 9N119,9000 Rockville Pike, Bethesda, MD 20892 USA. RP Rodgers, GP (reprint author), NHLBI, Mol & Clin Hematol Branch, NIH, Bldg 10,Room 9N119,9000 Rockville Pike, Bethesda, MD 20892 USA. EM gr5n@nih.gov NR 59 TC 1 Z9 1 U1 3 U2 11 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-7659 EI 1573-7233 J9 CANCER METAST REV JI Cancer Metastasis Rev. PD JUN PY 2016 VL 35 IS 2 BP 201 EP 212 DI 10.1007/s10555-016-9624-2 PG 12 WC Oncology SC Oncology GA DP8TX UT WOS:000378771900004 PM 27178440 ER PT J AU Stoehr, A Yang, YQ Patel, S Evangelista, AM Aponte, A Wang, GH Liu, PC Boylston, J Kloner, PH Lin, YS Gucek, M Zhu, J Murphy, E AF Stoehr, Andrea Yang, Yanqin Patel, Sajni Evangelista, Alicia M. Aponte, Angel Wang, Guanghui Liu, Poching Boylston, Jennifer Kloner, Philip H. Lin, Yongshun Gucek, Marjan Zhu, Jun Murphy, Elizabeth TI Prolyl hydroxylation regulates protein degradation, synthesis, and splicing in human induced pluripotent stem cell-derived cardiomyocytes SO CARDIOVASCULAR RESEARCH LA English DT Article DE Prolyl hydroxylation; Hypoxia; Proteomics; Protein degradation; Splicing ID MESSENGER-RNA TRANSLATION; HYPOXIA-INDUCIBLE FACTOR; HIF-ALPHA; METABOLISM; INHIBITION; COMPLEX; OGFOD1; DOMAIN; HEART; 2-OXOGLUTARATE AB Protein hydroxylases are oxygen- and alpha-ketoglutarate-dependent enzymes that catalyse hydroxylation of amino acids such as proline, thus linking oxygen and metabolism to enzymatic activity. Prolyl hydroxylation is a dynamic post-translational modification that regulates protein stability and protein-protein interactions; however, the extent of this modification is largely uncharacterized. The goals of this study are to investigate the biological consequences of prolyl hydroxylation and to identify new targets that undergo prolyl hydroxylation in human cardiomyocytes. We used human induced pluripotent stem cell-derived cardiomyocytes in combination with pulse-chase amino acid labelling and proteomics to analyse the effects of prolyl hydroxylation on protein degradation and synthesis. We identified 167 proteins that exhibit differences in degradation with inhibition of prolyl hydroxylation by dimethyloxalylglycine (DMOG); 164 were stabilized. Proteins involved in RNA splicing such as serine/arginine-rich splicing factor 2 (SRSF2) and splicing factor and proline- and glutamine-rich (SFPQ) were stabilized with DMOG. DMOG also decreased protein translation of cytoskeletal and sarcomeric proteins such as alpha-cardiac actin. We searched the mass spectrometry data for proline hydroxylation and identified 134 high confidence peptides mapping to 78 unique proteins. We identified SRSF2, SFPQ, alpha-cardiac actin, and cardiac titin as prolyl hydroxylated. We identified 29 prolyl hydroxylated proteins that showed a significant difference in either protein degradation or synthesis. Additionally, we performed next-generation RNA sequencing and showed that the observed decrease in protein synthesis was not due to changes in mRNA levels. Because RNA splicing factors were prolyl hydroxylated, we investigated splicing +/- inhibition of prolyl hydroxylation and detected 369 alternative splicing events, with a preponderance of exon skipping. This study provides the first extensive characterization of the cardiac prolyl hydroxylome and demonstrates that inhibition of alpha-ketoglutarate hydroxylases alters protein stability, translation, and splicing. C1 [Stoehr, Andrea; Evangelista, Alicia M.; Boylston, Jennifer; Kloner, Philip H.; Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bldg 10,Room 8N202,10 Ctr Dr, Bethesda, MD 20892 USA. [Yang, Yanqin; Liu, Poching; Zhu, Jun] NHLBI, DNA Sequencing & Genom Core, NIH, Bldg 10, Bethesda, MD 20892 USA. [Patel, Sajni; Aponte, Angel; Wang, Guanghui; Gucek, Marjan] NHLBI, Prote Core Facil, NIH, Bldg 10, Bethesda, MD 20892 USA. [Lin, Yongshun] NHLBI, IPS Cell Core Facil, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Murphy, E (reprint author), NHLBI, Syst Biol Ctr, NIH, Bldg 10,Room 8N202,10 Ctr Dr, Bethesda, MD 20892 USA. EM murphy1@nhlbi.nih.gov FU NIH-NHLBI Intramural Program FX This work was supported by the NIH-NHLBI Intramural Program. NR 49 TC 1 Z9 1 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 EI 1755-3245 J9 CARDIOVASC RES JI Cardiovasc. Res. PD JUN 1 PY 2016 VL 110 IS 3 BP 346 EP 358 DI 10.1093/cvr/cvw081 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DP4CJ UT WOS:000378442700010 PM 27095734 ER PT J AU Chen, WH Cohen, MB Kirkpatrick, BD Brady, RC Galloway, D Gurwith, M Hall, RH Kessler, RA Lock, M Haney, D Lyon, CE Pasetti, MF Simon, JK Szabo, F Tennant, S Levine, MM AF Chen, Wilbur H. Cohen, Mitchell B. Kirkpatrick, Beth D. Brady, Rebecca C. Galloway, David Gurwith, Marc Hall, Robert H. Kessler, Robert A. Lock, Michael Haney, Douglas Lyon, Caroline E. Pasetti, Marcela F. Simon, Jakub K. Szabo, Flora Tennant, Sharon Levine, Myron M. TI Single-dose Live Oral Cholera Vaccine CVD 103-HgR Protects Against Human Experimental Infection With Vibrio cholerae O1 El Tor SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE cholera; vaccine; volunteer; challenge; efficacy ID UNITED-STATES; TYPHOID VACCINE; BLOOD-GROUPS; IMMUNITY; BANGLADESH; TRIAL; IMMUNOGENICITY; DURATION; EFFICACY; STRAINS AB Background. No licensed cholera vaccine is presently available in the United States. Cholera vaccines available in other countries require 2 spaced doses. A single-dose cholera vaccine that can rapidly protect short-notice travelers to high-risk areas and help control explosive outbreaks where logistics render 2-dose immunization regimens impractical would be a major advance. PXVX0200, based on live attenuated Vibrio cholerae O1 classical Inaba vaccine strain CVD 103-HgR, elicits seroconversion of vibriocidal antibodies (a correlate of protection) within 10 days of a single oral dose. We investigated the protection conferred by this vaccine in a human cholera challenge model. Methods. Consenting healthy adult volunteers, 18-45 years old, were randomly allocated 1:1 to receive 1 oral dose of vaccine (approximately 5 x 10(8) colony-forming units [CFU]) or placebo in double-blind fashion. Volunteers ingested approximately 1 x 10(5) CFU of wild-type V. cholerae O1 El Tor Inaba strain N16961 10 days or 3 months after vaccination and were observed on an inpatient research ward for stool output measurement and management of hydration. Results. The vaccine was well tolerated, with no difference in adverse event frequency among 95 vaccinees vs 102 placebo recipients. The primary endpoint, moderate (>= 3.0 L) to severe (>= 5.0 L) diarrheal purge, occurred in 39 of 66 (59.1%) placebo controls but only 2 of 35 (5.7%) vaccinees at 10 days (vaccine efficacy, 90.3%; P<.0001) and 4 of 33 (12.1%) vaccinees at 3 months (vaccine efficacy, 79.5%; P<.0001). Conclusions. The significant vaccine efficacy documented 10 days and 3 months after 1 oral dose of PXVX0200 supports further development as a single-dose cholera vaccine. C1 [Chen, Wilbur H.; Kessler, Robert A.; Pasetti, Marcela F.; Tennant, Sharon; Levine, Myron M.] Univ Maryland, Sch Med, Ctr Vaccine Dev, 685 W Baltimore St,Ste 480, Baltimore, MD 21201 USA. [Cohen, Mitchell B.; Brady, Rebecca C.; Galloway, David; Szabo, Flora] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Kirkpatrick, Beth D.; Lyon, Caroline E.] Univ Vermont, Vaccine Testing Ctr, Coll Med, Burlington, VT 05405 USA. [Gurwith, Marc; Lock, Michael; Haney, Douglas; Simon, Jakub K.] PaxVax Inc, Menlo Pk, CA USA. [Hall, Robert H.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Cohen, Mitchell B.] Univ Alabama Birmingham, Birmingham, AL USA. [Simon, Jakub K.] Merck & Co Inc, Kenilworth, NJ USA. RP Chen, WH (reprint author), Univ Maryland, Sch Med, Ctr Vaccine Dev, 685 W Baltimore St,Ste 480, Baltimore, MD 21201 USA. EM wchen@medicine.umaryland.edu OI Cohen, Mitchell/0000-0002-4412-350X FU PaxVax, Inc. FX This work was fully funded by PaxVax, Inc. NR 40 TC 10 Z9 10 U1 1 U2 3 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 JUN 1 PY 2016 VL 62 IS 11 BP 1329 EP 1335 DI 10.1093/cid/ciw145 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DP3YX UT WOS:000378433400006 PM 27001804 ER PT J AU Freeman, ML Mudd, JC Shive, CL Younes, SA Panigrahi, S Sieg, SF Lee, SA Hunt, PW Calabrese, LH Gianella, S Rodriguez, B Lederman, MM AF Freeman, Michael L. Mudd, Joseph C. Shive, Carey L. Younes, Souheil-Antoine Panigrahi, Soumya Sieg, Scott F. Lee, Sulggi A. Hunt, Peter W. Calabrese, Leonard H. Gianella, Sara Rodriguez, Benigno Lederman, Michael M. TI Cytomegalovirus Immunity and Exhaustive CD8(+) T Cell Proliferation in Treated Human Immunodeficiency Virus Infection Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID HIV-INFECTION; DISEASE; CMV; INFLAMMATION; EXPRESSION; SEMEN; CD57 C1 [Freeman, Michael L.; Younes, Souheil-Antoine; Panigrahi, Soumya; Sieg, Scott F.; Rodriguez, Benigno; Lederman, Michael M.] Case Western Reserve Univ, Dept Med, Div Infect Dis & HIV Med, Ctr AIDS Res,Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Mudd, Joseph C.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Shive, Carey L.] Vet Adm Med Ctr, 10701 East Blvd, Cleveland, OH 44106 USA. [Lee, Sulggi A.; Hunt, Peter W.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Calabrese, Leonard H.] Cleveland Clin Fdn, Dept Rheumat & Immunol Dis, Cleveland, OH 44195 USA. [Gianella, Sara] Univ Calif San Diego, Div Infect Dis, La Jolla, CA 92093 USA. RP Lederman, MM (reprint author), Case Western Reserve Univ, Sch Med, 2061 Cornell Rd, Cleveland, OH 44106 USA. EM mxl6@case.edu FU NIAID NIH HHS [P30 AI036219, U01 AI069501, UM1 AI069501] NR 19 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 1 PY 2016 VL 62 IS 11 BP 1468 EP U162 DI 10.1093/cid/ciw152 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DP3YX UT WOS:000378433400032 PM 27001803 ER PT J AU Ellefsen, KN Concheiro, M Pirard, S Gorelick, DA Huestis, MA AF Ellefsen, Kayla N. Concheiro, Marta Pirard, Sandrine Gorelick, David A. Huestis, Marilyn A. TI Pharmacodynamic effects and relationships to plasma and oral fluid pharmacokinetics after intravenous cocaine administration SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Cocaine; Benzoylecgonine; Plasma; Oral fluid; Pharmacodynamics; Pharmacokinetics ID MASS-SPECTROMETRY; WHOLE-BLOOD; HUMANS; SALIVA; METABOLITES; DRUGS; HEROIN; URINE; ABUSE; ELIMINATION AB Background: No controlled cocaine administration data describe cocaine and metabolite disposition in oral fluid (OF) collected with commercially-available collection devices, OF-plasma ratios, and pharmacodynamic relationships with plasma and OF cocaine and metabolite concentrations. Methods: Eleven healthy, cocaine-using adults received 25 mg intravenous cocaine. Physiological and subjective effects (visual analogue scales), and plasma were collected one hour prior, and up to 21 h post-dose. OF was collected with the Quantisal(TM) device up to 69 h post-dose. Cocaine, benzoylecgonine (BE) and ecgonine methyl ester were quantified in plasma by liquid chromatography-tandem mass spectrometry; cocaine and BE were quantified in OF by two dimensional-gas chromatography-mass spectrometry. Results: Increases in heart rate, blood pressure and positive subjective effects occurred within the first 15 min, persisting up to 1 h ("Rush"), with clockwise hysteresis observed for plasma and OF concentrations and some subjective measures. Peak subjective effects ("Rush," "Good drug effect" and "Bad drug effect") occurred prior to peak OF cocaine concentration, whereas observed peak plasma concentrations and subjective measures occurred simultaneously, most likely due to significantly earlier plasma T-max. compared to OF T-max., T-last, T-max. compared to OF T-max T-last was generally longer in OF (12.5 h cocaine; 33.0 h BE) than plasma (9.5 h cocaine; >21 h BE, cutoffs 1 mu g/L); 8 and 10 mu g/L OF cocaine confirmatory cutoffs yielded detection times similar to cocaine's impairing effects, suggesting usefulness for DUID testing. Conclusions: OF offers advantages as an alternative matrix to blood and plasma for identifying cocaine intake, defining pharmacokinetic parameters at different confirmation cutoffs, and aiding different drug testing programs to best achieve their monitoring goals. (c) 2016 Published by Elsevier Ireland Ltd. C1 [Ellefsen, Kayla N.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, IRP, 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. [Pirard, Sandrine] Univ Maryland, Ctr Hlth, College Pk, MD 20742 USA. [Gorelick, David A.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Sect, IRP, NIH, 251 Bayview Blvd,Suite 200,Room 05A-721, Baltimore, MD 21224 USA. EM marilyn.huestis@gmail.com FU National Institutes of Health (NIH), National Institute on Drug Abuse (NIDA); Intramural Research Program (IRP) FX This research was supported by the National Institutes of Health (NIH), National Institute on Drug Abuse (NIDA) and its Intramural Research Program (IRP). NR 43 TC 0 Z9 0 U1 13 U2 13 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 JUN 1 PY 2016 VL 163 BP 116 EP 125 DI 10.1016/j.drugalcdep.2016.04.004 PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DP4HM UT WOS:000378457000015 PM 27114201 ER PT J AU Sells, JR Waters, AJ Schwandt, ML Kwako, LE Heilig, M George, DT Ramchandani, VA AF Sells, Joanna R. Waters, Andrew J. Schwandt, Melanie L. Kwako, Laura E. Heilig, Markus George, David T. Ramchandani, Vijay A. TI Characterization of comorbid PTSD in treatment-seeking alcohol dependent inpatients: Severity and personality trait differences SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Alcohol dependence; Alcoholism; PTSD; Neuroticism; Aggression ID POSTTRAUMATIC-STRESS-DISORDER; SUBSTANCE USE DISORDERS; NEUROTICISM; INDIVIDUALS; MECHANISMS; EXPOSURE; TRAUMA; ANGER; QUESTIONNAIRE; IMPULSIVITY AB Background: Post-traumatic stress disorder (PTSD) is often comorbid with alcohol dependence (AD), but little is known about the characteristics of AD treatment-seeking inpatients with PTSD. We examined differences between treatment-seeking alcohol dependent inpatients with and without comorbid PTSD. We hypothesized that those with AD and PTSD would have higher levels of: (1) alcohol use and AD severity; (2) anxiety and mood disorders; (3) neuroticism. Methods: Individuals (N = 411, mean age = 41.7 +/- 10.0 years) with AD were monitored over 30 days in a suburban inpatient alcohol treatment setting. Patients were evaluated to identify AD and comorbid PTSD, mood and anxiety disorders, alcohol use and dependence severity, personality, and aggression. Results: Those with PTSD (19% of the sample) did not differ in the amount of alcohol consumed, but had greater: (1) severity of AD (p = 0.001, d = 0.44); (2) diagnosis of anxiety (p = 0.000, OR = 3.64) and mood (p = 0.000, OR = 4.83) disorders; and (3) levels of neuroticism (p < 0.001, d = 0.67) and aggression (p < 0.001, d = 0.81). Conclusions: AD patients with comorbid PTSD present a more severe phenotype across AD severity, frequency of anxiety and mood disorders, and levels of neuroticism and aggression. This group may benefit from concurrent treatment of both AD and PTSD. Future research can investigate neuroticism as a potential treatment target. Published by Elsevier Ireland Ltd. C1 [Sells, Joanna R.; Ramchandani, Vijay A.] NIAAA, Sect Human Psychopharmacol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sells, Joanna R.; Waters, Andrew J.] Uniformed Serv Univ Hlth Sci, Lab Cognit Intervent, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. [Schwandt, Melanie L.; Kwako, Laura E.; George, David T.] NIAAA, Off Clin Director, NIH, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. [Heilig, Markus] Linkoping Univ, Dept Clin & Expt Med, Ctr Social & Affect Neurosci, Linkoping, Sweden. RP Ramchandani, VA (reprint author), Lab Clin & Translat Studies, Sect Human Psychopharmacol, 10Ctr Dr,MSC 1540,Bldg 10 CRC,Room 2-2352, Bethesda, MD 20892 USA. EM joanna.sells@nih.gov; andrew.waters@usuhs.edu; melanies@mail.nih.gov; laura.kwako@nih.gov; markus.heilig@liu.se; tedg@mail.nih.gov; vijayr@mail.nih.gov RI Schwandt, Melanie/L-9866-2016 FU Intramural NIH HHS [ZIA AA000466-10] NR 43 TC 0 Z9 0 U1 6 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUN 1 PY 2016 VL 163 BP 242 EP 246 DI 10.1016/j.drugalcdep.2016.03.016 PG 5 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DP4HM UT WOS:000378457000032 PM 27114205 ER PT J AU Tschapalda, K Zhang, YQ Liu, L Golovnina, K Schlemper, T Eichmann, TO Lal-Nag, M Sreenivasan, U McLenithan, J Ziegler, S Sztalryd, C Lass, A Auld, D Oliver, B Waldmann, H Li, ZY Shen, M Boxer, MB Beller, M AF Tschapalda, Kirsten Zhang, Ya-Qin Liu, Li Golovnina, Kseniya Schlemper, Thomas Eichmann, Thomas O. Lal-Nag, Madhu Sreenivasan, Urmila McLenithan, John Ziegler, Slava Sztalryd, Carole Lass, Achim Auld, Douglas Oliver, Brian Waldmann, Herbert Li, Zhuyin Shen, Min Boxer, Matthew B. Beller, Mathias TI A Class of Diacylglycerol Acyltransferase 1 Inhibitors Identified by a Combination of Phenotypic High-throughput Screening, Genomics, and Genetics SO EBIOMEDICINE LA English DT Article ID SMALL-MOLECULE INHIBITORS; LIPID DROPLETS; FAT STORAGE; TARGET IDENTIFICATION; HISTONE ACETYLATION; DGAT1 INHIBITORS; CHEMICAL BIOLOGY; ECTOPIC FAT; DROSOPHILA; DISEASE AB Excess lipid storage is an epidemic problemin human populations. Thus, the identification of small molecules to treat or prevent lipid storage-related metabolic complications is of great interest. Here we screened >320.000 compounds for their ability to prevent a cellular lipid accumulation phenotype. We used fly cells because the multifarious tools available for this organism should facilitate unraveling the mechanism-of-action of active small molecules. Of the several hundred lipid storage inhibitors identified in the primary screen we concentrated on three structurally diverse and potent compound classes active in cells of multiple species (including human) and negligible cytotoxicity. Together with Drosophila in vivo epistasis experiments, RNA-Seq expression profiles suggested that the target of one of the small molecules was diacylglycerol acyltransferase 1 (DGAT1), a key enzyme in the production of triacylglycerols and prominent human drug target. We confirmed this prediction by biochemical and enzymatic activity tests. (C) 2016 The Authors. Published by Elsevier B.V. C1 [Tschapalda, Kirsten; Schlemper, Thomas; Beller, Mathias] Univ Dusseldorf, Syst Biol Lipid Metab, Dusseldorf, Germany. [Tschapalda, Kirsten; Schlemper, Thomas; Beller, Mathias] Univ Dusseldorf, Inst Math Modeling Biol Syst, Dusseldorf, Germany. [Tschapalda, Kirsten; Ziegler, Slava; Waldmann, Herbert] Max Planck Inst Mol Physiol, Dept Biol Chem, Rheinlanddamm 201, D-44139 Dortmund, Germany. [Tschapalda, Kirsten] Max Planck Inst Biophys Chem, Dept Mol Dev Biol, D-37077 Gottingen, Germany. [Zhang, Ya-Qin; Liu, Li; Lal-Nag, Madhu; Auld, Douglas; Li, Zhuyin; Shen, Min; Boxer, Matthew B.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Golovnina, Kseniya; Oliver, Brian] NIDDK, NIH, Bethesda, MD 20892 USA. [Eichmann, Thomas O.; Lass, Achim] Graz Univ, Inst Mol Biosci, A-8010 Graz, Austria. [Sreenivasan, Urmila; McLenithan, John; Sztalryd, Carole] Univ Maryland, Sch Med, Dept Med, Div Endocrinol, College Pk, MD 20742 USA. [Sztalryd, Carole] Univ Maryland, Sch Med, GRECC, Baltimore VA Med Ctr,VA Res Serv, College Pk, MD 20742 USA. [Sztalryd, Carole] Univ Maryland, Sch Med, Dept Med, Div Endocrinol,VA Maryland Hlth Care Syst, College Pk, MD 20742 USA. [Auld, Douglas] Novartis Inst Biomed Res, Ctr Prote Chem, Cambridge, MA 02139 USA. [Li, Zhuyin] Bristol Myers Squibb, Lead Discovery & Optimizat, 5 Res Pkwy, Wallingford, CT 06492 USA. RP Beller, M (reprint author), Univ Dusseldorf, Syst Biol Lipid Metab, Dusseldorf, Germany.; Beller, M (reprint author), Univ Dusseldorf, Inst Math Modeling Biol Syst, Dusseldorf, Germany. EM mathias.beller@hhu.de OI Waldmann, Herbert/0000-0002-9606-7247; Beller, Mathias/0000-0003-0987-0080 FU Austrian Science Fund FWF [P 25193] NR 70 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-3964 J9 EBIOMEDICINE JI EBioMedicine PD JUN PY 2016 VL 8 BP 49 EP 59 DI 10.1016/j.ebiom.2016.04.014 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DP6QI UT WOS:000378622200019 PM 27428418 ER PT J AU Li, YL Simonds, WF AF Li, Yulong Simonds, William F. TI Endocrine neoplasms in familial syndromes of hyperparathyroidism SO ENDOCRINE-RELATED CANCER LA English DT Review DE multiple endocrine neoplasia type 1 (MEN1); multiple endocrine neoplasia type 2A (MEN2A); hyperparathyroidism-jaw tumor (HPT-JT); malignant tumor; neuroendocrine tumor ID PANCREATIC NEUROENDOCRINE TUMORS; MEDULLARY-THYROID CANCER; METASTATIC PARATHYROID CARCINOMA; ZOLLINGER-ELLISON-SYNDROME; ADRENAL-SPARING SURGERY; GENOTYPE-PHENOTYPE CORRELATION; NUCLEAR-LOCALIZATION SIGNAL; DES TUMEURS ENDOCRINES; PROGNOSTIC-FACTORS; CDC73 GENE AB Familial syndromes of hyperparathyroidism, including multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2A (MEN2A), and the hyperparathyroidism-jaw tumor (HPT-JT), comprise 2-5% of primary hyperparathyroidism cases. Familial syndromes of hyperparathyroidism are also associated with a range of endocrine and nonendocrine tumors, including potential malignancies. Complications of the associated neoplasms are the major causes of morbidities and mortalities in these familial syndromes, e.g., parathyroid carcinoma in HPT-JT syndrome; thymic, bronchial, and enteropancreatic neuroendocrine tumors in MEN1; and medullary thyroid cancer and pheochromocytoma in MEN2A. Because of the different underlying mechanisms of neoplasia, these familial tumors may have different characteristics compared with their sporadic counterparts. Large-scale clinical trials are frequently lacking due to the rarity of these diseases. With technological advances and the development of new medications, the natural history, diagnosis, and management of these syndromes are also evolving. In this article, we summarize the recent knowledge on endocrine neoplasms in three familial hyperparathyroidism syndromes, with an emphasis on disease characteristics, molecular pathogenesis, recent developments in biochemical and radiological evaluation, and expert opinions on surgical and medical therapies. Because these familial hyperparathyroidism syndromes are associated with a wide variety of tumors in different organs, this review is focused on those endocrine neoplasms with malignant potential. C1 [Li, Yulong; Simonds, William F.] NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Simonds, WF (reprint author), NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. EM wfs@helix.nih.gov FU Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX This work was supported by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). NR 142 TC 1 Z9 1 U1 2 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 JUN PY 2016 VL 23 IS 6 BP R229 EP R247 DI 10.1530/ERC-16-0059 PG 19 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA DP8MV UT WOS:000378753200002 ER PT J AU Stratakis, CA AF Stratakis, Constantine A. TI Diagnosis and Clinical Genetics of Cushing Syndrome in Pediatrics SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Article DE Pituitary gland; Adrenal gland; Cyclic AMP (cAMP); PRKAR1A gene; AIP gene; ARMC5 gene; USP8 gene; GNAS1 gene ID MACRONODULAR ADRENAL-HYPERPLASIA; NODULAR ADRENOCORTICAL DISEASE; CORTICOTROPIN-RELEASING HORMONE; CARNEY COMPLEX; CATALYTIC SUBUNIT; ARMC5 MUTATIONS; SURGICAL CURE; CHILDREN; TUMORS; ADOLESCENTS AB Endogenous Cushing syndrome (CS) in pediatrics is rare; it may be caused by tumors that produce corticotropin in the pituitary gland or elsewhere, tumors that produce corticotropin-releasing hormone and adrenocortical masses that produce cortisol. Adrenocortical cancer is a rare cause of CS in children, but should be excluded first. CS in children is often caused by germline or somatic mutations with implications for patient prognosis and for their families. CS should be recognized early in children; otherwise, it can lead to significant morbidity and mortality. Patients with suspected CS should be referred to specialized clinical centers for workup. C1 [Stratakis, Constantine A.] NICHD, Sect Endocrinol & Genet SEGEN, NIH, CRC,East Labs, Bldg 10,Room 1-3330,10 Ctr Dr, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHD, Sect Endocrinol & Genet SEGEN, NIH, CRC,East Labs, Bldg 10,Room 1-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Intramural Research Program, NICHD, NIH, Bethesda, MD, USA [Z01-HD008920-01] FX Funding for this work was provided exclusively by the Intramural Research Program, NICHD, NIH, Bethesda, MD 20892, USA (Grant: Z01-HD008920-01). NR 44 TC 2 Z9 2 U1 5 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8529 EI 1558-4410 J9 ENDOCRIN METAB CLIN JI Endocrinol. Metabol. Clin. North Amer. PD JUN PY 2016 VL 45 IS 2 BP 311 EP + DI 10.1016/j.ecl.2016.01.006 PG 19 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP6BT UT WOS:000378582600008 PM 27241967 ER PT J AU Wakabayashi, KT Spekterman, L Kiyatkin, EA AF Wakabayashi, Ken T. Spekterman, Laurence Kiyatkin, Eugene A. TI Experience-dependent escalation of glucose drinking and the development of glucose preference over fructose - association with glucose entry into the brain SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE nucleus accumbens; rat; reinforcement; sugars; taste ID INTRAVENOUS COCAINE; EXTRACELLULAR GLUTAMATE; FLAVOR PREFERENCES; SENSING NEURONS; RAPID CHANGES; BLOOD-FLOW; RAT; FLUCTUATIONS; APPETITE; REWARD AB Glucose, a primary metabolic substrate for cellular activity, must be delivered to the brain for normal neural functions. Glucose is also a unique reinforcer; in addition to its rewarding sensory properties and metabolic effects, which all natural sugars have, glucose crosses the blood-brain barrier and acts on glucoreceptors expressed on multiple brain cells. To clarify the role of this direct glucose action in the brain, we compared the neural and behavioural effects of glucose with those induced by fructose, a sweeter yet metabolically equivalent sugar. First, by using enzyme-based biosensors in freely moving rats, we confirmed that glucose rapidly increased in the nucleus accumbens in a dose-dependent manner after its intravenous delivery. In contrast, fructose induced a minimal response only after a large-dose injection. Second, we showed that naive rats during unrestricted access consumed larger volumes of glucose than fructose solution; the difference appeared with a definite latency during the initial exposure and strongly increased during subsequent tests. When rats with equal sugar experience were presented with either glucose or fructose in alternating order, the consumption of both substances was initially equal, but only the consumption of glucose increased during subsequent sessions. Finally, rats with equal glucose-fructose experience developed a strong preference for glucose over fructose during a two-bottle choice procedure; the effect appeared with a definite latency during the initial test and greatly amplified during subsequent tests. Our results suggest that direct entry of glucose in the brain and its subsequent effects on brain cells could be critical for the experience-dependent escalation of glucose consumption and the development of glucose preference over fructose. C1 [Wakabayashi, Ken T.; Spekterman, Laurence; Kiyatkin, Eugene A.] NIDA, In Vivo Electrophysiol Unit, Behav Neurosci Branch, DHHS,Intramural Res Program,NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. RP Kiyatkin, EA (reprint author), NIDA, In Vivo Electrophysiol Unit, Behav Neurosci Branch, DHHS,Intramural Res Program,NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM ekiyatki@intra.nida.nih.gov FU National Institute on Drug Abuse - Intramural Research Program [DA000445-14] FX This work was supported by the National Institute on Drug Abuse - Intramural Research Program (DA000445-14). We greatly appreciate the valuable comments of Dr Roy A. Wise, who introduced us to the historical aspects of the taste-metabolism problem. NR 43 TC 2 Z9 2 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X EI 1460-9568 J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD JUN PY 2016 VL 43 IS 11 BP 1422 EP 1430 DI 10.1111/ejn.13137 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DP5UE UT WOS:000378562500004 PM 26613356 ER PT J AU Evans, AE Tripathi, A LaPorte, HM Brueggemann, LI Singh, AK Albee, LJ Byron, KL Tarasova, NI Volkman, BF Cho, TY Gaponenko, V Majetschak, M AF Evans, Ann E. Tripathi, Abhishek LaPorte, Heather M. Brueggemann, Lioubov I. Singh, Abhay Kumar Albee, Lauren J. Byron, Kenneth L. Tarasova, Nadya I. Volkman, Brian F. Cho, Thomas Yoonsang Gaponenko, Vadim Majetschak, Matthias TI New Insights into Mechanisms and Functions of Chemokine (C-X-C Motif) Receptor 4 Heteromerization in Vascular Smooth Muscle SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES LA English DT Article DE atypical chemokine receptor 3; (C-X-C motif) receptor 7; adrenergic receptor; vascular function; blood pressure; G protein-coupled receptor; receptor heteromer; structural modeling ID PROTEIN-COUPLED RECEPTOR; CELL-DERIVED FACTOR-1-ALPHA; BETA(2)-ADRENERGIC RECEPTORS; BETA-ARRESTIN; ALPHA(2C)-ADRENERGIC RECEPTORS; IN-VIVO; CXCR4; OLIGOMERIZATION; HETERODIMERS; COMPLEXES AB Recent evidence suggests that C-X-C chemokine receptor type 4 (CXCR4) heteromerizes with alpha(1A/B)-adrenoceptors (AR) and atypical chemokine receptor 3 (ACKR3) and that CXCR4: alpha(1A/B)-AR heteromers are important for alpha(1)-AR function in vascular smooth muscle cells (VSMC). Structural determinants for CXCR4 heteromerization and functional consequences of CXCR4: alpha(1A/B)-AR heteromerization in intact arteries, however, remain unknown. Utilizing proximity ligation assays (PLA) to visualize receptor interactions in VSMC, we show that peptide analogs of transmembrane-domain (TM) 2 and TM4 of CXCR4 selectively reduce PLA signals for CXCR4: alpha(1A)-AR and CXCR4: ACKR3 interactions, respectively. While both peptides inhibit CXCL12-induced chemotaxis, only the TM2 peptide inhibits phenylephrine-induced Ca2+-fluxes, contraction of VSMC and reduces efficacy of phenylephrine to constrict isolated arteries. In a Cre-loxP mouse model to delete CXCR4 in VSMC, we observed 60% knockdown of CXCR4. PLA signals for CXCR4: alpha(1A/B)-AR and CXCR4: ACKR3 interactions in VSMC, however, remained constant. Our observations point towards TM2/4 of CXCR4 as possible contact sites for heteromerization and suggest that TM-derived peptide analogs permit selective targeting of CXCR4 heteromers. A molecular dynamics simulation of a receptor complex in which the CXCR4 homodimer interacts with alpha(1A)-AR via TM2 and with ACKR3 via TM4 is presented. Our findings further imply that CXCR4: alpha(1A)-AR heteromers are important for intrinsic alpha(1)-AR function in intact arteries and provide initial and unexpected insights into the regulation of CXCR4 heteromerization in VSMC. C1 [Evans, Ann E.; Tripathi, Abhishek; LaPorte, Heather M.; Albee, Lauren J.; Majetschak, Matthias] Loyola Univ Chicago, Stritch Sch Med, Dept Surg, Burn & Shock Trauma Res Inst, 2160 S First Ave, Maywood, IL 60153 USA. [Brueggemann, Lioubov I.; Byron, Kenneth L.; Majetschak, Matthias] Loyola Univ Chicago, Stritch Sch Med, Dept Mol Pharmacol & Therapeut, 2160 S First Ave, Maywood, IL 60153 USA. [Singh, Abhay Kumar; Cho, Thomas Yoonsang] St Louis Univ, Sch Med, Edward A Doisy Dept Biochem & Mol Biol, 1100 South Grand Blvd, St Louis, MO 63104 USA. [Tarasova, Nadya I.] NCI, Canc & Inflammat Program, POB B, Frederick, MD 21702 USA. [Volkman, Brian F.] Med Coll Wisconsin, Dept Biochem, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [Gaponenko, Vadim] Univ Illinois, Dept Biochem & Mol Genet, 900 S Ashland, Chicago, IL 60607 USA. RP Majetschak, M (reprint author), Loyola Univ Chicago, Stritch Sch Med, Dept Surg, Burn & Shock Trauma Res Inst, 2160 S First Ave, Maywood, IL 60153 USA.; Majetschak, M (reprint author), Loyola Univ Chicago, Stritch Sch Med, Dept Mol Pharmacol & Therapeut, 2160 S First Ave, Maywood, IL 60153 USA. EM anevans@lumc.edu; omnamahshiva80@gmail.com; hlaporte@luc.edu; lalbee@luc.edu; singh@slu.edu; lalbee@luc.edu; lbruegg@luc.edu; tarasovn@mail.nih.gov; bvolkman@gmail.com; ycho9@slu.edu; vadimg@uic.edu; mmajetschak@luc.edu OI Byron, Kenneth/0000-0002-3875-9667 FU National Institute of General Medical Sciences of the National Institutes of Health [R01GM107495, T32GM008750]; American Heart Association [13GRNT17230072]; National Cancer Institute [R01CA135341, R01CA188427]; National Heart, Lung, and Blood Institute [R21HL118588]; National Institute of Allergy and Infectious Diseases [R01AI058072]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [K01AR060300]; National Cancer Institute of the National Institutes of Health FX This research was supported by the National Institute of General Medical Sciences (Awards R01GM107495 and T32GM008750) of the National Institutes of Health; by the American Heart Association (Award 13GRNT17230072); by the National Cancer Institute (Awards R01CA135341 and R01CA188427); by the National Heart, Lung, and Blood Institute (Award R21HL118588); by the National Institute of Allergy and Infectious Diseases (Award R01AI058072); by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Award K01AR060300); and by the Intramural Program, National Cancer Institute of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health and the American Heart Association. NR 59 TC 0 Z9 0 U1 4 U2 5 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1422-0067 J9 INT J MOL SCI JI Int. J. Mol. Sci. PD JUN PY 2016 VL 17 IS 6 AR 971 DI 10.3390/ijms17060971 PG 19 WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary SC Biochemistry & Molecular Biology; Chemistry GA DP9EK UT WOS:000378799300183 ER PT J AU Hu, JP Feng, ZW Ma, SF Zhang, Y Tong, Q Alqarni, MH Gou, XJ Xie, XQ AF Hu, Jianping Feng, Zhiwei Ma, Shifan Zhang, Yu Tong, Qin Alqarni, Mohammed Hamed Gou, Xiaojun Xie, Xiang-Qun TI Difference and Influence of Inactive and Active States of Cannabinoid Receptor Subtype CB2: From Conformation to Drug Discovery SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID PROTEIN-COUPLED RECEPTOR; MOLECULAR-DYNAMICS SIMULATIONS; BETA(2) ADRENERGIC-RECEPTOR; CRYSTAL-STRUCTURE; OSTEOCLAST INHIBITORS; BIOLOGICAL EVALUATION; BINDING MECHANISMS; SELECTIVE LIGANDS; INVERSE AGONISTS; GPCR STRUCTURE AB Cannabinoid receptor 2 (CB2), a G protein-coupled receptor (GPCR), is a promising target for the treatment of neuropathic pain, osteoporosis, immune system, cancer, and drug abuse. The lack of an experimental three-dimensional CB2 structure has hindered not only the development of studies of conformational differences between the inactive and active CB2 but also the rational discovery of novel functional compounds targeting CB2. In this work, we constructed models of both inactive and active CB2 by homology modeling. Then we conducted two comparative 100 ns molecular dynamics (MD) simulations on the two systems-the active CB2 bound with both the agonist and G protein and the inactive CB2 bound with inverse agonist-to analyze the conformational difference of CB2 proteins and the key residues involved in molecular recognition. Our results showed that the inactive CB2 and the inverse agonist remained stable during the MD simulation. However, during the MD simulations, we observed dynamical details about the breakdown of the "ionic lock" between R131(3.50) and D240(6.30) as well as the outward/inward movements of transmembrane domains of the active CB2 that bind with G proteins and agonist (TMS, TM6, and TM7). All of these results are congruent with the experimental data and recent reports. Moreover, our results indicate that W258(6.48) in TM6 and residues in TM4 (V164(4.56) L169(4.61)) contribute greatly to the binding of the agonist on the basis of the binding energy decomposition, while residues S180-F183 in extracellular loop 2 (ECL2) may be of importance in recognition of the inverse agonist. Furthermore, pharmacophore modeling and virtual screening were carried out for the inactive and active CB2 models in parallel. Among all 10 hits, two compounds exhibited novel scaffolds and can be used as novel chemical probes for future studies of CB2. Importantly, our studies show that the hits obtained from the inactive CB2 model mainly act as inverse agonist(s) or neutral antagonist(s) at low concentration. Moreover, the hit from the active CB2 model also behaves as a neutral antagonist at low concentration. Our studies provide new insight leading to a better understanding of the structural and conformational differences between two states of CB2 and illuminate the effects of structure on virtual screening and drug design. C1 [Hu, Jianping; Feng, Zhiwei; Ma, Shifan; Zhang, Yu; Tong, Qin; Alqarni, Mohammed Hamed; Xie, Xiang-Qun] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15260 USA. [Hu, Jianping; Feng, Zhiwei; Ma, Shifan; Zhang, Yu; Tong, Qin; Alqarni, Mohammed Hamed; Xie, Xiang-Qun] Univ Pittsburgh, Computat Chem Genom Screening Ctr, Natl Ctr Excellence Computat Drug Abuse Res, NIH,Sch Pharm,Drug Discovery Inst, Pittsburgh, PA 15260 USA. [Hu, Jianping; Feng, Zhiwei; Ma, Shifan; Zhang, Yu; Tong, Qin; Alqarni, Mohammed Hamed; Xie, Xiang-Qun] Univ Pittsburgh, Dept Computat Biol & Struct Biol, Sch Med, Pittsburgh, PA 15260 USA. [Hu, Jianping] Leshan Normal Univ, Coll Chem, Leshan 614004, Sichuan, Peoples R China. [Hu, Jianping; Gou, Xiaojun] Chengdu Univ, Key Lab Med & Edible Plants Resources Dev, Sch Pharm & Bioengn, Chengdu 610106, Sichuan, Peoples R China. RP Xie, XQ (reprint author), Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15260 USA.; Xie, XQ (reprint author), Univ Pittsburgh, Computat Chem Genom Screening Ctr, Natl Ctr Excellence Computat Drug Abuse Res, NIH,Sch Pharm,Drug Discovery Inst, Pittsburgh, PA 15260 USA.; Xie, XQ (reprint author), Univ Pittsburgh, Dept Computat Biol & Struct Biol, Sch Med, Pittsburgh, PA 15260 USA. EM xix15@pitt.edu FU NIH NIDA [P30 DA035778A1]; NIH [R01 DA025612]; National Natural Science Foundation of China [11147175, 11247018]; Sichuan Provincial Education Bureau [12ZA066]; Leshan Science and Technology Administration [14GZD022] FX The project was supported by funding provided to the Xie laboratory by NIH NIDA (P30 DA035778A1) and NIH (R01 DA025612) and in part by the National Natural Science Foundation of China (11147175 and 11247018), the Key Project of Sichuan Provincial Education Bureau (12ZA066), and the Project of Leshan Science and Technology Administration (14GZD022). NR 64 TC 2 Z9 2 U1 10 U2 18 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 EI 1549-960X J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD JUN PY 2016 VL 56 IS 6 SI SI BP 1152 EP 1163 DI 10.1021/acs.jcim.5b00739 PG 12 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA DP9OX UT WOS:000378826800024 PM 27186994 ER PT J AU Clarke, BL Brown, EM Collins, MT Juppner, H Lakatos, P Levine, MA Mannstadt, MM Bilezikian, JP Romanischen, AF Thakker, RV AF Clarke, Bart L. Brown, Edward M. Collins, Michael T. Juppner, Harald Lakatos, Peter Levine, Michael A. Mannstadt, Michael M. Bilezikian, John P. Romanischen, Anatoly F. Thakker, Rajesh V. TI Epidemiology and Diagnosis of Hypoparathyroidism SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PSEUDOHYPOPARATHYROIDISM TYPE IB; BASAL GANGLIA CALCIFICATION; PROGRESSIVE OSSEOUS HETEROPLASIA; XL-ALPHA-S; PARATHYROID-HORMONE; TOTAL THYROIDECTOMY; GNAS MUTATIONS; POSTSURGICAL HYPOPARATHYROIDISM; PSEUDO-PSEUDOHYPOPARATHYROIDISM; IDIOPATHIC HYPOPARATHYROIDISM AB Context: Hypoparathyroidism is a disorder characterized by hypocalcemia due to insufficient secretion of PTH. Pseudohypoparathyroidism is a less common disorder due to target organ resistance to PTH. This report summarizes the results of the findings and recommendations of the Working Group on Epidemiology and Diagnosis of Hypoparathyroidism. Evidence Acquisition: Each contributing author reviewed the recent published literature regarding epidemiology and diagnosis of hypoparathyroidism using PubMed and other medical literature search engines. Evidence Synthesis: The prevalence of hypoparathyroidism is an estimated 37 per 100 000 person-years in the United States and 22 per 100 000 person-years in Denmark. The incidence inDenmarkis approximately 0.8 per 100 000 person-years. Estimates of prevalence and incidence of hypoparathyroidism are currently lacking inmostother countries. Hypoparathyroidism increases the risk of renal insufficiency, kidney stones, posterior subcapsular cataracts, and intracerebral calcifications, but it does not appear to increase overall mortality, cardiovascular disease, fractures, or malignancy. The diagnosis depends upon accurate measurement of PTH by second-and third-generation assays. The most common etiology is postsurgical hypoparathyroidism, followed by autoimmune disorders and rarely genetic disorders. Even more rare are etiologies including parathyroid gland infiltration, external radiation treatment, and radioactive iodine therapy for thyroid disease. Differentiation between these different etiologies is aided by the clinical presentation, serum biochemistries, and in some cases, genetic testing. Conclusions: Hypoparathyroidism is often associated with complications and comorbidities. It is important for endocrinologists and other physicians who care for these patients to be aware of recent advances in the epidemiology, diagnosis, and genetics of this disorder. C1 [Clarke, Bart L.] Mayo Clin, Div Endocrinol Diabet Metab & Nutr, Rochester, MN 55905 USA. [Brown, Edward M.] Harvard Univ, Sch Med, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Juppner, Harald] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Juppner, Harald] Massachusetts Gen Hosp, Pediat Nephrol Unit, Boston, MA 02114 USA. [Juppner, Harald] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Lakatos, Peter] Semmelweis Univ, Sch Med, Dept Med 1, H-1085 Budapest, Hungary. [Levine, Michael A.] Univ Penn, Perelman Sch Med, Childrens Hosp Philadelphia, Div Endocrinol & Diabet,Dept Pediat, Philadelphia, PA 19104 USA. [Mannstadt, Michael M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bilezikian, John P.] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Romanischen, Anatoly F.] St Petersburg State Pediat Med Acad, Dept Hosp Surg & Oncol, St Petersburg 194100, Russia. [Thakker, Rajesh V.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Churchill Hosp, Acad Endocrine Unit,Radcliffe Dept Med, Oxford OX3 7LJ, England. RP Clarke, BL (reprint author), Mayo Clin, Div Endocrinol Diabet Metab & Nutr, Med, 200 First St SW, Rochester, MN 55905 USA. EM clarke.bart@mayo.edu OI Thakker, Rajesh/0000-0002-1438-3220; Levine, Michael/0000-0003-0036-7809 FU Shire Pharmaceuticals FX B.L.C. receives research support from Shire Pharmaceuticals and serves on two Data Monitoring Committees: Denosumab Oncology and Glucocorticoid-Induced Osteoporosis (Amgen). E.M.B. has a financial interest in the calcimimetic, Cinacalcet. M.A.L. is a member of the Scientific Advisory Board and receives research support from Shire Pharmaceuticals. M.M.M. is a member of the Scientific Advisory Board for Shire Pharmaceuticals. J.P.B. is a consultant for Amgen, Radius, Lilly, and Merck and receives research support from Shire Pharmaceuticals. R.V.T. serves in an advisory capacity for ENETS, Novartis, and Ipsen and is a consultant for AstraZeneca. The other authors have no disclosures to report. NR 75 TC 3 Z9 4 U1 5 U2 10 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2016 VL 101 IS 6 BP 2284 EP 2299 DI 10.1210/jc.2015-3908 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP9MU UT WOS:000378821100003 PM 26943720 ER PT J AU Bilezikian, JP Brandi, ML Cusano, NE Mannstadt, M Rejnmark, L Rizzoli, R Rubin, MR Winer, KK Liberman, UA Potts, JT AF Bilezikian, John P. Brandi, Maria Luisa Cusano, Natalie E. Mannstadt, Michael Rejnmark, Lars Rizzoli, Rene Rubin, Mishaela R. Winer, Karen K. Liberman, Uri A. Potts, John T., Jr. TI Management of Hypoparathyroidism: Present and Future SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID HUMAN PARATHYROID-HORMONE; QUALITY-OF-LIFE; DIETARY CALCIUM SUPPLEMENTS; RANDOMIZED CONTROLLED-TRIAL; 1-34 REPLACEMENT THERAPY; VITAMIN-D DEFICIENCY; LONG-TERM TREATMENT; CROSS-OVER TRIAL; DOUBLE-BLIND; FOLLOW-UP AB Context: Conventional management of hypoparathyroidism has focused upon maintaining the serum calcium with oral calcium and active vitamin D, often requiring high doses and giving rise to concerns about long-term consequences including renal and brain calcifications. Replacement therapy with PTH has recently become available. This paper summarizes the results of the findings and recommendations of the Working Group on Management of Hypoparathyroidism. Evidence Acquisition: Contributing authors reviewed the literature regarding physiology, pathophysiology, and nutritional aspects of hypoparathyroidism, management of acute hypocalcemia, clinical aspects of chronic management, and replacement therapy of hypoparathyroidism with PTH peptides. PubMed and other literature search engines were utilized. Evidence synthesis: Under normal circumstances, interactions between PTH and active vitamin D along with the dynamics of calcium and phosphorus absorption, renal tubular handing of those ions, and skeletal responsiveness help to maintain calcium homeostasis and skeletal health. In the absence of PTH, the gastrointestinal tract, kidneys, and skeleton are all affected, leading to hypocalcemia, hyperphosphatemia, reduced bone remodeling, and an inability to conserve filtered calcium. Acute hypocalcemia can be a medical emergency presenting with neuromuscular irritability. The recent availability of recombinant human PTH (1-84) has given hope that management of hypoparathyroidism with the missing hormone in this disorder will provide better control and reduced needs for calcium and vitamin D. Conclusions: Hypoparathyroidism is associated with abnormal calcium and skeletal homeostasis. Control with calcium and active vitamin D can be a challenge. The availability of PTH (1-84) replacement therapy may usher new opportunities for better control with reduced supplementation requirements. C1 [Bilezikian, John P.; Cusano, Natalie E.; Rubin, Mishaela R.] Columbia Univ Coll Phys & Surg, 630 W 168th St, New York, NY 10032 USA. [Brandi, Maria Luisa] Univ Florence, Dept Surg & Translat Med, I-50121 Florence, Italy. [Mannstadt, Michael; Potts, John T., Jr.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rejnmark, Lars] Aarhus Univ Hosp, DK-8000 Aarhus, Denmark. [Rizzoli, Rene] Geneva Univ Hosp & Fac Med, CH-1205 Geneva, Switzerland. [Winer, Karen K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Liberman, Uri A.] Tel Aviv Univ, Sackler Sch Med, IL-6997801 Tel Aviv, Israel. RP Bilezikian, JP (reprint author), Columbia Univ Coll Phys & Surg, Dept Med, 630 West 168th St,PH8W-864, New York, NY 10032 USA. EM jpb2@cumc.columbia.edu FU Shire Pharmaceuticals; Amgen; Eli Lilly; Merck; Chugai FX J.P.B. is a consultant for Amgen, Radius, and Merck and receives research support from Shire Pharmaceuticals. M.R.R. receives research support from Shire Pharmaceuticals. M.L.B. is a consultant for Alexion, Abiogen, Amgen, Bruno Farmaceutici, Eli Lilly, Merck, Shire Pharmaceuticals, SPA, and Servier and receives research support from Shire Pharmaceuticals, Amgen, Eli Lilly, and Merck. J.T.P. is a founder and consultant for Radius and a consultant for Merck and receives research support from Chugai. The other co-authors report no conflicts of interest. NR 90 TC 5 Z9 6 U1 1 U2 4 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2016 VL 101 IS 6 BP 2313 EP 2324 DI 10.1210/jc.2015-3910 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP9MU UT WOS:000378821100005 PM 26938200 ER PT J AU Krieger, CC Place, RF Bevilacqua, C Marcus-Samuels, B Abel, BS Skarulis, MC Kahaly, GJ Neumann, S Gershengorn, MC AF Krieger, Christine C. Place, Robert F. Bevilacqua, Carmine Marcus-Samuels, Bernice Abel, Brent S. Skarulis, Monica C. Kahaly, George J. Neumann, Susanne Gershengorn, Marvin C. TI TSH/IGF-1 Receptor Cross Talk in Graves' Ophthalmopathy Pathogenesis SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GROWTH-FACTOR-I; INDUCE HYALURONAN SYNTHESIS; THYROTROPIN RECEPTOR; ORBITAL FIBROBLASTS; BETA-ARRESTIN; THYROID-CELLS; DISEASE; INSULIN; ANTIBODY; TSH AB Context: The TSH receptor (TSHR) is considered the main target of stimulatory autoantibodies in the pathogenesis of Graves' ophthalmopathy (GO); however, it has been suggested that stimulatory IGF-1 receptor (IGF-1R) autoantibodies also play a role. Objective: We previously demonstrated that a monoclonal stimulatory TSHR antibody, M22, activates TSHR/IGF-1R cross talk in orbital fibroblasts/preadipocytes obtained from patients with GO (GO fibroblasts [GOFs]). We show that cross talk between TSHR and IGF-1R, not direct IGF-1R activation, is involved in the mediation of GO pathogenesis stimulated by Graves' autoantibodies. Design/Setting/Participants: Immunoglobulins were purified from the sera of 57 GO patients (GO-Igs) and tested for their ability to activate TSHR and/or IGF-1R directly and TSHR/IGF-1R cross talk in primary cultures of GOFs. Cells were treated with M22 or GO-Igs with or without IGF-1R inhibitory antibodies or linsitinib, an IGF-1R kinase inhibitor. Main Outcome Measures: Hyaluronan (hyaluronic acid [HA]) secretion was measured as a major biological response for GOF stimulation. IGF-1R autophosphorylation was used as a measure of direct IGF-1R activation. TSHR activation was determined through cAMP production. Results: A total of 42 out of 57 GO-Ig samples stimulated HA secretion. None of the GO-Ig samples exhibited evidence for IGF-1R autophosphorylation. Both anti-IGF-1R antibodies completely inhibited IGF-1 stimulation of HA secretion. By contrast, only 1 IGF-1R antibody partially blocked HA secretion stimulated by M22 or GO-Igs in a manner similar to linsitinib, whereas the other IGF-1R antibody had no effect on M22 or GO-Ig stimulation. These findings show that the IGF-1R is involved in GO-Igs stimulation of HA secretion without direct activation of IGF-1R. Conclusions: IGF-1R activation by GO-Igs occurs via TSHR/IGF-1R cross talk rather than direct binding to IGF-1R, and this cross talk is important in the pathogenesis of GO. C1 [Krieger, Christine C.; Place, Robert F.; Bevilacqua, Carmine; Marcus-Samuels, Bernice; Neumann, Susanne; Gershengorn, Marvin C.] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Place, Robert F.] Nova Therapeut LLC, Pasadena, CA USA. [Abel, Brent S.; Skarulis, Monica C.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Kahaly, George J.] Johannes Gutenberg Univ Mainz, Med Ctr, Mainz, Germany. RP Gershengorn, MC (reprint author), NIDDK, 50 South Dr,Bldg 50,Room 4134, Bethesda, MD 20892 USA. EM marving@mail.nih.gov OI Krieger, Christine/0000-0002-1856-415X FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD [DK011006]; Nova Therapeutics FX This work was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 (DK011006 to M.C.K.).; R.F.P. is supported by Nova Therapeutics. NR 35 TC 4 Z9 5 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2016 VL 101 IS 6 BP 2340 EP 2347 DI 10.1210/jc.2016-1315 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP9MU UT WOS:000378821100008 PM 27043163 ER PT J AU Plowden, TC Schisterman, EF Sjaarda, LA Zarek, SM Perkins, NJ Silver, R Galai, N DeCherney, AH Mumford, SL AF Plowden, Torie C. Schisterman, Enrique F. Sjaarda, Lindsey A. Zarek, Shvetha M. Perkins, Neil J. Silver, Robert Galai, Noya DeCherney, Alan H. Mumford, Sunni L. TI Subclinical Hypothyroidism and Thyroid Autoimmunity Are Not Associated With Fecundity, Pregnancy Loss, or Live Birth SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID LOW-DOSE ASPIRIN; RANDOMIZED-TRIAL; TSH LEVELS; POPULATION; MISCARRIAGE; OUTCOMES; RISK; AUTOANTIBODIES; CONCEPTION; DISORDERS AB Context: Prior studies examining associations between subclinical hypothyroidism and antithyroid antibodies with early pregnancy loss and live birth suggest mixed results and time to pregnancy (TTP) has not been studied in this patient population. Objective: This study sought to examine associations of prepregnancy TSH concentrations and thyroid autoimmunity with TTP, pregnancy loss, and live birth among women with proven fecundity and a history of pregnancy loss. Design and Setting: This was a prospective cohort study from a large, randomized controlled trial that took place at four medical centers in the United States. Patients or Other Participants: Healthy women, ages 18-40 y, who were actively attempting to conceive and had one or two prior pregnancy losses and no history of infertility were eligible for the study. Intervention: There were no interventions. Main Outcome Measure: TTP, pregnancy loss, and live birth. Results: Women with TSH >= 2.5 mIU/L did not have an increased risk of pregnancy loss (risk ratio, 1.07; 95% confidence interval [CI], 0.81-1.41) or a decrease in live birth rate (risk ratio, 0.97; 95% CI, 0.88-1.07) or TTP (fecundability odds ratio, 1.09; 95% CI, 0.90-1.31) compared with women with TSH <2.5 mIU/L after adjustment for age and body mass index. Similar findings were observed for women with thyroid autoimmunity and after additional adjustment for treatment assignment. Conclusions: Among healthy fecund women with a history pregnancy loss, TSH levels >= 2.5 mIU/L or the presence of antithyroid antibodies were not associated with fecundity, pregnancy loss, or live birth. Thus, women with subclinical hypothyroidism or thyroid autoimmunity can be reassured that their chances of conceiving and achieving a live birth are likely unaffected by marginal thyroid dysfunction. C1 [Plowden, Torie C.; Schisterman, Enrique F.; Sjaarda, Lindsey A.; Zarek, Shvetha M.; Perkins, Neil J.; Mumford, Sunni L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Rockville, MD 20852 USA. [Plowden, Torie C.; Zarek, Shvetha M.; DeCherney, Alan H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. [Silver, Robert] Univ Utah, Hlth Sci Ctr, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. [Galai, Noya] Univ Haifa, Dept Stat, IL-31905 Haifa, Israel. RP Mumford, SL (reprint author), 6100 Execut Blvd,7B03, Rockville, MD 20852 USA. EM mumfords@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Sjaarda, Lindsey/0000-0003-0539-8110; Schisterman, Enrique/0000-0003-3757-641X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD [HHSN267200603423, HHSN267200603424, HHSN267200603426] 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, Bethesda, MD (Contracts No. HHSN267200603423, HHSN267200603424, and HHSN267200603426). NR 28 TC 5 Z9 5 U1 4 U2 6 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2016 VL 101 IS 6 BP 2358 EP 2365 DI 10.1210/jc.2016-1049 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP9MU UT WOS:000378821100010 PM 27023447 ER PT J AU Kim, SH Xiao, S Collins, PL Samal, SK AF Kim, Shin-Hee Xiao, Sa Collins, Peter L. Samal, Siba K. TI LaSota fusion (F) cleavage motif-mediated fusion activity is affected by other regions of the F protein from different genotype Newcastle disease virus in a chimeric virus: implication for virulence attenuation SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID HEMAGGLUTININ-NEURAMINIDASE PROTEIN; MEMBRANE-FUSION; WEST-AFRICA; CHICKEN; VACCINE; HEAD; SITE AB The cleavage site sequence of the fusion (F) protein contributes to a wide range of virulence of Newcastle disease virus (NDV). In this study, we identified other important amino acid sequences of the F protein that affect cleavage and modulation of fusion. We generated chimeric Beaudette C (BC) viruses containing the cleavage site sequence of avirulent strain LaSota (Las-Fc) together with various regions of the F protein of another virulent strain AKO. We found that the F1 subunit is important for cleavage inhibition. Further dissection of the F1 subunit showed that replacement of four amino acids in the BC/Las-Fc protein with their AKO counterparts (T341S, M384I, T385A and I386L) resulted in an increase in fusion and replication in vitro. In contrast, the mutation N403D greatly reduced cleavage and viral replication, and affected protein conformation. These findings will be useful in developing improved live NDV vaccines and vaccine vectors. C1 [Kim, Shin-Hee; Xiao, Sa; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, 8075 Greenmead Dr, College Pk, MD 20742 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, 8075 Greenmead Dr, College Pk, MD 20742 USA. EM ssamal@umd.edu FU National Institute of Allergy and Infection Diseases [N01A060009]; National Institute of Allergy and Infection Diseases, National Institutes of Health Intramural Research Program FX We thank Daniel Rockemann, Girmay Gebreluul, Yonas Araya and our laboratory members for excellent technical assistance. We thank Dr Bernard Moss (National Institute of Allergy and Infection Diseases, National Institutes of Health) for providing the vaccinia 7 recombinant virus and Dr Mark Peeples (Nationwide Children's Hospital) for providing the anti-F mAb (mAb 3-1G5). This research was supported by National Institute of Allergy and Infection Diseases contract N01A060009 (85% support) and National Institute of Allergy and Infection Diseases, National Institutes of Health Intramural Research Program (15% support). The views expressed herein do not necessarily reflect the official policies of the Department of Health and Human Services, nor does mention of trade names, commercial practices or organizations imply endorsement by the US Government. NR 20 TC 1 Z9 1 U1 1 U2 4 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 JUN PY 2016 VL 97 BP 1297 EP 1303 DI 10.1099/jgv.0.000439 PN 6 PG 7 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA DQ0LV UT WOS:000378891700002 ER PT J AU Striebel, JF Race, B Carroll, JA Phillips, K Chesebro, B AF Striebel, James F. Race, Brent Carroll, James A. Phillips, Katie Chesebro, Bruce TI Knockout of fractalkine receptor Cx3cr1 does not alter disease or microglial activation in prion-infected mice SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID NEURODEGENERATION; NEUROTOXICITY; DEPOSITION; DELETION; HEALTH; BRAIN; CELLS; MODEL; CNS AB Microglial activation is a hallmark of the neuroimmunological response to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and prion disease. The CX3C chemokine axis consists of fractalkine (CX3CL1) and its receptor (CX3CR1); these are expressed by neurons and microglia respectively, and are known to modulate microglial activation. In prion-infected mice, both Cx3cr1 and Cx3cl1 are altered, suggesting a role in disease. To investigate the influence of CX3C axis signalling on prion disease, we infected Cx3cr1 knockout (Cx3cr1-KO) and control mice with scrapie strains 22L and RML. Deletion of Cx3cr1 had no effect on development of clinical signs or disease incubation period. In addition, comparison of brain tissue from Cx3cr1-KO and control mice revealed no significant differences in cytokine levels, spongiosis, deposition of disease-associated prion protein or microglial activation. Thus, microglial activation during prion infection did not require CX3C axis signalling. C1 [Striebel, James F.; Race, Brent; Carroll, James A.; Phillips, Katie; Chesebro, Bruce] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Chesebro, B (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM bchesebro@niaid.nih.gov FU NIH, NIAID FX We thank Jeffrey Severson for assistance with animal husbandry, Nancy Kurtz and Lori Lubke for immunohistochemistry preparation, and Anita Mora for graphics assistance. This research was supported by the Intramural Research Program of the NIH, NIAID. NR 28 TC 1 Z9 1 U1 8 U2 8 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 JUN PY 2016 VL 97 BP 1481 EP 1487 DI 10.1099/jgv.0.000442 PN 6 PG 7 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA DQ0LV UT WOS:000378891700023 PM 26935332 ER PT J AU Zhao, M Cheng, SM Yuan, WP Xi, YY Li, XB Dong, JY Huang, KX Gustafson, KR Yan, PC AF Zhao, Min Cheng, Shimiao Yuan, Weiping Xi, Yiyuan Li, Xiubao Dong, Jianyong Huang, Kexin Gustafson, Kirk R. Yan, Pengcheng TI Cembranoids from a Chinese Collection of the Soft Coral Lobophytum crassum SO MARINE DRUGS LA English DT Article DE soft coral; Lobophytum crassum; cembrane-based diterpenes; NO inhibition ID SARCOPHYTON-TROCHELIOPHORUM MARENZELLER; ANTIINFLAMMATORY CEMBRANOIDS; RED-SEA; DITERPENOIDS; ALCYONACEA; OCTOCORALLIA; COELENTERATA; TERPENOIDS AB Ten new cembrane-based diterpenes, locrassumins A-G (1-7), (-)-laevigatol B (8), (-)-isosarcophine (9), and (-)-7R, 8S-dihydroxydeepoxysarcophytoxide (10), were isolated from a South China Sea collection of the soft coral Lobophytum crassum, together with eight known analogues (11-18). The structures of the new compounds were determined by extensive spectroscopic analysis and by comparison with previously reported data. Locrassumin C (3) possesses an unprecedented tetradecahydrobenzo[3,4]cyclobuta[1,2][8]annulene ring system. Compounds 1, 7, 12, 13, and 17 exhibited moderate inhibition against lipopolysaccharide (LPS)-induced nitric oxide (NO) production with IC50 values of 8-24 mu M. C1 [Zhao, Min; Yuan, Weiping; Xi, Yiyuan; Dong, Jianyong; Huang, Kexin; Yan, Pengcheng] Wenzhou Med Univ, Sch Pharmaceut Sci, Wenzhou 325035, Peoples R China. [Cheng, Shimiao] Wenzhou Med Univ, Affiliated Hosp 5, Lishui 323000, Peoples R China. [Li, Xiubao] Chinese Acad Sci, South China Sea Inst Oceanol, Key Lab Marine Bioresources Sustainable Utilizat, Guangzhou 510301, Guangdong, Peoples R China. [Gustafson, Kirk R.; Yan, Pengcheng] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Yan, PC (reprint author), Wenzhou Med Univ, Sch Pharmaceut Sci, Wenzhou 325035, Peoples R China.; Gustafson, KR; Yan, PC (reprint author), NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM miniezhao09@163.com; lschengshimiao@163.com; yuan0525@126.com; xiyiyuan2@163.com; lixiubao@scsio.ac.cn; jianyd@wzmc.edu.cn; hkx@wzmc.edu.cn; gustafki@mail.nih.gov; yanpc@wzmc.edu.cn FU NSFC [21202123]; ZJNSF [LQ12B02002]; CSC [201408330121]; Wenzhou Medical University [QTJ10018]; NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by grants from NSFC (No. 21202123), ZJNSF (No. LQ12B02002), CSC (No. 201408330121), and Start-Up Funding from Wenzhou Medical University (No. QTJ10018). This research was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 42 TC 0 Z9 0 U1 6 U2 6 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-3397 J9 MAR DRUGS JI Mar. Drugs PD JUN PY 2016 VL 14 IS 6 AR 111 DI 10.3390/md14060111 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DP8TH UT WOS:000378770300008 ER PT J AU Hall, MD Yasgar, A Peryea, T Braisted, JC Jadhav, A Simeonov, A Coussens, NP AF Hall, Matthew D. Yasgar, Adam Peryea, Tyler Braisted, John C. Jadhav, Ajit Simeonov, Anton Coussens, Nathan P. TI Fluorescence polarization assays in high-throughput screening and drug discovery: a review SO METHODS AND APPLICATIONS IN FLUORESCENCE LA English DT Review DE fluorescence polarization; anisotropy; high-throughput screening; assay development; enzyme; protein-protein interaction; drug discovery ID VITAMIN-D-RECEPTOR; INTERFERENCE COMPOUNDS PAINS; SMALL-MOLECULE INHIBITORS; PROTEIN-BINDING; SELECTIVE INHIBITORS; FINGERPRINT METHODS; BETA/DELTA AGONIST; CHEMICAL BIOLOGY; LIGAND COMPLEX; PPAR-DELTA AB The sensitivity of fluorescence polarization (FP) and fluorescence anisotropy (FA) to molecular weight changes has enabled the interrogation of diverse biological mechanisms, ranging from molecular interactions to enzymatic activity. Assays based on FP/FA technology have been widely utilized in high-throughput screening (HTS) and drug discovery due to the homogenous format, robust performance and relative insensitivity to some types of interferences, such as inner filter effects. Advancements in assay design, fluorescent probes, and technology have enabled the application of FP assays to increasingly complex biological processes. Herein we discuss different types of FP/FA assays developed for HTS, with examples to emphasize the diversity of applicable targets. Furthermore, trends in target and fluorophore selection, as well as assay type and format, are examined using annotated HTS assays within the PubChem database. Finally, practical considerations for the successful development and implementation of FP/FA assays for HTS are provided based on experience at our center and examples from the literature, including strategies for flagging interference compounds among a list of hits. C1 [Hall, Matthew D.; Yasgar, Adam; Peryea, Tyler; Braisted, John C.; Jadhav, Ajit; Simeonov, Anton; Coussens, Nathan P.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. RP Coussens, NP (reprint author), NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. EM coussensn@mail.nih.gov FU NCATS Division of Pre-Clinical Innovation Intramural Program FX This work was supported by the NCATS Division of Pre-Clinical Innovation Intramural Program. We thank Dr R MacArthur for the critical reading of this manuscript. NR 106 TC 2 Z9 2 U1 29 U2 40 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 2050-6120 J9 METHODS APPL FLUORES JI Methods Appl. Fluoresc. PD JUN PY 2016 VL 4 IS 2 AR 022001 DI 10.1088/2050-6120/4/2/022001 PG 20 WC Chemistry, Analytical; Chemistry, Physical SC Chemistry GA DP9QH UT WOS:000378831000001 ER PT J AU Tran, TM Hong, S Edwan, JH Colbert, RA AF Tran, Tri M. Hong, Sohee Edwan, Jehad H. Colbert, Robert A. TI ERAP1 reduces accumulation of aberrant and disulfide-linked forms of HLA-B27 on the cell surface SO MOLECULAR IMMUNOLOGY LA English DT Article DE Epistasis; Major histocompatibility complex; Misfolding; Ankylosing spondylitis ID RETICULUM AMINOPEPTIDASE 1; UNFOLDED PROTEIN RESPONSE; HLA CLASS-I; GENOME-WIDE ASSOCIATION; ENDOPLASMIC-RETICULUM; ANKYLOSING-SPONDYLITIS; ANTIGEN PRESENTATION; TRANSGENIC RATS; HEAVY-CHAINS; MONOCLONAL-ANTIBODIES AB Objective: Endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) variants contribute to the risk of ankylosing spondylitis in HLA-B27 positive individuals, implying a disease-related interaction between these gene products. The aim of this study was to determine whether reduced ERAP1 expression would alter the cell surface expression of HLA-B27 and the formation of aberrant disulfide-linked forms that have been implicated in the pathogenesis of spondyloarthritis. Methods: ERAP1 expression was knocked down in monocytic U937 cells expressing HLA-B27 and endogenous HLA class I. The effect of ERAP1 knockdown on the accumulation HLA-B alleles (B18, B51, and B27) was assessed using immunoprecipitation, isoelectric focusing, and immunoblotting, as well as flow cytometry with antibodies specific for different forms of HLA-B27. Cell surface expression of aberrant disulfide-linked HLA-B27 dimers was assessed by immunoprecipitation and electrophoresis on non reducing polyacrylamide gels. Results: ERAP1 knockdown increased the accumulation of HLA-B27 on the cell surface including disulfide linked dimers, but had no effect on levels of HLA-B18 or-B51. Antibodies with unique specificity for HLA-B27 confirmed increased cell surface expression of complexes shown previously to contain long peptides. IFN-y treatment resulted in striking increases in the expression of disulfide-linked HLA-B27 heavy chains, even in cells with normal ERAP1 expression. Conclusions: Our results suggest that normal levels of ERAP1 reduce the accumulation of aberrant and disulfide-linked forms of HLA-B27 in monocytes, and thus help to maintain the integrity of cell surface HLA-B27 complexes. Published by Elsevier Ltd. C1 [Tran, Tri M.; Hong, Sohee; Edwan, Jehad H.; Colbert, Robert A.] NIAMSD, Pediat Translat Res Branch, NIH, Bethesda, MD 20892 USA. RP Colbert, RA (reprint author), NIAMSD, Pediat Translat Res Branch, NIH, Bethesda, MD 20892 USA. EM colbertr@mail.nih.gov NR 48 TC 1 Z9 1 U1 5 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD JUN PY 2016 VL 74 BP 10 EP 17 DI 10.1016/j.molimm.2016.04.002 PG 8 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA DP7IF UT WOS:000378671700002 PM 27107845 ER PT J AU Deniger, DC Pasetto, A Tran, E Parkhurst, MR Cohen, CJ Robbins, PF Cooper, LJN Rosenberg, SA AF Deniger, Drew C. Pasetto, Anna Tran, Eric Parkhurst, Maria R. Cohen, Cyrille J. Robbins, Paul F. Cooper, Laurence J. N. Rosenberg, Steven A. TI Stable, Nonviral Expression of Mutated Tumor Neoantigen-specific T-cell Receptors Using the Sleeping Beauty Transposon/Transposase System SO MOLECULAR THERAPY LA English DT Article ID CHIMERIC ANTIGEN RECEPTOR; CLINICAL-SCALE SELECTION; INFILTRATING LYMPHOCYTES; GENE-TRANSFER; ADOPTIVE IMMUNOTHERAPY; METASTATIC MELANOMA; FUNCTIONAL AVIDITY; EPITHELIAL CANCER; RETROVIRAL VECTOR; EFFECTOR FUNCTION AB Neoantigens unique to each patient's tumor can be recognized by autologous T cells through their T-cell receptor (TCR) but the low frequency and/or terminal differentiation of mutation-specific T cells in tumors can limit their utility as adoptive T-cell therapies. Transfer of TCR genes into younger T cells from peripheral blood with a high proliferative potential could obviate this problem. We generated a rapid, cost-effective strategy to genetically engineer cancer patient T cells with TCRs using the clinical Sleeping Beauty transposon/transposase system. Patient-specific TCRs reactive against HLA-A*0201-restriced neoantigens AHNAK(S2580F) or ERBB2(H473Y) or the HLA-DQB*0601-restricted neoantigen ERBB2IP(E805G) were assembled with murine constant chains and cloned into Sleeping Beauty transposons. Patient peripheral blood lymphocytes were coelectro-porated with SB11 transposase and Sleeping Beauty transposon, and transposed T cells were enriched by sorting on murine TCR beta (mTCR beta) expression. Rapid expansion of mTCR beta(+) T cells with irradiated allogeneic peripheral blood lymphocytes feeders, OKT3, -interleukin-2 (IL-2), IL-15, and IL-21 resulted in a preponderance of effector (CD27(-)CD45RA(-)) and less-differentiated (CD27(+)CD45RA(+)) T cells. Transposed T cells specifically mounted a polyfunctional response against cognate mutated neoantigens and tumor cell lines. Thus, Sleeping Beauty transposition of mutation-specific TCRs can facilitate the use of personalized T-cell therapy targeting unique neoantigens. C1 [Deniger, Drew C.; Pasetto, Anna; Tran, Eric; Parkhurst, Maria R.; Robbins, Paul F.; Rosenberg, Steven A.] NCI, Surg Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Cohen, Cyrille J.] Bar Ilan Univ, Tumor Immunol & Immunotherapy, Ramat Gan, Israel. [Cooper, Laurence J. N.] Univ Texas MD Anderson Canc Ctr, Div Pediat, Houston, TX 77030 USA. [Cooper, Laurence J. N.] ZIOPHARM Oncol Inc, Boston, MA USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, 10 Ctr Dr MSC 1201,CRC Room 3-3940, Bethesda, MD 20892 USA. EM sar@nih.gov FU Intramural Research Program of the NIH at the National Cancer Institute FX We would like to thank Perry Hackett (University of Minnesota) and Simon Olivares (M.D. Anderson Cancer Center) for their assistance with the Sleeping Beauty system. This research was supported by the Intramural Research Program of the NIH at the National Cancer Institute. On 7 May 2015, L.J.N.C. was appointed as the Chief Executive Officer at ZIOPHARM Oncology and remains at MD Anderson Cancer Center as a Visiting Scientist. The authors declare no other competing financial interests. NR 66 TC 5 Z9 5 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD JUN PY 2016 VL 24 IS 6 BP 1078 EP 1089 DI 10.1038/mt.2016.51 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DP1WL UT WOS:000378280000009 PM 26945006 ER PT J AU Noonan, AM Farren, MR Geyer, SM Huang, Y Tahiri, S Ahn, D Mikhail, S Ciombor, KK Pant, S Aparo, S Sexton, J Marshall, JL Mace, TA Wu, CS El-Rayes, B Timmers, CD Zwiebel, J Lesinski, GB Villalona-Calero, MA Bekaii-Saab, TS AF Noonan, Anne M. Farren, Matthew R. Geyer, Susan M. Huang, Ying Tahiri, Sanaa Ahn, Daniel Mikhail, Sameh Ciombor, Kristen K. Pant, Shubham Aparo, Santiago Sexton, Jennifer Marshall, John L. Mace, Thomas A. Wu, Christina S. El-Rayes, Bassel Timmers, Cynthia D. Zwiebel, James Lesinski, Gregory B. Villalona-Calero, Miguel A. Bekaii-Saab, Tanios S. TI Randomized Phase 2 Trial of the Oncolytic Virus Pelareorep (Reolysin) in Upfront Treatment of Metastatic Pancreatic Adenocarcinoma SO MOLECULAR THERAPY LA English DT Article ID ANTICANCER CHEMOTHERAPY; MYELOID CELLS; CANCER; REOVIRUS; PACLITAXEL; GEMCITABINE; CARCINOMA; IMMUNOSUPPRESSION; IMMUNOTHERAPY; RADIOTHERAPY AB Pelareorep causes oncolysis in tumor cells with activated Ras. We hypothesized that pelareorep would have efficacy and immunomodulatory activity in metastatic pancreatic adenocarcinoma (MPA) when combined with carboplatin and paclitaxel. A randomized phase 2 study (NCT01280058) was conducted in treatment-naive patients with MPA randomized to two treatment arms: paclitaxel/carboplatin + pelareorep (Arm A, n = 36 evaluable patients) versus paclitaxel/ carboplatin (Arm B, n = 37 evaluable patients). There was no difference in progression-free survival (PFS) between the arms (Arm A PFS = 4.9 months, Arm B PFS = 5.2 months, P = 0.6), and Kirsten rat sarcoma viral oncogene (KRAS) status did not impact outcome. Quality-adjusted Time without Symptoms or Toxicity analysis revealed that the majority of PFS time was without toxicity or progression (4.3 months). Patient immunophenotype appeared important, as soluble immune biomarkers were associated with treatment outcome (fractalkine, interleukin (IL)-6, IL-8, regulated on activation, normal T cell expressed and secreted (RANTES), and vascular endothelial growth factor (VEGF)). Increased circulating T and natural killer (NK)-cell subsets were also significantly associated with treatment outcome. Addition of pelareorep was associated with higher levels of 14 proinflammatory plasma cytokines/chemokines and cells with an immunosuppressive phenotype (Tregs, cytotoxic T lymphocyte associated protein 4 (CTLA4)(+) T cells). Overall, pelareorep was safe but does not improve PFS when administered with carboplatin/paclitaxel, regardless of KRAS mutational status. Immunologic studies suggest that chemotherapy backbone improves immune-reconstitution and that targeting remaining immunosuppressive mediators may improve oncolytic virotherapy. C1 [Noonan, Anne M.; Farren, Matthew R.; Huang, Ying; Tahiri, Sanaa; Ahn, Daniel; Mikhail, Sameh; Ciombor, Kristen K.; Sexton, Jennifer; Mace, Thomas A.; Wu, Christina S.; Lesinski, Gregory B.; Villalona-Calero, Miguel A.; Bekaii-Saab, Tanios S.] Ohio State Univ, Dept Internal Med, Div Med Oncol, Columbus, OH 43210 USA. [Geyer, Susan M.] Univ S Florida, Hlth Informat Inst, Tampa, FL USA. [Pant, Shubham] Univ Oklahoma, Inst Canc, Hematol Oncol, Dept Med, Oklahoma City, OK USA. [Aparo, Santiago] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Med Oncol, Bronx, NY 10467 USA. [Marshall, John L.] Georgetown Univ, Med Ctr, Georgetown Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [El-Rayes, Bassel] Emory Univ, Winship Canc Inst, Dept Med Oncol, Atlanta, GA 30322 USA. [Timmers, Cynthia D.] Ohio State Univ, James Comprehens Canc Ctr, Solid Tumor Translat Sci Shared Resource, Columbus, OH 43210 USA. [Zwiebel, James] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Rockville, MD USA. RP Bekaii-Saab, TS (reprint author), Mayo Clin, Div Hematol & Oncol, 5777 E Mayo Blvd, Phoenix, AZ 85054 USA. EM Bekaii-Saab.tanios@mayo.edu OI Farren, Matthew/0000-0001-5510-8869 FU US National Cancer Institute's Cancer Therapy Evaluation Program [NCT01280058]; Phase 2 N01 program [HHSN261201100070C]; NIH [5 T32 CA 90223-12, 1 T32 CA 165998-01]; William Hall Fund for Liver and Pancreatic Cancer Research, Oncolytics; Pelotonia Fellowship Program; Pelotonia Research Foundation; Pfizer; Boston Biomedical; MedImmune; Onyx Pharmaceuticals; Bayer; Boehringer Ingelheim; Bristol-Myers Squibb; Albert Einstein College of Medicine; NIH/NCI; Georgetown University; Merrimack; Genentech; Oncolytics; NCI; Karyopharm; Chirhoclin; American College for Gastroenterology; Merck; Hoosier Cancer Research Network; US National Cancer Institute; National Comprehensive Cancer Network FX We would like to thank OSU CCC Analytical Cytometry Shared Resource and Clinical Trials Office for assistance with these studies. We are especially grateful to all patients who participated in this study. This study would not have been possible without the support of the following sources: the US National Cancer Institute's Cancer Therapy Evaluation Program (NCT01280058) and associated Phase 2 N01 program grant (HHSN261201100070C), an NIH postdoctoral training grant (5 T32 CA 90223-12) the William Hall Fund for Liver and Pancreatic Cancer Research, Oncolytics, and the Pelotonia Fellowship Program. Any opinions, findings, and conclusions expressed in this material are those of the authors and do not necessarily reflect those of the Pelotonia Fellowship Program. Anne Noonan (the Ohio State University) was a paid member of a data safety monitoring board for Helsinn. Matthew Farren (the Ohio State University) received salary support from the Pelotonia Research Foundation and an NIH training grant (5 T32 CA 90223-12). Susan Geyer (University of South Florida) reported no outside funding to disclose. Ying Huang (the Ohio State University) reported no outside funding to disclose. Sanaa Tahiri (the Ohio State University) reported no outside funding to disclose. Daniel Ahn (the Ohio State University) received salary support from an NIH training grant (1 T32 CA 165998-01). Sameh Mikhail (the Ohio State University) is a consultant/advisory board member for Bayer. Kristen Ciombor (the Ohio State University) received research support from Pfizer, Boston Biomedical, MedImmune, Onyx Pharmaceuticals, Bayer, Boehringer Ingelheim, and Bristol-Myers Squibb. Shubham Pant (Oklahoma University Cancer Institute) reported no outside funding to disclose. Santiago Aparo (Albert Einstein College of Medicine) reported no outside funding to disclose. Jennifer Sexton (the Ohio State University) received NIH/NCI salary support. John Marshall (Georgetown University) reported no outside funding to disclose. Thomas Mace (the Ohio State University) received NIH funding and institutional support. Christina Wu (the Ohio State University) served on a Bayer advisory board. Bassel El-Rayes (Emory University) received consulting fees (Merrimack, Genentech) research support (Bristol Myers Squibb, Boston Biomedical, Cleave Biosciences, SYNTA Pharmaceuticals, AVEO Pharmaceuticals, Taiho Oncology, Genentech, the Hoosier Cancer Research Network) and NIH research support. Cynthia Timmers (the Ohio State University) received research and salary support from Oncolytics and the NCI. James Zwiebel (US National Cancer Institute) had no funding to disclose. Gregory Lesinski (the Ohio State University) received institutional and divisional start-up funds (Ohio State University) NIH funding and independent grant support (Oncolytics, Karyopharm, Chirhoclin, the American College for Gastroenterology, Merck, and the Hoosier Cancer Research Network). Miguel Villalona-Calero (the Ohio State University) was the PI on the Phase 2 N01 program grant (HHSN261201100070C) under which this study was carried out. Tanios Bekaii-Saab (the Ohio State University) received research support from Oncolytics, the US National Cancer Institute, and the National Comprehensive Cancer Network. Greg Lesinski, Cynthia Timmers, and Tanios Bekaii-Saab received funding support from Oncolytics to support correlative laboratory research for this study; all other authors report no relevant potential conflicts of interest. NR 40 TC 2 Z9 2 U1 7 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 JUN PY 2016 VL 24 IS 6 BP 1150 EP 1158 DI 10.1038/mt.2016.66 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DP1WL UT WOS:000378280000016 PM 27039845 ER PT J AU Cho, N Kim, HW Kim, TB Ransom, TT Beutler, JA Sung, SH AF Cho, Namki Kim, Hyun Woo Kim, Tae Bum Ransom, Tanya T. Beutler, John A. Sung, Sang Hyun TI Preparative Purification of Anti-Proliferative Diarylheptanoids from Betula platyphylla by High-Speed Counter-Current Chromatography SO MOLECULES LA English DT Article DE HSCCC; diarylheptanoid; anti-proliferation ID VAR. JAPONICA; ANTICANCER ACTIVITY; RHUS-VERNICIFLUA; CARCINOMA CELLS; ALNUS-JAPONICA; INNER BARK; GLYCOSIDES; INHIBITION; EXTRACT; CONSTITUENTS AB A simple and rapid method using high-speed counter-current chromatography (HSCCC), along with bioassay-guided fractionation based on the anti-proliferative activity against renal and colon cancer cells, has been developed for the preparative separation of aceroside VIII (1) and platyphylloside (2) from Betula platyphylla. A solvent system composed of ethyl acetate/acetonitrile/water (1:0.1:1, v/v/v) was optimized for the separation. The upper phase was used as the stationary phase, and the lower phase was used as the mobile phase. Among these isolated diarylheptanoids, platyphylloside (2) showed anti-proliferative activity in the COLO205 and KM12 colon cells and renal cancer cell lines A498, U031, as well as in MG63 and MG63.3 osteosarcoma cells. In addition, it showed dose dependent inhibitory effects in the NCI 60 cell line assay. These results suggest that the diarylheptanoids isolated from B. platyphylla with an efficient HSCCC method could be potential multi-targeted therapeutic agents for cancer. C1 [Cho, Namki; Kim, Hyun Woo; Kim, Tae Bum; Sung, Sang Hyun] Seoul Natl Univ, Coll Pharm, Seoul 08826, South Korea. [Cho, Namki; Kim, Hyun Woo; Kim, Tae Bum; Sung, Sang Hyun] Seoul Natl Univ, Pharmaceut Sci Res Inst, Seoul 08826, South Korea. [Cho, Namki; Ransom, Tanya T.; Beutler, John A.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Sung, SH (reprint author), Seoul Natl Univ, Coll Pharm, Seoul 08826, South Korea.; Sung, SH (reprint author), Seoul Natl Univ, Pharmaceut Sci Res Inst, Seoul 08826, South Korea. EM cnamki@naver.com; kimkami2@snu.ac.kr; gtato311@snu.ac.kr; ransomt@mail.nih.gov; beutlerj@mail.nih.gov; shsung@snu.ac.kr FU Forest Science and Technology Project [S121214L120100]; Korea Forest Service; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX This work was supported by the Forest Science and Technology Project (S121214L120100) with funding provided by the Korea Forest Service. Additionally, this research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 29 TC 0 Z9 0 U1 8 U2 8 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1420-3049 J9 MOLECULES JI Molecules PD JUN PY 2016 VL 21 IS 6 DI 10.3390/molecules21060700 PG 12 WC Chemistry, Organic SC Chemistry GA DP8ON UT WOS:000378757600026 ER PT J AU Dettmer, AM Kaburu, SSK Simpson, EA Paukner, A Sclafani, V Byers, KL Murphy, AM Miller, M Marquez, N Miller, GM Suomi, SJ Ferrari, PF AF Dettmer, Amanda M. Kaburu, Stefano S. K. Simpson, Elizabeth A. Paukner, Annika Sclafani, Valentina Byers, Kristen L. Murphy, Ashley M. Miller, Michelle Marquez, Neal Miller, Grace M. Suomi, Stephen J. Ferrari, Pier F. TI Neonatal face-to-face interactions promote later social behaviour in infant rhesus monkeys SO NATURE COMMUNICATIONS LA English DT Article ID HAIR CORTISOL; EYE CONTACT; MACAQUES; ENGAGE; AUTISM; GAZE AB In primates, including humans, mothers engage in face-to-face interactions with their infants, with frequencies varying both within and across species. However, the impact of this variation in face-to-face interactions on infant social development is unclear. Here we report that infant monkeys (Macaca mulatta) who engaged in more neonatal face-to-face interactions with mothers have increased social interactions at 2 and 5 months. In a controlled experiment, we show that this effect is not due to physical contact alone: monkeys randomly assigned to receive additional neonatal face-to-face interactions (mutual gaze and intermittent lip-smacking) with human caregivers display increased social interest at 2 months, compared with monkeys who received only additional handling. These studies suggest that face-to-face interactions from birth promote young primate social interest and competency. C1 [Dettmer, Amanda M.; Kaburu, Stefano S. K.; Simpson, Elizabeth A.; Paukner, Annika; Sclafani, Valentina; Byers, Kristen L.; Murphy, Ashley M.; Miller, Michelle; Marquez, Neal; Miller, Grace M.; Suomi, Stephen J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, NIH, Poolesville, MD 20837 USA. [Kaburu, Stefano S. K.] Univ Calif Davis, Dept Populat Hlth & Reprod, Davis, CA 95616 USA. [Simpson, Elizabeth A.] Univ Miami, Dept Psychol, Coral Gables, FL 33146 USA. [Sclafani, Valentina] Univ Reading, Winnicott Res Unit, Reading RG 6AL, Berks, England. [Miller, Michelle] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Marquez, Neal] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. [Miller, Grace M.] Univ Virginia, Clin & Sch Psychol, Charlottesville, VA 22904 USA. [Ferrari, Pier F.] Univ Parma, Dept Neurosci, I-43125 Parma, Italy. RP Dettmer, AM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, NIH, Poolesville, MD 20837 USA. EM dettmera@mail.nih.gov OI Dettmer, Amanda/0000-0003-1360-3567; Simpson, Elizabeth/0000-0003-2715-2533 FU NICHD Division of Intramural Research; NICHD [PO1HD064653] FX This work was supported by NICHD Division of Intramural Research and NICHD grant PO1HD064653 (P.F.F.). We are grateful to the animal care and veterinary staff at the NIH Animal Center. NR 41 TC 3 Z9 3 U1 6 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 JUN PY 2016 VL 7 AR 11940 DI 10.1038/ncomms11940 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP7LM UT WOS:000378680700001 PM 27300086 ER PT J AU Czajkowski, SM AF Czajkowski, Susan M. TI National Institutes of Health Update: Translating Basic Behavioral Science into New Pediatric Obesity Interventions SO PEDIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Basic behavioral science; Early phase behavioral translation; Intervention development; Pediatric obesity; Obesity-related behavioral intervention trials (ORBIT) model ID EPISODIC FUTURE THINKING; FAMILY-BASED TREATMENT; BODY-MASS INDEX; OVERWEIGHT CHILDREN; CHILDHOOD OVERWEIGHT; CARDIOVASCULAR RISK; SELF-REGULATION; ENERGY-INTAKE; DIET QUALITY; WEIGHT-LOSS AB Pediatric obesity increases the risk of later-life obesity and chronic diseases. Basic research to better understand factors associated with excessive weight gain in early life and studies translating research findings into preventive and therapeutic strategies are essential to our ability to better prevent and treat childhood obesity. This overview describes several National Institutes of Health efforts designed to stimulate basic and translational research in childhood obesity prevention and treatment. These examples demonstrate the value of research in early phase translational pediatric obesity research and highlight some promising directions for this important area of research. C1 [Czajkowski, Susan M.] NCI, Hlth Behav Res Branch, Behav Res Program, Div Canc Control & Populat Sci,NIH, 9609 Med Ctr Dr,Room 3E108, Rockville, MD 20892 USA. RP Czajkowski, SM (reprint author), NCI, Hlth Behav Res Branch, Behav Res Program, Div Canc Control & Populat Sci,NIH, 9609 Med Ctr Dr,Room 3E108, Rockville, MD 20892 USA. EM Susan.Czajkowski@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 47 TC 1 Z9 1 U1 4 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0031-3955 EI 1557-8240 J9 PEDIATR CLIN N AM JI Pediatr. Clin. N. Am. PD JUN PY 2016 VL 63 IS 3 BP 389 EP + DI 10.1016/j.pcl.2016.02.009 PG 12 WC Pediatrics SC Pediatrics GA DP9OB UT WOS:000378824600004 PM 27261541 ER PT J AU Stanley, IH Horowitz, LM Bridge, JA Wharff, EA Pao, M Teach, SJ AF Stanley, Ian H. Horowitz, Lisa M. Bridge, Jeffrey A. Wharff, Elizabeth A. Pao, Maryland Teach, Stephen J. TI Bullying and Suicide Risk Among Pediatric Emergency Department Patients! SO PEDIATRIC EMERGENCY CARE LA English DT Article DE bullying; suicide risk; youth ID BULLIED CHILDREN; PUBLIC-HEALTH; ADOLESCENTS; PREVENTION; YOUTH; ASSOCIATION; DEPRESSION; MEDICINE; BEHAVIOR; GAY AB Objectives This study aimed to describe the association between recent bullying victimization and risk of suicide among pediatric emergency department (ED) patients. Methods Patients presenting to 1 of 3 different urban pediatric EDs with either medical/surgical or psychiatric chief complaints completed structured interviews as part of a study to develop a suicide risk screening instrument, the Ask Suicide-Screening Questions. Seventeen candidate items and the criterion reference Suicidal Ideation Questionnaire were administered to patients ages 10 to 21 years. Bullying victimization was assessed by a single candidate item (In the past few weeks, have you been bullied or picked on so much that you felt like you couldn't stand it anymore?). Results A total of 524 patients completed the interview (34.4% psychiatric chief complaints; 56.9% female; 50.4% white, non-Hispanic; mean [SD] age, 15.2 [2.6] years). Sixty patients (11.5%) reported recent bullying victimization, and of these, 33 (55.0%) screened positive for suicide risk on the Ask Suicide-Screening Questions or the previously validated Suicidal Ideation Questionnaire. After controlling for demographic and clinical variables, including a history of depression and drug use, the odds of screening positive for suicide risk were significantly greater in patients who reported recent bullying victimization (adjusted odds ratio, 3.19; 95% confidence interval, 1.66-6.11). After stratification by chief complaint, this association persisted for medical/surgical patients but not for psychiatric patients. Conclusions Recent bullying victimization was associated with increased odds of screening positive for elevated suicide risk among pediatric ED patients presenting with medical/surgical complaints. Understanding this important correlate of suicide risk in pediatric ED patients may help inform ED-based suicide prevention interventions. C1 [Stanley, Ian H.; Horowitz, Lisa M.; Pao, Maryland] NIMH, Off Clin Director, Bethesda, MD 20892 USA. [Bridge, Jeffrey A.] Nationwide Childrens Hosp, Res Inst, Ctr Innovat Pediat Practice, Columbus, OH USA. [Bridge, Jeffrey A.] Ohio State Univ, Coll Med, Dept Pediat, Columbus, OH 43210 USA. [Wharff, Elizabeth A.] Boston Childrens Hosp, Emergency Psychiat Serv, Boston, MA USA. [Wharff, Elizabeth A.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Teach, Stephen J.] Childrens Natl Hlth Syst, Div Emergency Med, Washington, DC USA. RP Horowitz, LM (reprint author), NIMH, Off Clin Director, NIH, 10 Ctr Dr,10-CRC MSC 1276, Bethesda, MD 20892 USA. EM horowitzl@mail.nih.gov FU National Institute of Mental Health; Research Institute at Nationwide Children's Hospital, CDC [R01 CE-002129]; NIMH [K01 MH-69948, R01 MH-93552]; Program for Patient Safety and Quality at Boston Children's Hospital FX All phases of this study were supported by the Intramural Research Program of the National Institute of Mental Health. Dr Bridge was supported by institutional research funds from the Research Institute at Nationwide Children's Hospital, CDC grant R01 CE-002129, and NIMH grants K01 MH-69948 and R01 MH-93552. Dr Wharff was supported by institutional research funds from the Program for Patient Safety and Quality at Boston Children's Hospital. NR 28 TC 1 Z9 1 U1 7 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0749-5161 EI 1535-1815 J9 PEDIATR EMERG CARE JI Pediatr. Emerg. Care PD JUN PY 2016 VL 32 IS 6 BP 347 EP 351 DI 10.1097/PEC.0000000000000537 PG 5 WC Emergency Medicine; Pediatrics SC Emergency Medicine; Pediatrics GA DP8AH UT WOS:000378719800001 PM 26417959 ER PT J AU Boghossian, NS Hansen, NI Bell, EF Brumbaugh, JE Stoll, BJ Laptook, AR Shankaran, S Wyckoff, MH Colaizy, TT Das, A Higgins, RD AF Boghossian, Nansi S. Hansen, Nellie I. Bell, Edward F. Brumbaugh, Jane E. Stoll, Barbara J. Laptook, Abbot R. Shankaran, Seetha Wyckoff, Myra H. Colaizy, Tarah T. Das, Abhik Higgins, Rosemary D. CA Eunice Kennedy Shriver Natl Inst C TI Outcomes of Extremely Preterm Infants Born to Insulin-Dependent Diabetic Mothers SO PEDIATRICS LA English DT Article ID BIRTH-WEIGHT INFANTS; NECROTIZING ENTEROCOLITIS; PREGNANT-WOMEN; RISK; MELLITUS; POPULATION; GRAMS AB BACKGROUND AND OBJECTIVE: Little is known about in-hospital morbidities and neurodevelopmental outcomes among extremely preterm infants born to women with insulin-dependent diabetes mellitus (IDDM). We examined risks of mortality, in-hospital morbidities, and neurodevelopmental outcomes at 18 to 22 months' corrected age between extremely preterm infants of women with insulin use before pregnancy (IBP), with insulin use started during pregnancy (IDP), and without IDDM. METHODS: Infants 22 to 28 weeks' gestation born or cared for at a Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network center (2006-2011) were studied. Regression models compared the association between maternal IDDM and timing of insulin use and the outcomes of the 3 groups. RESULTS: Of 10781 infants, 536 (5%) were born to women with IDDM; 58% had IBP, and 36% had IDP. Infants of mothers with IBP had higher risks of necrotizing enterocolitis (adjusted relative risk [RR] = 1.55 [95% confidence interval (CI) 1.17-2.05]) and late-onset sepsis (adjusted RR = 1.26 [95% CI 1.07-1.48]) than infants of mothers without IDDM. There was some indication of higher in-hospital mortality risk among infants of mothers with IBP compared with those with IDP (adjusted RR = 1.33 [95% CI 1.00-1.79]). Among survivors evaluated at 18 to 22 months' corrected age, average head circumference z score was lower for infants of mothers with IBP compared with those without IDDM, but there were no differences in risk of neurodevelopmental impairment. CONCLUSIONS: In this cohort of extremely preterm infants, infants of mothers with IBP had higher risks of necrotizing enterocolitis, sepsis, and small head circumference. C1 [Boghossian, Nansi S.] Univ S Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. [Hansen, Nellie I.] RTI Int, Social Stat & Environm Sci Unit, Res Triangle Pk, NC USA. [Bell, Edward F.; Brumbaugh, Jane E.; Colaizy, Tarah T.] Univ Iowa, Dept Pediat, 200 Hawkins Dr, Iowa City, IA 52242 USA. [Stoll, Barbara J.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Stoll, Barbara J.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Laptook, Abbot R.] Brown Univ, Dept Pediat, Providence, RI 02912 USA. [Laptook, Abbot R.] Women & Infants Hosp Rhode Isl, Providence, RI 02908 USA. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Wyckoff, Myra H.] Univ Texas SW Med Ctr Dallas, Parkland Hlth & Hosp Syst, Dept Pediat, Dallas, TX 75390 USA. [Wyckoff, Myra H.] Childrens Med Ctr, Dallas, TX 75235 USA. [Das, Abhik] RTI Int, Social Stat & Environm Sci Unit, Rockville, MD USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Bell, EF (reprint author), Univ Iowa, Dept Pediat, 200 Hawkins Dr, Iowa City, IA 52242 USA. EM edward-bell@uiowa.edu FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institutes of Health (NIH) FX The Neonatal Research Network is funded by the National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Rosemary D. Higgins is employed by the NICHD. Funded by the National Institutes of Health (NIH). NR 40 TC 1 Z9 1 U1 0 U2 0 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 JUN PY 2016 VL 137 IS 6 AR e20153424 DI 10.1542/peds.2015-3424 PG 14 WC Pediatrics SC Pediatrics GA DP5EZ UT WOS:000378520100020 ER PT J AU Goldstein, RD Kinney, HC Willinger, M AF Goldstein, Richard D. Kinney, Hannah C. Willinger, Marian TI Sudden Unexpected Death in Fetal Life Through Early Childhood SO PEDIATRICS LA English DT Article ID HEALTHY TERM INFANTS; BRAIN-STEM ABNORMALITIES; MATERNAL SLEEP PRACTICES; NORTHERN PLAINS INDIANS; TEMPORAL-LOBE EPILEPSY; TRIPLE-RISK MODEL; HEART-RATE; SUBPLATE NEURONS; RAT PUPS; CEREBRAL OXYGENATION AB In March 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development held a workshop entitled "Sudden Unexpected Death in Fetal Life Through Early Childhood: New Opportunities." Its objective was to advance efforts to understand and ultimately prevent sudden deaths in early life, by considering their pathogenesis as a potential continuum with some commonalities in biological origins or pathways. A second objective of this meeting was to highlight current issues surrounding the classification of sudden infant death syndrome (SIDS), and the implications of variations in the use of the term "SIDS" in forensic practice, and pediatric care and research. The proceedings reflected the most current knowledge and understanding of the origins and biology of vulnerability to sudden unexpected death, and its environmental triggers. Participants were encouraged to consider the application of new technologies and "omics" approaches to accelerate research. The major advances in delineating the intrinsic vulnerabilities to sudden death in early life have come from epidemiologic, neural, cardiac, metabolic, genetic, and physiologic research, with some commonalities among cases of unexplained stillbirth, SIDS, and sudden unexplained death in childhood observed. It was emphasized that investigations of sudden unexpected death are inconsistent, varying by jurisdiction, as are the education, certification practices, and experience of death certifiers. In addition, there is no practical consensus on the use of "SIDS" as a determination in cause of death. Major clinical, forensic, and scientific areas are identified for future research. C1 [Goldstein, Richard D.] Harvard Univ, Sch Med, Dept Med, Dept Psychosocial Oncol & Palliat Care,Dana Farbe, Boston, MA 02115 USA. [Kinney, Hannah C.] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. [Willinger, Marian] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD 20892 USA. RP Goldstein, RD (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,D2008, Boston, MA 02115 USA. EM richard_goldstein@dfci.harvard.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health (NIH) FX This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Funded by the National Institutes of Health (NIH). NR 108 TC 2 Z9 2 U1 6 U2 8 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 JUN PY 2016 VL 137 IS 6 AR e20154661 DI 10.1542/peds.2015-4661 PG 11 WC Pediatrics SC Pediatrics GA DP5EZ UT WOS:000378520100037 ER PT J AU Johnson, KA Sjaarda, LA Mumford, SL Garbose, RA Schliep, KC Mattison, D Perkins, NJ Wactawski-Wende, J Schisterman, EF AF Johnson, Kristen A. Sjaarda, Lindsey A. Mumford, Sunni L. Garbose, Rebecca A. Schliep, Karen C. Mattison, Donald Perkins, Neil J. Wactawski-Wende, Jean Schisterman, Enrique F. TI Patterns and prevalence of medication use across the menstrual cycle among healthy, reproductive aged women SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE medication use; over-the-counter; prescription; menstrual cycle; pharmacoepidemiology ID PREMENOPAUSAL WOMEN; PROSPECTIVE COHORT; UNITED-STATES; PREGNANCY; BIOCYCLE; ANTIBIOTICS; POPULATION; CARE AB PurposeThe purpose of this study is to characterize the patterns of medication intake in healthy, reproductive-age women not using hormonal contraception. MethodsTwo hundered fifty-nine healthy, premenopausal women (18-44years of age) enrolled in the BioCycle Study (2005-2007) were followed over two menstrual cycles. Women were excluded if they were currently using oral contraceptives or other chronic medications. Over-the-counter and prescription medication use among participants was evaluated daily throughout the study via a diary assessing type of medication, dosage, units, and frequency. Medications were categorized as allergy, antibiotics, central nervous system (CNS), cold and cough, gastrointestinal, musculoskeletal, and pain medication based on primary active ingredient. Medication use within each category was assessed across standardized 28-day cycles to evaluate differences in use across cycle phases (i.e., early, middle, and late). ResultsMedication use was reported by 73% of participants. The most and least frequently used medications, respectively, were pain (69%) and musculoskeletal medications (1%). Pain, CNS, and antibiotic medication use varied significantly across the cycle, with pain and CNS medication more frequently reported during menses and antibiotics more frequently during the luteal phase. Allergy, cold and cough, gastrointestinal, and musculoskeletal medication use did not vary across the cycle. ConclusionsPatterns of medication use among reproductive age women vary across the menstrual cycle for certain types of medications, particularly in pain (e.g., Ibuprofen), antibiotics (e,g, Amoxicillin), and CNS (e.g., Adderall) medications. Future studies involving use of these types of medication in premenopausal women may need to consider the relationship of their use to the menstrual cycle. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Johnson, Kristen A.; Sjaarda, Lindsey A.; Mumford, Sunni L.; Garbose, Rebecca A.; Schliep, Karen C.; Perkins, Neil J.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. [Wactawski-Wende, Jean] Univ Buffalo, Sch Publ Hlth & Hlth Profess, Dept Epidemiol & Environm Hlth, Buffalo, NY USA. [Mattison, Donald] Univ Ottawa, Risk Sci Int & McLaughlin Ctr Populat Hlth Risk A, Ottawa, ON, Canada. RP Sjaarda, LA (reprint author), NICHD, Epidemiol Branch, DIPHR, 6100 Execut Blvd,7B03, Rockville, MD 20852 USA. EM lindsey.sjaarda@nih.gov OI Perkins, Neil/0000-0002-6802-4733; Sjaarda, Lindsey/0000-0003-0539-8110; Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN275200403394C] 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 (Contract Number: HHSN275200403394C). The authors thank Ya-Ling Lu, Ph.D. for her assistance in reviewing recent scientific literature and revising the final manuscript. NR 24 TC 0 Z9 0 U1 7 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JUN PY 2016 VL 25 IS 6 BP 618 EP 627 DI 10.1002/pds.3993 PG 10 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DP5PF UT WOS:000378548800002 PM 26954695 ER PT J AU Newman, DJ Cragg, GM AF Newman, David J. Cragg, Gordon M. TI Drugs and Drug Candidates from Marine Sources: An Assessment of the Current "State of Play" SO PLANTA MEDICA LA English DT Review DE marine-sourced drugs; clinical trials; cancer; HIV ID CONJUGATE GLEMBATUMUMAB VEDOTIN; BRYOSTATIN ANTITUMOR MACROLIDES; METASTATIC BREAST-CANCER; NATURAL-PRODUCTS; BRENTUXIMAB VEDOTIN; IN-VITRO; ECTEINASCIDIA-TURBINATA; HALAVEN(R) SYNTHESIS; NORHALICHONDRIN-B; ANTIMITOTIC DRUG AB The potential of the marine environment to produce candidate compounds (structures) as leads to, or even direct drugs from, has been actively discussed for the last 50 or so years. Over this time frame, several compounds have led to drugs, usually in the area of cancer (due to funding sources). This review is designed to show where there have been successes, but also to show that in a number of disease areas, there are structures originally isolated from marine invertebrates and free-living microbes that have potential, but will need to be "adopted" by pharmaceutical houses in order to maximize their potential. C1 [Newman, David J.; Cragg, Gordon M.] NCI, NIH Special Volunteers, Nat Prod Branch, Frederick, MD 21701 USA. RP Newman, DJ (reprint author), 664 Crestwood Rd, Wayne, PA 19087 USA. EM djnewman664@verizon.net NR 152 TC 4 Z9 4 U1 18 U2 31 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUN PY 2016 VL 82 IS 9-10 SI SI BP 775 EP 789 DI 10.1055/s-0042-101353 PG 15 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA DQ0TN UT WOS:000378913600005 PM 26891002 ER PT J AU Rowland, JH AF Rowland, Julia H. TI Psycho-Oncology, 3rd edition SO PSYCHO-ONCOLOGY LA English DT Book Review C1 [Rowland, Julia H.] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, NIH,DHHS, Bethesda, MD 20892 USA. RP Rowland, JH (reprint author), NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, NIH,DHHS, Bethesda, MD 20892 USA. EM rowlandj@mail.nih.gov 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 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD JUN PY 2016 VL 25 IS 6 BP 745 EP 746 DI 10.1002/pon.4151 PG 2 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA DP8DB UT WOS:000378727000020 ER PT J AU Wendler, D Johnson, R AF Wendler, David Johnson, Rebecca TI When clinical care is like research: the need for review and consent SO THEORETICAL MEDICINE AND BIOETHICS LA English DT Review DE Learning health care; Consent; Independent review; Exploitation ID INFORMED-CONSENT; EQUIPOISE; ETHICS; TRIALS; SYSTEM AB The prevailing "segregated model" for understanding clinical research sharply separates it from clinical care and subjects it to extensive regulations and guidelines. This approach is based on the fact that clinical research relies on procedures and methods-research biopsies, blinding, randomization, fixed treatment protocols, placebos-that pose risks and burdens to participants in order to collect data that might benefit all patients. Reliance on these methods raises the potential for exploitation and unfairness, and thus points to the need for independent ethical review and more extensive informed consent. In contrast, it is widely assumed that clinical care does not raise these ethical concerns because it is designed to promote the best interests of individual patients. The segregation of clinical research from clinical care has been largely effective at protecting research participants. At the same time, this approach ignores the fact that several aspects of standard clinical care, such as clinician training and scheduling, also pose some risks and burdens to present patients for the benefit of all patients. We argue that recently proposed learning health care systems offer a way to address this concern, and better protect patients, by developing integrated review and consent procedures. Specifically, current approaches base the need for independent ethical review and more extensive informed consent on whether an activity is categorized as clinical research or clinical care. An ethically sounder approach, which could be incorporated into learning health care systems, would be to base the need for independent ethical review and more extensive informed consent on the extent to which an activity poses risks to present patients for the benefit of all patients. C1 [Wendler, David] NIH Clin Ctr, Dept Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. [Johnson, Rebecca] Princeton Univ, Dept Sociol, Princeton, NJ 08544 USA. RP Wendler, D (reprint author), NIH Clin Ctr, Dept Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM dwendler@nih.gov FU NIH Clinical Center intramural funds FX Thanks to Christine Grady, Steven Pearson, and Franklin Miller for their helpful comments on early versions of the manuscript. This work was supported by NIH Clinical Center intramural funds. However, the views expressed are those of the authors. They do not represent the position or policy of the NIH or DHHS. NR 31 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1386-7415 EI 1573-1200 J9 THEOR MED BIOETH JI Theor. Med. Bioeth. PD JUN PY 2016 VL 37 IS 3 BP 193 EP 209 DI 10.1007/s11017-016-9364-x PG 17 WC Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Social Issues; Biomedical Social Sciences GA DP9WI UT WOS:000378848200002 PM 27188333 ER PT J AU Glynn, SA Klein, HG Ness, PM AF Glynn, Simone A. Klein, Harvey G. Ness, Paul M. TI The red blood cell storage lesion: the end of the beginning SO TRANSFUSION LA English DT Editorial Material ID STORED-BLOOD; NITRIC-OXIDE; EXCHANGE-TRANSFUSION; CLINICAL-OUTCOMES; CARDIAC-SURGERY; S-NITROSYLATION; ANIMAL-MODELS; BANKED BLOOD; IN-VITRO; AGE C1 [Glynn, Simone A.] NHLBI, Blood Epidemiol & Clin Therapeut Branch, Div Blood Dis & Resources, NIH, Bldg 10, Bethesda, MD 20892 USA. [Klein, Harvey G.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Ness, Paul M.] Johns Hopkins Med Inst, Dept Pathol, Transfus Med Div, Baltimore, MD 21205 USA. RP Glynn, SA (reprint author), NHLBI, Blood Epidemiol & Clin Therapeut Branch, Div Blood Dis & Resources, NIH, Bldg 10, Bethesda, MD 20892 USA. EM glynnsa@nhlbi.nih.gov NR 48 TC 14 Z9 14 U1 6 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD JUN PY 2016 VL 56 IS 6 BP 1462 EP 1468 DI 10.1111/trf.13609 PG 7 WC Hematology SC Hematology GA DP5QU UT WOS:000378553200060 PM 27080455 ER PT J AU Kuhn, JH Wiley, MR Rodriguez, SE Bao, YM Prieto, K da Rosa, APAT Guzman, H Savji, N Ladner, JT Tesh, RB Wada, J Jahrling, PB Bente, DA Palacios, G AF Kuhn, Jens H. Wiley, Michael R. Rodriguez, Sergio E. Bao, Yiming Prieto, Karla da Rosa, Amelia P. A. Travassos Guzman, Hilda Savji, Nazir Ladner, Jason T. Tesh, Robert B. Wada, Jiro Jahrling, Peter B. Bente, Dennis A. Palacios, Gustavo TI Genomic Characterization of the Genus Nairovirus (Family Bunyaviridae) SO VIRUSES-BASEL LA English DT Article DE Bunyaviridae; bunyavirus; nairovirus; Dera Ghazi Khan virus; Erve virus; Ganjam virus; Hughes virus; Qalyub virus; Sakhalin virus; Tunis virus; virus classification; virus taxonomy ID HEMORRHAGIC-FEVER-VIRUS; TICK-BORNE PHLEBOVIRUSES; HIDDEN MARKOV MODEL; PHYLOGENETIC CHARACTERIZATION; SAKHALIN-GROUP; GENETIC-CHARACTERIZATION; SEGMENT REASSORTMENT; ORNITHODOROS TICKS; SPECIES COMPLEX; IXODES-URIAE AB Nairovirus, one of five bunyaviral genera, includes seven species. Genomic sequence information is limited for members of the Dera Ghazi Khan, Hughes, Qalyub, Sakhalin, and Thiafora nairovirus species. We used next-generation sequencing and historical virus-culture samples to determine 14 complete and nine coding-complete nairoviral genome sequences to further characterize these species. Previously unsequenced viruses include Abu Mina, Clo Mor, Great Saltee, Hughes, Raza, Sakhalin, Soldado, and Tillamook viruses. In addition, we present genomic sequence information on additional isolates of previously sequenced Avalon, Dugbe, Sapphire II, and Zirqa viruses. Finally, we identify Tunis virus, previously thought to be a phlebovirus, as an isolate of Abu Hammad virus. Phylogenetic analyses indicate the need for reassignment of Sapphire II virus to Dera Ghazi Khan nairovirus and reassignment of Hazara, Tofla, and Nairobi sheep disease viruses to novel species. We also propose new species for the Kasokero group (Kasokero, Leopards Hill, Yogue viruses), the Ketarah group (Gossas, Issyk-kul, Keterah/soft tick viruses) and the Burana group (Wenzhou tick virus, Huangpi tick virus 1, Tacheng tick virus 1). Our analyses emphasize the sister relationship of nairoviruses and arenaviruses, and indicate that several nairo-like viruses (Shayang spider virus 1, Xinzhou spider virus, Sanxia water strider virus 1, South Bay virus, Wuhan millipede virus 2) require establishment of novel genera in a larger nairovirus-arenavirus supergroup. C1 [Kuhn, Jens H.; Wada, Jiro; Jahrling, Peter B.] NIAID, Integrated Res Facil Ft Detrick, Div Clin Res, NIH, Frederick, MD 21702 USA. [Wiley, Michael R.; Prieto, Karla; Ladner, Jason T.; Palacios, Gustavo] US Army, Ctr Genome Sci, Med Res Inst Infect Dis, Frederick, MD 21702 USA. [Rodriguez, Sergio E.; da Rosa, Amelia P. A. Travassos; Guzman, Hilda; Tesh, Robert B.; Bente, Dennis A.] Univ Texas Med Branch, Dept Microbiol & Immunol, Inst Human Infect & Immun, Galveston Natl Lab, Galveston, TX 77555 USA. [Bao, Yiming] NIH, Informat Engn Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Savji, Nazir] NYU, Sch Med, New York, NY 10016 USA. RP Palacios, G (reprint author), US Army, Ctr Genome Sci, Med Res Inst Infect Dis, Frederick, MD 21702 USA. EM kuhnjens@mail.nih.gov; michael.r.wiley19.ctr@mail.mil; seerodri@utmb.edu; bao@ncbi.nlm.nih.gov; karla.prieto.ctr@mail.mil; aptravas@utmb.edu; hguzman@utmb.edu; nazir.savji@gmail.com; jason.t.ladner.ctr@mail.mil; rtesh@utmb.edu; wadaj@mail.nih.gov; jahrlingp@niaid.nih.gov; dabente@utmb.edu; gustavo.f.palacios.ctr@mail.mil RI Palacios, Gustavo/I-7773-2015; OI Palacios, Gustavo/0000-0001-5062-1938; Kuhn, Jens H./0000-0002-7800-6045 FU Defense Threat Reduction Agency [1881290]; United States Department of Defense, Defense Biological Products Assurance Office; US National Institutes of Health (NIH) [HHSN272201000040I/HHSN27200004/D04]; Intramural Research Program of the NIH, National Library of Medicine; Battelle Memorial Institute; US National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200700016I] FX The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, or the institutions and companies affiliated with the authors. This work was supported by the Defense Threat Reduction Agency #1881290, and the United States Department of Defense, Defense Biological Products Assurance Office. A.P.A.T.d.R., H.G., and R.B.T. were supported by US National Institutes of Health (NIH) contract HHSN272201000040I/HHSN27200004/D04. Y.B. was supported by the Intramural Research Program of the NIH, National Library of Medicine. This work was supported in part through Battelle Memorial Institute's prime contract with the US National Institute of Allergy and Infectious Diseases (NIAID) under Contract No. HHSN272200700016I. A Battelle employee involved in this work is: J.W. A subcontractor to Battelle Memorial Institute who performed this work is: J.H.K., an employee of Tunnell Government Services, Inc. We thank Laura Bollinger (Battelle Memorial Institute) for editing this manuscript. NR 128 TC 2 Z9 2 U1 2 U2 10 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD JUN PY 2016 VL 8 IS 6 AR 164 DI 10.3390/v8060164 PG 27 WC Virology SC Virology GA DP9WM UT WOS:000378848600016 ER PT J AU Woodrum, BW Maxwell, J Allen, DM Wilson, J Krumpe, LRH Bobkov, AA Hill, RB Kibler, KV O'Keefe, BR Ghirlanda, G AF Woodrum, Brian W. Maxwell, Jason Allen, Denysia M. Wilson, Jennifer Krumpe, Lauren R. H. Bobkov, Andrey A. Hill, R. Blake Kibler, Karen V. O'Keefe, Barry R. Ghirlanda, Giovanna TI A Designed "Nested" Dimer of Cyanovirin-N Increases Antiviral Activity SO VIRUSES-BASEL LA English DT Article DE Cyanovirin-N; antiviral lectins; glycan-binding proteins; oligomannose; gp120 ID HIV-INACTIVATING PROTEIN; CARBOHYDRATE-BINDING AGENTS; RECOMBINANT VACCINIA VIRUS; DOMAIN-SWAPPED STRUCTURE; T-CELL LINES; ENVELOPE GLYCOPROTEIN; PRIMARY MACROPHAGES; CRYSTAL-STRUCTURE; TYPE-1 TROPISM; CONTAINS 2 AB Cyanovirin-N (CV-N) is an antiviral lectin with potent activity against enveloped viruses, including HIV. The mechanism of action involves high affinity binding to mannose-rich glycans that decorate the surface of enveloped viruses. In the case of HIV, antiviral activity of CV-N is postulated to require multivalent interactions with envelope protein gp120, achieved through a pseudo-repeat of sequence that adopts two near-identical glycan-binding sites, and possibly involves a 3D-domain-swapped dimeric form of CV-N. Here, we present a covalent dimer of CV-N that increases the number of active glycan-binding sites, and we characterize its ability to recognize four glycans in solution. A CV-N variant was designed in which two native repeats were separated by the "nested" covalent insertion of two additional repeats of CV-N, resulting in four possible glycan-binding sites. The resulting Nested CV-N folds into a wild-type-like structure as assessed by circular dichroism and NMR spectroscopy, and displays high thermal stability with a T-m of 59 degrees C, identical to WT. All four glycan-binding domains encompassed by the sequence are functional as demonstrated by isothermal titration calorimetry, which revealed two sets of binding events to dimannose with dissociation constants K-d of 25 mu M and 900 mu M, assigned to domains B and B' and domains A and A' respectively. Nested CV-N displays a slight increase in activity when compared to WT CV-N in both an anti-HIV cellular assay and a fusion assay. This construct conserves the original binding specifityies of domain A and B, thus indicating correct fold of the two CV-N repeats. Thus, rational design can be used to increase multivalency in antiviral lectins in a controlled manner. C1 [Woodrum, Brian W.; Maxwell, Jason; Allen, Denysia M.; Ghirlanda, Giovanna] Arizona State Univ, Sch Mol Sci, Tempe, AZ 85287 USA. [Wilson, Jennifer; O'Keefe, Barry R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Krumpe, Lauren R. H.] Leidos Biomed Res Inc, Basic Sci Program, Frederick Natl Lab, Frederick, MD 21702 USA. [Bobkov, Andrey A.] Sanford Burnham Prebys Med Discovery Inst, 10901 North Torrey Pines Rd, La Jolla, CA 92037 USA. [Hill, R. Blake] Med Coll Wisconsin, Dept Biochem, Milwaukee, WI 53226 USA. [Kibler, Karen V.] Arizona State Univ, Sch Life Sci, Tempe, AZ 85287 USA. [Kibler, Karen V.] Arizona State Univ, Biodesign Inst, Tempe, AZ 85287 USA. RP Ghirlanda, G (reprint author), Arizona State Univ, Sch Mol Sci, Tempe, AZ 85287 USA. EM bwoodrum@asu.edu; jdmaxwe1@asu.edu; Denysia.Allen@gmail.com; wilsonje@mail.nih.gov; haughl@mail.nih.gov; abobkov@sbpdiscovery.org; rbhill@mcw.edu; Karen.Kibler@asu.edu; okeefeba@mail.nih.gov; gghirlanda@asu.edu FU National Science Foundation-Division of Molecular and Cellular Biosciences [1121276]; National Institutes of Health [U54 GM094599]; center for Membrane Proteins in Infectious Diseases (MPID) - NIH PSI: Biology Initiative; National Cancer Institute, National Institutes of Health [HHSN26120080001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; NIH Intramural AIDS Targeted Antiviral Program; Center for Cancer Research at the National Cancer Institute FX This work was supported by the National Science Foundation-Division of Molecular and Cellular Biosciences, under award number 1121276 (to G.G.). B.W.W. and J.D.M. were supported in part by National Institutes of Health award U54 GM094599, the center for Membrane Proteins in Infectious Diseases (MPID), which is funded as part of the NIH PSI: Biology Initiative. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E, and supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This work was supported in part by funds from the NIH Intramural AIDS Targeted Antiviral Program and Center for Cancer Research at the National Cancer Institute (to B.O). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. We gratefully acknowledge the NIH AIDS Research and Reference Reagent Program Division of AIDS, NIAID, NIH for reagents (see Methods). We thank Ashini Bolia for help with building the model of Nested CV-N. Chemical shift assignments for wild type CV-N were provided by Carole Bewley. Brian Cherry assisted in setting up NMR experiemnts at the ASU Magnetic Resonance Facility. This paper is dedicated to our friend and colleague Barbara Giomarelli, in memoriam. NR 49 TC 0 Z9 0 U1 4 U2 4 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD JUN PY 2016 VL 8 IS 6 AR 158 DI 10.3390/v8060158 PG 15 WC Virology SC Virology GA DP9WM UT WOS:000378848600010 ER PT J AU Hoffman, AF Spivak, CE Lupica, CR AF Hoffman, Alexander F. Spivak, Charles E. Lupica, Carl R. TI Enhanced Dopamine Release by Dopamine Transport Inhibitors Described by a Restricted Diffusion Model and Fast-Scan Cyclic Voltammetry SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE Voltammetry; kinetics; dopamine transporter; drug abuse; cathinones; brain slice ID CARBON-FIBER MICROELECTRODES; KAPPA-OPIOID RECEPTOR; BRAIN EXTRACELLULAR-SPACE; NUCLEUS-ACCUMBENS; TRANSMITTER RELEASE; AMPHETAMINE ACTION; EVOKED DOPAMINE; COCAINE; RAT; ACTIVATION AB Fast-scan cyclic voltammetry (FSCV) using carbon fiber electrodes is widely used to rapidly monitor changes in dopamine (DA) levels in vitro and in vivo. Current analytical approaches utilize parameters such as peak oxidation current amplitude and decay times to estimate release and uptake processes, respectively. However, peak amplitude changes are often observed with uptake inhibitors, thereby confounding the interpretation of these parameters. To overcome this limitation, we demonstrate that a simple five-parameter, two-compartment model mathematically describes DA signals as a balance of release (r/k(e)) and uptake (k(u)), summed with adsorption (k(ads) and k(des)) of DA to the carbon electrode surface. Using nonlinear regression, we demonstrate that our model precisely describes measured DA signals obtained in brain slice recordings. The parameters extracted from these curves were then validated using pharmacological manipulations that selectively alter vesicular release or DA transporter (DAT)-mediated uptake. Manipulation of DA release through altering the Ca2+/Mg2+ ratio or adding tetrodotoxin reduced the release parameter with no effect on the uptake parameter. DAT inhibitors methylenedioxypyrovalerone, cocaine, and nomifensine significantly reduced uptake and increased vesicular DA release. In contrast, a low concentration of amphetamine reduced uptake but had no effect on DA release. Finally, the kappa opioid receptor agonist U50,488 significantly reduced vesicular DA release but had no effect on uptake. Together, these data demonstrate a novel analytical approach to distinguish the effects of manipulations on DA release or uptake that can be used to interpret FSCV data. C1 [Hoffman, Alexander F.; Spivak, Charles E.; Lupica, Carl R.] NIDA, Electrophysiol Res Sect, Cellular Neurobiol Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Hoffman, AF (reprint author), NIDA, Electrophysiol Res Sect, Cellular Neurobiol Branch, Intramural Res Program, Baltimore, MD 21224 USA. EM ahoffman@mail.nih.gov OI Hoffman, Alex/0000-0002-2676-0628 FU NIDA Intramural Research Program FX Support was provided by the NIDA Intramural Research Program. NR 42 TC 2 Z9 2 U1 10 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD JUN PY 2016 VL 7 IS 6 BP 700 EP 709 DI 10.1021/acschemneuro.5b00277 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA DP0QY UT WOS:000378195500003 PM 27018734 ER PT J AU Cheng, JP Leary, JB Sembhi, A Edwards, CM Bondi, CO Kline, AE AF Cheng, Jeffrey P. Leary, Jacob B. Sembhi, Aerin Edwards, Clarice M. Bondi, Corina O. Kline, Anthony E. TI 5-hydroxytryptamine(1A) (5-HT1A) receptor agonists: A decade of empirical evidence supports their use as an efficacious therapeutic strategy for brain trauma SO BRAIN RESEARCH LA English DT Review DE 5-HT1A receptor agonists; Behavioral outcome; Controlled cortical impact; Functional recovery; Hippocampus; Learning and memory; Morris water maze; Serotonin(1A); Traumatic brain injury ID CONTROLLED CORTICAL IMPACT; BAY X 3702; ENVIRONMENTAL ENRICHMENT; METHYLPHENIDATE TREATMENT; NEUROBEHAVIORAL BENEFIT; MODERATE HYPOTHERMIA; BEHAVIORAL RECOVERY; COGNITIVE FUNCTION; TREATMENT REGIMEN; CLINICAL-TRIALS AB Traumatic brain injury (TBI) is a significant and enduring health care issue with limited treatment options. While several pre-clinical therapeutic approaches have led to enhanced motor and/or cognitive performance, the benefits of these treatments have not translated to the clinic. One plausible explanation is that the therapies may not have been rigorously evaluated, thus rendering the bench-to-bedside leap premature and subsequently unsuccessful. An approach that has undergone considerable empirical research after TBI is pharmacological targeting of 5-HT1A receptors with agonists such as repinotan HCl, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), and buspirone. The goal of this review is to integrate and interpret the findings from a series of studies that evaluated the efficacy of 5-HT1A receptor agonists on functional, histological, and molecular outcome after acquired brain injury. The overwhelming consensus of this exhaustive review is that a decade of empirical evidence supports their use as an efficacious therapeutic strategy for brain trauma. This article is part of a Special Issue entitled SI:Brain injury and recovery. (c) 2015 Elsevier B.V. All rights reserved. C1 [Cheng, Jeffrey P.; Leary, Jacob B.; Sembhi, Aerin; Edwards, Clarice M.; Bondi, Corina O.; Kline, Anthony E.] Univ Pittsburgh, Phys Med & Rehabil, Pittsburgh, PA 15213 USA. [Cheng, Jeffrey P.; Leary, Jacob B.; Edwards, Clarice M.; Bondi, Corina O.; Kline, Anthony E.] Univ Pittsburgh, Safar Ctr Resuscitat Res, Pittsburgh, PA 15213 USA. [Kline, Anthony E.] Univ Pittsburgh, Psychol, Pittsburgh, PA 15213 USA. [Kline, Anthony E.] Univ Pittsburgh, Crit Care Med, Pittsburgh, PA 15213 USA. [Bondi, Corina O.; Kline, Anthony E.] Univ Pittsburgh 1letab, Ctr Neurosci, Pittsburgh, PA 15213 USA. [Kline, Anthony E.] Univ Pittsburgh, Ctr Neural Basis Cognit, Pittsburgh, PA 15213 USA. [Leary, Jacob B.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Kline, AE (reprint author), Univ Pittsburgh, Dept Phys Med & Rehabil, 3471 Fifth Ave,Suite 201, Pittsburgh, PA 15213 USA.; Kline, AE (reprint author), Univ Pittsburgh, Dept Crit Care Med, 3471 Fifth Ave,Suite 201, Pittsburgh, PA 15213 USA.; Kline, AE (reprint author), Univ Pittsburgh, Dept Psychol, 3471 Fifth Ave,Suite 201, Pittsburgh, PA 15213 USA. EM klineae@upmc.edu FU NICHD NIH HHS [R01 HD069620]; NINDS NIH HHS [R01 NS060005, R01 NS084967] NR 76 TC 3 Z9 3 U1 6 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD JUN 1 PY 2016 VL 1640 SI SI BP 5 EP 14 DI 10.1016/j.brainres.2015.11.026 PN A PG 10 WC Neurosciences SC Neurosciences & Neurology GA DP4DY UT WOS:000378447600002 PM 26612522 ER PT J AU Ho, JE Enserro, D Brouwers, FP Kizer, JR Shah, SJ Psaty, BM Bartz, TM Santhanakrishnan, R Lee, DS Chan, C Liu, K Blaha, MJ Hillege, HL van der Harst, P van Gilst, WH Kop, WJ Gansevoort, RT Vasan, RS Gardin, JM Levy, D Gottdiener, JS de Boer, RA Larson, MG AF Ho, Jennifer E. Enserro, Danielle Brouwers, Frank P. Kizer, Jorge R. Shah, Sanjiv J. Psaty, Bruce M. Bartz, Traci M. Santhanakrishnan, Rajalakshmi Lee, Douglas S. Chan, Cheeling Liu, Kiang Blaha, Michael J. Hillege, Hans L. van der Harst, Pim van Gilst, Wiek H. Kop, Willem J. Gansevoort, Ron T. Vasan, Ramachandran S. Gardin, Julius M. Levy, Daniel Gottdiener, John S. de Boer, Rudolf A. Larson, Martin G. TI Predicting Heart Failure With Preserved and Reduced Ejection Fraction The International Collaboration on Heart Failure Subtypes SO CIRCULATION-HEART FAILURE LA English DT Article DE diastolic heart failure; phenotype; primary prevention; risk factor; systolic heart failure ID LEFT-VENTRICULAR HYPERTROPHY; COMMUNITY-BASED COHORT; NATRIURETIC PEPTIDE; RISK PREDICTION; CARDIOVASCULAR HEALTH; ATHEROSCLEROSIS RISK; OUTCOMES RESEARCH; EUROPEAN-SOCIETY; LIFETIME RISK; OF-CARDIOLOGY AB Background-Heart failure (HF) is a prevalent and deadly disease, and preventive strategies focused on at-risk individuals are needed. Current HF prediction models have not examined HF subtypes. We sought to develop and validate risk prediction models for HF with preserved and reduced ejection fraction (HFpEF, HFrEF). Methods and Results-Of 28,820 participants from 4 community-based cohorts, 982 developed incident HFpEF and 909 HFrEF during a median follow-up of 12 years. Three cohorts were combined, and a 2: 1 random split was used for derivation and internal validation, with the fourth cohort as external validation. Models accounted for multiple competing risks (death, other HF subtype, and unclassified HF). The HFpEF-specific model included age, sex, systolic blood pressure, body mass index, antihypertensive treatment, and previous myocardial infarction; it had good discrimination in derivation (c-statistic 0.80; 95% confidence interval [CI], 0.78-0.82) and validation samples (internal: 0.79; 95% CI, 0.77-0.82 and external: 0.76; 95% CI: 0.71-0.80). The HFrEF-specific model additionally included smoking, left ventricular hypertrophy, left bundle branch block, and diabetes mellitus; it had good discrimination in derivation (c-statistic 0.82; 95% CI, 0.80-0.84) and validation samples (internal: 0.80; 95% CI, 0.78-0.83 and external: 0.76; 95% CI, 0.71-0.80). Age was more strongly associated with HFpEF, and male sex, left ventricular hypertrophy, bundle branch block, previous myocardial infarction, and smoking with HFrEF (P value for each comparison <= 0.02). Conclusions-We describe and validate risk prediction models for HF subtypes and show good discrimination in a large sample. Some risk factors differed between HFpEF and HFrEF, supporting the notion of pathogenetic differences among HF subtypes. C1 [Ho, Jennifer E.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Santhanakrishnan, Rajalakshmi] Boston Univ, Cardiovasc Med Sect, Dept Med, Sch Med, Boston, MA 02215 USA. [Vasan, Ramachandran S.] Boston Univ, Sect Prevent Med & Epidemiol, Sch Med, Boston, MA 02215 USA. [Ho, Jennifer E.; Vasan, Ramachandran S.; Levy, Daniel; Larson, Martin G.] Natl Heart Lung & Blood Inst & Boston Univ Framin, Boston, MA USA. [Enserro, Danielle; Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Brouwers, Frank P.; Hillege, Hans L.; van der Harst, Pim; van Gilst, Wiek H.; de Boer, Rudolf A.] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9713 AV Groningen, Netherlands. [Gansevoort, Ron T.] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Div Nephrol, NL-9713 AV Groningen, Netherlands. [Kizer, Jorge R.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Shah, Sanjiv J.] Northwestern Univ, Feinberg Sch Med, Div Cardiol, Chicago, IL 60611 USA. [Chan, Cheeling; Liu, Kiang] Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. [Chan, Cheeling; Liu, Kiang] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Bartz, Traci M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Lee, Douglas S.] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Lee, Douglas S.] Univ Toronto, Univ Hlth Network, Toronto, ON M5S 1A1, Canada. [Blaha, Michael J.] Johns Hopkins Univ, Ciccarone Ctr Prevent Heart Dis, Baltimore, MD USA. [Gardin, Julius M.] Hackensack Univ, Med Ctr, Dept Med, Hackensack, NJ USA. [Gardin, Julius M.] Rutgers New Jersey Med Sch, Hackensack, NJ USA. [Kop, Willem J.] Tilburg Univ, Ctr Res Psychol Somat Dis, Dept Med & Clin Psychol, NL-5000 LE Tilburg, Netherlands. [Levy, Daniel] NHLBI, Populat Sci Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Gottdiener, John S.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. RP Ho, JE (reprint author), Massachusetts Gen Hosp, 185 Cambridge St,CPZN 3224, Boston, MA 02114 USA. FU National Heart, Lung, and Blood Institute [N01-HC25195, HHSN268201500001I, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083]; National Center for Research Resources [UL1-TR-000040, UL1-TR-001079]; Canadian Institutes of Health Research; The National Heart, Lung, and Blood Institute [N01HC85086, U01HL080295, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; [K23-HL116780] FX This work was partially supported by the National Heart, Lung, and Blood Institute (Framingham Heart Study, contract N01-HC25195 and HHSN268201500001I; Cardiovascular Health Study, contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grant U01HL080295; and Multi-Ethnic Study of Atherosclerosis contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169) and the National Center for Research Resources (Multi-Ethnic Study of Atherosclerosis UL1-TR-000040 and UL1-TR-001079). The Cardiovascular Health Study received additional contribution from the National Institute of Neurological Disorders and Stroke, and R01AG023629 from the National Institute on Aging. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. Dr Ho is supported by K23-HL116780. Dr Lee is supported by a clinician-scientist award from the Canadian Institutes of Health Research. Dr Ho had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 51 TC 4 Z9 4 U1 0 U2 1 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 JUN PY 2016 VL 9 IS 6 AR UNSP e003116 DI 10.1161/CIRCHEARTFAILURE.115.003116 PG 26 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO9WP UT WOS:000378139000011 ER PT J AU Ma, CX Sanchez, C Gao, F Crowder, R Naughton, M Pluard, T Creekmore, A Guo, ZF Hoog, J Lockhart, AC Doyle, A Erlichman, C Ellis, MJ AF Ma, Cynthia X. Sanchez, Cesar Gao, Feng Crowder, Robert Naughton, Michael Pluard, Timothy Creekmore, Allison Guo, Zhanfang Hoog, Jeremy Lockhart, A. Craig Doyle, Austin Erlichman, Charles Ellis, Matthew J. TI A Phase I Study of the AKT Inhibitor MK-2206 in Combination with Hormonal Therapy in Postmenopausal Women with Estrogen Receptor-Positive Metastatic Breast Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID ADVANCED SOLID TUMORS; SEQUENCING DATA; ANASTROZOLE; PATHWAY; FULVESTRANT; BIOMARKERS; TAMOXIFEN; SURVIVAL; TRIAL AB Purpose: PI3K/AKT pathway activation is an important endocrine resistance mechanism in estrogen receptor-positive (ER+) breast cancer. After promising preclinical modeling of MK-2206, an allosteric pan-AKT inhibitor, with either estrogen deprivation or fulvestrant, we conducted a phase I trial in patients with metastatic ER(+)HER2(+) breast cancer to determine the recommended phase II treatment dose (RPTD) of MK-2206 when combined with either anastrozole, fulvestrant, or anastrozole/fulvestrant. Experimental Design: ER+ breast cancer cell lines were exposed in vitro to MK-2206 plus estrogen deprivation with or without fulvestrant and monitored for apoptosis. A standard 3+3 design was employed to first determine the maximum tolerated dose (MTD) of MK-2206 plus anastrozole based on cycle 1 toxicity. Each cycle was 28 days. The RPTD was determined on the basis of toxicities observed at MTD level during the first 3 cycles. Subsequent patients received MK-2206, at the RPTD determined above, plus fulvestrant or anastrozole/fulvestrant to define RPTD for these additional regimens. Results: MK-2206 induced apoptosis in parental ER+ but not in long-term estrogen-deprived cell lines, for which fulvestrant was required for apoptosis induction. Thirty-one patients enrolled. The RPTD was defined as MK-2206 150 mg orally weekly with prednisone prophylaxis for each combination. Grade 3 rash was dose limiting. 42% (95% CI, 23%-63%) patients derived clinical benefit without progression within 6 months. Response was not associated with tumor PIK3CA mutation. Conclusions: MK-2206 plus endocrine treatments were tolerable. MK-2206 in combination with anastrozole is being further evaluated in a phase II neoadjuvant trial for newly diagnosed ER+ HER2(+) breast cancer. C1 [Ma, Cynthia X.; Sanchez, Cesar; Crowder, Robert; Naughton, Michael; Pluard, Timothy; Creekmore, Allison; Guo, Zhanfang; Hoog, Jeremy; Lockhart, A. Craig] Washington Univ, Sch Med, Dept Internal Med, Div Oncol, St Louis, MO 63110 USA. [Gao, Feng] Washington Univ, Sch Med, Dept Surg, Div Publ Hlth Sci, St Louis, MO 63110 USA. [Doyle, Austin] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Erlichman, Charles] Mayo Clin, Rochester, MN USA. [Ellis, Matthew J.] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA. RP Ma, CX; Ellis, MJ (reprint author), Washington Univ, Sch Med, 660 South Euclid Ave,Campus Box 8076, St Louis, MO 63110 USA. EM cma@dom.wustl.edu; mjellis@bcm.edu FU Siteman Cancer Center Breast Cancer Research Program; Fashion Footwear Association of New York, Mayo PIIC [N01-CM2011-00099]; NCI Cancer Clinical Investigator Team Leadership Award FX This work is funded in part by Siteman Cancer Center Breast Cancer Research Program, Fashion Footwear Association of New York, Mayo PIIC (N01-CM2011-00099), and NCI Cancer Clinical Investigator Team Leadership Award (to C.X. Ma). NR 38 TC 9 Z9 9 U1 4 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 1 PY 2016 VL 22 IS 11 BP 2650 EP 2658 DI 10.1158/1078-0432.CCR-15-2160 PG 9 WC Oncology SC Oncology GA DP2RN UT WOS:000378338200010 PM 26783290 ER PT J AU Yao, Y Ye, HX Qi, ZX Mo, LJ Yue, Q Baral, A Hoon, DSB Vera, JC Heiss, JD Chen, CC Hua, W Zhang, JM Jin, KL Wang, Y Zang, XX Mao, Y Zhou, LF AF Yao, Yu Ye, Hongxing Qi, Zengxin Mo, Lianjie Yue, Qi Baral, Aparajita Hoon, Dave S. B. Vera, Juan Carlos Heiss, John D. Chen, Clark C. Hua, Wei Zhang, Jianmin Jin, Kunlin Wang, Yin Zang, Xingxing Mao, Ying Zhou, Liangfu TI B7-H4(B7x)-Mediated Cross-talk between Glioma-Initiating Cells and Macrophages via the IL6/JAK/STAT3 Pathway Lead to Poor Prognosis in Glioma Patients SO CLINICAL CANCER RESEARCH LA English DT Article ID STEM-LIKE CELLS; B7 FAMILY-MEMBER; B7-H4 EXPRESSION; TUMOR MICROENVIRONMENT; BRAIN-TUMORS; SERUM B7-H4; CANCER; ACTIVATION; CARCINOMA; IMMUNITY AB Purpose: The objective of this study was to evaluate clinical significance and immunosuppressive mechanisms of B7-H4 (B7x/B7S1), a B7 family member, in glioma. Experimental Design: B7-H4 levels in glioma tissue/cerebral spinal fluid (CSF) were compared between different grades of glioma patients. Survival data were analyzed with Kaplan-Meier to determine the prognostic value of B7-H4. Cytokines from CD133(+) cells to stimulate the expression of B7-H4 on human macrophages (M Phi s) were investigated by FACS, neutralizing antibodies, and Transwell chemotaxis assay. shRNA, reporter vector, and chromatin immunoprecipitation were used to determine the binding of STAT3 to the B7-H4 promoter. The function of B7-H4(+) M Phi s in vitro was evaluated through phagocytosis, T-cell proliferation/apoptosis, and cytokine production as well as in the xenografted model for in vivo analysis. Results: We found that B7-H4 expression in tumors was associated with prognosis of human glioblastoma and correlated directly with malignant grades. Mechanistically, glioma initiating CD133(+) cells and M Phi s/microglia cointeraction activated expression of B7-H4 via IL6 and IL10 in both tumor cells and microenvironment supporting cells. IL6-activated STAT3 bound to the promoter of B7-H4 gene and enhanced B7-H4 expression. Furthermore, CD133(+) cells mediated immunosuppression through B7-H4 expression on M Phi s/microglia by silencing of B7-H4 expression on these cells, which led to increased microenvironment T-cell function and tumor regression in the xenograft glioma mouse model. Conclusions: We have identified B7-H4 activation on M Phi s/microglia in the microenvironment of gliomas as an important immunosuppressive event blocking effective T-cell immune responses. (C) 2016 AACR. C1 [Yao, Yu; Hua, Wei; Mao, Ying; Zhou, Liangfu] Fudan Univ, Dept Neurosurg, Huashan Hosp, Shanghai 200040, Peoples R China. [Yao, Yu; Hua, Wei; Mao, Ying; Zhou, Liangfu] Fudan Univ, Shanghai Med Coll, Dept Neurosurg, Shanghai 200040, Peoples R China. [Ye, Hongxing] Zhejiang Univ, Sch Med, Affiliated Hosp 1, Dept Neurosurg, Hangzhou 310003, Zhejiang, Peoples R China. [Qi, Zengxin; Yue, Qi] Fudan Univ, Shanghai Med Coll, Shanghai 200040, Peoples R China. [Mo, Lianjie] Zhejiang Univ, Sch Med, Dept Neurosurg, Sir Run Shaw Hosp, Hangzhou 310003, Zhejiang, Peoples R China. [Baral, Aparajita] Wuhan Univ, Zhongnan Hosp, Dept Neurosurg, Wuhan 430072, Hubei, Peoples R China. [Hoon, Dave S. B.] John Wayne Canc Inst, Dept Mol Oncol, Santa Monica, CA USA. [Vera, Juan Carlos; Heiss, John D.] NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Chen, Clark C.] Univ Calif San Diego, Ctr Theoret & Appl Oncol, San Diego, CA 92103 USA. [Zhang, Jianmin] Zhejiang Univ, Sch Med, Hangzhou 310003, Zhejiang, Peoples R China. [Jin, Kunlin] Univ N Texas, Hlth Sci Ctr, Dept Pharmacol, Ft Worth, TX USA. [Wang, Yin] Fudan Univ, Huashan Hosp, Dept Neuropathol, Shanghai 200040, Peoples R China. [Zang, Xingxing] Albert Einstein Coll Med, Dept Microbiol & Immunol, New York, NY USA. [Mao, Ying] Fudan Univ, Sch Basic Med Sci, State Key Lab Med Neurobiol, Shanghai 200040, Peoples R China. [Mao, Ying] Fudan Univ, Inst Brain Sci, Shanghai 200040, Peoples R China. RP Mao, Y (reprint author), Fudan Univ, Huashan Hosp, 12 Wulumuqi Middle Rd, Shanghai 200040, Peoples R China.; Zang, XX (reprint author), Albert Einstein Coll Med, New York, NY USA. EM xing-xing.zang@einstein.yu.edu; maoying@fudan.edu.cn OI Heiss, John/0000-0002-3890-0165 FU National Science Foundation for Distinguished Young Scholars of China [81025013]; National Natural Science Foundation of China [81372708, 81272797]; "Dawn Tracking" Program of Shanghai Education Commission, and China grant [10GG01]; Project for Science and Technology Commission of Shanghai Municipality grant [13JC1408000]; innovation Program of Shanghai Municipal Education Commission [13ZZ010]; Project for National 985 Engineering of China [985-YFX0102] FX This work was supported by the National Science Foundation for Distinguished Young Scholars of China (grant no. 81025013; to Y. Mao), the National Natural Science Foundation of China (grant no. 81372708 and 81272797; to Y. Yao), the Project for National 985 Engineering of China (No. 985-YFX0102; to Y. Mao), the "Dawn Tracking" Program of Shanghai Education Commission, and China grant 10GG01 (to Y. Mao), the Project for Science and Technology Commission of Shanghai Municipality grant 13JC1408000 (to L. Zhou), innovation Program of Shanghai Municipal Education Commission (grant no. 13ZZ010; to Y. Yao). NR 39 TC 2 Z9 2 U1 7 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 1 PY 2016 VL 22 IS 11 BP 2778 EP 2790 DI 10.1158/1078-0432.CCR-15-0858 PG 13 WC Oncology SC Oncology GA DP2RN UT WOS:000378338200022 PM 27001312 ER PT J AU Krupovic, M Koonin, EV AF Krupovic, Mart Koonin, Eugene V. TI Self-synthesizing transposons: unexpected key players in the evolution of viruses and defense systems SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID STRANDED-DNA VIRUSES; CRISPR-CAS SYSTEMS; ADAPTIVE IMMUNITY; GIANT VIRUSES; COMPUTATIONAL ANALYSIS; SPACER ACQUISITION; GENETIC ELEMENTS; GENOME SIZE; VIROPHAGE; EUKARYOTES AB Self-synthesizing transposons are the largest known transposable elements that encode their own DNA polymerases (DNAP). The Polinton/Maverick family of self-synthesizing transposons is widespread in eukaryotes and abundant in the genomes of some protists. In addition to the DNAP and a retrovirus-like integrase, most of the polintons encode homologs of the major and minor jelly-roll capsid proteins, DNA-packaging ATPase and capsid maturation protease. Therefore, polintons are predicted to alternate between the transposon and viral lifestyles although virion formation remains to be demonstrated. Polintons are related to a group of eukaryotic viruses known as virophages that parasitize on giant viruses of the family Mimiviridae and another recently identified putative family of polinton-like viruses (PLV) predicted to lead a similar, dual life style. Comparative genomic analysis of polintons, virophages, PLV and the other viruses with double-stranded (ds)DNA genomes infecting eukaryotes and prokaryotes suggests that the polintons evolved from bacterial tectiviruses and could have been the ancestors of a broad range of eukaryotic viruses including adenoviruses and members of the proposed order `Megavirales' as well as linear cytoplasmic plasmids. Recently, a group of predicted self-synthesizing transposons was discovered also in prokaryotes. These elements, denoted casposons, encode a DNAP and a homolog of the CRISPR-associated Cast endonuclease that has an integrase activity but no capsid proteins. Thus, unlike polintons, casposons appear to be limited to the transposon life style although they could have evolved from viruses. The casposons are thought to have played a pivotal role in the origin of the prokaryotic adaptive immunity, giving rise to the adaptation module of the CRISPR-Cas systems. C1 [Krupovic, Mart] Inst Pasteur, Dept Microbiol, Unite Biol Mol Gene Chez Extremophiles, Paris, France. [Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Krupovic, M (reprint author), Inst Pasteur, Dept Microbiol, Unite Biol Mol Gene Chez Extremophiles, Paris, France.; Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM krupovic@pasteur.fr; koonin@ncbi.nlm.nih.gov RI Krupovic, Mart/I-4209-2012 OI Krupovic, Mart/0000-0001-5486-0098 FU US Department of Health and Human Services FX EVK was supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). NR 63 TC 6 Z9 6 U1 10 U2 21 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 EI 1879-0364 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD JUN PY 2016 VL 31 BP 25 EP 33 DI 10.1016/j.mib.2016.01.006 PG 9 WC Microbiology SC Microbiology GA DP4GK UT WOS:000378454200006 PM 26836982 ER PT J AU Chou, WYS Moskowitz, M AF Chou, Wen-ying Sylvia Moskowitz, Michal TI Social media use in adolescent and young adult (AYA) cancer survivors SO CURRENT OPINION IN PSYCHOLOGY LA English DT Review ID NATIONAL TRENDS SURVEY; ONLINE SUPPORT; INTERVENTION; NARRATIVES; FACEBOOK; OUTCOMES; NEEDS; CARE AB Cancer remains the leading cause of disease-related death in the Adolescent and Young Adult (AYA) population. AYA cancer survivors face unique challenges, particularly social-psychological impacts in identity development, coping, distress, and social relationships. Given the high prevalence of Internet use and social media engagement, AYA survivors and clinicians and organizations charged with their care are increasingly turning to social media and other technology-mediated platforms. While there has been limited empirical evidence on the utility of social media in addressing AYA survivors' needs, the last 5-6 years have experienced a growth in online, technology-mediated advocacy, and patient organizations and related publications. This review highlights key research and practical efforts, their impacts to date, and discusses future directions. C1 [Chou, Wen-ying Sylvia; Moskowitz, Michal] NCI, Hlth Commun & Informat Res Branch, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,3E614, Rockville, MD 20892 USA. RP Chou, WYS (reprint author), NCI, Hlth Commun & Informat Res Branch, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,3E614, Rockville, MD 20892 USA. EM chouws@mail.nih.gov NR 32 TC 1 Z9 1 U1 5 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-250X J9 CURR OPIN PSYCHOL JI Curr. Opin. Psychol. PD JUN PY 2016 VL 9 BP 88 EP 91 DI 10.1016/j.copsyc.2016.01.003 PG 4 WC Psychology, Multidisciplinary SC Psychology GA DP0WT UT WOS:000378212300017 ER PT J AU Green, DS Nunes, AT Annunziata, CM Zoon, KC AF Green, Daniel S. Nunes, Ana T. Annunziata, Christina M. Zoon, Kathryn C. TI Monocyte and interferon based therapy for the treatment of ovarian cancer SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Article; Proceedings Paper CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc DE Monocyte; Interferon alpha; Interferon gamma; Ovarian cancer; Immunotherapy ID TUMOR-INFILTRATING LYMPHOCYTES; RECOMBINANT GAMMA-INTERFERON; PROTEIN-KINASE PKR; ADOPTIVE IMMUNOTHERAPY; PHASE-I; CELL-PROLIFERATION; IFN-GAMMA; PERITONEAL CARCINOMATOSIS; ANTITUMOR-ACTIVITY; BLOOD MONOCYTES AB Cytokines and cells of the innate immune system have been shown to be critical regulators in the elimination, equilibrium and escape of malignant cells. Despite in vitro and in vivo evidence, components of the innate immune system have shown limited efficacy in the treatment of ovarian cancer. Intraperitoneal immunotherapies are a promising field that has not yet been fully explored in ovarian cancer. Cytokine immunotherapy using interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma) has predominantly been used intraperitoneally in ovarian cancer, with promising results. Early studies also showed that autologous monocytes infused into the peritoneum have anti-tumor properties. Combination therapies have been shown to be more effective in treating cancer than mono-therapies. Based on these observations the combination of cell therapy with cytokine therapy may provide a unique strategy for the treatment of chemotherapy resistant solid cancers. Published by Elsevier Ltd. C1 [Green, Daniel S.; Zoon, Kathryn C.] NIAID, Cytokine Biol Sect, NIH, 50 South Dr,RM 5515, Bethesda, MD 20892 USA. [Nunes, Ana T.] NCI, Med Oncol Branch, 10 Ctr DR,RM 12N226, Bethesda, MD 20814 USA. [Annunziata, Christina M.] NCI, Womens Malignancy Branch, NIH, Translat Genom Sect, 10 Ctr DR RM 3B43A, Bethesda, MD 20892 USA. RP Green, DS (reprint author), NIAID, Cytokine Biol Sect, NIH, 50 South Dr,RM 5515, Bethesda, MD 20892 USA. EM Daniel.green2@nih.gov; ana.nunes@nih.gov; ca180n@nih.gov; kz15m@nih.gov RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 FU Intramural NIH HHS [Z99 AI999999] NR 87 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 EI 1879-0305 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD JUN PY 2016 VL 29 SI SI BP 109 EP 115 DI 10.1016/j.cytogfr.2016.02.006 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DP4FS UT WOS:000378452300013 PM 27026228 ER PT J AU Maurer, JM Steele, VR Cope, LM Vincent, GM Stephen, JM Calhoun, VD Kiehl, KA AF Maurer, J. Michael Steele, Vaughn R. Cope, Lora M. Vincent, Gina M. Stephen, Julia M. Calhoun, Vince D. Kiehl, Kent A. TI Dysfunctional error-related processing in incarcerated youth with elevated psychopathic traits SO DEVELOPMENTAL COGNITIVE NEUROSCIENCE LA English DT Article DE Juvenile delinquency; Psychopathy; Event-related potentials; Principal component analysis; Error-related processing ID CALLOUS-UNEMOTIONAL TRAITS; BEHAVIORAL-INHIBITION; BONFERRONI PROCEDURE; ANTERIOR CINGULATE; CONDUCT PROBLEMS; MULTIPLE TESTS; BRAIN ACTIVITY; GRAY-MATTER; ADOLESCENTS; OFFENDERS AB Adult psychopathic offenders show an increased propensity towards violence, impulsivity, and recidivism. A subsample of youth with elevated psychopathic traits represent a particularly severe subgroup characterized by extreme behavioral problems and comparable neurocognitive deficits as their adult counterparts, including perseveration deficits. Here, we investigate response-locked event-related potential (ERP) components (the error-related negativity [ERN/Ne] related to early error-monitoring processing and the error-related positivity [Pe] involved in later error-related processing) in a sample of incarcerated juvenile male offenders (n = 100) who performed a response inhibition Go/NoGo task. Psychopathic traits were assessed using the Hare Psychopathy Checklist: Youth Version (PCL:YV). The ERN/Ne and Pe were analyzed with classic windowed ERP components and principal component analysis (PCA). Using linear regression analyses, PCL:YV scores were unrelated to the ERN/Ne, but were negatively related to Pe mean amplitude. Specifically, the PCL:YV Facet 4 subscale reflecting antisocial traits emerged as a significant predictor of reduced amplitude of a subcomponent underlying the Pe identified with PCA. This is the first evidence to suggest a negative relationship between adolescent psychopathy scores and Pe mean amplitude. (C) 2016 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license. C1 [Maurer, J. Michael; Steele, Vaughn R.; Stephen, Julia M.; Calhoun, Vince D.; Kiehl, Kent A.] LBERI, Mind Res Network, Albuquerque, NM USA. [Maurer, J. Michael; Steele, Vaughn R.; Kiehl, Kent A.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. [Steele, Vaughn R.] NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH, Baltimore, MD USA. [Cope, Lora M.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Cope, Lora M.] Univ Michigan, Addict Res Ctr, Ann Arbor, MI 48109 USA. [Vincent, Gina M.] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01655 USA. [Calhoun, Vince D.] Univ New Mexico, Dept Elect Engn, Albuquerque, NM 87131 USA. RP Maurer, JM; Kiehl, KA (reprint author), Mind Res Network, 1101 Yale Blvd NE, Albuquerque, NM 87106 USA. EM jmmaurer@unm.edu; kkiehl@unm.edu OI Stephen, Julia/0000-0003-2486-747X FU NICHD NIH HHS [R01 HD082257]; NIDA NIH HHS [K01 DA026502]; NIMH NIH HHS [R01 MH071896] NR 75 TC 0 Z9 0 U1 4 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1878-9293 EI 1878-9307 J9 DEV COGN NEUROS-NETH JI Dev. Cogn. Neurosci. PD JUN PY 2016 VL 19 BP 70 EP 77 DI 10.1016/j.dcn.2016.02.006 PG 8 WC Neurosciences SC Neurosciences & Neurology GA DO8KK UT WOS:000378032000007 PM 26930170 ER PT J AU Cachia, A Borst, G Tissier, C Fisher, C Plaze, M Gay, O Riviere, D Gogtay, N Giedd, J Mangin, JF Houde, O Raznahan, A AF Cachia, A. Borst, G. Tissier, C. Fisher, C. Plaze, M. Gay, O. Riviere, D. Gogtay, N. Giedd, J. Mangin, J. -F. Houde, O. Raznahan, A. TI Longitudinal stability of the folding pattern of the anterior cingulate cortex during development SO DEVELOPMENTAL COGNITIVE NEUROSCIENCE LA English DT Article DE ACC; Fetal life; Sulcal pattern; Neurodevelopment; MRI; Executive control ID CEREBRAL-CORTEX; INDIVIDUAL-DIFFERENCES; BRAIN-DEVELOPMENT; CORTICAL SURFACE; EXECUTIVE FUNCTIONS; STRUCTURAL BASIS; SEX-DIFFERENCES; MRI; MORPHOLOGY; ASYMMETRY AB Prenatal processes are likely critical for the differences in cognitive ability and disease risk that unfold in postnatal life. Prenatally established cortical folding patterns are increasingly studied as an adult proxy for earlier development events - under the as yet untested assumption that an individual's folding pattern is developmentally fixed. Here, we provide the first empirical test of this stability assumption using 263 longitudinally-acquired structural MRI brain scans from 75 typically developing individuals spanning ages 7 to 32 years. We focus on the anterior cingulate cortex (ACC) - an intensely studied cortical region that presents two qualitatively distinct and reliably classifiable sulcal patterns with links to postnatal behavior. We show - without exception-that individual ACC sulcal patterns are fixed from childhood to adulthood, at the same time that quantitative anatomical ACC metrics are undergoing profound developmental change. Our findings buttress use of folding typology as a postnatally-stable marker for linking variations in early brain development to later neurocognitive outcomes in ex utero life. (C) 2016 The Authors. Published by Elsevier Ltd. C1 [Cachia, A.; Borst, G.; Tissier, C.; Houde, O.] CNRS, UMR 8240, Lab Psychol Child Dev & Educ, Paris, France. [Cachia, A.; Borst, G.; Tissier, C.; Houde, O.] Univ Paris 05, Sorbonne Paris Cite, Paris, France. [Cachia, A.; Tissier, C.; Plaze, M.; Gay, O.] INSERM, UMR 894, Ctr Psychiat & Neurosci, Paris, France. [Cachia, A.; Houde, O.] Inst Univ France, Paris, France. [Fisher, C.; Mangin, J. -F.] CATI Multictr Neuroimaging Plaform, Paris, France. [Fisher, C.; Riviere, D.; Mangin, J. -F.] CEA, UNATI, Neurospin, Gif Sur Yvette, France. [Gogtay, N.; Giedd, J.; Raznahan, A.] NIMH, Bethesda, MD 20892 USA. [Gogtay, N.; Giedd, J.; Raznahan, A.] NIH, Intramural Res Program, Bldg 10, Bethesda, MD 20892 USA. RP Cachia, A (reprint author), CNRS, UMR 8240 Sorbonne, Lab Psychol Child Dev & Educ, 46 Rue St Jacques, F-75005 Paris, France. EM arnaud.cachia@parisdescartes.fr FU Intramural NIH HHS [Z99 MH999999] NR 57 TC 2 Z9 2 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1878-9293 EI 1878-9307 J9 DEV COGN NEUROS-NETH JI Dev. Cogn. Neurosci. PD JUN PY 2016 VL 19 BP 122 EP 127 DI 10.1016/j.dcn.2016.02.001 PG 6 WC Neurosciences SC Neurosciences & Neurology GA DO8KK UT WOS:000378032000013 PM 26974743 ER PT J AU Adleman, NE Chen, G Reynolds, RC Frackman, A Razdan, V Weissman, DH Pine, DS Leibenluft, E AF Adleman, Nancy E. Chen, Gang Reynolds, Richard C. Frackman, Anna Razdan, Varun Weissman, Daniel H. Pine, Daniel S. Leibenluft, Ellen TI Age-related differences in the neural correlates of trial-to-trial variations of reaction time SO DEVELOPMENTAL COGNITIVE NEUROSCIENCE LA English DT Article DE Reaction time; Variation; fMRI; Development; RT BOLD ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; INCREASED INTRASUBJECT VARIABILITY; GENERALIZED ANXIETY DISORDER; NORMAL BRAIN-DEVELOPMENT; RESPONSE-TIME; LIFE-SPAN; PREFRONTAL CORTEX; INTRAINDIVIDUAL VARIABILITY; SELECTIVE ATTENTION; COGNITIVE-PROCESSES AB Intra-subject variation in reaction time (ISVRT) is a developmentally-important phenomenon that decreases from childhood through young adulthood in parallel with the development of executive functions and networks. Prior work has shown a significant association between trial-by-trial variations in reaction time (RT) and trial-by-trial variations in brain activity as measured by the blood-oxygenated level-dependent (BOLD) response in functional magnetic resonance imaging (fMRI) studies. It remains unclear, however, whether such "RT-BOLD" relationships vary with age. Here, we determined whether such trial-by-trial relationships vary with age in a cross-sectional design. We observed an association between age and RT-BOLD relationships in 11 clusters located in visual/occipital regions, frontal and parietal association cortex, precentral/postcentral gyrus, and thalamus. Some of these relationships were negative, reflecting increased BOLD associated with decreased RT, manifesting around the time of stimulus presentation and positive several seconds later. Critically for present purposes, all RT-BOLD relationships increased with age. Thus, RT-BOLD relationships may reflect robust, measurable changes in the brain-behavior relationship across development. (C) 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license. C1 [Adleman, Nancy E.] Catholic Univ Amer, Dept Psychol, 303 Boyle Hall,620 Michigan Ave,NE, Washington, DC 20064 USA. [Adleman, Nancy E.; Frackman, Anna; Razdan, Varun; Pine, Daniel S.; Leibenluft, Ellen] NIMH, Emot & Dev Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Chen, Gang; Reynolds, Richard C.] NIMH, Sci & Stat Comp Core, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Weissman, Daniel H.] Univ Michigan, Dept Psychol, 530 Church St, Ann Arbor, MI 48109 USA. [Frackman, Anna] Harvard Univ, Sch Med, 25 Shattuck St, Boston, MA 02115 USA. [Razdan, Varun] Virginia Tech, Caril Sch Med, 2 Riverside Cir, Roanoke, VA 24016 USA. RP Adleman, NE (reprint author), Catholic Univ Amer, Dept Psychol, 303 Boyle Hall,620 Michigan Ave,NE, Washington, DC 20064 USA. EM adleman@cua.edu; gangchen@mail.nih.gov; reynoldr@mail.nih.gov; Frackman@hms.harvard.edu; vrazdan@carilionclinic.org; danweiss@umich.edu; pined@mail.nih.gov; leibs@mail.nih.gov FU Intramural Program of the National Institute of Mental Health (NIMH); National Institutes of Health (NIH) FX This research was supported by the Intramural Program of the National Institute of Mental Health (NIMH), National Institutes of Health (NIH). The authors gratefully acknowledge the work of the staff of the Section on Bipolar Spectrum Disorders and the NIH functional magnetic resonance imaging facility. Most importantly, they thank the children and families who participated in this research and made it possible. NR 66 TC 0 Z9 0 U1 7 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1878-9293 EI 1878-9307 J9 DEV COGN NEUROS-NETH JI Dev. Cogn. Neurosci. PD JUN PY 2016 VL 19 BP 248 EP 257 DI 10.1016/j.dcn.2016.05.001 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DO8KK UT WOS:000378032000025 PM 27239972 ER PT J AU Dias, JP Schrack, JA Shardell, MD Egan, JM Studenski, S AF Dias, Jenny Pena Schrack, Jennifer A. Shardell, Michelle D. Egan, Josephine M. Studenski, Stephanie TI Association of abdominal fat with serum amylase in an older cohort: The Baltimore Longitudinal Study of Aging SO DIABETES RESEARCH AND CLINICAL PRACTICE LA English DT Article DE Abdominal visceral/subcutaneous fat; Aging; Diabetes; Serum amylase ID INSULIN-RESISTANCE; ADIPOSE-TISSUE; METABOLIC SYNDROME; SEX-HORMONES; OBESITY; NUMBER; ACIDS; GENE AB Aims: Abdominal fat is a major determinant of metabolic diseases in older individuals. Obesity and diabetes are associated with low serum amylase (SA) levels, but the association between SA and metabolic disease is poorly understood. We investigated the association of low SA with diabetes and sex-specific associations of serum amylase with abdominal fat in older adults. Methods: In community-dwelling volunteers from the Baltimore Longitudinal Study of Aging (778 participants, age 66.8 +/- 13.6 years), we assessed abdominal fat by computed tomography and diabetes status using the American Diabetes Association criteria. Linear regression analyses assessed the cross-sectional associations between abdominal fat and SA, and logistic regression assessed the odds of diabetes, given low SA. Results: In unadjusted analyses, individuals in the lowest SA quartile (<48 mu/L) had 1.97 greater odds of diabetes, (95% CI, 1.01-3.83) than those in the highest quartile (>= 80 mu/L). This association was no longer significant after adjusting for visceral adipose tissue area (VAT, dm(2)), abdominal subcutaneous adipose tissue (SAT, dm(2)) or BMI. In adjusted analyses, VAT and SATwere significantly associated with SA in both sexes. Among women, SA was more strongly associated with VAT than with SAT or BMI; VAT (beta = -0.117 +/- 0.048, P < 0.001), SAT (beta = -0.023 +/- 0.025, P = 0.346) and BMI (beta = -0.0052 +/- 0.075, P = 0.49). Conclusions: The association between SA and diabetes was explained mainly by abdominal visceral fat. In women, SA was more strongly associated with VAT than with BMI or SAT. These findings provide motivation for future mechanistic studies on SA's role in metabolic diseases. Published by Elsevier Ireland Ltd. C1 [Dias, Jenny Pena; Egan, Josephine M.] NIA, Lab Clin Investigat, Baltimore, MD 21225 USA. [Shardell, Michelle D.; Studenski, Stephanie] NIA, Translat Gerontol Branch, Baltimore, MD 21225 USA. [Schrack, Jennifer A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21225 USA. RP Dias, JP (reprint author), NIA, Lab Clin Investigat, Baltimore, MD 21225 USA. EM diasjp@mail.nih.gov FU Intramural Research Program of the National Institute of Health (NIH); National Institute on Aging (NIA), United States FX This research was supported by the Intramural Research Program of the National Institute of Health (NIH), National Institute on Aging (NIA), United States. NR 28 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0168-8227 EI 1872-8227 J9 DIABETES RES CLIN PR JI Diabetes Res. Clin. Pract. PD JUN PY 2016 VL 116 BP 212 EP 217 DI 10.1016/j.diabres.2016.04.015 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DO8ZF UT WOS:000378073400030 PM 27321338 ER PT J AU Gitelman, SE Gottlieb, PA Felner, EI Willi, SM Fisher, LK Moran, A Gottschalk, M Moore, WV Pinckney, A Keyes-Elstein, L Harris, KM Kanaparthi, S Phippard, D Ding, LN Bluestone, JA Ehlers, MR AF Gitelman, Stephen E. Gottlieb, Peter A. Felner, Eric I. Willi, Steven M. Fisher, Lynda K. Moran, Antoinette Gottschalk, Michael Moore, Wayne V. Pinckney, Ashley Keyes-Elstein, Lynette Harris, Kristina M. Kanaparthi, Sai Phippard, Deborah Ding, Linna Bluestone, Jeffrey A. Ehlers, Mario R. CA ITN START Study Team TI Antithymocyte globulin therapy for patients with recent-onset type 1 diabetes: 2 year results of a randomised trial SO DIABETOLOGIA LA English DT Article DE ATG; Beta cells; C-peptide; START trial; Tcells; Thymoglobulin; Tregs; Type 1 diabetes ID STEM-CELL TRANSPLANTATION; C-PEPTIDE; INDEPENDENCE; TEPLIZUMAB; MELLITUS AB Aims/hypothesis Type 1 diabetes results from T cell mediated destruction of beta cells. We conducted a trial of antithymocyte globulin (ATG) in new-onset type 1 diabetes (the Study of Thymoglobulin to ARrest T1D [START] trial). Our goal was to evaluate the longer-term safety and efficacy of ATG in preserving islet function at 2 years. Methods A multicentre, randomised, double-blind, placebo-controlled trial of 6.5 mg/kg ATG (Thymoglobulin) vs placebo in patients with new-onset type 1 diabetes was conducted at seven university medical centres and one Children's Hospital in the USA. The site-stratified randomisation scheme was computer generated at the data coordinating centre using permuted-blocks of size 3 or 6. Eligible participants were between the ages of 12 and 35, and enrolled within 100 days from diagnosis. Subjects were randomised to 6.5 mg/kg ATG ( thymoglobulin) vs placebo in a 2: 1 ratio. Participants were blinded, and the study design included two sequential patient-care teams: an unblinded study-drug administration team ( for the first 8 weeks), and a blinded diabetes management team ( for the remainder of the study). Endpoints assessed at 24 months included meal-stimulated C-peptide AUC, safety and immunological responses. Results Fifty-eight patients were enrolled; at 2 years, 35 assigned to ATG and 16 to placebo completed the study. The pre-specified endpoints were not met. In post hoc analyses, older patients (age 22-35 years) in the ATG group had significantly greater C-peptide AUCs at 24 months than placebo patients. Using complete preservation of baseline C-peptide at 24 months as threshold, nine of 35 ATG-treated participants (vs 2/16 placebo participants) were classified as responders; nine of 11 responders (67%) were older. All participants reported at least one adverse event (AE), with 1,148 events in the 38 ATG participants vs 415 in the 20 placebo participants; a comparable number of infections were noted in the ATG and placebo groups, with no opportunistic infections nor difficulty clearing infections in either group. Circulating T cell subsets depleted by ATG partially reconstituted, but regulatory, naive and central memory subsets remained significantly depleted at 24 months. Beta cell autoantibodies did not change over the 24 months in the ATG-treated or placebo participants. At 12 months, ATG-treated participants had similar humoral immune responses to tetanus and HepA vaccines as placebo-treated participants, and no increased infections. Conclusions/interpretation A brief course of ATG substantially depleted T cell subsets, including regulatory cells, but did not preserve islet function 24 months later in the majority of patients with new-onset type 1 diabetes. ATG preserved C-peptide secretion in older participants, which may warrant further study. C1 [Gitelman, Stephen E.] Univ Calif San Francisco, Div Pediat Endocrinol, Mission Hall,550 16th St,4th Floor,Box 0434, San Francisco, CA 94158 USA. [Gitelman, Stephen E.; Bluestone, Jeffrey A.] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA USA. [Gottlieb, Peter A.] Univ Colorado, Barbara Davis Ctr, Aurora, CO USA. [Felner, Eric I.] Emory Univ, Sch Med, Div Pediat Endocrinol, Atlanta, GA 30322 USA. [Willi, Steven M.] Childrens Hosp Philadelphia, Div Endocrinol & Diabet, Philadelphia, PA 19104 USA. [Willi, Steven M.] Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Fisher, Lynda K.] Childrens Hosp Los Angeles, Dept Endocrinol & Metab, Los Angeles, CA 90027 USA. [Moran, Antoinette] Univ Minnesota, Dept Pediat, Div Pediat Endocrinol, Minneapolis, MN 55455 USA. [Gottschalk, Michael] Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA. [Moore, Wayne V.] Childrens Mercy Hosp, Dept Pediat, Div Pediat Endocrinol, Kansas City, MO 64108 USA. [Moore, Wayne V.] Univ Missouri, Kansas City, MO 64110 USA. [Pinckney, Ashley; Keyes-Elstein, Lynette] Rho Fed Syst Div, Chapel Hill, NC USA. [Harris, Kristina M.; Kanaparthi, Sai; Phippard, Deborah] Immune Tolerance Network, Bethesda, MD USA. [Phippard, Deborah] Precis Med, Bethesda, MD USA. [Ding, Linna] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ehlers, Mario R.] Immune Tolerance Network, San Francisco, CA USA. RP Gitelman, SE (reprint author), Univ Calif San Francisco, Div Pediat Endocrinol, Mission Hall,550 16th St,4th Floor,Box 0434, San Francisco, CA 94158 USA.; Gitelman, SE (reprint author), Univ Calif San Francisco, Ctr Diabet, San Francisco, CA USA. EM sgitelma@ucsf.edu FU National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) [NO1-AI-15416, UM1AI109565]; NIAID; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); JDRF; multiple Clinical & Translational Awards grant (NIH/NCRR UCSF-CTSI) [UL1TR000004]; multiple Clinical & Translational Awards grant (Minnesota) [UL1TR000114]; multiple Clinical & Translational Awards grant (CHOP-NCRR) [UL1RR024134]; multiple Clinical & Translational Awards grant (CHOP-NCATS) [UL1TR000003]; multiple Clinical & Translational Awards grant (U. Colorado-CTSI) [UL1TR001082]; multiple Clinical & Translational Awards grant (UCSD) [N01-AI-15416]; multiple Clinical & Translational Awards grant (Emory) [UL1TR000454]; multiple Clinical & Translational Awards grant (CMH) [N01-AI-15416] FX Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under award numbers NO1-AI-15416 and UM1AI109565. The trial was conducted by the Immune Tolerance Network (ITN) and sponsored by the NIAID. Additional funding was provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the JDRF, and multiple Clinical & Translational Awards grants (NIH/NCRR UCSF-CTSI UL1TR000004, Minnesota-UL1TR000114, CHOP-NCRR UL1RR024134, CHOP-NCATS UL1TR000003, U. Colorado-CTSI UL1TR001082, UCSD N01-AI-15416, Emory-UL1TR000454 and CMH N01-AI-15416). Genzyme (Cambridge, MA, USA) provided ATG (Thymoglobulin (R)) and LifeScan, Inc. (Milpitas, CA, USA) provided blood glucose monitoring meters and test strips. NR 22 TC 3 Z9 3 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD JUN PY 2016 VL 59 IS 6 BP 1153 EP 1161 DI 10.1007/s00125-016-3917-4 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DO8QN UT WOS:000378048500012 PM 27053235 ER PT J AU Lewis, KL Hooker, GW Connors, PD Hyams, TC Wright, MF Caldwell, S Biesecker, LG Biesecker, BB AF Lewis, Katie L. Hooker, Gillian W. Connors, Philip D. Hyams, Travis C. Wright, Martha F. Caldwell, Samantha Biesecker, Leslie G. Biesecker, Barbara B. TI Participant use and communication of findings from exome sequencing: a mixed-methods study SO GENETICS IN MEDICINE LA English DT Article DE experiences; genome; outcomes; sequencing; utility ID INCIDENTAL FINDINGS; CLINICAL-RESEARCH; GENOMIC MEDICINE; GENETIC RISK; RECOMMENDATIONS; CANCER; RETURN; PREFERENCES; VARIANTS; DISEASE AB Purpose: This study investigated how genome sequencing results affect health behaviors, affect, and communication. Methods: We report on 29 participants who received a sequence result in the ClinSeq study, a cohort of well-educated, postreproductive volunteers. A mixed-methods design was used to explore respondents' use, communication, and perceived utility of results. Results: Most participants (72%) shared their result with at least one health-care provider, and 31% reported subsequent changes in the health care they received. Participants scored high on the Positive Experiences subscale and low on the Distress subscale of a modified version of the Multidimensional Impact of Cancer Risk Assessment. The majority (93%) shared their result with at least one family member. Participants described deriving personal utility from their results. Conclusion: This article is the first to describe research participants' reactions to actionable sequencing results. Our findings suggest clinical and personal benefit from receiving sequencing results, both of which may contribute to improved health for the recipients. Given the participants' largely positive or neutral affective responses and disclosure of their results to physicians and relatives, health-care providers should redirect concern from the potential for distress and attend to motivating patients to follow their medical recommendations. C1 [Lewis, Katie L.; Hyams, Travis C.; Wright, Martha F.; Biesecker, Leslie G.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. [Hooker, Gillian W.; Connors, Philip D.; Caldwell, Samantha; Biesecker, Barbara B.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Hooker, Gillian W.] NextGxDx, Franklin, TN USA. [Connors, Philip D.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Hyams, Travis C.] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Wright, Martha F.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Caldwell, Samantha] Univ N Carolina, Greensboro, NC 27412 USA. RP Lewis, KL (reprint author), NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. EM lewiskatie@mail.nih.gov FU Intramural Research Program of. the National Human Genome Research Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of. the National Human Genome Research Institute, National Institutes of Health. The authors thank Flavia Facio for her input on preliminary drafts of the interview guide, Taylor Montminy for her help recruiting participants, and the ClinSeq participants for their time and participation. NR 30 TC 5 Z9 5 U1 4 U2 7 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 JUN PY 2016 VL 18 IS 6 BP 577 EP 583 DI 10.1038/gim.2015.133 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA DP0MQ UT WOS:000378184300006 PM 26540156 ER PT J AU Bone, WP Washington, NL Buske, OJ Adams, DR Davis, J Draper, D Flynn, ED Girdea, M Godfrey, R Golas, G Groden, C Jacobsen, J Kohler, S Lee, EMJ Links, AE Markello, TC Mungall, CJ Nehrebecky, M Robinson, PN Sincan, M Soldatos, AG Tifft, CJ Toro, C Trang, H Valkanas, E Vasilevsky, N Wahl, C Wolfe, LA Boerkoel, CF Brudno, M Haendel, MA Gahl, WA Smedley, D AF Bone, William P. Washington, Nicole L. Buske, Orion J. Adams, David R. Davis, Joie Draper, David Flynn, Elise D. Girdea, Marta Godfrey, Rena Golas, Gretchen Groden, Catherine Jacobsen, Julius Koehler, Sebastian Lee, Elizabeth M. J. Links, Amanda E. Markello, Thomas C. Mungall, Christopher J. Nehrebecky, Michele Robinson, Peter N. Sincan, Murat Soldatos, Ariane G. Tifft, Cynthia J. Toro, Camilo Trang, Heather Valkanas, Elise Vasilevsky, Nicole Wahl, Colleen Wolfe, Lynne A. Boerkoel, Cornelius F. Brudno, Michael Haendel, Melissa A. Gahl, William A. Smedley, Damian TI Computational evaluation of exome sequence data using human and model organism phenotypes improves diagnostic efficiency SO GENETICS IN MEDICINE LA English DT Article DE exome sequencing; model organisms; phenotype; semantic comparison; undiagnosed diseases ID UNDIAGNOSED DISEASES; PRIORITIZATION; GENES; ONSET; INTERACTOME; ZEBRAFISH; MUTATIONS; PROJECT; WALKING AB Purpose: Medical diagnosis and molecular or biochemical :confirmation typically rely on the knowledge of the clinician. Although this is very difficult in extremely rare diseases, we hypothesized that the recording of patient phenotypes in Human Phenotype Ontology (HPO) terms and computationally ranking putative disease-associated sequence variants improves diagnosis, particularly for patients with atypical clinical profiles. Methods: Using simulated exomes and the National Institutes of Health Undiagnosed Diseases Program (UDP) patient cohort and associated exome sequence, we tested our hypothesis using Exomiser. Exomiser ranks candidate variants based on patient phenotype similarity to (i) known disease-gene phenotypes, (ii) model organism phenotypes of candidate orthologs, and (iii) phenotypes of protein protein association neighbors. Results: Benchmarking showed Exomiser ranked the causal variant as the top hit in 97% of known disease-gene associations and ranked the correct seeded variant in up to 87% when detectable disease-gene associations were unavailable. Using UDP data, Exomiser ranked the causative variant(s) within the top 10 variants for 11 previously diagnosed variants and achieved a diagnosis for 4 of 23 cases undiagnosed by clinical evaluation. Conclusion: Structured phenotyping of patients and computational analysis are effective adjuncts for diagnosing patients with genetic disorders. C1 [Bone, William P.; Adams, David R.; Davis, Joie; Draper, David; Flynn, Elise D.; Godfrey, Rena; Golas, Gretchen; Groden, Catherine; Lee, Elizabeth M. J.; Links, Amanda E.; Markello, Thomas C.; Nehrebecky, Michele; Sincan, Murat; Soldatos, Ariane G.; Tifft, Cynthia J.; Toro, Camilo; Valkanas, Elise; Wahl, Colleen; Wolfe, Lynne A.; Boerkoel, Cornelius F.; Gahl, William A.] NIH, Undiagnosed Dis Program, Common Fund, Off Director, Bldg 10, Bethesda, MD 20892 USA. [Washington, Nicole L.; Mungall, Christopher J.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Genom Div, Berkeley, CA 94720 USA. [Buske, Orion J.; Girdea, Marta; Trang, Heather; Brudno, Michael] Hosp Sick Children, Ctr Computat Med, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Buske, Orion J.; Girdea, Marta; Trang, Heather; Brudno, Michael] Univ Toronto, Dept Comp Sci, Toronto, ON, Canada. [Draper, David; Tifft, Cynthia J.; Gahl, William A.] NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. [Jacobsen, Julius; Smedley, Damian] Wellcome Trust Sanger Inst, Skarnes Fac Grp, Hinxton, England. [Koehler, Sebastian; Robinson, Peter N.] Charite, Inst Med Genet & Human Genet, D-13353 Berlin, Germany. [Vasilevsky, Nicole; Haendel, Melissa A.] Oregon Hlth & Sci Univ, Lib, Portland, OR 97201 USA. [Vasilevsky, Nicole; Haendel, Melissa A.] Oregon Hlth & Sci Univ, Dept Med Informat & Epidemiol, Portland, OR 97201 USA. RP Smedley, D (reprint author), Wellcome Trust Sanger Inst, Skarnes Fac Grp, Hinxton, England. EM ds5@sanger.ac.uk OI Flynn, Elise/0000-0003-0221-8196; Vasilevsky, Nicole/0000-0001-5208-3432 FU Intramural Research Program of the National Human Genome Research Institute; Common Fund of the NIH Office of the Director; NIH Office of Director [1R24OD011883]; NIH-UDP [HHSN268201300036C]; Wellcome Trust [098051]; National Institutes of Health grant (NIH) [1 U54 HG006370-01] FX We thank Megan Kane, Mariska Davids, Katherine Schaffer, Christopher Adams, and Michael Warburton for critical review of the manuscript. This work was supported by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund of the NIH Office of the Director. Monarch grants: This work was supported by the NIH Office of Director (1R24OD011883) and NIH-UDP (HHSN268201300036C). Sanger grants: This work was supported by the Wellcome Trust grant (098051) and National Institutes of Health grant (NIH) (1 U54 HG006370-01). NR 31 TC 10 Z9 10 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD JUN PY 2016 VL 18 IS 6 BP 608 EP 617 DI 10.1038/gim.2015.137 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DP0MQ UT WOS:000378184300010 PM 26562225 ER PT J AU Scherer, AM Bruchmann, K Windschitl, PD Rose, JP Smith, AR Koestner, B Snetselaar, L Suls, J AF Scherer, Aaron M. Bruchmann, Kathryn Windschitl, Paul D. Rose, Jason P. Smith, Andrew R. Koestner, Bryan Snetselaar, Linda Suls, Jerry TI Sources of Bias in Peoples' Social-Comparative Estimates of Food Consumption SO JOURNAL OF EXPERIMENTAL PSYCHOLOGY-APPLIED LA English DT Article DE nutrition; comparative bias; optimistic bias; egocentrism; measurement issues ID COMPARATIVE-OPTIMISM; COMPARATIVE JUDGMENTS; UNREALISTIC OPTIMISM; RISK PERCEPTIONS; PERCEIVED VULNERABILITY; COMPARISON INFORMATION; IMPRESSION MANAGEMENT; COLORECTAL-CANCER; EVENT FREQUENCY; SELF-EVALUATION AB Understanding how healthfully people think they eat compared to others has implications for their motivation to engage in dietary change and the adoption of health recommendations. Our goal was to investigate the scope, sources, and measurements of bias in comparative food consumption beliefs. Across 4 experiments, participants made direct comparisons of how their consumption compared to their peers' consumption and/or estimated their personal consumption of various foods/nutrients and the consumption by peers, allowing the measurement of indirect comparisons. Critically, the healthiness and commonness of the foods varied. When the commonness and healthiness of foods both varied, indirect comparative estimates were more affected by the healthiness of the food, suggesting a role for self-serving motivations, while direct comparisons were more affected by the commonness of the food, suggesting egocentrism as a nonmotivated source of comparative bias. When commonness did not vary, the healthiness of the foods impacted both direct and indirect comparisons, with a greater influence on indirect comparisons. These results suggest that both motivated and nonmotivated sources of bias should be taken into account when creating interventions aimed at improving eating habits and highlights the need for researchers to be sensitive to how they measure perceptions of comparative eating habits. C1 [Scherer, Aaron M.] Univ Michigan, Ctr Bioeth & Social Sci Med, 4800 Plymouth Rd,Bldg 16,Rm 430W, Ann Arbor, MI 48109 USA. [Bruchmann, Kathryn] Santa Clara Univ, Dept Psychol, Santa Clara, CA 95053 USA. [Windschitl, Paul D.] Univ Iowa, Dept Psychol, Iowa City, IA 52242 USA. [Rose, Jason P.] Univ Toledo, Dept Psychol, Toledo, OH USA. [Smith, Andrew R.] Appalachian State Univ, Dept Psychol, Boone, NC 28608 USA. [Koestner, Bryan] Univ Iowa, Carver Coll Med, Iowa City, IA 52242 USA. [Snetselaar, Linda] Univ Iowa, Dept Epidemiol, Iowa City, IA 52242 USA. [Suls, Jerry] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Scherer, AM (reprint author), Univ Michigan, Ctr Bioeth & Social Sci Med, 4800 Plymouth Rd,Bldg 16,Rm 430W, Ann Arbor, MI 48109 USA. EM aaschere@med.umich.edu OI Scherer, Aaron M/0000-0002-4134-9300 FU NIH HHS [DP2 OD007483] NR 50 TC 0 Z9 0 U1 5 U2 8 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1076-898X EI 1939-2192 J9 J EXP PSYCHOL-APPL JI J. Exp. Psychol.-Appl. PD JUN PY 2016 VL 22 IS 2 BP 173 EP 183 DI 10.1037/xap0000081 PG 11 WC Psychology, Applied SC Psychology GA DP1FG UT WOS:000378235300004 PM 27054551 ER PT J AU Yeom, YS Kim, HS Nguyen, TT Choi, C Han, MC Kim, CH Lee, JK Zankl, M Petoussi-Henss, N Bolch, WE Lee, C Chung, BS AF Yeom, Yeon Soo Kim, Han Sung Thang Tat Nguyen Choi, Chansoo Han, Min Cheol Kim, Chan Hyeong Lee, Jai Ki Zankl, Maria Petoussi-Henss, Nina Bolch, Wesley E. Lee, Choonsik Chung, Beom Sun TI New small-intestine modeling method for surface-based computational human phantoms SO JOURNAL OF RADIOLOGICAL PROTECTION LA English DT Article DE computational human phantom; surface phantom; small intestine modeling; Monte Carlo simulation ID REGISTRATION-BASED SEGMENTATION; COLOR SLICE IMAGES; ADULT MALE; RADIATION-DOSIMETRY; HAUSDORFF DISTANCE; HYBRID PHANTOMS; UF FAMILY; IN-VIVO; FEMALE; MESH AB When converting voxel phantoms to a surface format, the small intestine ( SI), which is usually not accurately represented in a voxel phantom due to its complex and irregular shape on one hand and the limited voxel resolutions on the other, cannot be directly converted to a high-quality surface model. Currently, stylized pipe models are used instead, but they are strongly influenced by developer's subjectivity, resulting in unacceptable geometric and dosimetric inconsistencies. In this paper, we propose a new method for the construction of SI models based on the Monte Carlo approach. In the present study, the proposed method was tested by constructing the SI model for the polygon-mesh version of the ICRP reference male phantom currently under development. We believe that the new SI model is anatomically more realistic than the stylized SI models. Furthermore, our simulation results show that the new SI model, for both external and internal photon exposures, leads to dose values that are more similar to those of the original ICRP male voxel phantom than does the previously constructed stylized SI model. C1 [Yeom, Yeon Soo; Kim, Han Sung; Thang Tat Nguyen; Choi, Chansoo; Han, Min Cheol; Kim, Chan Hyeong; Lee, Jai Ki] Hanyang Univ, Dept Nucl Engn, 222 Wangsimni Ro, Seoul 133791, South Korea. [Zankl, Maria; Petoussi-Henss, Nina] Deutsch Forschungszentrum Gesundheit & Umwelt Gmb, Helmholtz Zentrum Munchen, Res Unit Med Radiat Phys & Diagnost, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany. [Bolch, Wesley E.] Univ Florida, J Crayton Pruitt Family Dept Biomed Engn, POB 116131, Gainesville, FL 32611 USA. [Lee, Choonsik] NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Chung, Beom Sun] Ajou Univ, Sch Med, Dept Anat, 164 Worldcup Ro, Suwon 443380, South Korea. RP Kim, CH (reprint author), Hanyang Univ, Dept Nucl Engn, 222 Wangsimni Ro, Seoul 133791, South Korea. EM chkim@hanyang.ac.kr FU Nuclear Safety and Security Commission (NSSC) through Korea Foundation of Nuclear Safety (KOFONS); Ministry of Science, ICT and Future Planning through the National Research Foundation of Korea; Electronics and Telecommunications Research Institute (ETRI) [1403012, 2011-0025496, 15ZC1810]; Global PhD Fellowship program [2011-0007318, 2011-0030970] FX This project was supported by Nuclear Safety and Security Commission (NSSC) through Korea Foundation of Nuclear Safety (KOFONS), by Ministry of Science, ICT and Future Planning through the National Research Foundation of Korea, and by Electronics and Telecommunications Research Institute (ETRI) (Project No.: 1403012, 2011-0025496, 15ZC1810). Two of the authors were supported by the Global PhD Fellowship program (Project No.: 2011-0007318, 2011-0030970). NR 50 TC 2 Z9 2 U1 1 U2 1 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0952-4746 EI 1361-6498 J9 J RADIOL PROT JI J. Radiol. Prot. PD JUN PY 2016 VL 36 IS 2 BP 230 EP 245 DI 10.1088/0952-4746/36/2/230 PG 16 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 DP0JR UT WOS:000378176600024 PM 27007802 ER PT J AU Kwak, L Berrigan, D Van Domelen, D Sjostrom, M Hagstromer, M AF Kwak, Lydia Berrigan, David Van Domelen, Dane Sjostrom, Michael Hagstromer, Maria TI Examining differences in physical activity levels by employment status and/or job activity level: Gender-specific comparisons between the United States and Sweden SO JOURNAL OF SCIENCE AND MEDICINE IN SPORT LA English DT Article DE Occupational; Cross-country; Gender; Comparison; Work-type ID ACTIVITY DOMAINS; ACCELEROMETER; ADULTS; HEALTH; PREVALENCE; INACTIVITY; SPENT AB Objectives: The aim of the study was to examine the relationship between employment status and job activity level with physical activity (PA) and sedentary time, stratified by gender and country. Design: Cross-sectional study design. Methods: Data from working age adults (18-65 years) from two cross-sectional studies, the Swedish 2001-2002 and 2007-2008 Attitude Behavior and Change Study (ABC; n = 1165) and the 2003-2006 US National Health and Nutrition Examination Survey (NHANES; 17 = 4201), were stratified by employment status (employed and not employed) and job activity level (active, sedentary and mixed). PA in counts x min(-1) and time spent in sedentary, low and moderate or higher intensity were measured with accelerometers. Analyses were conducted in 2012-2013. Results: In NHANES, the employed had significantly higher counts x mint and spent more time in moderate or higher intensity PA than those not employed. In ABC, no significant differences were observed between employed and unemployed. Adults with active versus sedentary occupations had higher counts x min(-1) and less sedentary time in both the USA and Sweden and in both men and women. For example, counts x min(-1) were 20-40% greater in active versus sedentary jobs. Conclusions: Employment status is related to PA and sedentary time among men and women in the USA but not in Sweden. Among the employed, occupational PA is associated with total PA and sedentary time for both genders and in both countries. Comparisons of PA levels based on objective measurements can refine understanding of country differences in activity. (C) 2015 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved. C1 [Kwak, Lydia] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [Berrigan, David] NCI, Bethesda, MD 20892 USA. [Van Domelen, Dane] Emory Univ, Dept Biostat, Atlanta, GA 30322 USA. [Sjostrom, Michael] Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden. [Hagstromer, Maria] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden. RP Kwak, L (reprint author), Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. EM lydia.kwak@ki.se FU Karolinska Institutet; Swedish Research Council for Health, Working Life and Welfare FX This study was supported by funding from Karolinska Institutet, Strategic research funding (MH) and the Swedish Research Council for Health, Working Life and Welfare (LK). The authors gratefully acknowledge the help of Lisa Kahle IMS Inc who assisted with the statistical analysis, Penny Randall-Levy for formatting the bibliography, and Anne Rodgers for editorial assistance. The authors declare no potential conflicts of interest, real or perceived. The study funders had no involvement in any parts of the study. NR 29 TC 1 Z9 1 U1 5 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1440-2440 EI 1878-1861 J9 J SCI MED SPORT JI J. Sci. Med. Sport PD JUN PY 2016 VL 19 IS 6 BP 482 EP 487 DI 10.1016/j.jsams.2015.05.008 PG 6 WC Sport Sciences SC Sport Sciences GA DP0NF UT WOS:000378185800008 PM 26095371 ER PT J AU Lee, JW AF Lee, Jae Wook TI RNA sequencing of the nephron transcriptome: a technical note (vol 34, pg 219, 2015) SO KIDNEY RESEARCH AND CLINICAL PRACTICE LA English DT Correction C1 [Lee, Jae Wook] NHLBI, Epithelial Syst Biol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Lee, Jae Wook] Seoul Natl Univ, Kidney Res Inst, Seoul, South Korea. RP Lee, JW (reprint author), Ctr Med Innovat, 28 Yongon Dong, Seoul, South Korea. EM jwleemd@gmail.com NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 2211-9132 EI 2211-9140 J9 KIDNEY RES CLIN PRAC JI Kidney Res. Clin. Pract. PD JUN PY 2016 VL 35 IS 2 BP 130 EP 130 DI 10.1016/j.krcp.2016.03.002 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA DO9WN UT WOS:000378138800015 PM 27366672 ER PT J AU Chang, TT Chen, SL Chang, YH Chen, PS Chu, CH Chen, SH Huang, SY Tzeng, NS Wang, LJ Wang, TY Li, CL Chung, YL Hsieh, TH Lee, IH Chen, KC Yang, YK Hong, JS Lu, RB Lee, SY AF Chang, Ting-Ting Chen, Shiou-Lan Chang, Yun-Hsuan Chen, Po-See Chu, Chun-Hsien Chen, Shih-Heng Huang, San-Yuan Tzeng, Nian-Sheng Wang, Liang-Jen Wang, Tzu-Yun Li, Chia-Ling Chung, Yi-Lun Hsieh, Tsai-Hsin Lee, I-Hui Chen, Kao-Ching Yang, Yen-Kuang Hong, Jau-Shyong Lu, Ru-Band Lee, Sheng-Yu TI The DRD3 Ser9Gly Polymorphism Predicted Metabolic Change in Drug-Naive Patients With Bipolar II Disorder SO MEDICINE LA English DT Article ID D3 RECEPTOR GENE; MOOD DISORDERS; RATING-SCALE; DOPAMINE; ASSOCIATION; SCHIZOPHRENIA; OBESITY; METAANALYSIS; EXPRESSION; DEPRESSION AB Patients with bipolar II disorder (BDII) have a higher prevalence rate of metabolic disturbance. Whether BDII itself, in addition to its current standard treatment, is a risk factor for metabolic syndrome warrants additional study. The dopamine receptor D3 (DRD3) gene, one of the candidate genes for BDII, is also involved in the dopaminergic system. We investigated whether it is related to changes in the metabolic indices of patients with BDII given 12 weeks of standard treatment. Patients with a first diagnosis of BDII (n = 117) were recruited. Metabolic profiles (cholesterol, triglycerides, fasting serum glucose, body mass index) were measured at baseline and at 2, 8, and 12 weeks. The genotype of the DRD3 Ser9Gly polymorphism (rs6280) was determined. Multiple linear regressions with generalized estimating equation methods were used. Seventy-six (65.0%) patients completed the 12-week intervention. Significant differences in triglyceride change were associated with the DRD3 Ser9Gly genotype (P = 0.03). Patients with the Ser/Ser genotype had significantly smaller triglyceride increases and a lower risk of developing metabolic syndrome than did those with the Ser/Gly_Gly/Gly genotype. However, the associations between the DRD3 Ser9Gly polymorphism with changes in triglyceride level become nonsignificant after correcting for multiple comparisons. We conclude that the DRD3 Ser9Gly polymorphism is nominally associated with changes in triglycerides and metabolic syndrome after 12 weeks of standard BDII treatment. C1 [Chang, Ting-Ting] Kaohsiung Med Univ, Dept Psychiat, E Da Hosp, Kaohsiung, Taiwan. [Chen, Shiou-Lan] Kaohsiung Med Univ, Grad Inst Med, Coll Med, Lipid Sci & Aging Res Ctr, Kaohsiung, Taiwan. [Chen, Shiou-Lan; Chang, Yun-Hsuan; Chen, Po-See; Wang, Tzu-Yun; Li, Chia-Ling; Chung, Yi-Lun; Hsieh, Tsai-Hsin; Lee, I-Hui; Chen, Kao-Ching; Yang, Yen-Kuang; Lu, Ru-Band; Lee, Sheng-Yu] Natl Cheng Kung Univ Hosp, Dept Psychiat, Tainan 70428, Taiwan. [Chang, Yun-Hsuan] Asia Univ, Dept Psychol, Taichung, Taiwan. [Chang, Yun-Hsuan; Lu, Ru-Band] Natl Cheng Kung Univ, Coll Med, Inst Mol Med, Inst Allied Hlth,Coll Med & Hosp, Tainan 70101, Taiwan. [Chen, Po-See; Wang, Tzu-Yun; Lee, I-Hui; Chen, Kao-Ching; Yang, Yen-Kuang; Lu, Ru-Band; Lee, Sheng-Yu] Natl Cheng Kung Univ, Coll Med, Inst Mol Med, Dept Psychiat,Coll Med & Hosp, Tainan 70101, Taiwan. [Chen, Po-See; Lu, Ru-Band] Natl Cheng Kung Univ, Coll Med & Hosp, Inst Mol Med, Addict Res Ctr, Tainan 701, Taiwan. [Chen, Shih-Heng; Hong, Jau-Shyong] NIEHS, Neurobiol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Huang, San-Yuan; Tzeng, Nian-Sheng] Natl Def Med Ctr, Dept Psychiat, Triserv Gen Hosp, Taipei, Taiwan. [Wang, Liang-Jen] Kaohsiung Chang Gung Mem Hosp, Dept Child & Adolescent Psychiat, Kaohsiung, Taiwan. [Wang, Liang-Jen] Chang Gung Univ, Coll Med, Kaohsiung, Taiwan. [Chung, Yi-Lun] Natl Cheng Kung Univ, Inst Basic Med Sci, Tainan 701, Taiwan. [Yang, Yen-Kuang] Natl Cheng Kung Univ Hosp, Dept Psychiat, Dou Liou Branch, Yunlin, Taiwan. [Lu, Ru-Band] Natl Cheng Kung Univ, Inst Behav Med Sci, Coll Med & Hosp, Tainan 701, Taiwan. [Lu, Ru-Band] Natl Hlth Res Inst, Ctr Neuropsychiat Res, Miaoli, Taiwan. [Lee, Sheng-Yu] Kaohsiung Vet Gen Hosp, Dept Psychiat, 386 Da Chung 1st Rd, Kaohsiung 81362, Taiwan. RP Lee, SY (reprint author), Kaohsiung Vet Gen Hosp, Dept Psychiat, 386 Da Chung 1st Rd, Kaohsiung 81362, Taiwan. EM shirleylee.ncku@gmail.com FU Taiwan National Science Council [NSC98-2314-B-006-022-MY3, NSC 99-2627-B-006-015, NSC 100-2627-B-006-013, NSC102-2622-B-002-CC2, NSC100-2314-B-075B-010-MY3]; Taiwan Ministry of Science and Technology [MOST 103-2622-B-006-006-CC2, MOST 103-2314-B-075B-006]; Kaohsiung Veterans General Hospital, Taiwan [VGHKS104-098, VGHKS105-122]; Taiwan Department of Health [DOH 95-TD-M-113-055]; Taiwan National Health Research Institute [NHRI-EX-97-9738NI]; National Cheng Kung University Project for Promoting Academic Excellence and Developing World Class Research Centers; I-Shou University, Taiwan [BR103071] FX This work was supported in part by grants NSC98-2314-B-006-022-MY3 (to RBL), NSC 99-2627-B-006-015 (to RBL), NSC 100-2627-B-006-013 (to RBL), NSC102-2622-B-002-CC2 (to RBL), and NSC100-2314-B-075B-010-MY3 (to SYL) from the Taiwan National Science Council; MOST 103-2622-B-006-006-CC2 (to RBL), MOST 103-2314-B-075B-006 (to SYL) from the Taiwan Ministry of Science and Technology; VGHKS104-098 (to SYL) and VGHKS105-122 (to SYL) from Kaohsiung Veterans General Hospital, Taiwan; DOH 95-TD-M-113-055 (to RBL) from the Taiwan Department of Health; NHRI-EX-97-9738NI (to RBL) from the Taiwan National Health Research Institute; and from the National Cheng Kung University Project for Promoting Academic Excellence and Developing World Class Research Centers.; Grant by I-Shou University, Taiwan BR103071. NR 50 TC 1 Z9 1 U1 2 U2 3 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 JUN PY 2016 VL 95 IS 24 AR e3488 DI 10.1097/MD.0000000000003488 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA DO8SD UT WOS:000378053000003 PM 27310943 ER PT J AU Akil, H Balice-Gordon, R Cardozo, DL Koroshetz, W Norris, SMP Sherer, T Sherman, SM Thiels, E AF Akil, Huda Balice-Gordon, Rita Cardozo, David Lopes Koroshetz, Walter Norris, Sheena M. Posey Sherer, Todd Sherman, S. Murray Thiels, Edda TI Neuroscience Training for the 21st Century SO NEURON LA English DT Review AB The field of neuroscience is enjoying a rapid expansion in scope, coupled with a remarkable broadening of conceptual approaches, scientific tools, and clinical applications. This growth poses new challenges for academic training programs as they prepare young neuroscientists for a more complex, competitive, and diverse career landscape. Multiple stakeholders, including academia, federal funding agencies, industry, scientific societies, private foundations, and other public and private sector contributors, need to be actively engaged in supporting this broad training effort. A renewed commitment to a more forward-looking, flexible yet integrative training vision offers opportunities for a bright future for young neuroscientists as they assume the role of vanguard of the enterprise that enriches our understanding of the brain. C1 [Akil, Huda] Univ Michigan, Ann Arbor, MI 48109 USA. [Balice-Gordon, Rita] Pfizer Inc, Neurosci & Pain Res Unit, Cambridge, MA 02139 USA. [Cardozo, David Lopes] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Koroshetz, Walter] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Norris, Sheena M. Posey] Natl Acad Sci, Forum Neurosci & Nervous Syst Disorders, Washington, DC 20001 USA. [Norris, Sheena M. Posey] Natl Acad Engn, Washington, DC 20001 USA. [Norris, Sheena M. Posey] Natl Acad Med, Washington, DC 20001 USA. [Sherer, Todd] Michael J Fox Fdn Parkinsons Res, New York, NY 10163 USA. [Sherman, S. Murray] Univ Chicago, Chicago, IL 60637 USA. [Thiels, Edda] Natl Sci Fdn, 4201 Wilson Blvd, Arlington, VA 22230 USA. RP Akil, H (reprint author), Univ Michigan, Ann Arbor, MI 48109 USA. EM akil@med.umich.edu NR 11 TC 3 Z9 3 U1 4 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD JUN 1 PY 2016 VL 90 IS 5 BP 917 EP 926 DI 10.1016/j.neuron.2016.05.030 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DP5GI UT WOS:000378523900006 PM 27253446 ER PT J AU Dobbs, LK Kaplan, AR Lemos, JC Matsui, A Rubinstein, M Alvarez, VA AF Dobbs, Lauren K. Kaplan, Alanna R. Lemos, Julia C. Matsui, Aya Rubinstein, Marcelo Alvarez, Veronica A. TI Dopamine Regulation of Lateral Inhibition between Striatal Neurons Gates the Stimulant Actions of Cocaine SO NEURON LA English DT Article ID MEDIUM SPINY NEURONS; INDUCED LOCOMOTOR-ACTIVITY; ACCUMBENS IN-VITRO; NUCLEUS-ACCUMBENS; CORTICOSTRIATAL TERMINALS; SYNAPTIC-TRANSMISSION; OPTOGENETIC CONTROL; PROJECTION NEURONS; RECEPTOR FUNCTION; VENTRAL PALLIDUM AB Striatal medium spiny neurons (MSNs) form inhibitory synapses on neighboring striatal neurons through axon collaterals. The functional relevance of this lateral inhibition and its regulation by dopamine remains elusive. We show that synchronized stimulation of collateral transmission from multiple indirect-pathway MSNs (iMSNs) potently inhibits action potentials in direct-pathway MSNs (dMSNs) in the nucleus accumbens. Dopamine D2 receptors (D2Rs) suppress lateral inhibition from iMSNs to disinhibit dMSNs, which are known to facilitate locomotion. Surprisingly, D2R inhibition of synaptic transmission was larger at axon collaterals from iMSNs than their projections to the ventral pallidum. Targeted deletion of D2Rs from iMSNs impaired cocaine's ability to suppress lateral inhibition and increase locomotion. These impairments were rescued by chemogenetic activation of G(i)-signaling in iMSNs. These findings shed light on the functional significance of lateral inhibition between MSNs and offer a novel synaptic mechanism by which dopamine gates locomotion and cocaine exerts its canonical stimulant response. C1 [Dobbs, Lauren K.; Kaplan, Alanna R.; Lemos, Julia C.; Matsui, Aya; Alvarez, Veronica A.] NIAAA, Sect Neuronal Struct, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. [Rubinstein, Marcelo] Univ Buenos Aires, Consejo Nacl Invest Cient & Tecn, Inst Invest Ingn Genet & Biol Mol, C1428ADN, Buenos Aires, DF, Argentina. [Rubinstein, Marcelo] Univ Buenos Aires, Fac Ciencias Exactas & Nat, C1428ADN, Buenos Aires, DF, Argentina. [Rubinstein, Marcelo] Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. RP Alvarez, VA (reprint author), NIAAA, Sect Neuronal Struct, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. EM alvarezva@mail.nih.gov RI Alvarez, Veronica /E-9745-2015; OI Alvarez, Veronica /0000-0003-2611-8675; Kaplan, Alanna/0000-0002-2612-4736 FU Intramural Program of NIAAA; Intramural Program of NINDS [ZIA-AA000421]; ANPCYT-Mincyt of Argentina; Universidad de Buenos Aires; Tourette Syndrome Association FX This study was funded by the Intramural Programs of NIAAA and NINDS (ZIA-AA000421) to V.A.A., and by ANPCYT-Mincyt of Argentina (M.R.), Universidad de Buenos Aires (M.R.) and Tourette Syndrome Association (M.R.). We are grateful to Roland Bock who wrote the Igor procedures used for the voltammetry analysis and to Dr. Ono for access to the confocal microscope and to the members of the V.A.A. lab for helpful comments and discussion. We also thank Dr. B. Roth (UNC) and K. Deisseroth (Stanford) who generously provided the hM4Di and ChR2 constructs, respectively. NR 59 TC 8 Z9 8 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD JUN 1 PY 2016 VL 90 IS 5 BP 1100 EP 1113 DI 10.1016/j.neuron.2016.04.031 PG 14 WC Neurosciences SC Neurosciences & Neurology GA DP5GI UT WOS:000378523900020 PM 27181061 ER PT J AU Regier, DS Proia, RL D'Azzo, A Tifft, CJ AF Regier, Debra S. Proia, Richard L. D'Azzo, Alessandra Tifft, Cynthia J. TI The GM1 and GM2 Gangliosidoses: Natural History and Progress toward Therapy SO PEDIATRIC ENDOCRINOLOGY REVIEWS PER LA English DT Article DE GM1 gangliosidosis; GM2 gangliosidosis; Tay Sachs disease; Animal models; Treatments ID TAY-SACHS-DISEASE; SUBSTRATE REDUCTION THERAPY; BONE-MARROW-TRANSPLANTATION; ONSET GM(2) GANGLIOSIDOSIS; CHEMICAL CHAPERONE THERAPY; SANDHOFF-DISEASE; BETA-GALACTOSIDASE; G(M2) GANGLIOSIDOSIS; MOUSE MODEL; MURINE G(M1)-GANGLIOSIDOSIS AB The gangliosidoses are lysosomal storage disorders caused by accumulation of GM1 or GM2 gangliosides. GM1 gangliosidosis has both central nervous system and systemic findings; while, GM2 gangliosidosis is restricted primarily to the central nervous system. Both disorders have autosomal recessive modes of inheritance and a continuum of clinical presentations from a severe infantile form to a milder, chronic adult form. Both are devastating diseases without cure or specific treatment however, with the use of supportive aggressive medical management, the lifespan and quality of life has been extended for both diseases. Naturally occurring and engineered animal models that mimic the human diseases have enhanced our understanding of the pathogenesis of disease progression. Some models have shown significant improvement in symptoms and lifespan with enzyme replacement, substrate reduction, and anti-inflammatory treatments alone or in combination. More recently gene therapy has shown impressive results in large and small animal models. Treatment with FDA-approved glucose analogs to reduce the amount of ganglioside substrate is used as off-label treatments for some patients. Therapies also under clinical development include small molecule chaperones and gene therapy. C1 [Regier, Debra S.] Childrens Natl Med Ctr, Genet & Metab, Washington, DC 20010 USA. [Proia, Richard L.] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [D'Azzo, Alessandra] St Jude Childrens Res Hosp, Dept Genet, 332 N Lauderdale St, Memphis, TN 38105 USA. [Tifft, Cynthia J.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Tifft, CJ (reprint author), NHGRI, Pediat Undiagnosed Dis Program, NIH, Bldg 10 CRC3-2551 MSC 1205,10 Ctr Dr, Bethesda, MD 20892 USA. EM cynthiat@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; NIH [GM60905, DK52025]; Assisi Foundation of Memphis; American Lebanese Syrian Associated Charities (ALSAC); National Tay-Sachs Et Allied Disease Association (NTSAD) FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Human Genome Research Institute (DR and CT) and National Institute of Diabetes and Digestive and Kidney Diseases (RP). A.d'A. holds the Jewelers for Children Endowed Chair in Genetics and Gene Therapy. A.d'A research was funded in part by NIH grants GM60905 and DK52025, the Assisi Foundation of Memphis, the American Lebanese Syrian Associated Charities (ALSAC) and the National Tay-Sachs Et Allied Disease Association (NTSAD). NR 84 TC 0 Z9 0 U1 9 U2 11 PU MEDICAL MEDIA PI NETANYA PA PO BOX 8214, NETANYA, 4250543, ISRAEL SN 1565-4753 J9 PEDIATR ENDOCR REV P JI Pediatr. Endocrinol. Rev. PER PD JUN PY 2016 VL 13 SU 1 BP 663 EP 673 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP4KD UT WOS:000378463900006 PM 27491214 ER PT J AU Chu, SF Liu, SL Duan, WZ Cheng, Y Jiang, XY Zhu, CJ Tang, K Wang, RS Xu, L Wang, XY Yu, XM Wu, KM Wang, Y Wang, MZ Huang, HY Zhang, JT AF Chu, Shifeng Liu, Shaolin Duan, Wenzhen Cheng, Yong Jiang, Xueying Zhu, Chuanjiang Tang, Kang Wang, Runsheng Xu, Lin Wang, Xiaoying Yu, Xiaoming Wu, Kemei Wang, Yan Wang, Muzou Huang, Huiyong Zhang, Juntian TI The anti-dementia drug candidate, (-)-clausenamide, improves memory impairment through its multi-target effect SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE Chirality; Clausenamide; Dementia; Long-term potentiation; Signaling pathway; Calcium ID LONG-TERM POTENTIATION; TAU-PROTEIN HYPERPHOSPHORYLATION; ALZHEIMERS-DISEASE; SYNAPTIC-TRANSMISSION; CLAUSENAMIDE ENANTIOMERS; DENTATE GYRUS; MOUSE-BRAIN; (-)CLAUSENAMIDE; RATS; TRANSIENT AB Multi-target drugs, such as the cocktail therapy used for treating AIDS, often show stronger efficacy than single target drugs in treating complicated diseases. This review will focus on clausenamide (clau), a small molecule compound originally isolated from the traditional Chinese herbal medicine, Clausenalansium. The finding of four chiral centers in clau molecules predicted the presence of 16 clau enantiomers, including (-)-dau and (+)-clau. All of the predicted enantiomers have been successfully synthesized via innovative chemical approaches, and pharmacological studies have demonstrated (-)-clau as a eutomer and (+)-clau as a distomer in improving cognitive function in both normal physiological and pathological conditions. Mechanistically, the nootropic effect of (-)-clau is mediated by its multi-target actions, which include mild elevation of intracellular Ca2+ concentrations, modulation of the cholinergic system, regulation of synaptic plasticity, and activation of cellular and molecular signaling pathways involved in learning and memory. Furthermore, (-)-clau suppresses the pathogenesis of Alzheimer's disease by inhibiting multiple etiological processes: (1) beta amyloid protein-induced intracellular Ca2+ overload and apoptosis and (2) tau hyperphosphorylation and neurodegeneration. In conclusion, the nature of the multi-target actions of (-)-clau substantiates it as a promising chiral drug candidate for enhancing human cognition in normal conditions and treating memory impairment in neurodegenerative diseases. (C) 2016 Elsevier Inc. All rights reserved. C1 [Chu, Shifeng; Cheng, Yong; Zhu, Chuanjiang; Yu, Xiaoming; Wu, Kemei; Wang, Yan; Wang, Muzou; Zhang, Juntian] Chinese Acad Med Sci, Inst Mat Med, Beijing 100050, Peoples R China. [Chu, Shifeng; Cheng, Yong; Zhu, Chuanjiang; Yu, Xiaoming; Wu, Kemei; Wang, Yan; Wang, Muzou; Zhang, Juntian] Peking Union Med Coll, 1 Xiannongtan St, Beijing 100050, Peoples R China. [Chu, Shifeng; Huang, Huiyong] Hunan Univ Chinese Med, Collaborat Innovat Ctr Digital Tradit Chinese Med, Key Lab Diagnost Tradit Chinese Med, Changsha 410208, Hunan, Peoples R China. [Liu, Shaolin] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Liu, Shaolin] Univ Maryland, Sch Med, Program Neurosci, Baltimore, MD 21201 USA. [Duan, Wenzhen] Johns Hopkins Univ, Sch Med, Program Cellular & Mol Med, Div Neurobiol,Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA. [Jiang, Xueying] NIMH, Bethesda, MD 20892 USA. [Tang, Kang] Univ Nebraska Med Ctr, Dept Pharmacol & Expt Neurosci, Omaha, NE 68198 USA. [Wang, Runsheng] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Xu, Lin] Franciscan Hosp Children, Brighton, MA 02135 USA. [Wang, Xiaoying] Chinese Acad Med Sci, Res Ctr Pharmacol & Tox, Beijing 100193, Peoples R China. [Wang, Xiaoying] Peking Union Med Coll, Inst Med Plant Dev, Beijing 100193, Peoples R China. RP Zhang, JT (reprint author), Peking Union Med Coll, 1 Xiannongtan St, Beijing 100050, Peoples R China.; Zhang, JT (reprint author), Chinese Acad Med Sci, Inst Mat Med, Dept Pharmacol, 1 Xiannongtan St, Beijing 100050, Peoples R China. EM zhangjt@imm.ac.cn FU National Natural Science Foundation of China [3080152730973887, U0832008]; National Key Major Item [2008ZX09101-015] FX This work was supported by the National Natural Science Foundation of China (3080152730973887 and U0832008) and the National Key Major Item (2008ZX09101-015). NR 65 TC 3 Z9 3 U1 8 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD JUN PY 2016 VL 162 BP 179 EP 187 DI 10.1016/j.pharmthera.2016.01.002 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DP2ZE UT WOS:000378361300014 PM 26812265 ER PT J AU Jarcho, JM Davis, MM Shechner, T Degnan, KA Henderson, HA Stoddard, J Fox, NA Leibenluft, E Pine, DS Nelson, EE AF Jarcho, Johanna M. Davis, Megan M. Shechner, Tomer Degnan, Kathryn A. Henderson, Heather A. Stoddard, Joel Fox, Nathan A. Leibenluft, Ellen Pine, Daniel S. Nelson, Eric E. TI Early-Childhood Social Reticence Predicts Brain Function in Preadolescent Youths During Distinct Forms of Peer Evaluation SO PSYCHOLOGICAL SCIENCE LA English DT Article DE adolescent development; brain; social cognition; social interaction; neuroimaging ID BEHAVIORAL-INHIBITION; COGNITIVE CONTROL; CINGULATE CORTEX; ANTERIOR INSULA; ANXIETY; REWARD; DISORDERS; ANTICIPATION; AMYGDALA; TRAJECTORIES AB Social reticence is expressed as shy, anxiously avoidant behavior in early childhood. With development, overt signs of social reticence may diminish but could still manifest themselves in neural responses to peers. We obtained measures of social reticence across 2 to 7 years of age. At age 11, preadolescents previously characterized as high (n = 30) or low (n = 23) in social reticence completed a novel functional-MRI-based peer-interaction task that quantifies neural responses to the anticipation and receipt of distinct forms of social evaluation. High (but not low) social reticence in early childhood predicted greater activity in dorsal anterior cingulate cortex and left and right insula, brain regions implicated in processing salience and distress, when participants anticipated unpredictable compared with predictable feedback. High social reticence was also associated with negative functional connectivity between insula and ventromedial prefrontal cortex, a region commonly implicated in affect regulation. Finally, among participants with high social reticence, negative evaluation was associated with increased amygdala activity, but only during feedback from unpredictable peers. C1 [Jarcho, Johanna M.; Stoddard, Joel; Leibenluft, Ellen; Pine, Daniel S.; Nelson, Eric E.] Natl Inst Mental Hlth, Emot & Dev Branch, Rockville, MD USA. [Jarcho, Johanna M.] SUNY Stony Brook, Dept Psychol, Psychol B Bldg, Stony Brook, NY 11794 USA. [Davis, Megan M.] Univ Illinois, Dept Psychol, Urbana, IL USA. [Shechner, Tomer] Univ Haifa, Dept Psychol, Haifa, Israel. [Degnan, Kathryn A.; Fox, Nathan A.] Univ Maryland, Dept Human Dev, College Pk, MD USA. [Henderson, Heather A.] Univ Waterloo, Dept Psychol, Waterloo, ON N2L 3G1, Canada. [Nelson, Eric E.] Nationwide Childrens Hosp, Ctr Biobehav Hlth, Columbus, OH USA. [Nelson, Eric E.] Ohio State Univ, Dept Psychol, Columbus, OH 43210 USA. RP Jarcho, JM (reprint author), SUNY Stony Brook, Dept Psychol, Psychol B Bldg, Stony Brook, NY 11794 USA. EM johanna.jarcho@stonybrook.edu FU Intramural Research Program at the National Institute of Mental Health; National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD) Young Investigator Award; Richard J. Wyatt Memorial Fellowship Award for Translational Research; National Institute of Child Health and Human Development [R37HD17899]; National Institute of Mental Health [R01MH093349] FX This work was supported by the Intramural Research Program at the National Institute of Mental Health (to D. S. Pine), by the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD) Young Investigator Award: Ellen Schapiro & Gerald Axelbaum Investigator (to J. M. Jarcho), by the Richard J. Wyatt Memorial Fellowship Award for Translational Research (to J. M. Jarcho), and by grants from the National Institute of Child Health and Human Development (R37HD17899) and National Institute of Mental Health (R01MH093349; both to N. A. Fox). NR 49 TC 2 Z9 2 U1 4 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0956-7976 EI 1467-9280 J9 PSYCHOL SCI JI Psychol. Sci. PD JUN PY 2016 VL 27 IS 6 BP 821 EP 835 DI 10.1177/0956797616638319 PG 15 WC Psychology, Multidisciplinary SC Psychology GA DP3UB UT WOS:000378420100006 PM 27150109 ER PT J AU Volpato, S Daragjati, J Simonato, M Fontana, A Ferrucci, L Pilotto, A AF Volpato, Stefano Daragjati, Julia Simonato, Matteo Fontana, Andrea Ferrucci, Luigi Pilotto, Alberto CA MPI-TriVeneto Study Grp TI Change in the Multidimensional Prognostic Index Score During Hospitalization in Older Patients SO REJUVENATION RESEARCH LA English DT Article ID COMPREHENSIVE GERIATRIC ASSESSMENT; LONG-TERM MORTALITY; ELDERLY-PATIENTS; FUNCTIONAL RECOVERY; ADVERSE OUTCOMES; PREDICTORS; VALIDATION; REGRESSION; ADULTS AB We investigated and describe change in the Multidimensional Prognostic Index (MPI) score between admission and discharge in 960 older patients admitted to 20 geriatric units for an acute disease or a relapse of a chronic disease. The MPI was calculated at admission and at discharge. Subjects were divided into three groups of MPI score, low risk (MPI-1 value <= 0.33), moderate risk (MPI-2 value 0.34-0.66), and severe risk of mortality (MPI-3 value >= 0.67), on the basis of previously established cutoffs. Variation of MPI values over length of hospital stay (LOS) was analyzed with a multivariable longitudinal linear model for repeated measurements. At admission, 23.5% subjects had an MPI-1 score, 33.3% had an MPI-2 score, and 43.0% had an MPI-3 score. Overall, for almost 60% of the patients, MPI score at hospital discharge was different compared with the score at admission, although the difference was not statistically significant (-0.003; p = 0.708). Patients with high and intermediate MPI scores at admission had a decrease of MPI score at discharge (delta-MPI -0.026, p < 0.001, and delta-MPI -0.066, p = 0.569, respectively), whereas patients in the MPI-low group, experienced a significant increase in MPI score (delta-MPI 0.041, p < 0.001). The evolution of MPI score as a function of LOS had a curvilinear shape because it significantly decreased for patients with short hospitalization (1-6 days) and tended to increase for those with longer LOS. The MPI, a well-established prognostic tool, is sensitive to change of patient's health status and might be used to objectively track and monitor the clinical evolution of acutely ill geriatric patients admitted to the hospital. C1 [Volpato, Stefano] Univ Ferrara, Dept Med Sci, Internal Med Sect, I-44100 Ferrara, Italy. [Daragjati, Julia; Simonato, Matteo; Pilotto, Alberto] Azienda ULSS 16 Padova, Geriatr Unit, Padua, Italy. [Daragjati, Julia; Pilotto, Alberto] Sci Inst Res & Care, Geriatr Gerontol Res Unit, San Giovanni Rotondo, Italy. [Fontana, Andrea] Sci Inst Res & Care, Unit Biostat, San Giovanni Rotondo, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Pilotto, Alberto] Natl Relevance & High Specializat Hosp, EO Galliera Hosp, Frailty Area, Dept Geriatr Care OrthoGeriatr & Rehabil, Genoa, Italy. RP Volpato, S (reprint author), Univ Ferrara, Dept Med Sci, Internal Med Sect, I-44100 Ferrara, Italy.; Volpato, S (reprint author), Univ Ferrara, Dept Med Sci, Via Savonarola 9, I-44100 Ferrara, Italy. EM vlt@unife.it RI VOLPATO, STEFANO/H-2977-2014; Fontana, Andrea/J-8584-2016 OI VOLPATO, STEFANO/0000-0003-4335-6034; Fontana, Andrea/0000-0002-6660-5315 NR 31 TC 1 Z9 1 U1 1 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1549-1684 EI 1557-8577 J9 REJUV RES JI Rejuv. Res. PD JUN PY 2016 VL 19 IS 3 BP 244 EP 251 DI 10.1089/rej.2015.1715 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA DO9YO UT WOS:000378144100008 PM 26905632 ER PT J AU Sweeney, CL Teng, RF Wang, HM Merling, RK Lee, J Choi, U Koontz, S Wright, DG Malech, HL AF Sweeney, Colin L. Teng, Ruifeng Wang, Hongmei Merling, Randall K. Lee, Janet Choi, Uimook Koontz, Sherry Wright, Daniel G. Malech, Harry L. TI Molecular Analysis of Neutrophil Differentiation from Human Induced Pluripotent Stem Cells Delineates the Kinetics of Key Regulators of Hematopoiesis SO STEM CELLS LA English DT Article DE Human induced pluripotent stem cells; MicroRNA; Transcription factors; CD34 antigen; Hematopoietic stem cells; Neutrophils ID HUMAN SOMATIC-CELLS; MICRORNA EXPRESSION; IN-VITRO; ERYTHROID-DIFFERENTIATION; LINEAGE COMMITMENT; AORTIC ENDOTHELIUM; BLOOD FORMATION; GENERATION; CANCER; GRANULOCYTE AB In vitro generation of mature neutrophils from human induced pluripotent stem cells (iPSCs) requires hematopoietic progenitor development followed by myeloid differentiation. The purpose of our studies was to extensively characterize this process, focusing on the critical window of development between hemogenic endothelium, hematopoietic stem/progenitor cells (HSPCs), and myeloid commitment, to identify associated regulators and markers that might enable the stem cell field to improve the efficiency and efficacy of iPSC hematopoiesis. We utilized a four-stage differentiation protocol involving: embryoid body (EB) formation (stage-1); EB culture with hematopoietic cytokines (stage-2); HSPC expansion (stage-3); and neutrophil maturation (stage-4). CD34(+)CD45(-) putative hemogenic endothelial cells were observed in stage-3 cultures, and expressed VEGFR-2/Flk-1/KDR and VE-cadherin endothelial markers, GATA-2, AML1/RUNX1, and SCL/TAL1 transcription factors, and endothelial/HSPC-associated microRNAs miR-24, miR-125a3p, miR-126/126*, and miR-155. Upon further culture, CD34(-)CD45(+) cells generated CD34(+)CD45(+) HSPCs that produced hematopoietic CFUs. Mid-stage-3 CD34(+)CD45(+) HSPCs exhibited increased expression of GATA-2, AML1/RUNX1, SCL/TAL1, C/EBP alpha, and PU.1 transcription factors, but exhibited decreased expression of HSPC-associated microRNAs, and failed to engraft in immune-deficient mice. Mid-stage-3 CD34(-)CD45(+) cells maintained PU.1 expression and exhibited increased expression of hematopoiesis-associated miR-142-3p/5p and a trend towards increased miR-223 expression, indicating myeloid commitment. By late Stage-4, increased CD15, CD16b, and C/EBP epsilon expression were observed, with 25%-65% of cells exhibiting morphology and functions of mature neutrophils. These studies demonstrate that hematopoiesis and neutrophil differentiation from human iPSCs recapitulates many features of embryonic hematopoiesis and neutrophil production in marrow, but reveals unexpected molecular signatures that may serve as a guide for enhancing iPSC hematopoiesis. C1 [Sweeney, Colin L.; Wang, Hongmei; Merling, Randall K.; Lee, Janet; Choi, Uimook; Koontz, Sherry; Malech, Harry L.] NIAID, Host Def Lab, NIH, Bldg 10,Rm 5-3750,10 Ctr Dr,MSC 1456, Bethesda, MD 20892 USA. [Teng, Ruifeng; Wright, Daniel G.] Natl Inst Diabet & Digest & Kidney Dis, Mol Med Branch, NIH, Bethesda, MD USA. RP Malech, HL (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Rm 5-3750,10 Ctr Dr,MSC 1456, Bethesda, MD 20892 USA. EM hmalech@nih.gov FU Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health [Z01-AI-000644, Z01-AI-000988]; National Institute of Diabetes and Digestive and Kidney Diseases; NIH Center for Regenerative Medicine FX This work was supported by the Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, projects Z01-AI-000644 and Z01-AI-000988, and by intramural awards from the National Institute of Diabetes and Digestive and Kidney Diseases to DGW and from the NIH Center for Regenerative Medicine to HLM. NR 88 TC 2 Z9 2 U1 5 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD JUN PY 2016 VL 34 IS 6 BP 1513 EP 1526 DI 10.1002/stem.2332 PG 14 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA DO9FF UT WOS:000378089500010 PM 26866427 ER PT J AU Fujita, A Uchida, N Haro-Mora, JJ Winkler, T Tisdale, J AF Fujita, Atsushi Uchida, Naoya Haro-Mora, Juan J. Winkler, Thomas Tisdale, John TI beta-Globin-Expressing Definitive Erythroid Progenitor Cells Generated from Embryonic and Induced Pluripotent Stem Cell-Derived Sacs SO STEM CELLS LA English DT Article DE Pluripotent stem cells; Erythroid differentiation; Primitive and definitive hematopoiesis; Globin expression ID FETAL-HEMOGLOBIN PRODUCTION; HUMAN SOMATIC-CELLS; RED-BLOOD-CELLS; YOLK-SAC; IN-VITRO; GENE-EXPRESSION; DEFINED FACTORS; HEMATOPOIESIS; DIFFERENTIATION; AORTA AB Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells represent a potential alternative source for red blood cell transfusion. However, when using traditional methods with embryoid bodies, ES cell-derived erythroid cells predominantly express embryonic type epsilon-globin, with lesser fetal type gamma-globin and very little adult type beta-globin. Furthermore, no beta-globin expression is detected in iPS cell-derived erythroid cells. ES cell-derived sacs (ES sacs) have been recently used to generate functional platelets. Due to its unique structure, we hypothesized that ES sacs serve as hemangioblast-like progenitors capable to generate definitive erythroid cells that express beta-globin. With our ES sac-derived erythroid differentiation protocol, we obtained similar to 120 erythroid cells per single ES cell. Both primitive (E-globin expressing) and definitive (gamma- and beta-globin expressing) erythroid cells were generated from not only ES cells but also iPS cells. Primitive erythropoiesis is gradually switched to definitive erythropoiesis during prolonged ES sac maturation, concurrent with the emergence of hematopoietic progenitor cells. Primitive and definitive erythroid progenitor cells were selected on the basis of glycophorin A or CD34 expression from cells within the ES sacs before erythroid differentiation. This selection and differentiation strategy represents an important step toward the development of in vitro erythroid cell production systems from pluripotent stem cells. Further optimization to improve expansion should be required for clinical application. C1 [Fujita, Atsushi; Uchida, Naoya; Haro-Mora, Juan J.; Tisdale, John] NHLBI, Mol & Clin Hematol Branch, Natl Inst Diabet & Digest & Kidney Dis NIDDK, NIH, Bldg 10, Bethesda, MD 20892 USA. [Winkler, Thomas] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Uchida, N (reprint author), Mol & Clin Hematol Branch, 9000 Rockville Pike,Bldg 10,9N112, Bethesda, MD 20892 USA. EM uchidan@nhlbi.nih.gov RI Haro Mora, Juan Jesus/F-6113-2010 OI Haro Mora, Juan Jesus/0000-0002-6679-7812 FU National Heart, Lung, and Blood Institute (NHLBI); National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH) FX This work was supported by the intramural research program of the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH). NR 37 TC 2 Z9 2 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD JUN PY 2016 VL 34 IS 6 BP 1541 EP 1552 DI 10.1002/stem.2335 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA DO9FF UT WOS:000378089500012 PM 26866725 ER PT J AU Latrofa, F Ricci, D Sisti, E Piaggi, P Nencetti, C Marino, M Vitti, P AF Latrofa, Francesco Ricci, Debora Sisti, Eleonora Piaggi, Paolo Nencetti, Chiara Marino, Michele Vitti, Paolo TI Significance of Low Levels of Thyroglobulin Autoantibodies Associated with Undetectable Thyroglobulin After Thyroidectomy for Differentiated Thyroid Carcinoma SO THYROID LA English DT Article ID SERUM THYROGLOBULIN; CANCER PATIENTS; FOLLOW-UP; STIMULATED THYROGLOBULIN; NECK ULTRASONOGRAPHY; PAPILLARY; ABLATION; RADIOIODINE; MANAGEMENT; EPITOPES AB Background: The management of patients with differentiated thyroid carcinoma (DTC) showing low levels of serum thyroglobulin autoantibodies (TgAb) and undetectable Tg after thyroidectomy is unsettled. This study sought to elucidate the clinical significance of low levels of TgAb and to evaluate their interference with Tg measurement in vitro. Methods: Tg and TgAb levels were correlated with the post-thyroidectomy staging of 177 consecutive DTC patients undergoing I-131 ablation after total thyroidectomy (clinical study). Tg was measured by an immunometric assay (functional sensitivity: 0.1 ng/mL), and TgAb were evaluated by six assays (functional sensitivities: 1.2-96 IU/mL; positive cutoffs: 4-150 IU/mL). The changes in Tg concentration (Tg recovery) of diluted specimens from DTC patients were also measured after incubation with 67 sera from DTC patients with undetectable Tg and low levels of TgAb (in vitro study). DTC sera containing Tg were diluted serially (from 330 to 0.1 ng/mL) and incubated with TgAb samples; Tg was then measured. Results: In the clinical study: all patients had residual thyroid tissue, and 10 had metastatic disease. Depending on the TgAb assay, median Tg values were 7.0-10.9, 0.0-5.3, and 0.0-0.0 ng/mL in patients with undetectable, borderline (between functional sensitivities and positive cutoffs), and positive TgAb, respectively (p < 0.001). An undetectable Tg value was associated with borderline levels of TgAb in five assays. Only two patients with metastatic disease had undetectable Tg; both were TgAb positive by three or more assays. Conversely, no patient with undetectable Tg and undetectable or borderline TgAb by sensitive assays had metastatic disease. In the in vitro study, TgAb interfered significantly with Tg recovery (p < 0.001), but low levels of TgAb did not abolish Tg recovery. Conclusions: While low levels of TgAb do not preclude Tg measurement in vitro, they can be associated with an undetectable Tg in DTC patients with residual thyroid tissue after thyroidectomy. However, the finding of low levels of TgAb by sensitive assays associated with an undetectable Tg rules out metastatic disease. C1 [Latrofa, Francesco; Ricci, Debora; Sisti, Eleonora; Nencetti, Chiara; Marino, Michele; Vitti, Paolo] Univ Hosp Pisa, Dept Clin & Expt Med, Endocrinol Unit 1, Via Paradisa 2, I-56124 Pisa, Italy. [Piaggi, Paolo] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. RP Latrofa, F (reprint author), Univ Hosp Pisa, Dept Clin & Expt Med, Endocrinol Unit 1, Via Paradisa 2, I-56124 Pisa, Italy. EM francesco.latrofa@unipi.it FU MIUR [311]; University of Pisa FX These studies were supported by the grant "Rientro dei cervelli" n. 311 from MIUR and University of Pisa to Francesco Latrofa. NR 41 TC 1 Z9 1 U1 1 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD JUN PY 2016 VL 26 IS 6 BP 798 EP 806 DI 10.1089/thy.2015.0621 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DO8UH UT WOS:000378059100007 PM 27020734 ER PT J AU Nockel, P Millo, C Keutgen, X Klubo-Gwiezdzinska, J Shell, J Patel, D Nilubol, N Herscovitch, P Sadowski, SM Kebebew, E AF Nockel, Pavel Millo, Corina Keutgen, Xavier Klubo-Gwiezdzinska, Joanna Shell, Jasmine Patel, Dhaval Nilubol, Naris Herscovitch, Peter Sadowski, Samira M. Kebebew, Electron TI The Rate and Clinical Significance of Incidental Thyroid Uptake as Detected by Gallium-68 DOTATATE Positron Emission Tomography/Computed Tomography SO THYROID LA English DT Article ID NEUROENDOCRINE TUMORS; PET/CT; DISEASE; CANCER AB Background: Gallium-68 (Ga-68) DOTATATE is a radiolabeled peptide-imaging modality that targets the somatostatin receptor (SSTR), especially subtype 2 (SSTR2). Benign and malignant thyroid tumors have been observed to express SSTR. The aim of this study was to evaluate the frequency and clinical significance of incidental atypical thyroid uptake as detected by Ga-68 DOTATATE positron emission tomography/computed tomography (PET/CT). Methods: A retrospective analysis was conducted of a prospective study in which 237 patients underwent Ga-68 DOTATATE PET/CT as part of a work-up for metastatic and unknown primary neuroendocrine tumors. The types of uptake in the thyroid gland (focal/diffuse) and maximum standardized uptake value (SUVmax) levels were evaluated and compared with the background uptake in the liver and salivary glands. Results: Of 237 patients, 26 (11%) had atypical thyroid uptake as detected by Ga-68 DOTATATE PET/CT. There were no significant clinical or biochemical variables associated with atypical thyroid uptake. Fourteen (54%) patients had positive focal uptake, and 12 (46%) patients had diffuse uptake. Of the 14 patients with atypical focal uptake, 10 (71%) had thyroid nodules on the corresponding side, as detected by anatomic imaging. Three of 10 patients (21%) were found to have papillary thyroid cancer, and seven (70%) had adenomatoid nodules. Of the 12 patients with diffuse increased uptake, six (50%) had a history of hypothyroidism, five (42%) had chronic lymphocytic thyroiditis, and one (8%) had nontoxic multinodular goiter. Conclusions: Patients with an incidental focal abnormal thyroid uptake on Ga-68 DOTATATE PET/CT scan should have further clinical evaluation to exclude a diagnosis of thyroid cancer. C1 [Nockel, Pavel; Keutgen, Xavier; Shell, Jasmine; Patel, Dhaval; Nilubol, Naris; Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Klubo-Gwiezdzinska, Joanna] NIDDK, Diabet Obes & Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Millo, Corina; Herscovitch, Peter] NIH, PET Dept, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Sadowski, Samira M.] Univ Hosp Geneva, Thorac & Endocrine Surg, Geneva, Switzerland. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov OI Patel, Dhaval/0000-0002-5744-568X NR 12 TC 0 Z9 0 U1 1 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD JUN PY 2016 VL 26 IS 6 BP 831 EP 835 DI 10.1089/thy.2016.0174 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DO8UH UT WOS:000378059100012 PM 27094616 ER PT J AU Moraski, GC Seeger, N Miller, PA Oliver, AG Boshoff, HI Cho, S Mulugeta, S Anderson, JR Franzblau, SG Miller, MJ AF Moraski, Garrett C. Seeger, Natalie Miller, Patricia A. Oliver, Allen G. Boshoff, Helena I. Cho, Sanghyun Mulugeta, Surafel Anderson, Jeffery R. Franzblau, Scott G. Miller, Marvin J. TI Arrival of Imidazo[2,1-b]thiazole-5-carboxamides: Potent Antituberculosis Agents That Target QcrB SO ACS INFECTIOUS DISEASES LA English DT Article DE imidazothiazoles; antituberculosis; SAR; respiration target ID MYCOBACTERIUM-TUBERCULOSIS; CLINICAL CANDIDATE; OPTIMIZATION; EXPLORATION; DERIVATIVES; THIAZOLES; DISCOVERY; RULE-OF-5; Q203; TB AB Increasing interest in the potent anti-tuberculosis activity and the novel target (QcrB) of imidazo[1,2-a]pyridine-3-carboxamides encouraged extended structure activity relationship studies of additional scaffolds. This study reports on the in vitro profiling of the imidazo[2,1-b]thiazole-5-carboxamides as a new promising class of anti-tuberculosis compounds endowed with nanomolar potency against replicating and drug-resistant Mycobacterium tuberculosis (Mtb) as well as low toxicity to VERO cells. Compounds 6, 16, and 17 had MIC values <10 nM and toxicity >100 mu M. On-target selectivity of this series was confirmed by cross-resistance of specific QcrB mutants as well as the hypersusceptibility of a mutant with a functional gene deletion of the alternative cytochrome bd oxidase. Additionally, to demonstrate selectivity, three analogues (6, 15, 17) were broadly screened against a diverse set of eight strains of bacteria, including both Gram-positive and Gram-negative as well as six disease-causing non-tuberculosis mycobacteria. Finally, compounds 16 and 17 were found to be active in macrophages infected with Mtb. C1 [Moraski, Garrett C.; Seeger, Natalie] Montana State Univ, Dept Chem & Biochem, 103 Chem & Biochem Bldg, Bozeman, MT 59717 USA. [Miller, Patricia A.; Oliver, Allen G.; Miller, Marvin J.] Univ Notre Dame, Dept Chem & Biochem, 251 Nieuwland Sci Hall, Notre Dame, IN 46556 USA. [Boshoff, Helena I.] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Cho, Sanghyun; Mulugeta, Surafel; Anderson, Jeffery R.; Franzblau, Scott G.] Univ Illinois, Inst TB Res, Coll Pharm, 833 South Wood St, Chicago, IL 60612 USA. RP Miller, MJ (reprint author), Univ Notre Dame, Dept Chem & Biochem, 251 Nieuwland Sci Hall, Notre Dame, IN 46556 USA. EM mmiller1@nd.edu FU Intramural Research Program of NIAID [2R01 AI054193]; NSF [CHE-0741793] FX This work was funded, in part, by the Intramural Research Program of NIAID (HB), by Grant 2R01 AI054193 (to M.J.M). The Mass Spectrometry and Proteomics Facility (Bill Boggess and Michelle Joyce) is supported by Grant CHE-0741793 from the NSF. We thank Prof. Jennifer DuBois, Jed Fisher, and Lowell Markley for regular scientific discussions. NR 41 TC 1 Z9 1 U1 7 U2 14 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 JUN PY 2016 VL 2 IS 6 BP 393 EP 398 DI 10.1021/acsinfecdis.5b00154 PG 6 WC Chemistry, Medicinal; Infectious Diseases SC Pharmacology & Pharmacy; Infectious Diseases GA DO5UM UT WOS:000377848300003 PM 27627627 ER PT J AU Wendler, D AF Wendler, David TI The Potential for Infrastructure Benefits and the Responsiveness Requirement SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material ID DEVELOPING-COUNTRIES; WORLD C1 [Wendler, David] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Wendler, D (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM dwendler@nih.gov FU Intramural Research Program of the NIH Clinical Center FX This research was supported by the Intramural Research Program of the NIH Clinical Center. NR 9 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD JUN PY 2016 VL 16 IS 6 BP 1 EP 2 DI 10.1080/15265161.2016.1184508 PG 2 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA DO3KU UT WOS:000377681300005 PM 27216088 ER PT J AU Kekre, N Mak, KS Stopsack, KH Binder, M Ishii, K Branvall, E Cutler, CS AF Kekre, Natasha Mak, Kimberley S. Stopsack, Konrad H. Binder, Moritz Ishii, Kazusa Branvall, Elsa Cutler, Corey S. TI Impact of HLA-Mismatch in Unrelated Donor Hematopoietic Stem Cell Transplantation: A Meta-Analysis SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID BONE-MARROW-TRANSPLANTATION; CLASS-I; SINGLE-CENTER; HLA-DPB1; MALIGNANCIES; SURVIVAL; LEUKEMIA; OUTCOMES; ALLELES; DISEASE AB The magnitude of risk associated with 9/10 mismatched unrelated donor (MMURD) hematopoietic stem cell transplantation and that of mismatches at the individual HLA loci remain unclear. We performed a meta-analysis to assess the difference in clinical outcomes between matched unrelated donor (MUD) and MMURD transplantation. A comprehensive search of Medline and Embase for manuscripts regarding transplantation outcomes in primarily adult patients with hematologic malignancies was performed. The pooled effect estimates were calculated using DerSimonian-Laird random effects models. A total of 13 studies were included, reporting on 13,446 transplants. 9/10 MMURD transplantation was associated with worse overall survival compared to 10/10 MUD transplantation (pooled HR: 1.27, 95% CI: 1.12-1.45; n=7 studies). Mismatch at HLA-A, -B, or -C was associated with significantly worse overall survival compared to MUD transplantation, while there was no significant difference associated with -DQ or -DPB1 mismatch. Inferior survival associated with HLA-DRB1 mismatch could not be ruled out. Data on acute and chronic graft-versus-host disease were scarce but favored MUD transplantation. In summary, this meta-analysis of the available literature favored MUD over MMURD transplantation in hematologic malignancies and further quantifies the risks associated with specific HLA-allele mismatches.(C) 2016 Wiley Periodicals, Inc. C1 [Kekre, Natasha] Ottawa Hosp Res Inst, Div Hematol, Ottawa, ON, Canada. [Mak, Kimberley S.] Boston Univ, Sch Med, Dept Radiat Oncol, Boston Med Ctr, Boston, MA 02118 USA. [Stopsack, Konrad H.; Binder, Moritz] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Ishii, Kazusa] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Branvall, Elsa] Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden. [Cutler, Corey S.] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. RP Kekre, N (reprint author), Univ Ottawa, Blood & Marrow Transplant Program, Ottawa Hosp Res Inst, Ottawa, ON, Canada. EM nkekre@toh.on.ca OI Binder, Moritz/0000-0001-9014-9658 NR 28 TC 0 Z9 1 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD JUN PY 2016 VL 91 IS 6 BP 551 EP 555 DI 10.1002/ajh.24342 PG 5 WC Hematology SC Hematology GA DO2CE UT WOS:000377586400012 PM 26927727 ER PT J AU Viboud, C Simonsen, L Chowell, G AF Viboud, Cecile Simonsen, Lone Chowell, Gerardo TI A generalized-growth model to characterize the early ascending phase of infectious disease outbreaks SO EPIDEMICS LA English DT Article ID EBOLA-VIRUS DISEASE; MOUTH-DISEASE; TRANSMISSION DYNAMICS; REPRODUCTION NUMBER; EPIDEMIOLOGIC MODELS; PANDEMIC INFLUENZA; GREAT-BRITAIN; UNITED-STATES; HONG-KONG; EPIDEMICS AB Background: A better characterization of the early growth dynamics of an epidemic is needed to dissect the important drivers of disease transmission, refine existing transmission models, and improve disease forecasts. Materials and methods: We introduce a 2-parameter generalized-growth model to characterize the ascending phase of an outbreak and capture epidemic profiles ranging from sub-exponential to exponential growth. We test the model against empirical outbreak data representing a variety of viral pathogens in historic and contemporary populations, and provide simulations highlighting the importance of sub exponential growth for forecasting purposes. Results: We applied the generalized-growth model to 20 infectious disease outbreaks representing a range of transmission routes. We uncovered epidemic profiles ranging from very slow growth (p = 0.14 for the Ebola outbreak in Bomi, Liberia (2014)) to near exponential (p > 0.9 for the smallpox outbreak in Khulna (1972), and the 1918 pandemic influenza in San Francisco). The foot-and-mouth disease outbreak in Uruguay displayed a profile of slower growth while the growth pattern of the HIV/AIDS epidemic in Japan was approximately linear. The West African Ebola epidemic provided a unique opportunity to explore how growth profiles vary by geography; analysis of the largest district-level outbreaks revealed substantial growth variations (mean p = 0.59, range: 0.14-0.97). The districts of Margibi in Liberia and Bombali and Bo in Sierra Leone had near-exponential growth, while the districts of Bomi in Liberia and Kenema in Sierra Leone displayed near constant incidences. Conclusions: Our findings reveal significant variation in epidemic growth patterns across different infectious disease outbreaks and highlights that sub-exponential growth is a common phenomenon, especially for pathogens that are not airborne. Sub-exponential growth profiles may result from heterogeneity in contact structures or risk groups, reactive behavior changes, or the early onset of interventions strategies, and consideration of "deceleration parameters" may be useful to refine existing mathematical transmission models and improve disease forecasts. (C) 2016 The Authors. Published by Elsevier B.V. C1 [Viboud, Cecile; Chowell, Gerardo] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Simonsen, Lone] Univ Copenhagen, Dept Publ Hlth, Copenhagen, Denmark. [Simonsen, Lone] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Global Hlth, Washington, DC USA. [Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. RP Chowell, G (reprint author), Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. EM gchowell@gsu.edu OI Simonsen, Lone/0000-0003-1535-8526 FU Division of International Epidemiology and Population Studies, The Fogarty International Center, United States National Institutes of Health - Office of Pandemics and Emerging Threats at the United States Department of Health and Human Services; European Union Horizon 2020 "Marie Curie" senior fellowship FX We acknowledge financial support from the Division of International Epidemiology and Population Studies, The Fogarty International Center, United States National Institutes of Health, funded in part by the Office of Pandemics and Emerging Threats at the United States Department of Health and Human Services. LS acknowledges support from the European Union Horizon 2020 "Marie Curie" senior fellowship. NR 68 TC 9 Z9 9 U1 4 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD JUN PY 2016 VL 15 BP 27 EP 37 DI 10.1016/j.epidem.2016.01.002 PG 11 WC Infectious Diseases SC Infectious Diseases GA DO6CK UT WOS:000377870200004 PM 27266847 ER PT J AU Coussens, NP Daines, DA AF Coussens, Nathan P. Daines, Dayle A. TI Wake me when it's over - Bacterial toxin-antitoxin proteins and induced dormancy SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Article DE Bacteria; biomedical; microbiology; protein-protein interactions; proteolysis; enzymes ID MESSENGER-RNA RECOGNITION; NONTYPABLE HAEMOPHILUS-INFLUENZAE; SUBSEAFLOOR MICROBIAL-CELLS; ABORTIVE INFECTION SYSTEM; 23S RIBOSOMAL-RNA; MYCOBACTERIUM-TUBERCULOSIS; ESCHERICHIA-COLI; MULTIDRUG TOLERANCE; CONDITIONAL COOPERATIVITY; INHIBITS TRANSLATION AB Toxin-antitoxin systems are encoded by bacteria and archaea to enable an immediate response to environmental stresses, including antibiotics and the host immune response. During normal conditions, the antitoxin components prevent toxins from interfering with metabolism and arresting growth; however, toxin activation enables microbes to remain dormant through unfavorable conditions that might continue over millions of years. Intense investigations have revealed a multitude of mechanisms for both regulation and activation of toxin-antitoxin systems, which are abundant in pathogenic microorganisms. This minireview provides an overview of the current knowledge regarding type II toxin-antitoxin systems along with their clinical and environmental implications. C1 [Coussens, Nathan P.] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Daines, Dayle A.] Old Dominion Univ, Dept Biol Sci, Norfolk, VA 23529 USA. RP Daines, DA (reprint author), Old Dominion Univ, Dept Biol Sci, Norfolk, VA 23529 USA. EM ddaines@odu.edu FU NIH [R01DC010187, U01DC014756]; NCATS Division of Pre-Clinical Innovation Intramural Program FX Work in our laboratories was supported by NIH grants R01DC010187 and U01DC014756, along with the NCATS Division of Pre-Clinical Innovation Intramural Program. We thank Dr. D.E. Sonenshine for valuable comments about our manuscript and L.J. Coussens for her contributions to Figure 3. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Space limitations of this minireview prevented citation of all relevant literature. NR 133 TC 1 Z9 1 U1 7 U2 9 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1535-3702 EI 1535-3699 J9 EXP BIOL MED JI Exp. Biol. Med. PD JUN PY 2016 VL 241 IS 12 BP 1332 EP 1342 DI 10.1177/1535370216651938 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DO8TR UT WOS:000378057200008 PM 27216598 ER PT J AU Mazzacuva, F Mills, P Mills, K Camuzeaux, S Gissen, P Nicoli, ER Wassif, C te Vruchte, D Porter, FD Maekawa, M Mano, N Iida, T Platt, F Clayton, PT AF Mazzacuva, Francesca Mills, Philippa Mills, Kevin Camuzeaux, Stephane Gissen, Paul Nicoli, Elena-Raluca Wassif, Christopher te Vruchte, Danielle Porter, Forbes D. Maekawa, Masamitsu Mano, Nariyasu Iida, Takashi Platt, Frances Clayton, Peter T. TI Identification of novel bile acids as biomarkers for the early diagnosis of Niemann-Pick C disease SO FEBS LETTERS LA English DT Article DE bile acids; Biomarkers; GlcNAc transferase; Niemann-Pick C; screening; UPLC-MS/MS ID CHOLESTEROL TRAFFICKING; MAJOR METABOLITES; ESTERIFICATION; MIGLUSTAT; DISORDER; PATIENT; DEFECT; GENE; MICE AB This article describes a rapid UPLC-MS/MS method to quantitate novel bile acids in biological fluids and the evaluation of their diagnostic potential in Niemann-Pick C (NPC). Two new compounds, NPCBA1 (3 beta-hydroxy, 7 beta-N-acetylglucosaminyl-5-cholenoic acid) and NPCBA2 (probably 3 beta,5 alpha,6 beta-trihydroxycholanoyl- glycine), were observed to accumulate preferentially in NPC patients: median plasma concentrations of NPCBA1 and NPCBA2 were 40- and 10-fold higher in patients than in controls. However, NPCBA1 concentrations were normal in some patients because they carried a common mutation inactivating the GlcNAc transferase required for the synthesis of this bile acid. NPCBA2, not containing a GlcNAc moiety, is thus a better NPC biomarker. C1 [Mazzacuva, Francesca; Mills, Philippa; Mills, Kevin; Camuzeaux, Stephane; Gissen, Paul; Clayton, Peter T.] UCL Inst Child Hlth, Ctr Translat Omics, Genet & Genom Med Programme, 30 Guilford St, London WC1N 1EH, England. [Gissen, Paul; Clayton, Peter T.] Great Ormond St Childrens Hosp, Metab Med, London, England. [Nicoli, Elena-Raluca; te Vruchte, Danielle; Platt, Frances] Univ Oxford, Dept Pharmacol, Oxford OX1 2JD, England. [Wassif, Christopher; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Maekawa, Masamitsu; Mano, Nariyasu] Tohoku Univ Hosp, Dept Pharmaceut Sci, Sendai, Miyagi, Japan. [Iida, Takashi] Nihon Univ, Coll Humanities & Sci, Tokyo, Japan. RP Clayton, PT (reprint author), UCL Inst Child Hlth, Ctr Translat Omics, Genet & Genom Med Programme, 30 Guilford St, London WC1N 1EH, England. EM peter.clayton@ucl.ac.uk FU Actelion Pharmaceuticals UK Ltd. FX Actelion Pharmaceuticals UK Ltd. NR 35 TC 1 Z9 1 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-5793 EI 1873-3468 J9 FEBS LETT JI FEBS Lett. PD JUN PY 2016 VL 590 IS 11 BP 1651 EP 1662 DI 10.1002/1873-3468.12196 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DO5AC UT WOS:000377795000010 PM 27139891 ER PT J AU Browning, SR Grinde, K Plantinga, A Gogarten, SM Stilp, AM Kaplan, RC Aviles-Santa, ML Browning, BL Laurie, CC AF Browning, Sharon R. Grinde, Kelsey Plantinga, Anna Gogarten, Stephanie M. Stilp, Adrienne M. Kaplan, Robert C. Aviles-Santa, M. Larissa Browning, Brian L. Laurie, Cathy C. TI Local Ancestry Inference in a Large US-Based Hispanic/Latino Study: Hispanic Community Health Study/Study of Latinos (HCHS/SOL) SO G3-GENES GENOMES GENETICS LA English DT Article DE Hispanic; Latino; local ancestry; principal components analysis ID POPULATIONS; ASSOCIATION; DESIGN; AMERICANS AB We estimated local ancestry on the autosomes and X chromosome in a large US-based study of 12,793 Hispanic/Latino individuals using the RFMix method, and we compared different reference panels and approaches to local ancestry estimation on the X chromosome by means of Mendelian inconsistency rates as a proxy for accuracy. We developed a novel and straightforward approach to performing ancestry-specific PCA after finding artifactual behavior in the results from an existing approach. Using the ancestry-specific PCA, we found significant population structure within African, European, and Amerindian ancestries in the Hispanic/Latino individuals in our study. In the African ancestral component of the admixed individuals, individuals whose grandparents were from Central America clustered separately from individuals whose grandparents were from the Caribbean, and also from reference Yoruba and Mandenka West African individuals. In the European component, individuals whose grandparents were from Puerto Rico diverged partially from other background groups. In the Amerindian ancestral component, individuals clustered into multiple different groups depending on the grandparental country of origin. Therefore, local ancestry estimation provides further insight into the complex genetic structure of US Hispanic/Latino populations, which must be properly accounted for in genotype-phenotype association studies. It also provides a basis for admixture mapping and ancestry-specific allele frequency estimation, which are useful in the identification of risk factors for disease. C1 [Browning, Sharon R.; Grinde, Kelsey; Plantinga, Anna; Gogarten, Stephanie M.; Stilp, Adrienne M.; Browning, Brian L.; Laurie, Cathy C.] Univ Washington, Dept Biostat, F-600,Hlth Sci Bldg,1705 NE Pacific St, Seattle, WA 98195 USA. [Browning, Brian L.] Univ Washington, Div Med Genet, Dept Med, Seattle, WA 98195 USA. [Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Browning, Sharon R.; Aviles-Santa, M. Larissa] NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Browning, SR (reprint author), Univ Washington, Dept Biostat, F-600,Hlth Sci Bldg,1705 NE Pacific St, Seattle, WA 98195 USA. EM sguy@uw.edu RI Browning, Sharon/B-1530-2008; OI Browning, Sharon/0000-0001-7251-9715; Gogarten, Stephanie/0000-0002-7231-9745 FU National Heart, Lung, and Blood Institute (NHLBI) [N01-HC65233, N01-HC65234, N01-HC65235, N01-HC65236, N01-HC65237]; NHLBI; NIDCR [HHSN268201300005C AM03, MOD03]; NIH [GM099568, T32GM081062]; National Science Foundation [DGE-1256082] FX The authors thank the staff and participants of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) for their important contributions, as well as Andres Ruiz-Linares, David Reich, and other authors of Reich et al. (2012) for providing reference data. The HCHS/SOL was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following Institutes/Centers/Offices contribute to the HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research (NIDCR), National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, and the National Institutes of Health (NIH) Institution-Office of Dietary Supplements. The Genetic Analysis Center at the University of Washington was supported by NHLBI and NIDCR contracts (HHSN268201300005C AM03 and MOD03). S.R.B. and B.L.B. were supported in part by NIH grant GM099568. K.G. was supported in part by NIH training grant T32GM081062. A.P. was supported by the National Science Foundation Graduate Research Fellowship Program grant DGE-1256082. This manuscript has been reviewed by the HCHS/SOL Publications Committee for scientific content and consistency of data interpretation with previous HCHS/SOL publications. NR 25 TC 0 Z9 0 U1 0 U2 3 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD JUN PY 2016 VL 6 IS 6 BP 1525 EP 1534 DI 10.1534/g3.116.028779 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DO5KI UT WOS:000377821600004 PM 27172203 ER PT J AU Li, G Hillier, LW Grahn, RA Zimin, AV David, VA Menotti-Raymond, M Middleton, R Hannah, S Hendrickson, S Makunin, A O'Brien, SJ Minx, P Wilson, RK Lyons, LA Warren, WC Murphy, WJ AF Li, Gang Hillier, LaDeana W. Grahn, Robert A. Zimin, Aleksey V. David, Victor A. Menotti-Raymond, Marilyn Middleton, Rondo Hannah, Steven Hendrickson, Sher Makunin, Alex O'Brien, Stephen J. Minx, Pat Wilson, Richard K. Lyons, Leslie A. Warren, Wesley C. Murphy, William J. TI A High-Resolution SNP Array-Based Linkage Map Anchors a New Domestic Cat Draft Genome Assembly and Provides Detailed Patterns of Recombination SO G3-GENES GENOMES GENETICS LA English DT Article DE Felis catus; Illumina 63K SNP array; genetic map; recombination; domestic cat ID COPY NUMBER VARIATION; RADIATION HYBRID; FELIS-CATUS; COLOR PHENOTYPE; X-CHROMOSOME; EVOLUTION; MUTATIONS; SEQUENCE; TYROSINASE; SELECTION AB High-resolution genetic and physical maps are invaluable tools for building accurate genome assemblies, and interpreting results of genome-wide association studies (GWAS). Previous genetic and physical maps anchored good quality draft assemblies of the domestic cat genome, enabling the discovery of numerous genes underlying hereditary disease and phenotypes of interest to the biomedical science and breeding communities. However, these maps lacked sufficient marker density to order thousands of shorter scaffolds in earlier assemblies, which instead relied heavily on comparative mapping with related species. A high-resolution map would aid in validating and ordering chromosome scaffolds from existing and new genome assemblies. Here, we describe a high-resolution genetic linkage map of the domestic cat genome based on genotyping 453 domestic cats from several multi-generational pedigrees on the Illumina 63K SNP array. The final maps include 58,055 SNP markers placed relative to 6637 markers with unique positions, distributed across all autosomes and the X chromosome. Our final sex-averaged maps span a total autosomal length of 4464 cM, the longest described linkage map for any mammal, confirming length estimates from a previous microsatellite-based map. The linkage map was used to order and orient the scaffolds from a substantially more contiguous domestic cat genome assembly (Felis catus v8.0), which incorporated approximate to 20 x coverage of Illumina fragment reads. The new genome assembly shows substantial improvements in contiguity, with a nearly fourfold increase in N50 scaffold size to 18 Mb. We use this map to report probable structural errors in previous maps and assemblies, and to describe features of the recombination landscape, including a massive (approximate to 50 Mb) recombination desert (of virtually zero recombination) on the X chromosome that parallels a similar desert on the porcine X chromosome in both size and physical location. C1 [Li, Gang; Murphy, William J.] Texas A&M Univ, Dept Vet Integrat Biosci, Interdisciplinary Program Genet, College Stn, TX 77843 USA. [Hillier, LaDeana W.; Minx, Pat; Wilson, Richard K.; Warren, Wesley C.] Washington Univ, Sch Med, McDonnell Genome Inst, 4444 Forest Pk Ave, St Louis, MO 63108 USA. [Grahn, Robert A.; Lyons, Leslie A.] Univ Missouri, Coll Vet Med, Dept Vet Med & Surg, Columbia, MO 65201 USA. [Grahn, Robert A.; Lyons, Leslie A.] Univ Calif Davis, Populat Hlth & Reprod, Davis, CA 95616 USA. [Zimin, Aleksey V.] Univ Maryland, Inst Phys Sci & Technol, College Pk, MD 20742 USA. [David, Victor A.; Menotti-Raymond, Marilyn; O'Brien, Stephen J.] NCI Frederick, NIH, Ft Detrick, MD 21702 USA. [Middleton, Rondo; Hannah, Steven] Nestle Purina PetCare Co, St Louis, MO 63134 USA. [Hendrickson, Sher] Shepherd Univ, Dept Biol, Shepherdstown, WV 25443 USA. [Hendrickson, Sher; Makunin, Alex; O'Brien, Stephen J.] St Petersburg State Univ, Theodosius Dobzhansky Ctr Genome Bioinformat, St Petersburg 199004, Russia. RP Warren, WC (reprint author), Washington Univ, Sch Med, McDonnell Genome Inst, 4444 Forest Pk Ave, St Louis, MO 63108 USA.; Murphy, WJ (reprint author), Texas A&M Univ, Vet Integrat Biosci, College Stn, TX 77843 USA. EM wwarren@genome.wustl.edu; wmurphy@cvm.tamu.edu RI li, gang/E-5640-2014; Makunin, Alexey/N-2055-2015 OI Makunin, Alexey/0000-0002-9555-5097 FU Morris Animal Foundation/Cat Health Network [D12FE019, D12FE502, D12FE-501, D12FE507, D12FE560]; Winn Feline Foundation [W11-041]; University of California-Davis, School of Veterinary Medicine, Center for Companion Animal Health [2010-09-F]; National Institutes of Health (NIH) National Center for Research Resources; NIH National Human Genome Research Institute [5U54HG00307907]; US Department of Agriculture, National Institute of Food and Agriculture, National Robotics Initiative [2009-35205-05209, 2008-04049]; NIH [R01-HG002945, R01-HG006677]; Russian Ministry of Science [11.G34.31.0068]; NIH, Center for Cancer Research, National Cancer Institute-Frederick FX We thank the animal husbandry staff at the University of California-Davis and Paul Samollow (Texas A&M) for helpful discussions. We acknowledge funding from the Morris Animal Foundation/Cat Health Network (grants D12FE019 and D12FE502 to W.J.M., D12FE-501 to S.J.O. and M.M.R., and D12FE507 and D12FE560 to L.A.L.); the Winn Feline Foundation (W11-041 to L.A.L.); the University of California-Davis, School of Veterinary Medicine, Center for Companion Animal Health (2010-09-F to L.A.L.); the National Institutes of Health (NIH) National Center for Research Resources (L.A.L.); the NIH National Human Genome Research Institute (5U54HG00307907 to R.K.W.); the US Department of Agriculture, National Institute of Food and Agriculture, National Robotics Initiative (2009-35205-05209 and 2008-04049 to A.V.Z.); the NIH (R01-HG002945 and R01-HG006677 to A.V.Z.); and the Russian Ministry of Science (Mega-grant no. 11.G34.31.0068 to S.J.O.). This research was supported (in part) by the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute-Frederick. NR 62 TC 1 Z9 1 U1 7 U2 9 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD JUN PY 2016 VL 6 IS 6 BP 1607 EP 1616 DI 10.1534/g3.116.028746 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DO5KI UT WOS:000377821600012 PM 27172201 ER PT J AU Justice, CM Bishop, K Carrington, B Mullikin, JC Swindle, K Marosy, B Sood, R Miller, NH Wilson, AF AF Justice, Cristina M. Bishop, Kevin Carrington, Blake Mullikin, Jim C. Swindle, Kandice Marosy, Beth Sood, Raman Miller, Nancy H. Wilson, Alexander F. TI Evaluation of IRX Genes and Conserved Noncoding Elements in a Region on 5p13.3 Linked to Families with Familial Idiopathic Scoliosis and Kyphosis SO G3-GENES GENOMES GENETICS LA English DT Article DE idiopathic scoliosis; IRX genes; zebrafish transgenesis; conserved noncoding regions; kyphoscoliosis ID FUNCTIONAL-ANALYSIS; LINKAGE ANALYSIS; HOMEOBOX GENES; IROQUOIS; SUSCEPTIBILITY; IDENTIFICATION; LOCUS; TRANSGENESIS; LOCALIZATION; ORGANIZATION AB Because of genetic heterogeneity present in idiopathic scoliosis, we previously defined clinical subsets (a priori) from a sample of families with idiopathic scoliosis to find genes involved with spinal curvature. Previous genome-wide linkage analysis of seven families with at least two individuals with kyphoscoliosis found linkage (P-value=0.002) in a 3.5-Mb region on 5p13.3 containing only three known genes, IRX1, IRX2, and IRX4. In this study, the exons of IRX1, IRX2, and IRX4, the conserved noncoding elements in the region, and the exons of a nonprotein coding RNA, LOC285577, were sequenced. No functional sequence variants were identified. An intrafamilial test of association found several associated noncoding single nucleotide variants. The strongest association was with rs12517904 (P=0.00004), located 6.5kb downstream from IRX1. In one family, the genotypes of nine variants differed from the reference allele in all individuals with kyphoscoliosis, and two of three individuals with scoliosis, but did not differ from the reference allele in all other genotyped individuals. One of these variants, rs117273909, was located in a conserved noncoding region that functions as an enhancer in mice. To test whether the variant allele at rs117273909 had an effect on enhancer activity, zebrafish transgenesis was performed with overlapping fragments of 198 and 687bp containing either the wild type or the variant allele. Our data suggests that this region acts as a regulatory element; however, its size and target gene(s) need to be identified to determine its role in idiopathic scoliosis. C1 [Justice, Cristina M.; Wilson, Alexander F.] NHGRI, Genometr Sect, Computat & Stat Genom Branch, NIH, 333 Cassell Dr,Suite 1200, Baltimore, MD 21224 USA. [Marosy, Beth] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21224 USA. [Bishop, Kevin; Carrington, Blake; Sood, Raman] NHLBI, Zebrafish Core, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. [Mullikin, Jim C.] NHGRI, NIH, Intramural Sequencing Ctr, Rockville, MD 20852 USA. [Swindle, Kandice; Miller, Nancy H.] Univ Colorado Anschutz Med Campus, Dept Orthoped Surg, Aurora, CO 80045 USA. RP Justice, CM (reprint author), NHGRI, Genometr Sect, Computat & Stat Genom Branch, NIH, 333 Cassell Dr,Suite 1200, Baltimore, MD 21224 USA. EM cmj@mail.nih.gov FU National Human Genome Research Institute, National Institutes of Health (NIH); National Center for Research Resources [1 P41 RR03655]; Scoliosis Research Society; National Scoliosis Foundation; Scoliosis Association, Inc.; Institute de France Foundation Yves Cotrel; Orthopedic Pediatric Society of North America; Orthopedic Research and Education Foundation; NIH [1-R01-AR048862-01A1]; NIH/National Cancer Institute Cancer Center [P30 CA046934] FX The ZED vector was kindly provided by Jose Bessa (Centro Andaluz de Biologia del Desarrollo, Universidad Pablo de Olavide, Carretera de Utrera Km1, 41013 Sevilla, Spain). We greatly appreciate the helpful suggestions provided by Valer Gotea, Laura Elnitski, and Tyra Wolfsberg. We also would like to thank the families who participated in this study. This research was supported, in part, by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (NIH). Some of the results were obtained with the program S.A.G.E., which was supported by grant 1 P41 RR03655 from the National Center for Research Resources. Grant funding was provided by the Scoliosis Research Society, the National Scoliosis Foundation, Scoliosis Association, Inc., the Institute de France Foundation Yves Cotrel, the Orthopedic Pediatric Society of North America, and the Orthopedic Research and Education Foundation, and NIH grant 1-R01-AR048862-01A1. The control samples were sequenced by the University of Colorado Cancer Center DNA Sequencing and Analysis Core (http://DNASequencingCore.ucdenver.edu), which is supported by a NIH/National Cancer Institute Cancer Center Core Support Grant (P30 CA046934). NR 37 TC 1 Z9 1 U1 1 U2 2 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD JUN PY 2016 VL 6 IS 6 BP 1707 EP 1712 DI 10.1534/g3.116.029975 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA DO5KI UT WOS:000377821600021 PM 27172222 ER PT J AU Kuniholm, MH O'Brien, TR Prokunina-Olsson, L Augenbraun, M Plankey, M Karim, R Sarkar, M French, AL Pierce, C Strickler, HD Anastos, K AF Kuniholm, Mark H. O'Brien, Thomas R. Prokunina-Olsson, Ludmila Augenbraun, Michael Plankey, Michael Karim, Roksana Sarkar, Monika French, Audrey L. Pierce, Chris Strickler, Howard D. Anastos, Kathryn TI Association of Hepatitis C Virus Infection With CD4/CD8 Ratio in HIV-Positive Women SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE CD4/CD8; hepatitis C virus; HCV; HIV; inflammation; immune activation ID T-CELL-ACTIVATION; HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL THERAPY; IMMUNE ACTIVATION; OBSERVATIONAL COHORT; INTERAGENCY HIV; INDIVIDUALS; SUPPRESSION; CLEARANCE; GENOTYPE AB Background: Recent studies reported that the CD4/CD8 T-cell ratio is inversely associated with biomarkers traditionally used to measure immune activation and systemic inflammation in highly active antiretroviral therapy-treated HIV-infected (HIV+) patients. The relation of hepatitis C virus (HCV) coinfection with the CD4/CD8 ratio in HIV+ patients is unknown. Methods: We examined 50,201 CD4/CD8 ratios measured over 20 years in 3 groups of HIV+ women enrolled in the Women's Interagency HIV Study: HCV antibody negative (n = 1734), cleared HCV (n = 231), and chronic HCV (n = 751) in multivariate models. IFNL4-Delta G genotype and HCV viral load were also considered. Results: Compared with HCV antibody negative status, chronic HCV infection was associated with lower CD4/CD8 ratios when HIV viral load was suppressed to the lower limit of quantification (beta = -0.08; P = 0.002). Cleared HCV (beta = -0.10; P = 0.0009), but not IFNL4-Delta G genotype or HCV viral load, was also associated with lower CD4/CD8 ratios when HIV viral load was suppressed to the lower limit of quantification. Conclusions: The association of HCV coinfection with CD4/CD8 ratio is consistent with previously observed associations of HCV coinfection with biomarkers traditionally used to measure immune activation and systemic inflammation in HIV+ patients. These data provide additional support for the use of CD4/CD8 ratio for routine monitoring of immune activation and inflammation in HIV+ patients, including those with HIV/HCV coinfection; however, the unexpected association between cleared HCV and lower CD4/CD8 ratio requires additional study. C1 [Kuniholm, Mark H.; Strickler, Howard D.; Anastos, Kathryn] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Belfer Bldg,Room 1308C,1300 Morris Pk Ave, Bronx, NY 10461 USA. [O'Brien, Thomas R.] NCI, Infect & Immunoepidemiol Branch, Bethesda, MD 20892 USA. [Prokunina-Olsson, Ludmila] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Augenbraun, Michael] Suny Downstate Med Ctr, Dept Med, Brooklyn, NY 11203 USA. [Plankey, Michael] Georgetown Univ, Med Ctr, Dept Med, Washington, DC 20007 USA. [Karim, Roksana] Univ So Calif, Dept Pediat, Los Angeles, CA 90089 USA. [Sarkar, Monika] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [French, Audrey L.] John H Stroger Jr Hosp Cook Cty, CORE Ctr, Dept Med, Chicago, IL USA. [Pierce, Chris] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Anastos, Kathryn] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Anastos, Kathryn] Montefiore Med Ctr, 111 E 210th St, Bronx, NY 10467 USA. RP Kuniholm, MH (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Belfer Bldg,Room 1308C,1300 Morris Pk Ave, Bronx, NY 10461 USA. EM mark.kuniholm@einstein.yu.edu FU National Institute of Allergy and Infectious Diseases (NIAID); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Cancer Institute (NCI); National Institute on Drug Abuse (NIDA); National Institute on Mental Health (NIMH); National Institute of Dental and Craniofacial Research (NIDCR); National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institute on Deafness and other Communication Disorders (NIDCD); NIH Office of Research on Women's Health FX Data in this manuscript were collected by the Women's Interagency HIV Study (WIHS). The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH). WIHS (Principal Investigators): UAB-MS WIHS (Michael Saag, Mirjam-Colette Kempf, and Deborah Konkle-Parker), U01-AI-103401; Atlanta WIHS (Ighovwerha Ofotokun and Gina Wingood), U01-AI-103408; Bronx WIHS (Kathryn Anastos), U01-AI-035004; Brooklyn WIHS (Howard Minkoff and Deborah Gustafson), U01-AI-031834; Chicago WIHS (Mardge Cohen and Audrey French), U01-AI-034993; Metropolitan Washington WIHS (Mary Young), U01-AI-034994; Miami WIHS (Margaret Fischl and Lisa Metsch), U01-AI-103397; UNC WIHS (Adaora Adimora), U01-AI-103390; Connie Wofsy Women's HIV Study, Northern California (Ruth Greenblatt, Bradley Aouizerat, and Phyllis Tien), U01-AI-034989; WIHS Data Management and Analysis Center (Stephen Gange and Elizabeth Golub), U01-AI-042590; and Southern California WIHS (Joel Milam), U01-HD-032632 (WIHS I - WIHS IV). The WIHS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), and the National Institute on Mental Health (NIMH). Targeted supplemental funding for specific projects is also provided by the National Institute of Dental and Craniofacial Research (NIDCR), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute on Deafness and other Communication Disorders (NIDCD), and the NIH Office of Research on Women's Health. WIHS data collection is also supported by UL1-TR000004 (UCSF CTSA) and UL1-TR000454 (Atlanta CTSA). NR 30 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUN 1 PY 2016 VL 72 IS 2 BP 162 EP 170 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DO8UI UT WOS:000378059300016 PM 27183178 ER PT J AU Philbin, MM Tanner, AE DuVal, A Ellen, JM Xu, JH Kapogiannis, B Bethel, J Fortenberry, JD AF Philbin, Morgan M. Tanner, Amanda E. DuVal, Anna Ellen, Jonathan M. Xu, Jiahong Kapogiannis, Bill Bethel, Jim Fortenberry, J. Dennis CA Adolescent Trials Network HIV AIDS TI HIV Testing, Care Referral, and Linkage to Care Intervals Affect Time to Engagement in Care for Newly Diagnosed HIV-Infected Adolescents in 15 Adolescent Medicine Clinics in the United States SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; adolescent; time to linkage; care engagement; care linkage ID ANTIRETROVIRAL THERAPY; POSITIVE ADOLESCENTS; MEASURING RETENTION; YOUNG-ADULTS; PREVENTION; LINKING; CASCADE; STIGMA AB Objective: To examine how the time from HIV testing to care referral and from referral to care linkage influenced time to care engagement for newly diagnosed HIV-infected adolescents. Methods: We evaluated the Care Initiative, a care linkage and engagement program for HIV-infected adolescents in 15 US clinics. We analyzed client-level factors, provider type, and intervals from HIV testing to care referral and from referral to care linkage as predictors of care engagement. Engagement was defined as a second HIV-related medical visit within 16 weeks of initial HIV-related medical visit (linkage). Results: At 32 months, 2143 youth had been referred. Of these, 866 were linked to care through the Care Initiative within 42 days and thus eligible for study inclusion. Of the linked youth, 90.8% were ultimately engaged in care. Time from HIV testing to referral (eg, <= 7 days versus >365 days) was associated with engagement [ adjusted odds ratio = 2.91; 95% confidence interval (CI): 1.43 to 5.94] and shorter time to engagement (adjusted hazard ratio = 1.41; 95% CI: 1.11 to 1.79). Individuals with shorter care referral to linkage intervals (eg, <= 7 days versus 22-42 days) engaged in care faster (adjusted hazard ratio = 2.90; 95% CI: 2.34 to 3.60) and more successfully (adjusted odds ratio = 2.01; 95% CI: 1.04 to 3.89). Conclusions: These data address a critical piece of the care continuum and can offer suggestions of where and with whom to intervene to best achieve the care engagement goals outlined in the US National HIV/AIDS Strategy. These results may also inform programs and policies that set concrete milestones and strategies for optimal care linkage timing for newly diagnosed adolescents. C1 [Philbin, Morgan M.] Columbia Univ, HIV Ctr Clin & Behav Studies, New York, NY USA. [Philbin, Morgan M.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Tanner, Amanda E.] Univ N Carolina, Dept Publ Hlth Educ, Greensboro, NC 27412 USA. [DuVal, Anna] Johns Hopkins Sch Med, Dept Emergency Med, Baltimore, MD USA. [Ellen, Jonathan M.] Johns Hopkins Univ, Sch Med, All Childrens Hosp, Dept Pediat,Johns Hopkins Med, St Petersburg, FL USA. [Xu, Jiahong; Bethel, Jim] Westat Corp, Rockville, MD USA. [Kapogiannis, Bill] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, Bethesda, MD USA. [Fortenberry, J. Dennis] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. RP Philbin, MM (reprint author), NY State Psychiat Inst, HIV Ctr Clin & Behav Studies, New York, NY USA.; Philbin, MM (reprint author), Columbia Univ, New York, NY USA. EM mp3243@cumc.columbia.edu FU National Institutes of Health through the National Institute of Child Health and Human Development [5 U01 HD 40533, 5 U01 HD 40474]; National Institutes on Drug Abuse; Mental Health; American Recovery and Reinvestment Act [3 U01 HD 040533-09S1]; National Institute of Mental Health at the HIV Center for Clinical and Behavioral Studies at NY State Psychiatric Institute [T32 MH19139]; Columbia University [P30-MH43520] FX Supported by grants to the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN): 5 U01 HD 40533 and 5 U01 HD 40474 from the National Institutes of Health through the National Institute of Child Health and Human Development (B.K., MD; Sonia Lee, PhD) with supplemental funding from the National Institutes on Drug Abuse (Shoshana Kahana, PhD) and Mental Health (Susannah Allison, PhD; Pim Brouwers, PhD). Additional support was provided by an administrative supplement, 3 U01 HD 040533-09S1, awarded through funds from the American Recovery and Reinvestment Act of 2009. The study was scientifically reviewed by the ATN Community Prevention Leadership Group. Network, scientific, and logistical support was provided by the ATN Coordinating Center (Craig Wilson, MD; Cynthia Partlow, MEd). Project support and coordination was provided by the ATN Data and Operations Center at Westat, Inc. (Jim Korelitz, PhD; Barbara Driver, RN, MS). Dr. Philbin was supported by a training grant from the National Institute of Mental Health (T32 MH19139, Behavioral Sciences Research in HIV Infection; Principal Investigator: Theo Sandfort, PhD) at the HIV Center for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University (P30-MH43520; Principal Investigator: Robert H. Remien, PhD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or DHHS. NR 30 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUN 1 PY 2016 VL 72 IS 2 BP 222 EP 229 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DO8UI UT WOS:000378059300024 PM 26885804 ER PT J AU Falchook, AD Green, R Knowles, ME Amdur, RJ Mendenhall, W Hayes, DN Grilley-Olson, JE Weiss, J Reeve, BB Mitchell, SA Basch, EM Chera, BS AF Falchook, Aaron D. Green, Rebecca Knowles, Mary E. Amdur, Robert J. Mendenhall, William Hayes, David N. Grilley-Olson, Juneko E. Weiss, Jared Reeve, Bryce B. Mitchell, Sandra A. Basch, Ethan M. Chera, Bhishamjit S. TI Comparison of Patient-and Practitioner-Reported Toxic Effects Associated With Chemoradiotherapy for Head and Neck Cancer SO JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Article ID SQUAMOUS-CELL CARCINOMA; RADIATION-THERAPY; CLINICIAN; OUTCOMES; SYSTEM; CHEMORADIATION; SYMPTOMS; ONCOLOGY; SURVIVAL; TRIAL AB IMPORTANCE Agreement between patient-and practitioner-reported toxic effects during chemoradiotherapy for head and neck cancer is unknown. OBJECTIVE To compare patient-reported symptom severity and practitioner-reported toxic effects among patients receiving chemoradiotherapy for head and neck cancer. DESIGN, SETTING, AND PARTICIPANTS Forty-four patients participating in a phase 2 trial of deintensified chemoradiotherapy for oropharyngeal carcinoma were included in the present study (conducted from February 8, 2012, to March 2, 2015). Most treatment (radiotherapy, 60 Gy, with concurrent weekly administration of cisplatin, 30mg/m(2)) was administered at academic medical centers. Included patients had no prior head and neck cancers, were 18 years or older, and had a smoking history of 10 pack-years or less or more than 10 pack-years but 30 pack-years or less and abstinent for the past 5 years. Cancer status was untreated human papillomavirus or p16-positive squamous cell carcinoma of the oropharynx or unknown head and neck primary site; and cancer staging was category T0 to T3, category N0 to N2c, M0, and Eastern Cooperative Oncology Group performance status 0 to 1. Baseline, weekly, and posttreatment toxic effects were assessed by physicians or nurse practitioners using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Patient-reported symptom severity was measured using the Patient-Reported Outcomes version of the CTCAE (PRO-CTCAE). Descriptive statistics were used to characterize raw agreement between CTCAE grades and PRO-CTCAE severity ratings. INTERVENTIONS Baseline, weekly, and posttreatment toxic effects assessed using CTCAE, version 4.0, and PRO-CTCAE. MAIN OUTCOMES AND MEASURES Rawagreement indices between patient-reported toxic effects, including symptom frequency, severity, and interference with daily activities (score range, 0 [none] to 4 [very severe]), and practitioner-measured toxic effects, including swallowing, oral pain, and hoarseness (score range, 1 [mild] to 5 [death]). RESULTS Of the 44 patients included in the analysis (39 men, 5 women; mean [SD] age, 61 [8.4] years), there were 327 analyzable pairs of CTCAE and PRO-CTCAE symptom surveys and no treatment delays due to toxic effects. Patient-reported and practitioner-reported symptom severity agreement was high at baseline when most symptoms were absent but declined throughout treatment as toxic effects increased. Most disagreement was due to lower severity of toxic effects reported by practitioners (eg, from 45% agreement at baseline to 27% at the final week of treatment for pain). This was particularly noted for domains that are not easily evaluated by physical examination, such as anxiety and fatigue (eg, severity of fatigue decreased from 43% at baseline to 12% in the final week of treatment). CONCLUSIONS AND RELEVANCE Practitioner-reported toxic effects are lower than patient self-reports during head and neck chemoradiotherapy. The inclusion of patient-reported symptomatic toxic effects provides information that can potentially enhance clinical management and improve data quality in clinical trials. C1 [Falchook, Aaron D.; Green, Rebecca; Knowles, Mary E.; Chera, Bhishamjit S.] Univ N Carolina, Dept Radiat Oncol, 101 Manning Dr,CB 7512, Chapel Hill, NC 27599 USA. [Amdur, Robert J.; Mendenhall, William] Univ Florida Hosp, Dept Radiat Oncol, Gainesville, FL USA. [Amdur, Robert J.; Mendenhall, William] Univ Florida Hosp, Shands Canc Ctr, Gainesville, FL USA. [Hayes, David N.; Grilley-Olson, Juneko E.; Weiss, Jared; Basch, Ethan M.; Chera, Bhishamjit S.] Univ N Carolina, Lineberger Comprehens Canc Ctr, 101 Manning Dr,CB 7512, Chapel Hill, NC 27599 USA. [Hayes, David N.; Grilley-Olson, Juneko E.; Weiss, Jared; Basch, Ethan M.] Univ N Carolina, Div Hematol Oncol, 101 Manning Dr,CB 7512, Chapel Hill, NC 27599 USA. [Reeve, Bryce B.] Univ N Carolina, Gillings Sch Global Publ Hlth, 101 Manning Dr,CB 7512, Chapel Hill, NC 27599 USA. [Mitchell, Sandra A.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. RP Chera, BS (reprint author), Univ N Carolina, Dept Radiat Oncol, 101 Manning Dr,CB 7512, Chapel Hill, NC 27599 USA. EM bchera@med.unc.edu FU AstraZeneca; Biodesix FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Weiss reported receiving personal fees from AstraZeneca and Biodesix and grants from Astellas, AstraZeneca, Celgene, Merck, and Novartis outside the submitted work. No other disclosures were reported. NR 24 TC 1 Z9 1 U1 5 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6181 EI 2168-619X J9 JAMA OTOLARYNGOL JI JAMA Otolaryngol-Head Neck Surg. PD JUN PY 2016 VL 142 IS 6 BP 517 EP 523 DI 10.1001/jamaoto.2016.0656 PG 7 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA DO6ZU UT WOS:000377932800002 PM 27149571 ER PT J AU Haider, AH Dankwa-Mullan, I Maragh-Bass, AC Torain, M Zogg, CK Lilley, EJ Kodadek, LM Changoor, NR Najjar, P Rose, JA Ford, HR Salim, A Stain, SC Shafi, S Sutton, B Hoyt, D Maddox, YT Britt, LD AF Haider, Adil H. Dankwa-Mullan, Irene Maragh-Bass, Allysha C. Torain, Maya Zogg, Cheryl K. Lilley, Elizabeth J. Kodadek, Lisa M. Changoor, Navin R. Najjar, Peter Rose, John A., Jr. Ford, Henri R. Salim, Ali Stain, Steven C. Shafi, Shahid Sutton, Beth Hoyt, David Maddox, Yvonne T. Britt, L. D. TI Setting a National Agenda for Surgical Disparities Research Recommendations From the National Institutes of Health and American College of Surgeons Summit SO JAMA SURGERY LA English DT Review ID TRAUMATIC BRAIN-INJURY; OVARIAN-CANCER CARE; SPINAL-CORD-INJURY; CELL LUNG-CANCER; RACIAL DISPARITIES; SOCIOECONOMIC-STATUS; UNITED-STATES; INSURANCE STATUS; RACIAL/ETHNIC DISPARITIES; ETHNIC DISPARITIES AB Health care disparities (differential access, care, and outcomes owing to factors such as race/ethnicity) are widely established. Compared with other groups, African American individuals have an increased mortality risk across multiple surgical procedures. Gender, sexual orientation, age, and geographic disparities are also well documented. Further research is needed to mitigate these inequities. To do so, the American College of Surgeons and the National Institutes of Health-National Institute of Minority Health and Disparities convened a research summit to develop a national surgical disparities research agenda and funding priorities. Sixty leading researchers and clinicians gathered in May 2015 for a 2-day summit. First, literature on surgical disparities was presented within 5 themes: (1) clinician, (2) patient, (3) systemic/access, (4) clinical quality, and (5) postoperative care and rehabilitation-related factors. These themes were identified via an exhaustive preconference literature review and guided the summit and its interactive consensus-building exercises. After individual thematic presentations, attendees contributed research priorities for each theme. Suggestions were collated, refined, and prioritized during the latter half of the summit. Breakout sessions yielded 3 to 5 top research priorities by theme. Overall priorities, regardless of theme, included improving patient-clinician communication, fostering engagement and community outreach by using technology, improving care at facilities with a higher proportion of minority patients, evaluating the longer-term effect of acute intervention and rehabilitation support, and improving patient centeredness by identifying expectations for recovery. The National Institutes of Health and American College of Surgeons Summit on Surgical Disparities Research succeeded in identifying a comprehensive research agenda. Future research and funding priorities should prioritize patients' care perspectives, workforce diversification and training, and systematic evaluation of health technologies to reduce surgical disparities. C1 [Haider, Adil H.; Maragh-Bass, Allysha C.; Torain, Maya; Zogg, Cheryl K.; Lilley, Elizabeth J.; Changoor, Navin R.; Najjar, Peter; Rose, John A., Jr.; Salim, Ali] Harvard Univ, Sch Med, Ctr Surg & Publ Hlth, Boston, MA USA. [Haider, Adil H.; Maragh-Bass, Allysha C.; Torain, Maya; Zogg, Cheryl K.; Lilley, Elizabeth J.; Changoor, Navin R.; Najjar, Peter; Rose, John A., Jr.; Salim, Ali] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Haider, Adil H.; Maragh-Bass, Allysha C.; Torain, Maya; Zogg, Cheryl K.; Lilley, Elizabeth J.; Changoor, Navin R.; Najjar, Peter; Rose, John A., Jr.; Salim, Ali] Brigham & Womens Hosp, Dept Surg, 1620 Tremont St,Ste 4-020, Boston, MA 02120 USA. [Dankwa-Mullan, Irene] NIMHHD, NIH, Bethesda, MD USA. [Kodadek, Lisa M.] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA. [Ford, Henri R.] Univ So Calif, Childrens Hosp Los Angeles, Dept Gen Pediat Surg, Los Angeles, CA USA. [Stain, Steven C.] Albany Med Coll, Dept Surg, Albany, NY 12208 USA. [Shafi, Shahid] Baylor Scott & White Hlth Syst, Off Chief Qual Officer, Dallas, TX USA. [Sutton, Beth] Kell West Reg Hosp, United Reg Hosp, Div Gen Surg, Wichita Falls, TX USA. [Hoyt, David] Amer Coll Surg, Chicago, IL USA. [Maddox, Yvonne T.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Britt, L. D.] Eastern Virginia Med Sch, Dept Surg, Norfolk, VA 23501 USA. RP Haider, AH (reprint author), Brigham & Womens Hosp, Dept Surg, Ctr Surg & Publ Hlth, 1620 Tremont St,Ste 4-020, Boston, MA 02120 USA. EM ahhaider@partners.org FU American College of Surgeons FX The American College of Surgeons provided financial support for travel expenses and conference organization materials for our invited guests. Summit attendees were not provided honoraria for their attendance and participation. NR 89 TC 10 Z9 10 U1 3 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6254 EI 2168-6262 J9 JAMA SURG JI JAMA Surg. PD JUN PY 2016 VL 151 IS 6 BP 554 EP 563 DI 10.1001/jamasurg.2016.0014 PG 10 WC Surgery SC Surgery GA DO6ZT UT WOS:000377932700016 PM 26982380 ER PT J AU Yuan, C Clish, CB Wu, C Mayers, JR Kraft, P Townsend, MK Zhang, MF Tworoger, SS Bao, Y Qian, ZR Rubinson, DA Ng, K Giovannucci, EL Ogino, S Stampfer, MJ Gaziano, JM Ma, J Sesso, HD Anderson, GL Cochrane, BB Manson, JE Torrence, ME Kimmelman, AC Amundadottir, LT Heiden, MGV Fuchs, CS Wolpin, BM AF Yuan, Chen Clish, Clary B. Wu, Chen Mayers, Jared R. Kraft, Peter Townsend, Mary K. Zhang, Mingfeng Tworoger, Shelley S. Bao, Ying Qian, Zhi Rong Rubinson, Douglas A. Ng, Kimmie Giovannucci, Edward L. Ogino, Shuji Stampfer, Meir J. Gaziano, John Michael Ma, Jing Sesso, Howard D. Anderson, Garnet L. Cochrane, Barbara B. Manson, JoAnn E. Torrence, Margaret E. Kimmelman, Alec C. Amundadottir, Laufey T. Heiden, Matthew G. Vander Fuchs, Charles S. Wolpin, Brian M. TI Circulating Metabolites and Survival Among Patients With Pancreatic Cancer SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ASSOCIATIONS; COHORT; HEALTH; 2-HYDROXYGLUTARATE; ADENOCARCINOMA; IDENTIFICATION; GEMCITABINE; MUTATIONS; CARCINOMA; VARIANTS AB Background: Pancreatic tumors cause changes in whole-body metabolism, but whether prediagnostic circulating metabolites predict survival is unknown. Methods: We measured 82 metabolites by liquid chromatography-mass spectrometry in prediagnostic plasma from 484 pancreatic cancer case patients enrolled in four prospective cohort studies. Association of metabolites with survival was evaluated using Cox proportional hazards models adjusted for age, cohort, race/ethnicity, cancer stage, fasting time, and diagnosis year. After multiple-hypothesis testing correction, a P value of .0006 or less (.05/82) was considered statistically significant. Based on the results, we evaluated 33 tagging single-nucleotide polymorphisms (SNPs) in the ACO1 gene, requiring a P value of less than .002 (.05/33) for statistical significance. All statistical tests were two-sided. Results: Two metabolites in the tricarboxylic acid (TCA) cycle-isocitrate and aconitate-were statistically significantly associated with survival. Participants in the highest vs lowest quintile had hazard ratios (HRs) for death of 1.89 (95% confidence interval [CI] = 1.06 to 3.35, P-trend <.001) for isocitrate and 2.54 (95% CI = 1.42 to 4.54, P-trend <.001) for aconitate. Isocitrate is interconverted with citrate via the intermediate aconitate in a reaction catalyzed by the enzyme aconitase 1 (ACO1). Therefore, we investigated the citrate to aconitate plus isocitrate ratio and SNPs in the ACO1 gene. The ratio was strongly associated with survival (P-trend <.001) as was the SNP rs7874815 in the ACO1 gene (hazard ratio for death per minor allele = 1.37, 95% CI = 1.16 to 1.61, P < .001). Patients had an approximately three-fold hazard for death when possessing one or more minor alleles at rs7874851 and high aconitate or isocitrate. Conclusions: Prediagnostic circulating levels of TCA cycle intermediates and inherited ACO1 genotypes were associated with survival among patients with pancreatic cancer. C1 [Yuan, Chen; Qian, Zhi Rong; Rubinson, Douglas A.; Ng, Kimmie; Ogino, Shuji; Heiden, Matthew G. Vander; Fuchs, Charles S.; Wolpin, Brian M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Yuan, Chen; Qian, Zhi Rong; Rubinson, Douglas A.; Ng, Kimmie; Ogino, Shuji; Heiden, Matthew G. Vander; Fuchs, Charles S.; Wolpin, Brian M.] Harvard Univ, Sch Med, Boston, MA USA. [Clish, Clary B.; Heiden, Matthew G. Vander] Broad Inst MIT & Harvard Univ, Cambridge, MA USA. [Wu, Chen] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Etiol & Carcinogenesis, Beijing 100730, Peoples R China. [Wu, Chen] Peking Union Med Coll, Beijing 100021, Peoples R China. [Mayers, Jared R.; Torrence, Margaret E.; Heiden, Matthew G. Vander] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Mayers, Jared R.; Torrence, Margaret E.; Heiden, Matthew G. Vander] MIT, Dept Biol, Cambridge, MA USA. [Kraft, Peter; Tworoger, Shelley S.; Giovannucci, Edward L.; Ogino, Shuji; Stampfer, Meir J.; Ma, Jing; Sesso, Howard D.; Manson, JoAnn E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Giovannucci, Edward L.; Stampfer, Meir J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Townsend, Mary K.; Tworoger, Shelley S.; Bao, Ying; Giovannucci, Edward L.; Stampfer, Meir J.; Ma, Jing; Manson, JoAnn E.; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Gaziano, John Michael; Sesso, Howard D.; Manson, JoAnn E.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Zhang, Mingfeng; Amundadottir, Laufey T.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Gaziano, John Michael] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA USA. [Anderson, Garnet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Cochrane, Barbara B.] Univ Washington, Sch Nursing, Seattle, WA 98195 USA. [Kimmelman, Alec C.] Dana Farber Canc Inst, Dept Radiat Oncol, Div Genom Stabil & DNA Repair, Boston, MA 02115 USA. RP Wolpin, BM (reprint author), 450 Brookline Ave, Boston, MA 02215 USA. EM bwolpin@partners.org OI Mayers, Jared/0000-0002-8607-1787 FU National Institutes of Health (NIH) [UM1 CA167552]; NIH [UM1 CA186107, P01 CA87969, R01 CA49449, CA 97193, CA 34944, CA 40360, HL 26490, HL 34595, N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221, R01 CA124908, P50 CA127003]; Nestle Research Center award NIH; Robert T. and Judith B. Hale Fund for Pancreatic Cancer; Perry S. Levy Fund for Gastrointestinal Cancer Research; Pappas Family Research Fund for Pancreatic Cancer; Department of Defense [CA130288]; Howard Hughes Medical Institute; Lustgarten Foundation; Promises for Purple FX HPFS is supported by National Institutes of Health (NIH) grant UM1 CA167552. NHS is supported by NIH grants UM1 CA186107, P01 CA87969, and R01 CA49449. PHS is supported by NIH grants CA 97193, CA 34944, CA 40360, HL 26490, and HL 34595. The Women's Health Initiative (WHI) program is funded by the NIH through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221.; Additional support came from a Nestle Research Center award to the Broad Institute; from the Robert T. and Judith B. Hale Fund for Pancreatic Cancer, Perry S. Levy Fund for Gastrointestinal Cancer Research, Pappas Family Research Fund for Pancreatic Cancer, NIH R01 CA124908, and NIH P50 CA127003 to CSF; and from Department of Defense CA130288, Howard Hughes Medical Institute, Lustgarten Foundation, and Promises for Purple to BMW. NR 45 TC 3 Z9 3 U1 4 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 JUN PY 2016 VL 108 IS 6 AR djv409 DI 10.1093/jnci/djv409 PG 8 WC Oncology SC Oncology GA DP2CS UT WOS:000378296300006 PM 26755275 ER PT J AU Kasoff, LI Ahn, K Gochman, P Broadnax, DD Rapoport, JL AF Kasoff, Lauren I. Ahn, Kwangmi Gochman, Peter Broadnax, Diane D. Rapoport, Judith L. TI Strong Treatment Response and High Maintenance Rates of Clozapine in Childhood-Onset Schizophrenia SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID HIGH-DOSE OLANZAPINE; TREATMENT-RESISTANT SCHIZOPHRENIA; DEFICIT HYPERACTIVITY DISORDER; DOUBLE-BLIND; REFRACTORY SCHIZOPHRENIA; SPECTRUM DISORDERS; TEMPORAL-LOBE; CHILDREN; ADOLESCENTS; RISPERIDONE AB Objective: Childhood-onset schizophrenia (COS) is a rare but severe form of the disorder, which is often treatment refractory. Short-term studies have indicated a greater differential efficacy, evident through effect sizes, favoring clozapine over other agents in alleviating negative symptoms in COS patients compared with adult-onset patients (AOS). There have been no data for COS patients on long-term compliance with clozapine treatment. Therefore, we wanted to know, over a span of up to 24 years, how many of our COS cohort had remained on clozapine for at least 2 years. We review short-term treatment data and present updated long-term data on compliance and functioning for our patients. Methods: Wepresent the results for long-term medication maintenance over a 24 year observation period for our cohort of 131 patients. Of this cohort, 91.6% (120) were available for follow-up information from either in-person or telephone contact with the patient and/or family members. We defined clozapine compliance as >= 2 years receiving this medication and doing well. Results: We were able to contact 120 of the 131 patients. In spite of the additional cost and inconvenience of regular blood monitoring, 87 patients (72.5%, 87/120) adhered to long-term clozapine maintenance therapy with dosages ranging from 50 to 900 mg, and a median dosage of 500 mg. This rate exceeds the long-term clozapine maintenance rates reported for AOS patients. Conclusions: Short-term data on differential efficacy and long-term maintenance data suggest a possibly greater efficacy of clozapine, relative to other antipsychotics, in COS than in AOS. Our overall findings indicate that very early-onset schizophrenic patients may be more responsive to clozapine. This extends other support for clozapine as an option in the treatment of early-onset schizophrenia. C1 [Kasoff, Lauren I.; Ahn, Kwangmi; Gochman, Peter; Broadnax, Diane D.; Rapoport, Judith L.] NIMH, Child Psychiat Branch, Div Intramural Res Program, Bldg 10, Bethesda, MD 20892 USA. RP Kasoff, LI (reprint author), Magnuson Clin Ctr, Room 4N244,MSC 1600, Bethesda, MD 20814 USA. EM Kasoffl14@mail.wlu.edu FU NIMH [NCT00049738 03-M-0035] FX This research was supported by the Intramural Research Program of the NIMH. NCT00049738 03-M-0035 NR 57 TC 1 Z9 1 U1 31 U2 31 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 EI 1557-8992 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD JUN PY 2016 VL 26 IS 5 BP 428 EP 435 DI 10.1089/cap.2015.0103 PG 8 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA DO8QJ UT WOS:000378048100003 PM 26784704 ER PT J AU Lin, CT Leibovitch, E Almira-Suarez, MI Jacobson, S AF Lin, Cheng-Te Leibovitch, Emily Almira-Suarez, M. Isabel Jacobson, Steven TI Human Herpesvirus Multiplex ddPCR Detection in Brain Tissue from Low- and High-Grade Astrocytoma Cases and Controls SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 92nd Annual Meeting of the American-Association-of-Neuropathologist-Inc CY JUN 16-19, 2016 CL Baltimore, MD SP Amer Assoc Neuropathologist Inc C1 [Lin, Cheng-Te; Leibovitch, Emily; Jacobson, Steven] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Lin, Cheng-Te; Leibovitch, Emily; Almira-Suarez, M. Isabel] George Washington Univ, Washington, DC 20052 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 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUN PY 2016 VL 75 IS 6 MA 53 BP 581 EP 581 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA DO3FC UT WOS:000377665000062 ER PT J AU Mente, K Nair, G Reich, D Ray-Chaudhury, A Pratt, D Edwards, N Horovitz, S Hallett, M AF Mente, Karin Nair, Govind Reich, Daniel Ray-Chaudhury, Abhik Pratt, Drew Edwards, Nancy Horovitz, Silvina Hallett, Mark TI Histological Validation of High Field MRI of the Human Brainstem SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 92nd Annual Meeting of the American-Association-of-Neuropathologist-Inc CY JUN 16-19, 2016 CL Baltimore, MD SP Amer Assoc Neuropathologist Inc C1 [Mente, Karin; Horovitz, Silvina; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Nair, Govind; Reich, Daniel] NINDS, Translat Neuroradiol Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Ray-Chaudhury, Abhik; Edwards, Nancy] NINDS, Neuropathol Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Pratt, Drew] NCI, Pathol Lab, NIH, 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 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUN PY 2016 VL 75 IS 6 MA 80 BP 588 EP 589 PG 2 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA DO3FC UT WOS:000377665000089 ER PT J AU Darbinyan, A Major, E Morgello, S Fowkes, M Naidich, T Holland, S Malaczynska, J Ryschkewitsch, C Monaco, MC Bederson, J Ye, F Gordon, R Cunningham-Rundles, C Ray-Chaudhury, A Tsankova, N AF Darbinyan, Armine Major, Eugene Morgello, Susan Fowkes, Mary Naidich, Thomas Holland, Steven Malaczynska, Joanna Ryschkewitsch, Caroline Monaco, Maria Chiara Bederson, Joshua Ye, Fei Gordon, Ronald Cunningham-Rundles, Charlotte Ray-Chaudhury, Abhik Tsankova, Nadejda TI BK Virus Encephalopathy and Sclerosing Vasculopathy in a Patient with Hypohidrotic Ectodermal Dysplasia and Immunodeficiency SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 92nd Annual Meeting of the American-Association-of-Neuropathologist-Inc CY JUN 16-19, 2016 CL Baltimore, MD SP Amer Assoc Neuropathologist Inc C1 [Darbinyan, Armine; Morgello, Susan; Fowkes, Mary; Malaczynska, Joanna; Ye, Fei; Gordon, Ronald; Tsankova, Nadejda] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA. [Major, Eugene; Ryschkewitsch, Caroline; Monaco, Maria Chiara] Lab Mol Med & Neurosci, Bethesda, MD 20892 USA. [Naidich, Thomas] Mt Sinai Med Ctr, Dept Radiol, New York, NY 10029 USA. [Holland, Steven] NIAID, Lab Clin Infect Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Bederson, Joshua] Mt Sinai Med Ctr, Dept Neurosurg, New York, NY 10029 USA. [Cunningham-Rundles, Charlotte] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. [Ray-Chaudhury, Abhik] 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 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUN PY 2016 VL 75 IS 6 MA 85 BP 590 EP 590 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA DO3FC UT WOS:000377665000094 ER PT J AU Safar, J Foutz, A Appleby, B Cohen, M Xiao, JX Hamlin, C Cohen, Y Chen, W Blevins, J Gambetti, P Hughson, A Schonberger, L Caughey, B AF Safar, Jiri Foutz, Aaron Appleby, Brian Cohen, Mark Xiao, Jianxin Hamlin, Clive Cohen, Yvonne Chen, Wei Blevins, Janis Gambetti, Pierluigi Hughson, Andrew Schonberger, Lawrence Caughey, Byron TI New Ultrasensitive Tests for Diagnosis and Differentiation of Human Prion Diseases SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 92nd Annual Meeting of the American-Association-of-Neuropathologist-Inc CY JUN 16-19, 2016 CL Baltimore, MD SP Amer Assoc Neuropathologist Inc C1 [Safar, Jiri; Foutz, Aaron; Appleby, Brian; Cohen, Mark; Xiao, Jianxin; Hamlin, Clive; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Gambetti, Pierluigi] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Hughson, Andrew; Caughey, Byron] NIH, Rocky Mt Labs, Hamilton, MT USA. [Schonberger, Lawrence] Ctr Dis Control & Prevent, Atlanta, GA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUN PY 2016 VL 75 IS 6 MA 99 BP 594 EP 594 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA DO3FC UT WOS:000377665000108 ER PT J AU Bell, W Pletnikova, O An, Y Kageyama, Y Crain, B Rudow, G Moghekar, A Thambisetty, M Albert, M Resnick, S Rabins, P Troncoso, J AF Bell, William Pletnikova, Olga An, Yang Kageyama, Yusuke Crain, Barbara Rudow, Gay Moghekar, Abhay Thambisetty, Madhav Albert, Marilyn Resnick, Susan Rabins, Peter Troncoso, Juan TI A Pathologic and Cognitive Comparison of Primary Age-Related Tauopathy (PART) to Alzheimer's Disease SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 92nd Annual Meeting of the American-Association-of-Neuropathologist-Inc CY JUN 16-19, 2016 CL Baltimore, MD SP Amer Assoc Neuropathologist Inc C1 [Bell, William] Johns Hopkins Sch Med, Neuropathol, Baltimore, MD USA. [Pletnikova, Olga; Kageyama, Yusuke; Rudow, Gay] Johns Hopkins Pathol, Baltimore, MD USA. [An, Yang] NIA, Baltimore, MD 21224 USA. [Crain, Barbara] Johns Hopkins Sch Med, Pathol Neurol Oncol, Baltimore, MD USA. [Moghekar, Abhay] Johns Hopkins Univ Hosp, Neurol, Baltimore, MD 21287 USA. [Thambisetty, Madhav; Resnick, Susan] NIA, NIH, Baltimore, MD 21224 USA. [Albert, Marilyn] Johns Hopkins Sch Med, Neurol Neurosci Pathol, Baltimore, MD USA. [Rabins, Peter] Johns Hopkins Sch Med, Psychiat, Baltimore, MD USA. [Troncoso, Juan] Johns Hopkins Sch Med, Pathol & Neurol, Baltimore, MD 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 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUN PY 2016 VL 75 IS 6 MA 124 BP 601 EP 601 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA DO3FC UT WOS:000377665000133 ER PT J AU Tempero, M AF Tempero, Margaret TI Did the IRB Approve This? SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Editorial Material C1 [Tempero, Margaret] Univ Calif San Francisco, Pancreas Ctr, Med, San Francisco, CA 94143 USA. [Tempero, Margaret] Univ Calif San Francisco, Pancreas Ctr, San Francisco, CA 94143 USA. [Tempero, Margaret] ASCO Board Directors, Alexandria, VA 22314 USA. [Tempero, Margaret] ASCO, Alexandria, VA 22314 USA. [Tempero, Margaret] ASCO, Conquer Canc Fdn Board, Alexandria, VA 22314 USA. [Tempero, Margaret] AACR ASCO Methods Clin Canc Res, Alexandria, VA 22314 USA. [Tempero, Margaret] NCI, Clin Oncol Study Sect, Bethesda, MD 20892 USA. [Tempero, Margaret] NCI, Board Sci Counselors Subcomm A, Bethesda, MD 20892 USA. [Tempero, Margaret] Lustgarten Fdn, Sci Advisory Boards, Bethpage, NY 11714 USA. [Tempero, Margaret] Pancreat Canc Act Network, Manhattan Beach, CA USA. [Tempero, Margaret] V Fdn, Cary, NC 27513 USA. [Tempero, Margaret] Alberta Canada Canc Board, Edmonton, AB, Canada. [Tempero, Margaret] EORTC, Brussels, Belgium. [Tempero, Margaret] UNMC, Eppley Canc Ctr, Omaha, NE 68198 USA. [Tempero, Margaret] Univ Calif San Francisco, Eppley Canc Ctr, San Francisco, CA 94143 USA. [Tempero, Margaret] Univ Calif San Francisco, Div Med Oncol, San Francisco, CA 94143 USA. [Tempero, Margaret] Univ Calif San Francisco, Res Programs, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. RP Tempero, M (reprint author), Univ Calif San Francisco, Pancreas Ctr, Med, San Francisco, CA 94143 USA.; Tempero, M (reprint author), Univ Calif San Francisco, Pancreas Ctr, San Francisco, CA 94143 USA.; Tempero, M (reprint author), ASCO Board Directors, Alexandria, VA 22314 USA.; Tempero, M (reprint author), ASCO, Alexandria, VA 22314 USA.; Tempero, M (reprint author), ASCO, Conquer Canc Fdn Board, Alexandria, VA 22314 USA.; Tempero, M (reprint author), AACR ASCO Methods Clin Canc Res, Alexandria, VA 22314 USA.; Tempero, M (reprint author), Lustgarten Fdn, Sci Advisory Boards, Bethpage, NY 11714 USA.; Tempero, M (reprint author), Pancreat Canc Act Network, Manhattan Beach, CA USA.; Tempero, M (reprint author), V Fdn, Cary, NC 27513 USA.; Tempero, M (reprint author), Alberta Canada Canc Board, Edmonton, AB, Canada.; Tempero, M (reprint author), EORTC, Brussels, Belgium.; Tempero, M (reprint author), UNMC, Eppley Canc Ctr, Omaha, NE 68198 USA.; Tempero, M (reprint author), Univ Calif San Francisco, Eppley Canc Ctr, San Francisco, CA 94143 USA.; Tempero, M (reprint author), Univ Calif San Francisco, Div Med Oncol, San Francisco, CA 94143 USA.; Tempero, M (reprint author), Univ Calif San Francisco, Res Programs, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD JUN PY 2016 VL 14 IS 6 BP 699 EP 699 PG 1 WC Oncology SC Oncology GA DO3OE UT WOS:000377690100001 PM 27283161 ER PT J AU Puumala, SE Burgess, KM Kharbanda, AB Zook, HG Castille, DM Pickner, WJ Payne, NR AF Puumala, Susan E. Burgess, Katherine M. Kharbanda, Anupam B. Zook, Heather G. Castille, Dorothy M. Pickner, Wyatt J. Payne, Nathaniel R. TI The Role of Bias by Emergency Department Providers in Care for American Indian Children SO MEDICAL CARE LA English DT Article DE American Indian health; bias; emergency medicine; pediatrics ID IMPLICIT ASSOCIATION TEST; CLINICAL DECISION-MAKING; ALASKA NATIVE CHILDREN; HEALTH-CARE; EXPLICIT ATTITUDES; ETHNIC DISPARITIES; MEDICAL-STUDENTS; UNCONSCIOUS RACE; US CHILDREN; PREJUDICE AB Background: American Indian children have high rates of emergency department (ED) use and face potential discrimination in health care settings. Objective: Our goal was to assess both implicit and explicit racial bias and examine their relationship with clinical care. Research Design: We performed a cross-sectional survey of care providers at 5 hospitals in the Upper Midwest. Questions included American Indian stereotypes (explicit attitudes), clinical vignettes, and the Implicit Association Test. Two Implicit Association Tests were created to assess implicit bias toward the child or the parent/caregiver. Differences were assessed using linear and logistic regression models with a random effect for study site. Results: A total of 154 care providers completed the survey. Agreement with negative American Indian stereotypes was 22%-32%. Overall, 84% of providers had an implicit preference for nonHispanic white adults or children. Older providers (50 y and above) had lower implicit bias than those middle aged (30-49 y) (P = 0.01). American Indian children were seen as increasingly challenging (P = 0.04) and parents/caregivers less compliant (P = 0.002) as the proportion of American Indian children seen in the ED increased. Responses to the vignettes were not related to implicit or explicit bias. Conclusions: The majority of ED care providers had an implicit preference for non-Hispanic white children or adults compared with those who were American Indian. Provider agreement with negative American Indian stereotypes differed by practice and respondents' characteristics. These findings require additional study to determine how these implicit and explicit biases influence health care or outcomes disparities. C1 [Puumala, Susan E.; Burgess, Katherine M.; Pickner, Wyatt J.] Sanford Res, Ctr Hlth Outcomes & Prevent Res, 2301 East 60th St North, Sioux Falls, SD 57104 USA. [Puumala, Susan E.] Univ S Dakota, Dept Pediat, Sanford Sch Med, Sioux Falls, SD USA. [Burgess, Katherine M.] Univ Colorado Denver, Dept Epidemiol, Colorado Sch Publ Hlth, Aurora, CO USA. [Kharbanda, Anupam B.] Childrens Hosp & Clin Minnesota, Dept Emergency Med, Minneapolis, MN USA. [Zook, Heather G.; Payne, Nathaniel R.] Childrens Hosp & Clin Minnesota, Dept Res & Sponsored Programs, Minneapolis, MN USA. [Castille, Dorothy M.] Natl Inst Minor Hlth & Hlth Dispar, Div Extramural Sci Programs, NIH, Bethesda, MD USA. [Payne, Nathaniel R.] Childrens Hosp & Clin Minnesota, Dept Qual, Minneapolis, MN USA. Childrens Hosp & Clin Minnesota, Dept Safety, Minneapolis, MN USA. RP Puumala, SE (reprint author), Sanford Res, Ctr Hlth Outcomes & Prevent Res, 2301 East 60th St North, Sioux Falls, SD 57104 USA. EM susan.puumala@sanfordhealth.org FU National Institute on Minority Health and Health Disparities of the National Institutes of Health [U54MD008164] FX Supported by the National Institute on Minority Health and Health Disparities of the National Institutes of Health, Award Number U54MD008164. 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 1 Z9 1 U1 6 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD JUN PY 2016 VL 54 IS 6 BP 562 EP 569 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DO8UR UT WOS:000378060400004 PM 26974675 ER PT J AU Kumar, A Chalamalasetty, RB Kennedy, MW Thomas, S Inala, SN Garriock, RJ Yamaguchi, TP AF Kumar, Amit Chalamalasetty, Ravindra B. Kennedy, Mark W. Thomas, Sara Inala, Shreya N. Garriock, Robert J. Yamaguchi, Terry P. TI Zfp703 Is a Wnt/beta-Catenin Feedback Suppressor Targeting the beta-Catenin/Tcf1 Complex SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID BETA-CATENIN; EMBRYONIC STEM; MESODERM DEVELOPMENT; PRESOMITIC MESODERM; NEGATIVE REGULATOR; COLORECTAL-CANCER; AXIS FORMATION; IN-VITRO; WNT; GENE AB The Wnt/beta-catenin signaling pathway controls embryonic development and adult stem cell maintenance through the regulation of transcription. Failure to downregulate Wnt signaling can result in embryonic malformations and cancer, highlighting the important role of negative regulators of the pathway. The Wnt pathway activates several negative feedback targets, including axin2 and Dkk1, that function at different levels of the signaling cascade; however, none have been identified that directly target active beta-catenin/Tcf1 transcriptional complexes. We show that Zfp703 is a Wnt target gene that inhibits Wnt/beta-catenin activity in Wnt reporter assays and in Wnt-dependent mesoderm differentiation in embryonic stem cells. Zfp703 binds directly to Tcf1 to inhibit beta-catenin/Tcf1 complex formation and does so independently of the Groucho/Tle transcriptional corepressor. We propose that Zfp703 is a novel feedback suppressor of Wnt/beta-catenin signaling that functions by inhibiting the association of beta-catenin with Tcf1 on Wnt response elements in target gene enhancers. C1 [Kumar, Amit; Chalamalasetty, Ravindra B.; Kennedy, Mark W.; Thomas, Sara; Inala, Shreya N.; Garriock, Robert J.; Yamaguchi, Terry P.] NCI, Cell Signaling Vertebrate Dev Sect, Canc & Dev Biol Lab, Ctr Canc Res,NIH, Frederick, MD 21701 USA. RP Yamaguchi, TP (reprint author), NCI, Cell Signaling Vertebrate Dev Sect, Canc & Dev Biol Lab, Ctr Canc Res,NIH, Frederick, MD 21701 USA. EM yamagute@mail.nih.gov 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. NR 61 TC 1 Z9 1 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2016 VL 36 IS 12 BP 1793 EP 1802 DI 10.1128/MCB.01010-15 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DO7BS UT WOS:000377937800006 PM 27090637 ER PT J AU Zhang, Y Huang, L Fu, HQ Smith, OK Lin, CM Utani, K Rao, M Reinhold, WC Redon, CE Ryan, M Kim, R You, Y Hanna, H Boisclair, Y Long, QM Aladjem, MI AF Zhang, Ya Huang, Liang Fu, Haiqing Smith, Owen K. Lin, Chii Mei Utani, Koichi Rao, Mishal Reinhold, William C. Redon, Christophe E. Ryan, Michael Kim, RyangGuk You, Yang Hanna, Harlington Boisclair, Yves Long, Qiaoming Aladjem, Mirit I. TI A replicator-specific binding protein essential for site-specific initiation of DNA replication in mammalian cells SO NATURE COMMUNICATIONS LA English DT Article ID BETA-GLOBIN LOCUS; DOMAIN-INTERACTING PROTEIN; GENOME-WIDE; GENE-REGULATION; ORIGINS; COMPLEX; REGION; PHIP; TRANSCRIPTION; REGULATOR AB Mammalian chromosome replication starts from distinct sites; however, the principles governing initiation site selection are unclear because proteins essential for DNA replication do not exhibit sequence-specific DNA binding. Here we identify a replication-initiation determinant (RepID) protein that binds a subset of replication-initiation sites. A large fraction of RepID-binding sites share a common G-rich motif and exhibit elevated replication initiation. RepID is required for initiation of DNA replication from RepID-bound replication origins, including the origin at the human beta-globin (HBB) locus. At HBB, RepID is involved in an interaction between the replication origin (Rep-P) and the locus control region. RepID-depleted murine embryonic fibroblasts exhibit abnormal replication fork progression and fewer replication-initiation events. These observations are consistent with a model, suggesting that RepID facilitates replication initiation at a distinct group of human replication origins. C1 [Zhang, Ya; Huang, Liang; Fu, Haiqing; Smith, Owen K.; Lin, Chii Mei; Utani, Koichi; Rao, Mishal; Reinhold, William C.; Redon, Christophe E.; You, Yang; Hanna, Harlington; Aladjem, Mirit I.] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ryan, Michael; Kim, RyangGuk] In Silico Solut, Fairfax, VA 22033 USA. [Boisclair, Yves; Long, Qiaoming] Cornell Univ, Dept Anim Sci, Ithaca, NY 14853 USA. RP Aladjem, MI (reprint author), NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM aladjemm@mail.nih.gov FU intramural programme of the CCR, National Cancer Institute, National Institutes of Health FX We thank Dr John Schimenti for kindly sharing RepID-deficient murine embryo fibroblasts and Ms Vidushani Jaylal for help with electrophoretic mobility assays. We are grateful for Dr James Doroshow for facilitating the bioinformatics pipeline data analysis. We thank Dr Yardena Samuels for sharing the melanoma cell line 2451 13T. We thank Dr Randall Smith for generation of the bed file randomization script and Ms Catherine Redmond for help in motif analyses. We thank Dr Sangmin Jang, Ms Amy Conner and Ms Anna Marks for reading and commenting on the manuscript. The intramural programme of the CCR, National Cancer Institute, National Institutes of Health, funded this work. NR 65 TC 2 Z9 2 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUN PY 2016 VL 7 AR 11748 DI 10.1038/ncomms11748 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO6NK UT WOS:000377900100001 PM 27272143 ER PT J AU Zhang, Y Cabarcas, SM Zheng, J Sun, L Mathews, LA Zhang, XH Lin, HS Farrar, WL AF Zhang, Ying Cabarcas, Stephanie M. Zheng, Ji Sun, Lei Mathews, Lesley A. Zhang, Xiaohu Lin, Hongsheng Farrar, William L. TI Cryptotanshinone targets tumor-initiating cells through down-regulation of stemness genes expression SO ONCOLOGY LETTERS LA English DT Article DE Cryptotanshinone; tumor-initiating cells; prostate cancer; stemness genes; Chinese medicine ID PROSTATE-CANCER CELLS; SESQUITERPENE LACTONE PARTHENOLIDE; SALVIA-MILTIORRHIZA BUNGE; IN-VITRO; TRANSCRIPTIONAL REGULATION; PROGENITOR CELLS; TANSHINONE-IIA; IDENTIFICATION; GLIOBLASTOMA; APOPTOSIS AB Recent evidence indicates that tumor-initiating cells (TICs), also called cancer stem cells (CSCs), are responsible for tumor initiation and progression, therefore representing an important cell population that may be used as a target for the development of future anticancer therapies. In the present study, Cryptotanshinone (CT), a traditional Chinese herbal medicine, was demonstrated to regulate the behaviors of LNCaP prostate cells and prostate LNCaP TICs. The results demonstrate that treatment with CT alters cellular proliferation, cell cycle status, migration, viability, colony formation and notably, sphere formation and down-regulation of stemness genes (Nanog, OCT4, SOX2, beta-catenin, CXCR4) in TICs. The present study demonstrates that CT targets the LNCaP CD44(+)CD24(-) population that is representative of prostate TICs and also affects total LNCaP cells as well via down-regulation of stemness genes. The strong effect with which CT has on prostate TICs suggests that CT may potentially function as a novel natural anticancer agent that specifically targets TICs. C1 [Zhang, Ying; Cabarcas, Stephanie M.; Zheng, Ji; Sun, Lei; Mathews, Lesley A.; Zhang, Xiaohu; Lin, Hongsheng; Farrar, William L.] NCI, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. [Zhang, Ying; Lin, Hongsheng] China Acad Chinese Med Sci, Guang An Men Hosp, Oncol Dept, 5 XianGe St, Beijing 100053, Peoples R China. RP Farrar, WL (reprint author), NCI, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA.; Lin, HS (reprint author), China Acad Chinese Med Sci, Guang An Men Hosp, Oncol Dept, 5 XianGe St, Beijing 100053, Peoples R China. EM drlinhongsheng@gmail.com; farrar@mail.ncifcrf.gov FU Federal funds from the National Cancer Institute, National Institutes of Health, U.S. [HHSN261200800001E]; National Natural Science Foundation of China [81473467] FX The authors acknowledge Ms Kathleen Noer, Ms Roberta Matthai and Ms Guity Mohammadi for their expert technical assistance in FACs separation and analysis of the cells lines. The authors also thank Dr. Jeffery White, Dr. Libin Jia for support for this project in the Office of Cancer Complementary and Alterative Medicine, National Cancer Institute (Rockville, MD, USA). This work has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, U.S. (contract no., HHSN261200800001E). This research was supported in part by the National Natural Science Foundation of China (grant no., 81473467). The content of this paper 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 65 TC 0 Z9 0 U1 1 U2 3 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1792-1074 EI 1792-1082 J9 ONCOL LETT JI Oncol. Lett. PD JUN PY 2016 VL 11 IS 6 BP 3803 EP 3812 DI 10.3892/ol.2016.4444 PG 10 WC Oncology SC Oncology GA DO2RD UT WOS:000377626700042 PM 27313698 ER PT J AU Brach, JS Francois, SJ VanSwearingen, JM Gilmore, S Perera, S Studenski, SA AF Brach, Jennifer S. Francois, Sara J. VanSwearingen, Jessie M. Gilmore, Sandra Perera, Subashan Studenski, Stephanie A. TI Translation of a Motor Learning Walking Rehabilitation Program Into a Group-Based Exercise Program for Community-Dwelling Older Adults SO PM&R LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; PHYSICAL-ACTIVITY; FUNCTIONAL DECLINE; 6-MINUTE WALK; PERFORMANCE; ABNORMALITIES; BARRIERS; HEALTH; BRAIN AB Background: Traditional exercise programs for older adults, which focus on aerobic and strength training, have had only modest effects on walking. Recently, a motor learning exercise program was shown to have greater effects on walking compared with a traditional exercise program. Translating this novel motor learning exercise program into a group exercise program would allow it to be offered as an evidence-based, community-based program for older adults. Objective: To translate a walking rehabilitation program based on motor learning theory from one-on-one to group delivery (On the Move) and evaluate multiple aspects of implementation in older adults with impaired mobility. Design: The translation process involved multiple iterations, including meetings of experts in the field (Phase I), focus groups (Phase II), and implementation of the newly developed program (Phase III). Phase III was based on a one-group model of intervention development for feasibility, safety, potential effects, and acceptability. Setting: Community sites, including 2 independent living facilities, an apartment building, and a community center. Participants: Adults 65 years of age or older who could ambulate independently and who were medically stable. Thirty-one adults, mean age 82.3 +/- 5.6 years, were eligible to participate. Methods: The group exercise program was held twice a week for 12 weeks. Main Outcome Measurements: Acceptability of the program was determined by retention and adherence rates and a satisfaction survey. Risk was measured by adverse events and questions on perceived challenge and safety. Mobility was assessed pre- and postintervention by gait speed, Figure of 8 Walk Test, and 6-minute walk test. Results: Modifications to the program included adjustments to format/length, music, education, and group interaction. The 12-week program was completed by 24 of 31 entrants (77%). Adherence was high, with participants attending on average 83% of the classes. Safety was excellent, with only 1 subject experiencing a controlled, noninjurious fall. There was preliminary evidence for improved mobility after the intervention: gait speed improved from 0.76 +/- 0.21 to 0.81 +/- 0.22 m/s, P = .06; Figure of 8 Walk Test from 13.0 +/- 3.9 to 12.0 +/- 3.9 seconds, P = .07; and 6-minute walk test from 246 +/- 75 to 281 +/- 67 m, P = .02. Conclusions: The group-based program was safe and acceptable to older adults with impaired mobility and resulted in potentially clinically meaningful improvements in mobility. C1 [Brach, Jennifer S.] Univ Pittsburgh, Dept Phys Therapy, Sch Hlth & Rehabil Sci, Bridgeside Point 1,100 Technol Dr, Pittsburgh, PA 15219 USA. [Francois, Sara J.] Washington Univ, Program Phys Therapy, St Louis, MO USA. [VanSwearingen, Jessie M.] Univ Pittsburgh, Dept Phys Therapy, Pittsburgh, PA 15219 USA. [Gilmore, Sandra] Univ Pittsburgh, Med Ctr, Community Provider Serv, Pittsburgh, PA 15219 USA. [Perera, Subashan] Univ Pittsburgh, Div Geriatr Med, Dept Med, Pittsburgh, PA 15219 USA. [Perera, Subashan] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15219 USA. [Studenski, Stephanie A.] NIA, Baltimore, MD 21224 USA. RP Brach, JS (reprint author), Univ Pittsburgh, Dept Phys Therapy, Sch Hlth & Rehabil Sci, Bridgeside Point 1,100 Technol Dr, Pittsburgh, PA 15219 USA. EM jbrach@pitt.edu OI Francois, Sara/0000-0001-8752-5309 FU Pittsburgh Older Americans Independence Center [NIA P30 AG024827]; Pittsburgh Training in Geriatrics and Gerontology [T32 AG021885]; University of Pittsburgh Aging Institutee, CTSI, Community-Based Participatory Research (NIH) [UL1 RR024153, UL1TR000005] FX Supported by the Pittsburgh Older Americans Independence Center (NIA P30 AG024827), Pittsburgh Training in Geriatrics and Gerontology (T32 AG021885), University of Pittsburgh Aging Institute, CTSI, Community-Based Participatory Research (NIH UL1 RR024153 and UL1TR000005). NR 33 TC 1 Z9 1 U1 4 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 EI 1934-1563 J9 PM&R JI PM&R PD JUN PY 2016 VL 8 IS 6 BP 520 EP 528 DI 10.1016/j.pmrj.2015.10.004 PG 9 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA DO6OX UT WOS:000377904100003 PM 26493856 ER PT J AU Miller, S Ringeisen, H Munoz, B Hedden, SL Colpe, LJ Rohloff, H Embry, V AF Miller, Shari Ringeisen, Heather Munoz, Breda Hedden, Sarra L. Colpe, Lisa J. Rohloff, Harley Embry, Venita TI Correlates of Mental Health Service Use Among Young Adults With Mental Illness: Results From the National Survey on Drug Use and Health SO PSYCHIATRIC SERVICES LA English DT Article ID COMORBIDITY SURVEY REPLICATION; UNITED-STATES; PSYCHIATRIC-DISORDERS; ETHNIC DISPARITIES; PREVALENCE; TRANSITION; CARE; SURVEILLANCE; CALIBRATION; EMPLOYMENT AB Objective: This study examined correlates of use of outpatient and inpatient mental health services and psychotropic medication in a large, nationally representative sample of young adults ages 18-26 with mental illness (N=22,600). Methods: Data were from the 2008-2012 National Survey on Drug Use and Health, an annual nationally representative survey of the civilian, noninstitutionalized U.S. population. Separate logistic regression models examined past-year use of three mental health service types (outpatient services, inpatient services, and psychotropic medication). Correlates included demographic characteristics, factors developmentally relevant to young adults, and general medical and mental health status. Results: Within this sample of young adults with mental illness, 20.4% used outpatient services, 3.6% used inpatient services, and 25.4% used psychotropic medication. Variables associated with use of one or more types of mental health services included being female (outpatient and medication), one to two moves in the past year (medication), having health insurance (all types), past-year criminal justice involvement (all types), poor health (inpatient and medication), substance use disorders (inpatient and medication), and mental illness with severe impairment (all types). Non-Hispanic blacks, Asians, and Hispanics were less likely than non-Hispanic whites to receive outpatient mental health services or psychotropic medications. Surprisingly, young adults employed full-time were less likely than those who were unemployed to receive services, and living with a partner (versus living alone) was not associated with a likelihood of using outpatient services. Conclusions: Results support the unique nature of young adulthood and the need to tailor mental health services to close gaps in service use during this developmental period. C1 [Miller, Shari; Ringeisen, Heather; Munoz, Breda; Rohloff, Harley; Embry, Venita] RTI Int, Res Triangle Pk, NC USA. [Hedden, Sarra L.] Subst Abuse & Mental Hlth Serv Adm, Ctr Behav Hlth Stat & Qual, Rockville, MD USA. [Colpe, Lisa J.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Miller, S (reprint author), RTI Int, Res Triangle Pk, NC USA. EM shari@rti.org FU National Institute of Mental Health [284-2010-0003C (0212800.002)] FX This study was funded under contract 284-2010-0003C (project 0212800.002), which was supported by funding from the National Institute of Mental Health. NR 54 TC 0 Z9 0 U1 6 U2 9 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 EI 1557-9700 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD JUN PY 2016 VL 67 IS 6 BP 641 EP 648 DI 10.1176/appi.ps.201400486 PG 8 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA DO4UK UT WOS:000377779900012 ER PT J AU Pacher, P AF Pacher, P. TI ENDOCANNABINOID RECEPTORS AS NOVEL TARGETS SO SHOCK LA English DT Meeting Abstract CT 39th Annual Conference of the Shock-Society on Shock CY JUN 11-14, 2016 CL Austin, TX SP Shock Soc C1 [Pacher, P.] NIAAA, NIH, Rockville, MD 20852 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 1073-2322 EI 1540-0514 J9 SHOCK JI Shock PD JUN PY 2016 VL 45 IS 6 SU 1 MA 69 BP 35 EP 35 PG 1 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA DO3OX UT WOS:000377692000070 ER PT J AU Roberts, D Miller, TW Soto-Pantoja, DR AF Roberts, D. Miller, T. W. Soto-Pantoja, D. R. TI TARGETING THROMBOSPONDIN-1 AND ITS RECEPTOR CD47 TO IMPROVE CELL AND TISSUE RESPONSES TO STRESS SO SHOCK LA English DT Meeting Abstract CT 39th Annual Conference of the Shock-Society on Shock CY JUN 11-14, 2016 CL Austin, TX SP Shock Soc C1 [Roberts, D.; Miller, T. W.] NCI, Pathol Lab, CCR, NIH, Bethesda, MD 20892 USA. [Soto-Pantoja, D. R.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1073-2322 EI 1540-0514 J9 SHOCK JI Shock PD JUN PY 2016 VL 45 IS 6 SU 1 MA 67 BP 35 EP 35 PG 1 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA DO3OX UT WOS:000377692000068 ER PT J AU Elmore, SA Farman, CA Hailey, JR Kovi, RC Malarkey, DE Morrison, JP Neel, J Pesavento, PA Porter, BF Szabo, KA Teixeira, LBC Quist, EM AF Elmore, Susan A. Farman, Cindy A. Hailey, James R. Kovi, Ramesh C. Malarkey, David E. Morrison, James P. Neel, Jennifer Pesavento, Patricia A. Porter, Brian F. Szabo, Kathleen A. Teixeira, Leandro B. C. Quist, Erin M. TI Proceedings of the 2015 National Toxicology Program Satellite Symposium SO TOXICOLOGIC PATHOLOGY LA English DT Article DE NTP Satellite Symposium; cardiomyopathy; pulmonary ultrastructure; crop milk; oral ornamentation; tuna heat exchanger; histoplasmosis; leukemia; - cytology; mammary gland whole mounts; diagnostic neuropathology; ocular inflammation; INHAND; neurocytoma; persistent fetal vasculature; persistent hyperplastic primary vitreous; persistent hyperplastic tunica vasculosa lentis; focal nodular hyperplasia; pulmonary metastatic tumor ID SPRAGUE-DAWLEY RATS; DRUG-INDUCED PHOSPHOLIPIDOSIS; CEREBELLAR CORTICAL DEGENERATION; JACKSON MEMORIAL LECTURE; DERMAL COLLAGEN ARRAYS; OLIGODENDROCYTE LINEAGE; HISTOPLASMA-CAPSULATUM; STRUCTURAL COLORATION; CONVERGENT EVOLUTION; MONOCLONAL-ANTIBODY AB The 2015 Annual National Toxicology Program Satellite Symposium, entitled Pathology Potpourri was held in Minneapolis, Minnesota, at the American College of Veterinary Pathologists/American Society for Veterinary Clinical Pathology/Society of Toxicologic Pathology combined meeting. The goal of this symposium is to present and discuss diagnostic pathology challenges or nomenclature issues. Because of the combined meeting, both laboratory and domestic animal cases were presented. This article presents summaries of the speakers' talks, including challenging diagnostic cases or nomenclature issues that were presented, along with select images that were used for audience voting and discussion. Some lesions and topics covered during the symposium included hepatocellular lesions, a proposed harmonized diagnostic approach to rat cardiomyopathy, crop milk in a bird, avian feeding accoutrement, heat exchanger in a tuna, metastasis of a tobacco carcinogen-induced pulmonary carcinoma, neurocytoma in a rat, pituicytoma in a rat, rodent mammary gland whole mounts, dog and rat alveolar macrophage ultrastructure, dog and rat pulmonary phospholipidosis, alveolar macrophage aggregation in a dog, degenerating yeast in a cat liver aspirate, myeloid leukemia in lymph node aspirates from a dog, Trypanosoma cruzi in a dog, solanum toxicity in a cow, bovine astrovirus, malignant microglial tumor, and nomenclature challenges from the Special Senses International Harmonization of Nomenclature and Diagnostic Criteria Organ Working Group. C1 [Elmore, Susan A.; Malarkey, David E.; Quist, Erin M.] NIEHS, Natl Toxicol Program, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Farman, Cindy A.] Genentech Inc, San Francisco, CA 94080 USA. [Hailey, James R.] Covance Labs Inc, Chantilly, VA USA. [Kovi, Ramesh C.] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. [Morrison, James P.; Szabo, Kathleen A.] Charles River Labs Inc, Durham, NC USA. [Neel, Jennifer] N Carolina State Univ, Coll Vet Med, Raleigh, NC USA. [Pesavento, Patricia A.] Univ Calif Davis, Sch Vet Med, Davis, CA 95616 USA. [Porter, Brian F.] Texas A&M Univ, College Stn, TX USA. [Teixeira, Leandro B. C.] Univ Wisconsin, Madison, WI USA. RP Elmore, SA (reprint author), NIEHS, Natl Toxicol Program, Cellular & Mol Pathol Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM elmore@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported [in part] by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS). NR 117 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 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUN PY 2016 VL 44 IS 4 BP 502 EP 535 DI 10.1177/0192623316631844 PG 34 WC Pathology; Toxicology SC Pathology; Toxicology GA DO2UC UT WOS:000377634600001 PM 27075180 ER PT J AU Schnabel, RB Maas, R Wang, N Yin, XY Larson, MG Levy, D Ellinor, PT Lubitz, SA McManus, D Magnani, JW Atzler, D Boger, RH Schwedhelm, E Vasan, RS Benjamin, EJ AF Schnabel, Renate B. Maas, Renke Wang, Na Yin, Xiaoyan Larson, Martin G. Levy, Daniel Ellinor, Patrick T. Lubitz, Steven A. McManus, DavidD. Magnani, Jared W. Atzler, Dorothee Boeger, Rainer H. Schwedhelm, Edzard Vasan, Ramachandran S. Benjamin, Emelia J. TI Asymmetric dimethylarginine, related arginine derivatives, and incident atrial fibrillation SO AMERICAN HEART JOURNAL LA English DT Article ID CONGESTIVE-HEART-FAILURE; OXIDE SYNTHASE INHIBITOR; COMMUNITY-BASED COHORT; CARDIOVASCULAR EVENTS; PLASMA-CONCENTRATIONS; ARTERIAL STIFFNESS; RISK PREDICTION; DISEASE; BIOMARKERS; MARKERS AB Background Oxidative stress plays an important role in the development of atrial fibrillation (AF). Arginine derivatives including asymmetric dimethylarginine (ADMA) are central to nitric oxide metabolism and nitrosative stress. Whether blood concentrations of arginine derivatives are related to incidence of AF is uncertain. Methods and Results In 3,310 individuals (mean age 58 +/- 10 years, 54% women) from the community-based Framingham Study, we prospectively examined the relations of circulating levels of ADMA, L-arginine, symmetric dimethylarginine (SDMA), and the ratio of L-arginine/ADMAto incidence of AF using proportional hazards regression models. Over a median follow-up time of 10 years, 247 AF cases occurred. Using age-and sex-adjusted regression models, ADMA was associated with a hazard ratio of 1.15 per 1-SD increase in loge-biomarker concentration (95% CI1.02-1.29, P = .02) for AF, which was no longer significant after further risk factor adjustment (hazard ratio 1.09, 95% CI 0.97-1.23, P = .15). Neither L-arginine nor SDMA was related to new-onset AF. A clinical model comprising clinical risk factors for AF (for age, sex, height, weight, systolic blood pressure, diastolic blood pressure, current smoking, diabetes, hypertension treatment, myocardial infarction, and heart failure; c statistic = 0.781; 95% CI 0.753-0.808) was not improved by the addition of ADMA (0.782; 95% CI 0.755-0.809). Conclusions Asymmetric dimethylarginine and related arginine derivatives were not associated with incident AF in the community after accounting for other clinical risk factors and confounders. Its role in the pathogenesis of AF needs further refinement. C1 [Schnabel, Renate B.; Yin, Xiaoyan; Larson, Martin G.; Levy, Daniel; Vasan, Ramachandran S.; Benjamin, Emelia J.] NHLBIs & Boston Univ Framingham Study, Framingham, MA USA. [Schnabel, Renate B.] Partner Site Hamburg Kiel Lubeck, DZHK German Ctr Cardiovasc Res, Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, Hamburg, Germany. [Maas, Renke] Univ Erlangen Nurnberg, Inst Expt & Clin Pharmacol & Toxicol, D-91054 Erlangen, Germany. [Wang, Na] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Levy, Daniel; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Evans Mem Med Dept, Boston, MA 02118 USA. [Levy, Daniel] NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Ellinor, Patrick T.] Univ Massachusetts, Sch Med, Cardiovasc Res Ctr, Worcester, MA USA. [Ellinor, Patrick T.; Lubitz, Steven A.] Broad Inst Harvard & Massachusetts Inst Technol, Program inMed Populat Genet, Cambridge, MA USA. [Ellinor, Patrick T.; Lubitz, Steven A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [McManus, DavidD.] Univ Massachusetts, Sch Med, Dept Med, Div Cardiol, Worcester, MA USA. [Magnani, Jared W.; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Atzler, Dorothee] Univ Oxford, Radcliffe Dept Med, Oxford, England. [Boeger, Rainer H.; Schwedhelm, Edzard] Univ Med Ctr Hamburg Eppendorf, Inst Clin Pharmacol & Toxicol, Hamburg, Germany. [Boeger, Rainer H.; Schwedhelm, Edzard] Univ Ctr Hamburg Eppendorf, Cardiovasc Res Ctr, Hamburg, Germany. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Whitaker Cardiovascular Inst, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Prevent Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Schnabel, RB (reprint author), Univ Heart Ctr, Dept Gen & Intervent Cardiol, Martinistr 52, D-20246 Hamburg, Germany. EM r.schnabel@uke.de OI Ramachandran, Vasan/0000-0001-7357-5970 FU Bayer HealthCare FX Dr Ellinor is the principal investigator on a grant from Bayer HealthCare to the Broad Institute related to AF genetics and therapeutics. NR 50 TC 0 Z9 0 U1 3 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD JUN PY 2016 VL 176 BP 100 EP 106 DI 10.1016/j.ahj.2016.03.007 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO0MC UT WOS:000377472000017 PM 27264226 ER PT J AU Moore, KR Smith, JS Cole, SR Schoenbach, VJ Schlusser, K Gaydos, CA Baird, DD AF Moore, Kristen R. Smith, Jennifer S. Cole, Stephen R. Schoenbach, Victor J. Schlusser, Katherine Gaydos, Charlotte A. Baird, Donna D. TI Herpes Simplex Virus Type 2 Seroprevalence and Ultrasound-Diagnosed Uterine Fibroids in a Large Population of Young African-American Women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE herpes simplex virus type 2; seroprevalence; uterine fibroids ID DEPOT-MEDROXYPROGESTERONE ACETATE; SEXUAL RISK-TAKING; HORMONAL CONTRACEPTION; REPRODUCTIVE FACTORS; UNITED-STATES; LEIOMYOMA; INFECTIONS; PREVALENCE; ACQUISITION; ASSOCIATION AB For decades reproductive tract infections (RTIs) have been hypothesized to play a role in uterine fibroid development. The few previous studies conducted used self-reported history of RTIs and had inconsistent findings. We investigated this hypothesis further using serological analysis, an immunological measure of past exposure. We focused on herpes simplex virus type 2 (HSV-2) because prior published data have suggested a possible association with fibroids, and serology for HSV-2 is much more sensitive than self-report. We used cross-sectional enrollment data from African-American women enrolled in a prospective study of fibroid incidence and growth (recruited 2010-2012) in the Detroit, Michigan, area. The women were aged 23-34 years and were screened for fibroids using a standardized ultrasound examination at their enrollment. Age- and multivariable-adjusted logistic regression models were used to estimate odds ratios. Of 1,696 participants, 1,658 had blood samples and HSV-2 serology results; 22% of participants with serology results had fibroids. There was no significant association between HSV-2 seropositivity and the presence of fibroids (multivariable-adjusted odds ratio = 0.94, 95% confidence interval: 0.73, 1.20), nor were there any associations with size of the largest fibroid, number of fibroids, or total fibroid volume. Our data provide no evidence for an influence of HSV-2 exposure on fibroid risk in young African-American women. Further study of other serologically measured RTIs is warranted. C1 [Moore, Kristen R.; Smith, Jennifer S.; Cole, Stephen R.; Schoenbach, Victor J.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Moore, Kristen R.; Baird, Donna D.] NIEHS, Epidemiol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. [Schlusser, Katherine; Gaydos, Charlotte A.] Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA. RP Moore, KR; Baird, DD (reprint author), NIEHS, Epidemiol Branch A3 05, POB 12233, Res Triangle Pk, NC 27709 USA. EM kristen.moore@nih.gov; baird@niehs.nih.gov RI Moore, Kristen/C-2303-2017; Baird, Donna/D-5214-2017 OI Moore, Kristen/0000-0001-9993-3270; Baird, Donna/0000-0002-5544-2653 FU National Institutes of Health, National Institute of Environmental Health Sciences [10-E-N044]; American Recovery and Reinvestment Act funds FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences ( grant 10-E-N044), and American Recovery and Reinvestment Act funds designated for NIH research. NR 47 TC 0 Z9 0 U1 2 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2016 VL 183 IS 11 BP 961 EP 968 DI 10.1093/aje/kwv313 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DN9RK UT WOS:000377417600001 PM 27188945 ER PT J AU Karas, MG Yee, LM Biggs, ML Djousse, L Mukamal, KJ Ix, JH Zieman, SJ Siscovick, DS Gottdiener, JS Rosenberg, MA Kronmal, RA Heckbert, SR Kizer, JR AF Karas, Maria G. Yee, Laura M. Biggs, Mary L. Djousse, Luc Mukamal, Kenneth J. Ix, Joachim H. Zieman, Susan J. Siscovick, David S. Gottdiener, John S. Rosenberg, Michael A. Kronmal, Richard A. Heckbert, Susan R. Kizer, Jorge R. TI Measures of Body Size and Composition and Risk of Incident Atrial Fibrillation in Older People SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE aging; atrial fibrillation; body size; obesity ID CARDIOVASCULAR HEALTH; HEART-FAILURE; ATHEROSCLEROSIS RISK; MASS INDEX; OBESITY; DISEASE; FAT; DETERMINANTS; COHORT; ADULTS AB Various anthropometric measures, including height, have been associated with atrial fibrillation (AF). This raises questions about the appropriateness of using ratio measures such as body mass index (BMI), which contains height squared in its denominator, in the evaluation of AF risk. Among older adults, the optimal anthropometric approach to risk stratification of AF remains uncertain. Anthropometric and bioelectrical impedance measures were obtained from 4,276 participants (mean age = 72.4 years) free of cardiovascular disease in the Cardiovascular Health Study. During follow-up (1989-2008), 1,050 cases of AF occurred. BMI showed a U-shaped association, whereas height, weight, waist circumference, hip circumference, fat mass, and fat-free mass were linearly related to incident AF. The strongest adjusted association occurred for height (per each 1-standard-deviation increment, hazard ratio = 1.38, 95% confidence interval: 1.25, 1.51), which exceeded all other measures, including weight (hazard ratio = 1.21, 95% confidence interval: 1.13, 1.29). Combined assessment of log-transformed weight and height showed regression coefficients that departed from the 1 to -2 ratio inherent in BMI, indicating a loss of predictive information. Risk estimates for AF tended to be stronger for hip circumference than for waist circumference and for fat-free mass than for fat mass, which was explained largely by height. These findings highlight the prominent role of body size and the inadequacy of BMI as determinants of AF in older adults. C1 [Karas, Maria G.] Weill Cornell Med Coll, Dept Med, Div Cardiol, New York, NY USA. [Yee, Laura M.; Biggs, Mary L.; Kronmal, Richard A.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Djousse, Luc] Brigham & Womens Hosp, Dept Med, Div Aging, 75 Francis St, Boston, MA 02115 USA. [Djousse, Luc; Mukamal, Kenneth J.] Harvard Univ, Sch Med, Boston, MA USA. [Mukamal, Kenneth J.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA USA. [Ix, Joachim H.] Univ Calif San Diego, Dept Med, Div Nephrol, San Diego, CA 92103 USA. [Ix, Joachim H.] Univ Calif San Diego, Dept Family & Publ Hlth, Div Prevent Med, San Diego, CA 92103 USA. [Zieman, Susan J.] NIA, Div Geriatr & Clin Gerontol, Bethesda, MD 20892 USA. [Siscovick, David S.] New York Acad Med, New York, NY USA. [Gottdiener, John S.] Univ Maryland, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21201 USA. [Rosenberg, Michael A.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Heckbert, Susan R.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Med, Div Cardiol, Bronx, NY 10467 USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. RP Kizer, JR (reprint author), Albert Einstein Coll Med, Dept Med, Cardiovasc Clin Res Unit, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM jorge.kizer@einstein.yu.edu RI Djousse, Luc/F-5033-2017 OI Djousse, Luc/0000-0002-9902-3047 FU National Heart, Lung, and Blood Institute [R01 HL094555, K23 HL127296, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295]; National Institute of Neurological Disorders and Stroke; National Institute on Aging [AG023629] FX This study was supported by grant R01 HL094555 from the National Heart, Lung, and Blood Institute to L. D., K. J. M, J. H. I, S. J. Z., and J. R. K. M. A. R. was supported by grant K23 HL127296 from the National Heart, Lung, and Blood Institute. The Cardiovascular Health Study was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grant HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by grant AG023629 from the National Institute on Aging. NR 46 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 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2016 VL 183 IS 11 BP 998 EP 1007 DI 10.1093/aje/kwv278 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DN9RK UT WOS:000377417600005 PM 27188936 ER PT J AU Nuche-Berenguer, B Ramos-Alvarez, I Jensen, RT AF Nuche-Berenguer, Bernardo Ramos-Alvarez, Irene Jensen, R. T. TI Src kinases play a novel dual role in acute pancreatitis affecting severity but no role in stimulated enzyme secretion SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE pancreatic acini; carboxy-terminal octapeptide of cholecystokinin; signaling; chemokines; caspases ID NF-KAPPA-B; ACTIVATED PROTEIN-KINASES; APICAL PLASMA-MEMBRANE; GROWTH-FACTOR RECEPTOR; CELL-DEATH PATHWAYS; ACINAR-CELLS; IN-VITRO; TYROSINE PHOSPHORYLATION; PKC-DELTA; TRYPSINOGEN ACTIVATION AB In pancreatic acinar cells, the Src family of kinases (SFK) is involved in the activation of several signaling cascades that are implicated in mediating cellular processes (growth, cytoskeletal changes, apoptosis). However, the role of SFKs in various physiological responses such as enzyme secretion or in pathophysiological processes such as acute pancreatitis is either controversial, unknown, or incompletely understood. To address this, in this study, we investigated the role/mechanisms of SFKs in acute pancreatitis and enzyme release. Enzyme secretion was studied in rat dispersed pancreatic acini, in vitro acute-pancreatitis-like changes induced by supramaximal COOH-terminal octapeptide of cholecystokinin (CCK). SFK involvement assessed using the chemical SFK inhibitor (PP2) with its inactive control, 4-amino-7-phenylpyrazol[3,4-d] pyrimidine (PP3), under experimental conditions, markedly inhibiting SFK activation. In CCK-stimulated pancreatic acinar cells, activation occurred of trypsinogen, various MAP kinases (p42/44, JNK), transcription factors (signal transducer and activator of transcription-3, nuclear factor-kappa B, activator protein-1), caspases (3, 8, and 9) inducing apoptosis, LDH release reflective of necrosis, and various chemokines secreted (monocyte chemotactic protein-1, macrophage inflammatory protein-1 alpha, regulated on activation, normal T cell expressed and secreted). All were inhibited by PP2, not by PP3, except caspase activation leading to apoptosis, which was increased, and trypsin activation, which was unaffected, as was CCK-induced amylase release. These results demonstrate SFK activation is playing a dual role in acute pancreatitis, inhibiting apoptosis and promoting necrosis as well as chemokine/cytokine release inducing inflammation, leading to more severe disease, as well as not affecting secretion. Thus, our studies indicate that SFK is a key mediator of inflammation and pancreatic acinar cell death in acute pancreatitis, suggesting it could be a potential therapeutic target in acute pancreatitis. C1 [Nuche-Berenguer, Bernardo; Ramos-Alvarez, Irene; Jensen, R. T.] NIDDK, Digest Dis Branch, NIH, Bldg 10,Rm 9C-103,10 Ctr Dr MSC 1804, Bethesda, MD 20892 USA. RP Jensen, RT (reprint author), NIDDK, Digest Dis Branch, NIH, Bldg 10,Rm 9C-103,10 Ctr Dr MSC 1804, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases FX This work was partially supported by intramural funds of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 92 TC 1 Z9 1 U1 2 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 EI 1522-1547 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD JUN 1 PY 2016 VL 310 IS 11 BP G1015 EP G1027 DI 10.1152/ajpgi.00349.2015 PG 13 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA DN9XE UT WOS:000377433200014 PM 27033118 ER PT J AU Matyas, C Varga, ZV Mukhopadhyay, P Paloczi, J Lajtos, T Erdelyi, K Nemeth, BT Nan, MT Hasko, G Gao, B Pacher, P AF Matyas, Csaba Varga, Zoltan V. Mukhopadhyay, Partha Paloczi, Janos Lajtos, Tamas Erdelyi, Katalin Nemeth, Balazs T. Nan, Mintong Hasko, Gyorgy Gao, Bin Pacher, Pal TI Chronic plus binge ethanol feeding induces myocardial oxidative stress, mitochondrial and cardiovascular dysfunction, and steatosis SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE alcoholic cardiomyopathy; heart failure; oxidative stress; mitochondrial dysfunction; cardiac steatosis ID SUDDEN CARDIAC DEATH; ALCOHOL-CONSUMPTION; CONTRACTILE DYSFUNCTION; YOUNG-ADULTS; HEART; CARDIOMYOPATHY; DRINKING; DISEASE; MICE; RATS AB Alcoholic cardiomyopathy in humans develops in response to chronic excessive alcohol consumption; however, good models of alcohol-induced cardiomyopathy in mice are lacking. Herein we describe mouse models of alcoholic cardiomyopathies induced by chronic and binge ethanol (EtOH) feeding and characterize detailed hemodynamic alterations, mitochondrial function, and redox signaling in these models. Mice were fed a liquid diet containing 5% EtOH for 10, 20, and 40 days (d) combined with single or multiple EtOH binges (5 g/kg body wt). Isocalorically pair-fed mice served as controls. Left ventricular (LV) function and morphology were assessed by invasive pressure-volume conductance approach and by echocardiography. Mitochondrial complex (I, II, IV) activities, 3-nitrotyrosine (3-NT) levels, gene expression of markers of oxidative stress (gp91phox, p47phox), mitochondrial biogenesis (PGC1 alpha, peroxisome proliferator-activated receptor alpha), and fibrosis were examined. Cardiac steatosis and fibrosis were investigated by histological/immunohistochemical methods. Chronic and binge EtOH feeding (already in 10 days EtOH plus single binge group) was characterized by contractile dysfunction (decreased slope of end-systolic pressure-volume relationship and preload recruitable stroke work), impaired relaxation (decreased time constant of LV pressure decay and maximal slope of systolic pressure decrement), and vascular dysfunction (impaired arterial elastance and lower total peripheral resistance). This was accompanied by enhanced myocardial oxidative/nitrative stress (3-NT; gp91phox; p47phox; angiotensin II receptor, type 1a) and deterioration of mitochondrial complex I, II, IV activities and mitochondrial biogenesis, excessive cardiac steatosis, and higher mortality. Collectively, chronic plus binge EtOH feeding in mice leads to alcohol-induced cardiomyopathies (National Institute on Alcohol Abuse and Alcoholism models) characterized by increased myocardial oxidative/nitrative stress, impaired mitochondrial function and biogenesis, and enhanced cardiac steatosis. C1 [Matyas, Csaba; Varga, Zoltan V.; Mukhopadhyay, Partha; Paloczi, Janos; Lajtos, Tamas; Erdelyi, Katalin; Nemeth, Balazs T.; Nan, Mintong; Pacher, Pal] NIAAA, Lab Cardiovasc Physiol & Tissue Injury, NIH, 5625 Fishers Lane,MSC 9413, Bethesda, MD 20892 USA. [Matyas, Csaba] Semmelweis Univ, Heart & Vasc Ctr, H-1085 Budapest, Hungary. [Hasko, Gyorgy] Rutgers New Jersey Med Sch, Dept Surg, Newark, NJ USA. [Gao, Bin] NIAAA, Lab Liver Dis, NIH, 5625 Fishers Lane,MSC 9413, Bethesda, MD 20892 USA. RP Pacher, P (reprint author), NIAAA, Lab Cardiovasc Physiol & Tissue Injury, NIH, 5625 Fishers Lane,MSC 9413, Bethesda, MD 20892 USA. EM pacher@mail.nih.gov RI Matyas, Csaba/K-6053-2016 OI Matyas, Csaba/0000-0001-6095-7611 FU Intramural Research Program of NIAAA/NIH; Hungarian-American Enterprise Scholarship Fund/Council on International Educational Exchange; Rosztoczy Foundation FX The recent work was supported by the Intramural Research Program of NIAAA/NIH (to P. Pacher). C. Matyas was supported by the scholarship of the Hungarian-American Enterprise Scholarship Fund/Council on International Educational Exchange. Z. V. Varga was supported by the Rosztoczy Foundation. NR 57 TC 3 Z9 3 U1 5 U2 12 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUN 1 PY 2016 VL 310 IS 11 BP H1658 EP H1670 DI 10.1152/ajpheart.00214.2016 PG 13 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA DN9XQ UT WOS:000377434400029 PM 27106042 ER PT J AU Stachowska-Pietka, J Waniewski, J Flessner, MF Lindholm, B AF Stachowska-Pietka, Joanna Waniewski, Jacek Flessner, Michael F. Lindholm, Bengt TI Concomitant bidirectional transport during peritoneal dialysis can be explained by a structured interstitium SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE peritoneal transport; distributed model; diffusion and convection; tissue transport; two phases ID SOLUTE TRANSPORT; FLUID TRANSPORT; INITIAL EQUILIBRATION; CAPD PATIENTS; HIND PAW; IN-VIVO; MACROMOLECULES; TISSUE; LYMPH; PLASMA AB Clinical and animal studies suggest that peritoneal absorption of fluid and protein from dialysate to peritoneal tissue, and to blood and lymph circulation, occurs concomitantly with opposite flows of fluid and protein, i.e., from blood to dialysate. However, until now a theoretical explanation of this phenomenon has been lacking. A two-phase distributed model is proposed to explain the bidirectional, concomitant transport of fluid, albumin and glucose through the peritoneal transport system (PTS) during peritoneal dialysis. The interstitium of this tissue is described as an expandable two-phase structure with phase F (water-rich, colloid-poor region) and phase C (water-poor, colloid-rich region) with fluid and solute exchange between them. A low fraction of phase F is assumed in the intact tissue, which can be significantly increased under the influence of hydrostatic pressure and tissue hydration. The capillary wall is described using the three-pore model, and the conditions in the peritoneal cavity are assumed commencing 3 min after the infusion of glucose 3.86% dialysis fluid. Computer simulations demonstrate that peritoneal absorption of fluid into the tissue, which occurs via phase F at the rate of 1.8 ml/min, increases substantially the interstitial pressure and tissue hydration in both phases close to the peritoneal cavity, whereas the glucose-induced ultrafiltration from blood occurs via phase C at the rate of 15 ml/min. The proposed model delineating the phenomenon of concomitant bidirectional transport through PTS is based on a two-phase structure of the interstitium and provides results in agreement with clinical and experimental data. C1 [Stachowska-Pietka, Joanna; Waniewski, Jacek] Polish Acad Sci, Nalecz Inst Biocybernet & Biomed Engn, 4 Trojdena Str, PL-02109 Warsaw, Poland. [Flessner, Michael F.] NIDDKD, Bethesda, MD USA. [Lindholm, Bengt] Karolinska Inst, Dept Clin Sci Intervent & Technol, Div Renal Med, Stockholm, Sweden. [Lindholm, Bengt] Karolinska Inst, Dept Clin Sci Intervent & Technol, Baxter Novum, Stockholm, Sweden. RP Stachowska-Pietka, J (reprint author), Polish Acad Sci, Nalecz Inst Biocybernet & Biomed Engn, 4 Trojdena Str, PL-02109 Warsaw, Poland. EM jstachowska@ibib.waw.pl FU Polish Ministry of Science and Higher Education [N518 417736]; Baxter Healthcare Corporation FX J. Stachowska-Pietka was supported by Polish Ministry of Science and Higher Education Grant N518 417736. Baxter Novum is the result of a grant from Baxter Healthcare Corporation to Karolinska Institutet. NR 55 TC 0 Z9 0 U1 4 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUN 1 PY 2016 VL 310 IS 11 BP H1501 EP H1511 DI 10.1152/ajpheart.00925.2014 PG 11 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA DN9XQ UT WOS:000377434400014 PM 26945084 ER PT J AU Min, DJ He, SP Green, JE AF Min, Dong-Joon He, Siping Green, Jeffrey E. TI Birinapant (TL32711) Improves Responses to GEM/AZD7762 Combination Therapy in Triple-negative Breast Cancer Cell Lines SO ANTICANCER RESEARCH LA English DT Article DE Combination treatment; triple-negative breast cancer; CHK1; TL32711 ID NF-KAPPA-B; SMAC MIMETICS; TARGETED THERAPIES; CHK1 INHIBITION; GEMCITABINE; SUBTYPES; MODELS; SENSITIZATION; ACTIVATION; ABROGATION AB Background: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer currently lacking targeted therapies. Our previous work demonstrated a therapeutic synergism with gemcitabine (GEM) and the CHK1 inhibitor (AZD7762) combination treatment in a TNBC cell line. We hypothesized that the response to this combination therapy would differ among heterogeneous TNBC patients and that addition of a SMAC mimetic (TL32711) could improve efficacy. Materials and Methods: Therapeutic responses to GEM, GEM/AZD7762, and GEM/AZD7762/TL32711 combinations were investigated by XTT assays and western blotting of cell cycle and apoptosis-related proteins in ten TNBC cell lines. Results: TNBC cell lines harboring low levels of endogenous CHK1, cIAP1 and cIAP2 were responsive to GEM alone, whereas cell lines demonstrating a minimal increase in phospho-S345 CHK1 after treatment were responsive to GEM/AZD7762 or GEM/AZD7762/TL32711 combination. Conclusion: The response of TNBC cells to particular therapies varies and will require development of predictive biomarkers. C1 [Min, Dong-Joon; He, Siping; Green, Jeffrey E.] NCI, Transgen Oncogenesis & Genom Sect, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. RP Green, JE (reprint author), Lab Canc Biol & Genet, Bldg 37,Room 4054,37 Convent Dr, Bethesda, MD 20892 USA. EM jegreen@nih.gov FU Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD FX The Authors are grateful to members of the Green lab for useful discussions and to Stan Lipkowitz and Elise Kohn for reviewing the manuscript. This work was supported by the intramural research program of the Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD. NR 35 TC 0 Z9 0 U1 0 U2 0 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 EI 1791-7530 J9 ANTICANCER RES JI Anticancer Res. PD JUN PY 2016 VL 36 IS 6 BP 2649 EP 2657 PG 9 WC Oncology SC Oncology GA DO0JC UT WOS:000377464200003 PM 27272773 ER PT J AU Hao, XP Xiao, H Ju, JY Hewitt, SM Morse, HC AF Hao, Xingpei Xiao, Hang Ju, Jihyueng Hewitt, Stephen M. Morse, Herbert C., III TI Decreased Expression of Retinoid X Receptors During Human and Azoxymethane-induced Colorectal Carcinogenesis in the Rat SO ANTICANCER RESEARCH LA English DT Article DE RXRs; immunohistochemistry; colonic cancer; carcinogenesis ID ABERRANT CRYPT FOCI; 2ND PRIMARY TUMORS; INDUCED COLON CARCINOGENESIS; ORAL LICHEN-PLANUS; RXR-ALPHA; TOPICAL TRETINOIN; INTRAEPITHELIAL NEOPLASIA; HEPATOCELLULAR-CARCINOMA; CELL CARCINOMA; HUMAN PROSTATE AB Background/Aim: The family of retinoid X receptors (RXRs) including RXR alpha, beta and gamma, is involved in regulating cell proliferation, differentiation, apoptosis and development. Materials and Methods: In order to characterize the role of RXRs during colorectal carcinogenesis, the expression of RXRs in human and azoxymethane (AOM)-induced rat colorectal tumors was profiled by immunohistochemistry. Results: Both human and rat normal colorectal epithelia and hyperplasia exhibited strong nuclear, but weak cytoplasmic staining for all three proteins. Expression of RXR alpha, beta and gamma was significantly reduced in rat carcinomas compared to high-grade dysplasia whether in aberrant crypt foci or in adenomas. All three proteins displayed dramatically reduced nuclear expression in both human adenomas and carcinomas. Reduced expression of RXR alpha and RXR gamma seems more significant than RXR beta in both human and rat carcinomas. Conclusion: Reduced expression of RXRs is associated with colorectal carcinogenesis in both humans and AOM-treated rats. C1 [Hao, Xingpei; Xiao, Hang; Ju, Jihyueng] Rutgers State Univ, Susan Lehman Cullman Lab Canc Res, Dept Biol Chem, Earnest Mario Sch Pharm, Piscataway, NJ USA. [Hewitt, Stephen M.] NCI, Pathol Lab, Bldg 10, Bethesda, MD 20892 USA. [Morse, Herbert C., III] NIAID, Immunogenet Lab, Rockville, MD 20852 USA. RP Hao, XP (reprint author), Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Pathol & Histotechnol Lab, POB B, Frederick, MD 21702 USA. EM xhao@mail.nih.gov FU NIH, National Institute of Allergy and Infectious Diseases FX This work was supported in part by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 31 TC 0 Z9 0 U1 0 U2 1 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 EI 1791-7530 J9 ANTICANCER RES JI Anticancer Res. PD JUN PY 2016 VL 36 IS 6 BP 2659 EP 2664 PG 6 WC Oncology SC Oncology GA DO0JC UT WOS:000377464200004 PM 27272774 ER PT J AU Rocha, YC Lopez, JA Orrego, JC Coll, Y Karduss, A Rosenzweig, S Franco, JL AF Carolina Rocha, Yermis Alvaro Lopez, Juan Cesar Orrego, Julio Coll, Yadira Karduss, Amado Rosenzweig, Sergio Luis Franco, Jose TI Successful immune reconstitution by means of hematopoietic stem cell transplantation in a Colombian patient with chronic granulomatous disease SO BIOMEDICA LA Spanish DT Article DE Granulomatous disease, chronic; neutrophils; NADPH oxidase; reactive oxygen species; hematopoietic stem cell transplantation; transplantation conditioning ID MANAGEMENT; DIAGNOSIS; MUTATION; CHILDREN AB Introduction: Chronic granulomatous disease is a primary immunodeficiency that results from mutations in proteins of the NADPH oxidase system that affect the microbicidal activity of phagocytes. Immune reconstitution by hematopoietic stem cell transplantation is currently the only curative therapy for this disease. Objective: To describe the clinical and molecular characterization of a patient with X-linked chronic granulomatous disease and the successful immune reconstitution by means of a hematopoietic stem cell transplantation. Methods: The respiratory burst was measured by flow cytometry using the dihydrorodamine 123 (DHR) oxidation test in neutrophils of peripheral blood. Mutational analysis of CYBB was performed by PCR amplification in complementary DNA, as well as sequencing and comparative genomic hybridization in genomic DNA. HLA-identical stem cells from the patient's younger brother were used for the transplantation and reduced intensity pre-transplantation conditioning was administered. Post-transplantation immune reconstitution was evaluated periodically by serial complete blood counts and DHR 123 in peripheral blood neutrophils. Results: The diagnosis of X-linked chronic granulomatous disease resulted from a hemizygous deletion affecting Xp21.1 that included the entire CYBB. Post-transplantation engraftment was documented in platelets and peripheral blood neutrophils at days 10 and 11, respectively. Total hematological reconstitution was achieved by day 30 post-transplantation and no complications or infections have been observed in the three years since the transplantation. Conclusion: Hemopoietic stem cell transplantation allows for total reconstitution of the immune function related to microbicidal activity of phagocytic cells from patients with X-linked chronic granulomatous disease. C1 [Carolina Rocha, Yermis; Alvaro Lopez, Juan; Cesar Orrego, Julio; Luis Franco, Jose] Univ Antioquia, Fac Med, Grp Inmunodeficiencias Primarias, Medellin, Colombia. [Alvaro Lopez, Juan] Univ Antioquia, Escuela Microbiol, Medellin, Colombia. [Coll, Yadira; Karduss, Amado] Inst Cancerol, Clin Las Amer, Unidad Trasplante Hematopoyet, Medellin, Colombia. [Coll, Yadira] Univ Antioquia, Fac Med, Dept Pediat & Puericultura, Medellin, Colombia. [Rosenzweig, Sergio] NIAID, Infect Dis Susceptibil Unit, NIH, Bethesda, MD 20892 USA. Univ Antioquia, Sede Invest Univ, Medellin, Colombia. RP Franco, JL (reprint author), Univ Antioquia, Sede Invest Univ, Calle 62 52-59,Lab 530, Medellin, Colombia. EM jose.franco@udea.edu.co NR 30 TC 0 Z9 0 U1 2 U2 2 PU INST NACIONAL SALUD PI BOGOTA D C PA AVENIDA CALLE 26 NO 51-60, APARTADO AEREO 80334 Y 80080, BOGOTA D C, 00000, COLOMBIA SN 0120-4157 J9 BIOMEDICA JI Biomedica PD JUN PY 2016 VL 36 IS 2 BP 204 EP 212 DI 10.7705/biomedica.v36i2.2870 PG 9 WC Tropical Medicine SC Tropical Medicine GA DN7KI UT WOS:000377253900006 PM 27622481 ER PT J AU Chan, KCG Qin, J AF Chan, Kwun Chuen Gary Qin, Jing TI Nonparametric maximum likelihood estimation for the multisample Wicksell corpuscle problem SO BIOMETRIKA LA English DT Article DE Abel-type integral equation; Expectation-maximization algorithm; Indirect measurement; Particle size ID SPHERE SIZE DISTRIBUTIONS; SELECTION BIAS MODELS; EMPIRICAL DISTRIBUTIONS; EMISSION-TOMOGRAPHY; PARTICLE-SIZE; STEREOLOGY AB We study nonparametric maximum likelihood estimation for the distribution of spherical radii using samples containing a mixture of one-dimensional, two-dimensional biased and three-dimensional unbiased observations. Since direct maximization of the likelihood function is intractable, we propose an expectation-maximization algorithm for implementing the estimator, which handles an indirect measurement problem and a sampling bias problem separately in the E- and M-steps, and circumvents the need to solve an Abel-type integral equation, which creates numerical instability in the one-sample problem. Extensions to ellipsoids are studied and connections to multiplicative censoring are discussed. C1 [Chan, Kwun Chuen Gary] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Qin, Jing] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. RP Chan, KCG (reprint author), Univ Washington, Dept Biostat, Seattle, WA 98195 USA. EM kcgchan@u.washington.edu; jingqin@niaid.nih.gov FU National Heart, Lung, and Blood Institute of the U.S. National Institutes of Health FX The authors thank the editor, an associate editor and three reviewers for their helpful comments and suggestions. They also thank Joe Tucker and Anthony Rollett for providing the Inconel 100 data. The first author is partially supported by the National Heart, Lung, and Blood Institute of the U.S. National Institutes of Health. NR 29 TC 1 Z9 1 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-3444 EI 1464-3510 J9 BIOMETRIKA JI Biometrika PD JUN PY 2016 VL 103 IS 2 BP 273 EP 286 DI 10.1093/biomet/asw011 PG 14 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA DN9VO UT WOS:000377429000003 PM 27279657 ER PT J AU Drahos, J Li, L Jick, SS Cook, MB AF Drahos, Jennifer Li, Lin Jick, Susan S. Cook, Michael B. TI Metabolic syndrome in relation to Barrett's esophagus and esophageal adenocarcinoma: Results from a large population-based case-control study in the Clinical Practice Research Datalink SO CANCER EPIDEMIOLOGY LA English DT Article DE (MeSH): Barrett esophagus; Esophageal Cancer; Metabolic syndrome X; Obesity; Gastroesophageal reflux ID GASTROESOPHAGEAL-REFLUX DISEASE; PRACTICE RESEARCH DATABASE; BODY-MASS INDEX; RISK-FACTORS; CENTRAL ADIPOSITY; CANCER; MORTALITY; SENSITIVITY; VALIDATION; DIAGNOSES AB Gastroesophageal reflux disease (GERD) causes local chronic inflammation that increases risks of Barrett's esophagus (BE) and esophageal adenocarcinoma (EA), yet symptomatic GERD is absent in approximately half of all such patients. Obesity exacerbates GERD and is also a component of metabolic syndrome (MetS). We evaluated the hypothesis that MetS is a GERD-independent mechanism by which obesity is associated with increased risks of BE and EA using data from the UK Clinical Practice Research Datalink. BE cases (n = 10,215) and EA cases (n = 592) were each individually matched to five population controls based on age, sex, and general practice. MetS was defined as occurrence of at least three of the following: obesity, type 2 diabetes, hypertension, and high cholesterol. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. MetS was marginally associated with BE (OR = 1.12, 95% CI 1.00-1.25). Similar effects were found for the individual component factors of obesity, hypertension, and high cholesterol. History of GERD modified the association (P-(effect) modification <1E-5), with the MetS-BE association confined to patients without a history of GERD (OR = 1.33, 95% CI 1.12-1.58). No association between MetS and risk of EA was detected in the main or stratified analyses. In this large population-based case-control study, individuals with MetS had a marginally increased risk of BE in the absence of GERD. The systemic inflammatory state (MetS) may represent a reflux-independent inflammatory pathway that increases the risk of BE. MetS did not increase risk of EA in this study population. Published by Elsevier Ltd. C1 [Drahos, Jennifer; Cook, Michael B.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Li, Lin; Jick, Susan S.] Boston Univ, Sch Publ Hlth, Boston Collaborat Drug Surveillance Program, Lexington, MA USA. RP Drahos, J (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 9609 Med Ctr Dr,MSC 9774, Bethesda, MD 20892 USA. EM jdrahos@gmail.com RI Cook, Michael/A-5641-2009; CPRD, CPRD/B-9594-2017 OI Cook, Michael/0000-0002-0533-7302; FU Intramural Program of the National Cancer Institute at the National Institutes of Health; Department of Health and Human Services FX This work was supported by the Intramural Program of the National Cancer Institute at the National Institutes of Health and Department of Health and Human Services. NR 38 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD JUN PY 2016 VL 42 BP 9 EP 14 DI 10.1016/j.canep.2016.02.008 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DN9RH UT WOS:000377417300002 PM 26972225 ER PT J AU Bassig, BA Au, WY Mang, O Ngan, R Morton, LM Ip, DKM Hu, W Zheng, TZ Seow, WJ Xu, J Lan, Q Rothman, N AF Bassig, Bryan A. Au, Wing-Yan Mang, Oscar Ngan, Roger Morton, Lindsay M. Ip, Dennis K. M. Hu, Wei Zheng, Tongzhang Seow, Wei Jie Xu, Jun Lan, Qing Rothman, Nathaniel TI Subtype-specific incidence rates of lymphoid malignancies in Hong Kong compared to the United States, 2001-2010 SO CANCER EPIDEMIOLOGY LA English DT Article DE Lymphoid malignancies; Hong Kong; Incidence rates; Non-Hodgkin lymphoma; Descriptive epidemiology ID NON-HODGKIN-LYMPHOMA; HEALTH-ORGANIZATION CLASSIFICATION; CHRONIC LYMPHOCYTIC-LEUKEMIA; BRITISH-COLUMBIA; GENETIC SUSCEPTIBILITY; CHINESE MIGRANTS; EPIDEMIOLOGY; NEOPLASMS; TRENDS; JAPAN AB Clinical studies of lymphoid malignancies (LMs) have suggested that the descriptive patterns of LMs differ in East Asia compared to Western populations. However, there are very limited available data on population-based, subtype-specific incidence rates of LMs in the East Asian population, particularly in Chinese. Using data from the Hong Kong (HK) Cancer Registry and United States (U.S.) SEER Program, we calculated and compared age-adjusted incidence rates of LM subtypes in HK to those in Whites and Asians living in the U.S. Overall and sex-specific rates were calculated for the period 2001-2010. The incidence of most subtypes was low in the HK population, with rates <1 case per 100,000 for all subtypes except for diffuse large B-cell lymphoma (3.26/100,000) and plasma cell neoplasms (1.99/100,000). Age-adjusted incidence rates of all evaluated B-cell subtypes were significantly higher in U.S. Whites compared to HK, with standardized rate ratios (SRRs) ranging from 1.6 (Burkitt lymphoma) to 9.1 (chronic lymphocytic leukemia/small lymphocytic lymphoma). Rates in U.S. Asians were generally intermediate to those in U.S. Whites and HK. Conversely, rates of extranodal NK/T-cell lymphoma were significantly lower in both U.S. Whites (SRR = 0.2) and U.S. Asians (SRR = 0.5) compared to HK. Our data provide new insight into the subtype-specific patterns of LMs in the Chinese population, and suggest the need for etiological studies of LMs in the East Asian population to elucidate the factors responsible for these differences in the geographic incidence patterns. Published by Elsevier Ltd. C1 [Bassig, Bryan A.; Morton, Lindsay M.; Hu, Wei; Seow, Wei Jie; Lan, Qing; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Au, Wing-Yan] Univ Hong Kong, Queen Mary Hosp, Dept Med, Hong Kong, Hong Kong, Peoples R China. [Mang, Oscar; Ngan, Roger] Queen Elizabeth Hosp, Dept Clin Oncol, Hong Kong, Hong Kong, Peoples R China. [Ip, Dennis K. M.] Univ Hong Kong, Sch Publ Hlth, Div Community Med & Publ Hlth Practice, Hong Kong, Hong Kong, Peoples R China. [Zheng, Tongzhang] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [Xu, Jun] Univ Hong Kong, Li Ka Shing Fac Med, Sch Publ Hlth, Hong Kong, Hong Kong, Peoples R China. RP Bassig, BA (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr MSC 9776,Rm 6E132, Bethesda, MD 20892 USA. EM bassigb@mail.nih.gov NR 26 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD JUN PY 2016 VL 42 BP 15 EP 23 DI 10.1016/j.canep.2016.02.007 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DN9RH UT WOS:000377417300003 PM 26991956 ER PT J AU Kuhs, KAL Pawlita, M Gibson, SP Schmitt, NC Trivedi, S Argiris, A Kreimer, AR Ferris, RL Waterboer, T AF Kuhs, Krystle A. Lang Pawlita, Michael Gibson, Sandra P. Schmitt, Nicole C. Trivedi, Sumita Argiris, Athanassios Kreimer, Aimee R. Ferris, Robert L. Waterboer, Tim TI Characterization of human papillomavirus antibodies in individuals with head and neck cancer SO CANCER EPIDEMIOLOGY LA English DT Article DE Human papillomavirus 16; HPV16; HPV16 E6; HPV antibodies; HPV seropositivity; Oropharyngeal cancer; OPC; Non-oropharyngeal cancer; Non-OPC ID OROPHARYNGEAL CANCER; UNITED-STATES; TRENDS; INFECTIONS; PREVALENCE; CARCINOMA AB Background: Human papillomavirus type 16 (HPV16) E6 antibodies are a promising biomarker of oropharyngeal cancer (OPC); however, seropositivity among non-OPC cases is not well characterized. Methods: Pre-treatment sera from 260 (38 OPC, 222 non-OPC) incident head and neck cancers diagnosed at the University of Pittsburgh between 2003 and 2006 were tested for HPV16 (L1, E1, E2, E4, E6, E7) and non-HPV16 E6 (HPV6,11,18,33) antibodies. Sensitivity and specificity of HPV16 E6 antibodies for HPV-driven tumors was evaluated among tumors with known HPV status (n = 25). Results: 63.2% of OPC versus 27.5% of non-OPC cases were HPV16 seropositive; HPV16 E6 seroprevalence was 60.5% and 6.3% respectively, odds ratio 22.8 (95% confidence interval [CI] 9.8-53.1). Sensitivity and specificity of HPV16 E6 antibodies for HPV-driven OPC was 100% [95% CI: 50-100%; n = 6] and 100% [95% CI: 60-100%, n = 4] compared to 0% (n = 2) and 0% (n = 13) for non-OPC cases. Conclusions: HPV16 antibodies were significantly more common in OPC versus non-OPC cases, particularly HPV16 E6 antibodies. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Kuhs, Krystle A. Lang; Kreimer, Aimee R.] NCI, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Pawlita, Michael; Waterboer, Tim] German Canc Res Ctr, Neuenheimer Feld 242, D-69120 Heidelberg, Germany. [Gibson, Sandra P.; Schmitt, Nicole C.; Ferris, Robert L.] Univ Pittsburgh, Inst Canc, 5150 Ctr Ave, Pittsburgh, PA 15232 USA. [Schmitt, Nicole C.] Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, 6420 Rockledge Dr,Suite 4920, Bethesda, MD USA. [Schmitt, Nicole C.] NIDCD, Tumor Biol Sect, NIH, 10 Ctr Dr,Bldg 10,Room 5B39, Bethesda, MD USA. [Trivedi, Sumita] Univ Pittsburgh, Inst Canc, Dept Otolaryngol, 200 Lothrop St, Pittsburgh, PA 15232 USA. [Trivedi, Sumita] Univ Pittsburgh, Inst Canc, Canc Immunol Program, 200 Lothrop St, Pittsburgh, PA 15232 USA. [Argiris, Athanassios] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Argiris, Athanassios] Hygeia Hosp, Erythrou Stavrou 5, Athens 15123, Greece. RP Ferris, RL (reprint author), Univ Pittsburgh, Inst Canc, 5150 Ctr Ave, Pittsburgh, PA 15232 USA.; Waterboer, T (reprint author), German Canc Res Ctr, Infect Inflammat & Canc Program, Mol Diagnost Oncogen Infect Div, Neuenheimer Feld 242, D-69120 Heidelberg, Germany. EM ferrrl@upmc.edu; t.waterboer@dkfz-heidelberg.de RI Waterboer, Tim/G-1252-2010; OI Pawlita, Michael/0000-0002-4720-8306 FU [1P50CA097190] FX This work was supported by the following grant awarded to Robert L. Ferris: 1P50CA097190. NR 23 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD JUN PY 2016 VL 42 BP 46 EP 52 DI 10.1016/j.canep.2016.03.003 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DN9RH UT WOS:000377417300007 ER PT J AU Shridhar, K Rajaraman, P Koyande, S Parikh, PM Chaturvedi, P Dhillon, PK Dikshit, RP AF Shridhar, Krithiga Rajaraman, Preetha Koyande, Shravani Parikh, Purvish M. Chaturvedi, Pankaj Dhillon, Preet K. Dikshit, Rajesh P. TI Trends in mouth cancer incidence in Mumbai, India (1995-2009): An age-period-cohort analysis SO CANCER EPIDEMIOLOGY LA English DT Article DE Mouth cancer; Cancer trend; India; Age-period-cohort analysis; Cancer registry; Age-specific rate; Age standardized rate; Risk factors; Mumbai; Net drift ID ORAL-CAVITY; OROPHARYNGEAL CANCERS; TEMPORAL VARIATION; RATES; RECOMMENDATIONS; EPIDEMIOLOGY; MODELS; RISK; MEN AB Introduction: Despite tobacco control and health promotion efforts, the incidence rates of mouth cancer are increasing across most regions in India. Analysing the influence of age, time period and birth cohort on these secular trends can point towards underlying factors and help identify high-risk populations for improved cancer control programmes. Methods: We evaluated secular changes in mouth cancer incidence among men and women aged 25-74 years in Mumbai between 1995 and 2009 by calculating age-specific and age-standardized incidence rates (ASR). We estimated the age-adjusted linear trend for annual percent change (EAPC) using the drift parameter, and conducted an age-period-cohort (APC) analysis to quantify recent time trends and to evaluate the significance of birth cohort and calendar period effects. Results: Over the 15-year period, age-standardized incidence rates of mouth cancer in men in Mumbai increased by 2.7% annually (95% CI: 1.9 to 3.4), p < 0.0001) while rates among women decreased (EAPC = -0.01% (95% CI: -0.02 to -0.002), p = 0.03). APC analysis revealed significant non-linear positive period and cohort effects in men, with higher effects among younger men (25-49 years). Non-significant increasing trends were observed in younger women (25-49 years). Conclusions: APC analyses from the Mumbai cancer registry indicate a significant linear increase of mouth cancer incidence from 1995 to 2009 in men, which was driven by younger men aged 25-49 years, and a non-significant upward trend in similarly aged younger women. Health promotion efforts should more effectively target younger cohorts. (C) 2016 The Authors. Published by Elsevier Ltd. C1 [Shridhar, Krithiga; Dhillon, Preet K.] Publ Hlth Fdn India, Ctr Chron Condit & Injuries, 4th Floor,Plot 47,Sect 44, Gurgaon 122002, Haryana, India. [Rajaraman, Preetha] NCI, Ctr Global Hlth, Bethesda, MD 20892 USA. [Koyande, Shravani; Parikh, Purvish M.] Mumbai Canc Registry, 74 Jerbai Wadia Rd, Bombay 400012, Maharashtra, India. [Chaturvedi, Pankaj] Tata Mem Hosp, Head & Neck Surg, Dr E Borges Rd, Bombay 400012, Maharashtra, India. [Dikshit, Rajesh P.] Tata Mem Hosp, Ctr Canc Epidemiol, Dr E Borges Rd, Bombay 400012, Maharashtra, India. RP Dikshit, RP (reprint author), Tata Mem Hosp, Ctr Canc Epidemiol, Dr E Borges Rd, Bombay 400012, Maharashtra, India. EM g.krithiga@phfi.org; rajarama@mail.nih.gov; bcrics@vsnl.com; purvish@rediffmail.com; drchaturvedip@rediffmail.com; preet.dhillon@phfi.org; dixr24@hotmail.com FU National Cancer Registry Program of the Indian Council of Medical Research; Wellcome Trust Strategic award-South Asia Network for Chronic Disease (SANCD) [WT 084674]; PHFI-UKC Wellcome Trust Capacity Building Programme-Extension Phase FX This work was conducted as part of a training programme at Tata Memorial Hospital and Cancer Registry, Mumbai, attended by Dr Krithiga Shridhar. The Mumbai Cancer registry has been partly funded by the National Cancer Registry Program of the Indian Council of Medical Research since 1982. Published data of Mumbai Cancer Registry were used for this study. Dr Krithiga Shridhar was supported by Wellcome Trust Strategic award-South Asia Network for Chronic Disease (SANCD) (WT 084674) and by the PHFI-UKC Wellcome Trust Capacity Building Programme-Extension Phase. NR 34 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD JUN PY 2016 VL 42 BP 66 EP 71 DI 10.1016/j.canep.2016.03.007 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DN9RH UT WOS:000377417300010 PM 27043865 ER PT J AU Petrick, JL Freedman, ND Demuth, J Yang, BY Van Den Eeden, SK Engel, LS McGlynn, KA AF Petrick, Jessica L. Freedman, Neal D. Demuth, Jane Yang, Baiyu Van Den Eeden, Stephen K. Engel, Lawrence S. McGlynn, Katherine A. TI Obesity, diabetes, serum glucose, and risk of primary liver cancer by birth cohort, race/ethnicity, and sex: Multiphasic health checkup study SO CANCER EPIDEMIOLOGY LA English DT Article ID HEPATOCELLULAR-CARCINOMA; UNITED-STATES; METAANALYSIS; POPULATION; MELLITUS; INFLAMMATION; DISEASES; TRENDS AB Objective: Obesity and diabetes have been associated with liver cancer. However, recent US-based studies have suggested a lack of association between obesity and liver cancer among blacks and women. Methods: We conducted a nested case-control study within the Multiphasic Health Checkup (MHC) cohort of Kaiser Permanente Northern California (KPNC) members. Liver cancer was diagnosed using the KPNC Cancer Registry. Detailed self-administered questionnaires and a standardized examination that included measurement of height and weight and a 1-h glucose tolerance test were completed prior to diagnosis of liver cancer for cases (n = 450) and matched controls (4489). Height and weight were utilized to calculate BMI (kg/m(2)) as a measure of adiposity: underweight (15-<= 8.5 kg/m(2)), normal weight (18.5-<= 25 kg/m(2)), overweight (25-<= 30 kg/m(2)), and obese (>= 30 kg/m(2)). Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the association between BMI, diabetes, and serum glucose with subsequent incidence of liver cancer, in models that were stratified by birth cohort, race/ethnicity, and sex. Results: Compared to normal weight individuals, obese individuals had a 2.4-fold increased risk of liver cancer (OR = 2.38, 95% CI: 1.68-3.36), and overweight individuals had a 32% increased risk (OR = 1.32, 95% CI: 1.03-1.70). This association did not differ when stratified by birth cohort, race/ethnicity, or sex (pint > 0.05). Among blacks and women, obesity was associated with at least a 2-fold increased risk of liver cancer (OR = 2.29, 95% CI: 1.22-4.28 and OR = 2.00, 95% CI: 1.14-3.52, respectively). More moderate increased odds ratios were noted for diabetes (OR = 1.28, 95% CI: 0.65-2.54) and serum glucose >= 200 mg/dL (OR = 1.63, 95% CI: 0.48-5.55), although the results did not attain statistical significance. Conclusion: In summary, our finding of a positive association between obesity and liver cancer suggests that a higher BMI may increase the risk of liver cancer in the US, for both sexes and all race/ethnicities. Published by Elsevier Ltd. C1 [Petrick, Jessica L.; Freedman, Neal D.; Yang, Baiyu; McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Demuth, Jane] Informat Management Serv Inc, Silver Spring, MD USA. [Van Den Eeden, Stephen K.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Engel, Lawrence S.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. RP Petrick, JL (reprint author), 9609 Med Ctr Dr,7E-230, Bethesda, MD 20892 USA. EM jessica.petrick@nih.gov FU National Institutes of Health (NIH) Intramural Research Program, National Cancer Institute; NIH, National Institute of Environmental Health Sciences [R01ES014662] FX This study was funded in part by the National Institutes of Health (NIH) Intramural Research Program, National Cancer Institute; and a grant from the NIH, National Institute of Environmental Health Sciences (R01ES014662). NR 32 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD JUN PY 2016 VL 42 BP 140 EP 146 DI 10.1016/j.canep.2016.04.009 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DN9RH UT WOS:000377417300019 PM 27148890 ER PT J AU Schinkel, JK Shao, S Zahm, SH McGlynn, KA Shriver, CD Zhu, KM AF Schinkel, Jill K. Shao, Stephanie Zahm, Shelia H. McGlynn, Katherine A. Shriver, Craig D. Zhu, Kangmin TI Overall and recurrence-free survival among black and white bladder cancer patients in an equal-access health system SO CANCER EPIDEMIOLOGY LA English DT Article DE Bladder cancer; Race; Survival ID UNITED-STATES; UROTHELIAL CARCINOMA; RACIAL-DIFFERENCES; LUNG-CANCER; STAGE; MORTALITY; ASSOCIATION; DISPARITIES; GENDER; CARE AB Background: While the incidence of bladder cancer is twice as high among whites than among blacks, mortality is higher among blacks than whites. Unequal access to medical care may be an important factor. Insufficient access to care could delay cancer detection and treatment, which can result in worse survival. The purpose of this study was to evaluate whether survival differed between black and white bladder cancer patients in the Department of Defense (DoD), which provides universal healthcare to all beneficiaries regardless of racial background. Methods: This study was based on data from the U. S. DoD Automated Central Tumor Registry (ACTUR). White and black patients histologically diagnosed with bladder cancer between 1990 and 2004 were included in the study and followed to the end of 2007. The outcomes were all-cause mortality and recurrence. We assessed the relationship between race and outcomes of interest using Cox proportional hazard ratios (HRs) for all, non-muscle invasive (NMIBC), and muscle invasive (MIBC) bladder cancers, separately. Results: The survival of black and white individuals did not differ statistically. No significant racial differences in survival (HR: 0.96, 95% CI: 0.76-1.22) or recurrence-free survival (HR: 0.94, 95% CI: 0.69-1.30) were observed after adjustment for demographic variables, tumor characteristics, and treatment. Similar findings were observed for NMIBC and MIBC patients, respectively. Conclusion: Black patients were more likely to present with MIBC than white patients. However, white and black patients with bladder cancer were not significantly different in overall and recurrence-free survival regardless of muscle invasion. Our study suggests the importance of equal access to healthcare in reducing racial disparities in bladder cancer survival. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Schinkel, Jill K.; Shao, Stephanie; Shriver, Craig D.; Zhu, Kangmin] Walter Reed Natl Mil Med Ctr, John P Murtha Canc Ctr, Bethesda, MD USA. [Zahm, Shelia H.; McGlynn, Katherine A.] NCI, NIH, Rockville, MD USA. [Shriver, Craig D.] Walter Reed Natl Mil Med Ctr, Gen Surg Serv, Bethesda, MD USA. [Shao, Stephanie; Shriver, Craig D.; Zhu, Kangmin] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Zhu, KM (reprint author), Walter Reed Natl Mil Med Ctr, John P Murtha Canc Ctr, 11300 Rockville Pike,Suite 1120, Rockville, MD 20852 USA. EM kzhu@murthacancercenter.org FU John P. Murtha Cancer Center; Walter Reed National Military Medical Center via the Uniformed Services University of the Health Sciences under the Henry M. Jackson Foundation for the Advancement of Military Medicine FX This project was supported by John P. Murtha Cancer Center, Walter Reed National Military Medical Center via the Uniformed Services University of the Health Sciences under the auspices of the Henry M. Jackson Foundation for the Advancement of Military Medicine. The authors thank the Joint Pathology Center (formerly Armed Forces Institute of Pathology) for providing the data. NR 31 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD JUN PY 2016 VL 42 BP 154 EP 158 DI 10.1016/j.canep.2016.04.012 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DN9RH UT WOS:000377417300021 PM 27161431 ER PT J AU Chaturvedi, AK Song, H Rosenberg, PS Ramqvist, T Anderson, WF Munck-Wikland, E Ye, WM Dalianis, T AF Chaturvedi, Anil K. Song, Huan Rosenberg, Phillip S. Ramqvist, Torbjorn Anderson, William F. Munck-Wikland, Eva Ye, Weimin Dalianis, Tina TI Tonsillectomy and Incidence of Oropharyngeal Cancers SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SQUAMOUS-CELL CARCINOMA; VIRAL-INDUCED CARCINOMA; HUMAN-PAPILLOMAVIRUS; UNITED-STATES; BILATERAL TONSILLECTOMY; POSITIVE TONSILLAR; UNKNOWN PRIMARY; EPIDEMIC; TRENDS; RATES AB Background: Rising incidence of oropharyngeal cancers in numerous countries since the 1970s has been attributed to increased oral human papillomavirus (HPV) exposure. However, the contribution of coincidental declines in the surgical removal of the tonsils (tonsillectomy) is unknown. We quantified the association of tonsillectomy with risk of tonsillar, other oropharyngeal, and other head and neck cancers and the contribution of declines in tonsillectomies to cancer incidence trends. Methods: We conducted a nation-wide cohort study in Sweden (1970-2009). Tonsillectomies (N = 225,718) were identified through national patient registers, which were linked with the cancer register. Cancer incidence in the tonsillectomy cohort was compared with Sweden's general population through standardized incidence ratios (SIR). Results: Tonsillectomies were associated with reduced risk of tonsil cancers [SIRs 1+ years post-tonsillectomy = 0.31; 95% confidence interval (CI), 0.08-0.79 and 5+ years post-tonsillectomy <0.17; 95% CI, 0.02-0.62], but unrelated to other oro-pharyngeal or other head and neck cancers (SIRs 1+ years post-tonsillectomy <1.61; 95% CI, 0.77-2.95 and 0.92; 95% CI, 0.64-1.27, respectively). The cumulative incidence of tonsillectomy declined significantly (40%-50%) during 1970-2009. However, tonsil cancer incidence significantly increased during 1970-2009 both without and with corrections for declines in tonsillectomies (relative risks per 5-year periods <1.23, P < 0.001 and 1.20, P < 0.001, respectively). Conclusions: The reduced tonsil cancer risk with tonsillectomy reflects the removal of most of the relevant tissue. The absence of associations with other head and neck cancers indicates that tonsillectomy may not impact carcinogenesis at other sites. Impact: The significant increases in oropharyngeal cancer incidence since the 1970s in Sweden appear independent of declines in tonsillectomies, reinforcing increased oral HPV exposure as the likely cause. (C) 2016 AACR. C1 [Chaturvedi, Anil K.; Rosenberg, Phillip S.; Anderson, William F.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Song, Huan; Ye, Weimin] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Ramqvist, Torbjorn; Dalianis, Tina] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Munck-Wikland, Eva] Karolinska Inst, Dept Clin Sci Intervent & Technol, Div ENT Dis, Stockholm, Sweden. RP Chaturvedi, AK (reprint author), NCI, 9609 Med Ctr Dr,Rm 6E-238, Rockville, MD 20852 USA. EM chaturva@mail.nih.gov FU Intramural Research Program, NCI; Swedish Cancer Foundation; Stockholm Cancer Society; Swedish Cancer and Allergy Foundation; Stockholm City Council FX This study is supported by grants from Intramural Research Program, NCI (to A.K. Chaturvedi), the Swedish Cancer Foundation (to T. Dalianis), the Stockholm Cancer Society (to T. Dalianis), the Swedish Cancer and Allergy Foundation (to T. Dalianis), and the Stockholm City Council (to T. Dalianis). NR 29 TC 2 Z9 2 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 JUN PY 2016 VL 25 IS 6 BP 944 EP 950 DI 10.1158/1055-9965.EPI-15-0907 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DO1HC UT WOS:000377528100007 PM 26976856 ER PT J AU Haznadar, M Cai, QY Krausz, KW Bowman, ED Margono, E Noro, R Thompson, MD Mathe, EA Munro, HM Steinwandel, MD Gonzalez, FJ Blot, WJ Harris, CC AF Haznadar, Majda Cai, Qiuyin Krausz, Kristopher W. Bowman, Elise D. Margono, Ezra Noro, Rintaro Thompson, Matthew D. Mathe, Ewy A. Munro, Heather M. Steinwandel, Mark D. Gonzalez, Frank J. Blot, William J. Harris, Curtis C. TI Urinary Metabolite Risk Biomarkers of Lung Cancer: A Prospective Cohort Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CIRCULATING TUMOR-CELLS; DOSE COMPUTED-TOMOGRAPHY; SERVICES-TASK-FORCE; MENTHOL CIGARETTES; UNITED-STATES; SMOKERS; MORTALITY; ADENOCARCINOMA; STATISTICS; STRATEGIES AB Background: Lung cancer is a major health burden causing 160,000 and 1.6 million deaths annually in the United States and worldwide, respectively. Methods: While seeking to identify stable and reproducible biomarkers in noninvasively collected biofluids, we assessed whether previously identified metabolite urinary lung cancer biomarkers, creatine riboside (CR), N-acetylneuraminic acid (NANA), cortisol sulfate, and indeterminate metabolite 561+, were elevated in the urines of subjects prior to lung cancer diagnosis in a well-characterized prospective Southern Community Cohort Study (SCCS). Urine was examined from 178 patients and 351 nondiseased controls, confirming that one of four metabolites was associated with lung cancer risk in the overall case-control set, whereas two metabolites were associated with lung cancer risk in European-Americans. Results: OR of lung cancer associated with elevated CR levels, and adjusted for smoking and other potential confounders, was 2.0 [95% confidence interval (CI), 1.2-3.4; P = 0.01]. In European-Americans, both CR and NANA were significantly associated with lung cancer risk (OR = 5.3; 95% CI, 1.6-17.6; P = 0.006 and OR = 3.5; 95% CI, 1.5-8.4; P = 0.004, respectively). However, race itself did not significantly modify the associations. ROC analysis showed that adding CR and NANA to a model containing previously established lung cancer risk factors led to a significantly improved classifier (P = 0.01). Increasing urinary levels of CR and NANA displayed a positive association with increasing tumor size, strengthening a previously established link to altered tumor metabolism. Conclusion and Impact: These replicated results provide evidence that identified urinary metabolite biomarkers have a potential utility as noninvasive, clinical screening tools for early diagnosis of lung cancer. (C) 2016 AACR. C1 [Haznadar, Majda; Bowman, Elise D.; Margono, Ezra; Harris, Curtis C.] NCI, Lab Human Carcinogenesis, Ctr Canc Res, Bethesda, MD 20892 USA. [Cai, Qiuyin; Blot, William J.] Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol,Vanderbilt Epidemiol Ctr,Vanderbilt, Nashville, TN 37212 USA. [Krausz, Kristopher W.; Thompson, Matthew D.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. [Noro, Rintaro] Nippon Med Sch, 1-1-5 Sendagi, Tokyo 113, Japan. [Mathe, Ewy A.] Ohio State Univ, Coll Med, Biomed Informat, Columbus, OH 43210 USA. [Munro, Heather M.; Steinwandel, Mark D.; Blot, William J.] Int Epidemiol Inst, 1455 Res Blvd,Suite 550, Rockville, MD 20850 USA. RP Blot, WJ (reprint author), Int Epidemiol Inst, 1455 Res Blvd,Suite 550, Rockville, MD 20850 USA.; Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Bldg 37,Room 3068,37 Convent Dr,MSC 4258, Bethesda, MD 20892 USA. EM blotw@iei.us; Curtis_Harris@nih.gov FU Center for Cancer Research Intramural Research Program, National Cancer Institute, NIH; NIH [R01 CA092447]; Vanderbilt-Ingram Cancer Center [P30 CA068485] FX The work was supported by funding from the Center for Cancer Research Intramural Research Program, National Cancer Institute, NIH, and from NIH grant R01 CA092447 (to W.J. Blot). SCCS sample preparation was conducted at the Survey and Biospecimen Shared Resource that is supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA068485 to Q. Cai). NR 47 TC 1 Z9 1 U1 6 U2 7 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 JUN PY 2016 VL 25 IS 6 BP 978 EP 986 DI 10.1158/1055-9965.EPI-15-1191 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DO1HC UT WOS:000377528100011 PM 27013655 ER PT J AU Huang, XF Nandakumar, V Tumurkhuu, G Wang, T Jiang, X Hong, B Jones, L Won, H Yoshii, H Ozato, K Masumi, A Chen, SY AF Huang, X. F. Nandakumar, V. Tumurkhuu, G. Wang, T. Jiang, X. Hong, B. Jones, L. Won, H. Yoshii, H. Ozato, K. Masumi, A. Chen, S-Y TI Mysm1 is required for interferon regulatory factor expression in maintaining HSC quiescence and thymocyte development SO CELL DEATH & DISEASE LA English DT Article ID HISTONE H2A DEUBIQUITINASE; SEQUENCE-BINDING-PROTEIN; HEMATOPOIETIC STEM-CELLS; FACTOR FAMILY; LYMPHOCYTE DIFFERENTIATION; EPIGENETIC REGULATION; MYELOID PROGENITOR; GENE-EXPRESSION; SELF-RENEWAL; ICSBP GENE AB Mysm1(-/)-mice have severely decreased cellularity in hematopoietic organs. We previously revealed that Mysm1 knockout impairs self-renewal and lineage reconstitution of HSCs by abolishing the recruitment of key transcriptional factors to the Gfi-1 locus, an intrinsic regulator of HSC function. The present study further defines a large LSKs in >8-week-old Mysm1(-/)-mice that exhibit increased proliferation and reduced cell lineage differentiation compared with those of WT LSKs. We found that IRF2 and IRF8, which are important for HSC homeostasis and commitment as transcription repressors, were expressed at lower levels in Mysm1(-/-) HSCs, and Mysm1 enhanced function of the IRF2 and IRF8 promoters, suggesting that Mysm1 governs the IRFs for HSC homeostasis. We further found that the lower expressions of IRF2 and IRF8 led to an enhanced transcription of p53 in Mysm1(-/-) HSCs, which was recently defined to have an important role in mediating Mysm1(-/-)-associated defects. The study also revealed that Mysm1(-/-) thymocytes exhibited lower IRF2 expression, but had higher Sca1 expression, which has a role in mediating thymocyte death. Furthermore, we found that the thymocytes from B16 melanoma-bearing mice, which display severe thymus atrophy at late tumor stages, exhibited reduced Mysm1 and IRF2 expression but enhanced Sca1 expression, suggesting that tumors may downregulate Mysm1 and IRF2 for thymic T-cell elimination. C1 [Huang, X. F.; Nandakumar, V.; Tumurkhuu, G.; Wang, T.; Jiang, X.; Hong, B.; Jones, L.; Won, H.; Chen, S-Y] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA. [Yoshii, H.; Ozato, K.] NICHHD, Lab Mol Growth Regulat, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Masumi, A.] Natl Inst Infect Dis, Dept Safety Res Blood & Biol Prod, Tokyo, Japan. RP Huang, XF (reprint author), Univ So Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Norris Res Tower 7509,1450 Biggy St, Los Angeles, CA 90033 USA. EM xuefhuan@usc.edu FU NIH [R01CA090427, R01AI084811, R21AI11625701A1, 1R21AI087185-A1]; Norris comprehensive Cancer Center/USC FX The work was supported by the NIH grants (R01CA090427, R01AI084811, and R21AI11625701A1 to SYC, and 1R21AI087185-A1 to XFH), and by the Norris comprehensive Cancer Center/USC. NR 52 TC 0 Z9 1 U1 1 U2 3 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 JUN PY 2016 VL 7 AR e2260 DI 10.1038/cddis.2016.162 PG 12 WC Cell Biology SC Cell Biology GA DO0XN UT WOS:000377502400022 PM 27277682 ER PT J AU Nayak, AP Green, BJ Lemons, AR Marshall, NB Goldsmith, WT Kashon, ML Anderson, SE Germolec, DR Beezhold, DH AF Nayak, A. P. Green, B. J. Lemons, A. R. Marshall, N. B. Goldsmith, W. T. Kashon, M. L. Anderson, S. E. Germolec, D. R. Beezhold, D. H. TI Subchronic exposures to fungal bioaerosols promotes allergic pulmonary inflammation in naive mice SO CLINICAL AND EXPERIMENTAL ALLERGY LA English DT Article DE allergy; Aspergillus fumigatus; asthma; fungi; immunotoxicity; subchronic ID ASPERGILLUS-FUMIGATUS CONIDIA; INNATE LYMPHOID-CELLS; ALTERNARIA-ALTERNATA; RESPIRATORY-TRACT; FLOW-CYTOMETRY; MOLD EXPOSURE; C57BL/6 MICE; US HOMES; ASTHMA; INHALATION AB BackgroundEpidemiological surveys indicate that occupants of mold contaminated environments are at increased risk of respiratory symptoms. The immunological mechanisms associated with these responses require further characterization. ObjectiveThe aim of this study was to characterize the immunotoxicological outcomes following repeated inhalation of dry Aspergillus fumigatus spores aerosolized at concentrations potentially encountered in contaminated indoor environments. MethodsAspergillus fumigatus spores were delivered to the lungs of naive BALB/cJ mice housed in a multi-animal nose-only chamber twice a week for a period of 13weeks. Mice were evaluated at 24 and 48h post-exposure for histopathological changes in lung architecture, recruitment of specific immune cells to the airways, and serum antibody responses. ResultGerminating A.fumigatus spores were observed in lungs along with persistent fungal debris in the perivascular regions of the lungs. Repeated exposures promoted pleocellular infiltration with concomitant epithelial mucus hypersecretion, goblet cell metaplasia, subepithelial fibrosis and enhanced airway hyperreactivity. Cellular infiltration in airways was predominated by CD4(+) T cells expressing the pro-allergic cytokine IL-13. Furthermore, our studies show that antifungal T cell responses (IFN-(+) or IL-17A(+)) co-expressed IL-13, revealing a novel mechanism for the dysregulated immune response to inhaled fungi. Total IgE production was augmented in animals repeatedly exposed to A.fumigatus. Conclusions & Clinical RelevanceRepeated inhalation of fungal aerosols resulted in significant pulmonary pathology mediated by dynamic shifts in specific immune populations and their cytokines. These studies provide novel insights into the immunological mechanisms and targets that govern the health outcomes that result from repeated inhalation of fungal bioaerosols in contaminated environments. C1 [Nayak, A. P.; Green, B. J.; Lemons, A. R.; Marshall, N. B.; Goldsmith, W. T.; Kashon, M. L.; Anderson, S. E.; Beezhold, D. H.] NIOSH, Hlth Effects Lab Div, Ctr Dis Control & Prevent, Morgantown, WV 26505 USA. [Germolec, D. R.] NIEHS, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. RP Nayak, AP (reprint author), NIOSH, Ctr Dis Control & Prevent, 1095 Willowdale Rd, Morgantown, WV 26505 USA. EM fyg1@cdc.gov OI Lemons, Angela/0000-0003-3057-9888 FU NIOSH [927ZLCT]; CDC/NIOSH [AES12007001-1-0-6]; National Institute of Environmental Health Sciences (NIEHS) [AES12007001-1-0-6] FX The authors gratefully acknowledge Dr. Donald Cook and Dr. Scott Auerbach for reviewing the manuscript. The authors also thank Amy Cumpston, Jared Cumpston, Walter McKinney and Howard Leonard for conducting animal exposures, Katie Anderson and Dr. Tara L. Croston for assistance in animal procedures and Dr. Ann Hubbs for histopathological analysis. This study was funded by internal NIOSH funding 927ZLCT to AN, and in part by an interagency agreement between CDC/NIOSH and National Institute of Environmental Health Sciences (NIEHS) (AES12007001-1-0-6) as a collaborative National Toxicology Program (NTP) research activity. The findings and the conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health (NIOSH). NR 41 TC 2 Z9 2 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0954-7894 EI 1365-2222 J9 CLIN EXP ALLERGY JI Clin. Exp. Allergy PD JUN PY 2016 VL 46 IS 6 BP 861 EP 870 DI 10.1111/cea.12724 PG 10 WC Allergy; Immunology SC Allergy; Immunology GA DO0YQ UT WOS:000377505500010 PM 26892490 ER PT J AU McCraw, DM Gallagher, JR Harris, AK AF McCraw, Dustin M. Gallagher, John R. Harris, Audray K. TI Characterization of Influenza Vaccine Hemagglutinin Complexes by Cryo-Electron Microscopy and Image Analyses Reveals Structural Polymorphisms SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID MEDIATED MEMBRANE-FUSION; HEPATITIS-B VACCINE; VIRUS HEMAGGLUTININ; H7N9 VIRUS; ELECTRON-MICROSCOPY; RECEPTOR-BINDING; IMMUNE-RESPONSE; HEALTHY-ADULTS; PH OPTIMUM; A VIRUSES AB Influenza virus afflicts millions of people worldwide on an annual basis. There is an ever-present risk that animal viruses will cross the species barrier to cause epidemics and pandemics resulting in great morbidity and mortality. Zoonosis outbreaks, such as the H7N9 outbreak, underscore the need to better understand the molecular organization of viral immunogens, such as recombinant influenza virus hemagglutinin (HA) proteins, used in influenza virus subunit vaccines in order to optimize vaccine efficacy. Here, using cryo-electron microscopy and image analysis, we show that recombinant H7 HA in vaccines formed macromolecular complexes consisting of variable numbers of HA subunits (range, 6 to 8). In addition, HA complexes were distributed across at least four distinct structural classes (polymorphisms). Three-dimensional (3D) reconstruction and molecular modeling indicated that HA was in the prefusion state and suggested that the oligomerization and the structural polymorphisms observed were due to hydrophobic interactions involving the transmembrane regions. These experiments suggest that characterization of the molecular structures of influenza virus HA complexes used in subunit vaccines will lead to better understanding of the differences in vaccine efficacy and to the optimization of subunit vaccines to prevent influenza virus infection. C1 [McCraw, Dustin M.; Gallagher, John R.; Harris, Audray K.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Harris, AK (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM harrisau@mail.nih.gov OI Gallagher, John/0000-0002-1954-8872 FU HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) FX This work, including the efforts of Audray K. Harris, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID). NR 59 TC 1 Z9 1 U1 3 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD JUN PY 2016 VL 23 IS 6 BP 483 EP 495 DI 10.1128/CVI.00085-16 PG 13 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DO0GO UT WOS:000377457600006 PM 27074939 ER PT J AU Gray, GE Mayer, KH Elizaga, ML Bekker, LG Allen, M Morris, L Montefiori, D De Rosa, SC Sato, A Gu, NY Tomaras, GD Tucker, T Barnett, SW Mkhize, NN Shen, XY Downing, K Williamson, C Pensiero, M Corey, L Williamson, AL AF Gray, Glenda E. Mayer, Kenneth H. Elizaga, Marnie L. Bekker, Linda-Gail Allen, Mary Morris, Lynn Montefiori, David De Rosa, Stephen C. Sato, Alicia Gu, Niya Tomaras, Georgia D. Tucker, Timothy Barnett, Susan W. Mkhize, Nonhlanhla N. Shen, Xiaoying Downing, Katrina Williamson, Carolyn Pensiero, Michael Corey, Lawrence Williamson, Anna-Lise TI Subtype C gp140 Vaccine Boosts Immune Responses Primed by the South African AIDS Vaccine Initiative DNA-C2 and MVA-C HIV Vaccines after More than a 2-Year Gap SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID B-CELL RESPONSES; CLINICAL-TRIALS; T-CELLS; IMMUNOGENICITY; NEUTRALIZATION; ANTIBODIES; INFECTION; SELECTION AB A phase I safety and immunogenicity study investigated South African AIDS Vaccine Initiative (SAAVI) HIV-1 subtype C (HIV-1C) DNA vaccine encoding Gag-RT-Tat-Nef and gp150, boosted with modified vaccinia Ankara (MVA) expressing matched antigens. Following the finding of partial protective efficacy in the RV144 HIV vaccine efficacy trial, a protein boost with HIV-1 subtype C V2-deleted gp140 with MF59 was added to the regimen. A total of 48 participants (12 U.S. participants and 36 Republic of South Africa [RSA] participants) were randomized to receive 3 intramuscular (i. m.) doses of SAAVI DNA-C2 of 4 mg (months 0, 1, and 2) and 2 i. m. doses of SAAVI MVA-C of 1.45 x 10(9) PFU (months 4 and 5) (n = 40) or of a placebo (n = 8). Approximately 2 years after vaccination, 27 participants were rerandomized to receive gp140/MF59 at 100 mu g or placebo, as 2 i. m. injections, 3 months apart. The vaccine regimen was safe and well tolerated. After the DNA-MVA regimen, CD4(+) T-cell and CD8(+) T-cell responses occurred in 74% and 32% of the participants, respectively. The protein boost increased CD4(+) T-cell responses to 87% of the subjects. All participants developed tier 1 HIV-1C neutralizing antibody responses as well as durable Env binding antibodies that recognized linear V3 and C5 peptides. The HIV-1 subtype C DNA-MVA vaccine regimen showed promising cellular immunogenicity. Boosting with gp140/MF59 enhanced levels of binding and neutralizing antibodies as well as CD4(+) T-cell responses to HIV-1 envelope. (This study has been registered at ClinicalTrials.gov under registration no. NCT00574600 and NCT01423825.) C1 [Gray, Glenda E.] Univ Witwatersrand, Fac Hlth Sci, Perinatal HIV Res Unit, Johannesburg, South Africa. [Gray, Glenda E.; Tucker, Timothy] South African Med Res Council, Cape Town, South Africa. [Mayer, Kenneth H.] Fenway Hlth, Boston, MA USA. [Mayer, Kenneth H.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Elizaga, Marnie L.; De Rosa, Stephen C.; Sato, Alicia; Gu, Niya; Corey, Lawrence] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Bekker, Linda-Gail; Downing, Katrina; Williamson, Carolyn; Williamson, Anna-Lise] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. [Allen, Mary; Pensiero, Michael] NIAID, DAIDS, NIH, Washington, DC USA. [Morris, Lynn; Mkhize, Nonhlanhla N.] Natl Hlth Lab Serv, Natl Inst Communicable Dis, Johannesburg, South Africa. [Montefiori, David; Tomaras, Georgia D.; Shen, Xiaoying] Duke Univ, Durham, NC USA. [Barnett, Susan W.] Novartis Vaccines, Cambridge, MA USA. [Williamson, Carolyn; Williamson, Anna-Lise] Natl Hlth Lab Serv, Cape Town, South Africa. RP Gray, GE (reprint author), Univ Witwatersrand, Fac Hlth Sci, Perinatal HIV Res Unit, Johannesburg, South Africa.; Gray, GE (reprint author), South African Med Res Council, Cape Town, South Africa. EM Glenda.gray@mrc.ac.za FU National Institute of Allergy and Infectious Diseases (NIAID) U.S. Public Health Service [UM1 AI068614, UM1 AI068635, UM1 AI068618, AI069412, AI069453, AI069519]; HIV vaccine development through SAAVI; NIAID-NIH [N01-AI-25473]; South African Research Chairs Initiative of the Department of Science and Technology; National Research Foundation FX This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) U.S. Public Health Service grants UM1 AI068614 (LOC; HIV Vaccine Trials Network), UM1 AI068635 (HVTN SDMC FHCRC), UM1 AI068618 (HVTN Laboratory program FHCRC), AI069412 (to Brigham and Women's Hospital and Fenway Health), AI069453 (to the Perinatal HIV Research Unit, Soweto), and AI069519 (to the Desmond Tutu HIV Centre, Cape Town). The SAMRC funded the HIV vaccine development through SAAVI. Funding for the production of gp140 Delta V2.TV1 was provided to Novartis Vaccines from NIAID-NIH contract N01-AI-25473, TO#1. Some of this work is based upon research supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation. NR 26 TC 2 Z9 2 U1 4 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD JUN PY 2016 VL 23 IS 6 BP 496 EP 506 DI 10.1128/CVI.00717-15 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DO0GO UT WOS:000377457600007 PM 27098021 ER PT J AU Gallicchio, L Calhoun, C Helzlsouer, K AF Gallicchio, Lisa Calhoun, Carla Helzlsouer, Kathy TI Effect of Aromatase Inhibitor Therapy on the Cardiovascular Health of Black and White Breast Cancer Patients SO CLINICAL BREAST CANCER LA English DT Article DE Carotid intima-medial thickness; Health disparities; High sensitivity C-reactive protein; Hormonal therapy ID INTIMA-MEDIA THICKNESS; CORONARY-HEART-DISEASE; POSTMENOPAUSAL WOMEN; SUBCLINICAL ATHEROSCLEROSIS; MUSCULOSKELETAL SYMPTOMS; MENOPAUSAL TRANSITION; RANDOMIZED-TRIAL; GRIP STRENGTH; TAMOXIFEN; METAANALYSIS AB A prospective cohort study was conducted to examine racial differences in the cardiovascular health effects of aromatase inhibitor (AI) treatment, analyzing data from 77 white and 35 black breast cancer patients initiating AI therapy and followed for 1 year. Results showed no large adverse cardiovascular health changes over the first year of AI therapy among black and white patients. Background: The present study examined racial differences in the cardiovascular health effects of aromatase inhibitors. Patients and Methods: Data were analyzed from 77 white and 35 black patients with early-stage breast cancer initiating aromatase inhibitor therapy and subsequently followed for 1 year. At baseline and a 1-year follow-up clinic visit, a comprehensive cardiovascular health assessment was conducted, which included measurement of carotid intima-medial thickness and a blood draw to measure high-sensitivity C-reactive protein and cholesterol concentrations. A detailed questionnaire was also completed. The information collected was used to calculate each patient's 10-year risk of atherosclerotic cardiovascular disease events at both measurement points. Paired t tests were used to examine the changes in the continuous outcome variables within groups during the study period. Independent t tests were conducted to examine the changes over time between the 2 groups. Results: No statistically significant changes in carotid intima-medial thickness, atherosclerotic cardiovascular disease risk score, or the other cardiovascular-related outcomes (high-sensitivity C-reactive protein, cholesterol levels, blood pressure) during the first year of aromatase inhibitor therapy were observed among either the black or white breast cancer patients or between the 2 groups. Mean grip strength in the dominant hand decreased significantly and similarly during the 1-year period for the white and black breast cancer patients. Conclusion: The findings from the present study suggest no large adverse cardiovascular health effects from aromatase inhibitors during the first year of therapy among either black or white breast cancer patients. However, the results of the present study cannot rule out the potential for long-term adverse changes over the duration of aromatase inhibitor therapy or beyond. (C) 2016 Elsevier Inc. All rights reserved. C1 [Gallicchio, Lisa; Calhoun, Carla; Helzlsouer, Kathy] Mercy Med Ctr, Prevent & Res Ctr, Weinberg Ctr Womens Hlth & Med, Baltimore, MD USA. [Gallicchio, Lisa; Helzlsouer, Kathy] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Gallicchio, Lisa] Univ Maryland, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. RP Gallicchio, L (reprint author), NCI, Epidemiol & Genet Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM lisagallicchio@gmail.com FU Susan G. Komen for the Cure [KG 110356] FX The present study was funded by Susan G. Komen for the Cure (Grant KG 110356). The funding source had no role in the study design; collection, analysis, and interpretation of data; writing of the report; or the decision to submit the article for publication. NR 36 TC 2 Z9 2 U1 2 U2 3 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1526-8209 EI 1938-0666 J9 CLIN BREAST CANCER JI Clin. Breast Cancer PD JUN PY 2016 VL 16 IS 3 BP E23 EP E31 DI 10.1016/j.clbc.2016.02.011 PG 9 WC Oncology SC Oncology GA DN9LU UT WOS:000377401900002 PM 26943989 ER PT J AU Hori, T Moore, R Negishi, M AF Hori, Takeshi Moore, Rick Negishi, Masahiko TI p38 MAP Kinase Links CAR Activation and Inactivation in the Nucleus via Phosphorylation at Threonine 38 SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID CONSTITUTIVE ACTIVE/ANDROSTANE RECEPTOR; PROTEIN-KINASE; ANDROSTANE RECEPTOR; X RECEPTOR; TRANSCRIPTIONAL ACTIVITY; BINDING DOMAIN; CYP2B6 GENE; HEAT-SHOCK; HNF4-ALPHA; STRESS AB Nuclear receptor constitutive androstane receptor (CAR, NR1I3), which regulates hepatic drug and energy metabolisms as well as cell growth and death, is sequestered in the cytoplasm as its inactive form phosphorylated at threonine 38. CAR activators elicit dephosphorylation, and nonphosphorylated CAR translocates into the nucleus to activate its target genes. CAR was previously found to require p38 mitogen-activated protein kinase (MAPK) to transactivate the cytochrome P450 2B (CYP2B) genes. Here we have demonstrated that p38 MAPK forms a complex with CAR, enables it to bind to the response sequence, phenobarbital-responsive enhancer module (PBREM), within the CYP2B promoter, and thus recruits RNA polymerase II to activate transcription. Subsequently, p38 MAPK elicited rephosphorylation of threonine 38 to inactivate CAR and exclude it from the nucleus. Thus, nuclear p38MAPK exerted dual regulation by sequentially activating and inactivating CAR-mediated transcription through phosphorylation of threonine C1 [Hori, Takeshi; Moore, Rick; Negishi, Masahiko] NIEHS, Pharmacogenet Sect, Reprod & Dev Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, NIH, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov FU National Institutes of Health; National Institute of Environmental Health Sciences [Z01ES71005-01] FX This work was supported by the Intramural Research Program of the National Institutes of Health and National Institute of Environmental Health Sciences [Grant Z01ES71005-01]. NR 39 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 EI 1521-009X J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD JUN PY 2016 VL 44 IS 6 BP 871 EP 876 DI 10.1124/dmd.116.070235 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DN8NS UT WOS:000377336500009 PM 27074912 ER PT J AU Cogliati, M D'Amicis, R Zani, A Montagna, MT Caggiano, G De Giglio, O Balbino, S De Donno, A Serio, F Susever, S Ergin, C Velegraki, A Ellabib, MS Nardoni, S Macci, C Oliveri, S Trovato, L Dipineto, L Rickerts, V McCormick-Smith, I Akcaglar, S Tore, O Mlinaric-Missoni, E Bertout, S Mallie, M Martins, MD Venca, ACF Vieira, ML Sampaio, AC Pereira, C Griseo, G Romeo, O Ranque, S Al-Yasiri, MHY Kaya, M Cerikcioglu, N Marchese, A Vezzulli, L Ilkit, M Desnos-Ollivier, M Pasquale, V Korem, M Polacheck, I Scopa, A Meyer, W Ferreira-Paim, K Hagen, F Theelen, B Boekhout, T Lockhart, SR Tintelnot, K Tortorano, AM Dromer, F Varma, A Kwon-Chung, KJ Inacio, J Alonso, B Colom, MF AF Cogliati, Massimo D'Amicis, Roberta Zani, Alberto Montagna, Maria Teresa Caggiano, Giuseppina De Giglio, Osvalda Balbino, Stella De Donno, Antonella Serio, Francesca Susever, Serdar Ergin, Cagri Velegraki, Aristea Ellabib, Mohamed S. Nardoni, Simona Macci, Cristina Oliveri, Salvatore Trovato, Laura Dipineto, Ludovico Rickerts, Volker McCormick-Smith, Ilka Akcaglar, Sevim Tore, Okan Mlinaric-Missoni, Emilija Bertout, Sebastien Mallie, Michele Martins, Maria da Luz Venca, Ana C. F. Vieira, Maria L. Sampaio, Ana C. Pereira, Cheila Griseo, Giuseppe Romeo, Orazio Ranque, Stephane Al-Yasiri, Mohammed H. Y. Kaya, Meltem Cerikcioglu, Nilgun Marchese, Anna Vezzulli, Luigi Ilkit, Macit Desnos-Ollivier, Marie Pasquale, Vincenzo Korem, Maya Polacheck, Itzhack Scopa, Antonio Meyer, Wieland Ferreira-Paim, Kennio Hagen, Ferry Theelen, Bart Boekhout, Teun Lockhart, Shawn R. Tintelnot, Kathrin Tortorano, Anna Maria Dromer, Francoise Varma, Ashok Kwon-Chung, Kyung J. Inacio, Joeao Alonso, Beatriz Colom, Maria F. TI Environmental distribution of Cryptococcus neoformans and C. gattii around the Mediterranean basin SO FEMS YEAST RESEARCH LA English DT Article DE Cryptococcus; C. neoformans; C. gattii; environment; Europe; epidemiology; molecular typing ID VAR. GATTII; IMMUNOCOMPETENT PATIENT; GENETIC DIVERSITY; BRITISH-COLUMBIA; SPECIES COMPLEX; MATING-TYPES; SEROTYPE-D; STRAINS; MENINGITIS; INFECTION AB In order to elucidate the distribution of Cryptococcus neoformans and C. gattii in the Mediterranean basin, an extensive environmental survey was carried out during 2012-2015. A total of 302 sites located in 12 countries were sampled, 6436 samples from 3765 trees were collected and 5% of trees were found to be colonized by cryptococcal yeasts. Cryptococcus neoformans was isolated from 177 trees and C. gattii from 13. Cryptococcus neoformans colonized 27% of Ceratonia, 10% of Olea, Platanus and Prunus trees and a lower percentage of other tree genera. The 13 C. gattii isolates were collected from five Eucalyptus, four Ceratonia, two Pinus and two Olea trees. Cryptococcus neoformans was distributed all around the Mediterranean basin, whereas C. gattii was isolated in Greece, Southern Italy and Spain, in agreement with previous findings from both clinical and environmental sources. Among C. neoformans isolates, VNI was the prevalent molecular type but VNII, VNIV and VNIII hybrid strains were also isolated. With the exception of a single VGIV isolate, all C. gattii isolates were VGI. The results confirmed the presence of both Cryptococcus species in the Mediterranean environment, and showed that both carob and olive trees represent an important niche for these yeasts. C1 [Cogliati, Massimo; D'Amicis, Roberta; Zani, Alberto; Tortorano, Anna Maria] Univ Milan, Dip Sci Biomed Salute, Via Pascal 36, I-20133 Milan, Italy. [Montagna, Maria Teresa; Caggiano, Giuseppina; De Giglio, Osvalda; Balbino, Stella] Univ Bari Aldo Moro, Dip Sci Biomed & Oncol Umana, Piazza Giulio Cesare 11, I-70124 Bari, Italy. [De Donno, Antonella; Serio, Francesca] Univ Salento, Dip Sci & Tecnol Biol & Ambientali, Via Monteroni, I-73100 Lecce, Italy. [Susever, Serdar] Cyprus Near East Univ, Dept Nutr & Dietet, Near East Blvd, CY-99138 Nicosia, Cyprus. [Ergin, Cagri] Pamukkale Univ, Sch Med, Klin Kampusu, TR-20160 Denizli, Turkey. [Velegraki, Aristea] Univ Athens, Sch Med, Mikras Asias 75, Athens 11527, Greece. [Ellabib, Mohamed S.] Univ Tripoli, Coll Med, Tripoli Univ Rd, Tripoli, Libya. [Nardoni, Simona] Univ Pisa, Dip Sci Vet, Via Piagge 2, I-56124 Pisa, Italy. [Macci, Cristina] CNR, Natl Res Council, Ist Studio Ecosistemi, Via Moruzzi 1, I-56124 Pisa, Italy. [Oliveri, Salvatore; Trovato, Laura] Univ Catania, Dip Sci Microbiol & Sci Ginecol, Via Androne 81, I-95124 Catania, Italy. [Dipineto, Ludovico] Univ Naples Federico II, Dip Med Vet & Prod Anim, I-80138 Naples, Italy. [Rickerts, Volker; McCormick-Smith, Ilka; Tintelnot, Kathrin] Robert Koch Inst, Dept Infect Dis, D-13302 Berlin, Germany. [Akcaglar, Sevim; Tore, Okan] Uludag Univ, Sch Med, Gorukle Kampusu, TR-16059 Bursa, Turkey. [Mlinaric-Missoni, Emilija] Croatian Natl Inst Publ Hlth, Rockefellerova 7, Zagreb 10000, Croatia. [Bertout, Sebastien; Mallie, Michele] Univ Montpellier, Unit Mixte Int Rech Translat VIH & Malad Infect, 15 Ave Charles Flahault, F-34093 Montpellier, France. [Martins, Maria da Luz; Venca, Ana C. F.; Vieira, Maria L.; Al-Yasiri, Mohammed H. Y.] Inst Higiene & Med Trop, Rua Junqueira 100, P-1349008 Lisbon, Portugal. [Sampaio, Ana C.; Pereira, Cheila] Univ Tras Os Montes & Alto Douro, CITAB, P-5000801 Vila Real, Portugal. [Griseo, Giuseppe; Romeo, Orazio] Univ Messina, Dept Chem Biol Pharmaceut & Environm Sci, Piazza Pugliatti 1, I-98122 Messina, Italy. [Ranque, Stephane] Aix Marseille Univ, IP TPT Infect Parasitaires Transmiss Pphysiopatho, 27 Blv Jean Moulin, F-13005 Marseille, France. [Kaya, Meltem; Cerikcioglu, Nilgun] Marmara Univ, Sch Med, MU Goztepe Kampusu, TR-34722 Istanbul, Turkey. [Marchese, Anna] Univ Genoa, IRCCS San Martino IST Genova, Sez Microbiol, DISC, Largo Benzi 10, I-16132 Genoa, Italy. [Vezzulli, Luigi] Univ Genoa, Dipartimento Sci Terra Ambiente & Vita DISTAV, C Soeuropa 26, I-16132 Genoa, Italy. [Ilkit, Macit] Univ Cukurova Saricam, Dept Microbiol, Cukurova Univ Rektorlugu, TR-01330 Adana, Turkey. [Desnos-Ollivier, Marie] CNRS, Inst Pasteur, Unite Mycol Mol, 25-28 Rue Dr Roux, F-75015 Paris, France. [Pasquale, Vincenzo] Univ Napoli Parthenope, Dip Sci & Tecnol, Via Amm F Acton 38, I-80133 Naples, Italy. [Korem, Maya; Polacheck, Itzhack] Hadassah Hebrew Univ, Med Ctr, Div Microbiol & Infect Dis, POB 12271, IL-12271 Jerusalem, Israel. [Scopa, Antonio] Univ Basilicata, Fac Sci Agr Forestali & Ambientali, Via Nazario Sauro 85, I-85100 Potenza, Italy. [Meyer, Wieland; Ferreira-Paim, Kennio] Univ Sydney, Westmead Hosp, Westmead Millennium Inst, Mol Mycol Res Lab,CIDM,MBI,Sydney Med School, 176 Hawkesbury Rd, Westmead, NSW 2145, Australia. [Hagen, Ferry] Canisius Wilhelmina Hosp, Weg Jonkerbos 100, NL-6532 SZ Nijmegen, Netherlands. [Theelen, Bart; Boekhout, Teun] CBS KNAW Fungal Biodivers Ctr, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands. [Lockhart, Shawn R.] Ctr Dis Control & Prevent, 1600 Clifton Rd, Atlanta, GA 30333 USA. [Varma, Ashok; Kwon-Chung, Kyung J.] NIAID, 31 Ctr Dr, Bethesda, MD 20892 USA. [Inacio, Joeao; Alonso, Beatriz] Univ Brighton, Sch Pharm & Biomol Sci, Lewes Rd, Brighton BN2 4GJ, E Sussex, England. [Colom, Maria F.] Univ Miguel Hernandez, Sch Med, Ave Univ, Alicante 03202, Spain. RP Cogliati, M (reprint author), Univ Milan, Dip Sci Biomed Salute, Via Pascal 36, I-20133 Milan, Italy. EM massimo.cogliati@unimi.it RI Hagen, Ferry/B-9044-2009; Sampaio, Ana/G-5787-2012; Colom Valiente, M Francisca/L-7803-2014; Ranque, Stephane/K-2317-2015; Vieira, Maria Luisa/B-3310-2008; Ferreira-Paim, Kennio /A-8194-2013; OI Hagen, Ferry/0000-0002-5622-1916; Sampaio, Ana/0000-0001-7989-0779; Colom Valiente, M Francisca/0000-0002-8672-5429; Ranque, Stephane/0000-0003-3293-5276; Vieira, Maria Luisa/0000-0002-8586-5534; Ferreira-Paim, Kennio /0000-0002-6035-8392; Tortorano, Anna Maria/0000-0003-2093-8250; Serio, Francesca/0000-0002-2782-2798 FU National Institute of Allergy and Infectious Diseases, NIH; CITAB [UID/AGR/04033/2013]; NHMRC, Australia [APP1031943]; CAPES from Brazil [9313133] FX The work by K.J. Kwon-Chung and A. Varma was supported by funds from the intramural program of the National Institute of Allergy and Infectious Diseases, NIH. The work by A. Sampaio and C. Pereira was in part supported by CITAB under the project UID/AGR/04033/2013. W. Meyer was supported by funding from the NH&MRC, Australia, grant # APP1031943. K. Ferreira-Paim was supported by a CAPES Science without Borders visiting fellow (No 9313133) from Brazil. NR 73 TC 3 Z9 3 U1 3 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1567-1356 EI 1567-1364 J9 FEMS YEAST RES JI FEMS Yeast Res. PD JUN PY 2016 VL 16 IS 4 AR fow045 DI 10.1093/femsyr/fow045 PG 12 WC Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biotechnology & Applied Microbiology; Microbiology; Mycology GA DO0PR UT WOS:000377481300015 ER PT J AU Banks, N Patounakis, G Devine, K DeCherney, AH Widra, E Levens, ED Whitcomb, BW Hill, MJ AF Banks, Nicole Patounakis, George Devine, Kate DeCherney, Alan H. Widra, Eric Levens, Eric D. Whitcomb, Brian W. Hill, Micah J. TI Is FMR1 CGG repeat length a predictor of in vitro fertilization stimulation response or outcome? SO FERTILITY AND STERILITY LA English DT Article DE ART; CGG repeats; FMRI; IVF; ovarian reserve ID PREMATURE OVARIAN FAILURE; FRAGILE-X-SYNDROME; ANTI-MULLERIAN HORMONE; SINGLE-BLASTOCYST TRANSFERS; PREMUTATION CARRIERS; LIVE BIRTH; GENE; RESERVE; WOMEN; INTERMEDIATE AB Objective: To study a broad range of FMRI CGG repeat lengths and assisted reproduction technology (ART) outcomes. Design: Retrospective cohort study. Setting: Private ART practice. Patient(s): Fresh autologous ART stimulation cycles. Intervention(s): None. Main Outcome Measure(s): Oocyte yield, live birth. Result(s): We screened 14,088 fresh autologous ART cycles from 2012 to 2015, of which 4,690 cycles in 3,290 patients met the inclusion criteria. The FMR1 repeat length was statistically significantly but weakly associated with oocyte yield and other markers of ovarian response. The receiver operating characteristic curve analysis suggested extremely limited predictive ability. Moreover, the FMRI repeat length was not statistically significantly associated with outcomes in multivariable models, including other markers of ovarian reserve. The FMR1 repeat length was not associated with embryo quality or live birth. Only patient age had a strong ability to predict live birth. Conclusion(s): The FMR1 repeat length is associated with ART response, but only weakly. It provides no incremental predictive ability beyond the conventionally used predictors, including patient age, antimullerian hormone concentration, antral follicle count, and follicle-stimulating hormone level. These data suggest a possible role of the FMRI repeat length within the normal range in ovarian response but demonstrate no clinically relevant indication for testing FMRI as a predictor of ART outcomes. (Feral Steril (R), 2016;105: 1537-46. (C) 2016 by American Society for Reproductive Medicine.) C1 [Banks, Nicole; Patounakis, George; Devine, Kate; DeCherney, Alan H.; Hill, Micah J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Devine, Kate; Widra, Eric; Levens, Eric D.] Shady Grove Fertil Sci Ctr, Rockville, MD USA. [Whitcomb, Brian W.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. RP Hill, MJ (reprint author), 10 Ctr Dr, Bethesda, MD 20876 USA. EM hillmicah@mail.nih.gov FU Intramural Research Program of the Program in Reproductive and Adult Endocrinology, NICHD, National Institutes of Health FX Supported in part by the Intramural Research Program of the Program in Reproductive and Adult Endocrinology, NICHD, National Institutes of Health. The views expressed in this manuscript are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U. S. Government. NR 44 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD JUN PY 2016 VL 105 IS 6 BP 1537 EP U218 DI 10.1016/j.fertnstert.2016.02.011 PG 18 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA DN7WM UT WOS:000377290900027 PM 26940792 ER PT J AU Hansen, KR He, ALW Styer, AK Wild, RA Butts, S Engmann, L Diamond, MP Legro, RS Coutifaris, C Alvero, R Robinson, RD Casson, P Christman, GM Huang, H Santoro, N Eisenberg, E Zhang, HP AF Hansen, Karl R. He, Amy Linnea W. Styer, Aaron K. Wild, Robert A. Butts, Samantha Engmann, Lawrence Diamond, Michael P. Legro, Richard S. Coutifaris, Christos Alvero, Ruben Robinson, Randal D. Casson, Peter Christman, Gregory M. Huang, Hao Santoro, Nanette Eisenberg, Esther Zhang, Heping CA Eunice Kennedy Shriver Natl Inst TI Predictors of pregnancy and live-birth in couples with unexplained infertility after ovarian stimulation intrauterine insemination SO FERTILITY AND STERILITY LA English DT Article DE Unexplained infertility; predictors; ovarian stimulation; intrauterine inseminate pregnancy ID FUNCTIONAL HYPOTHALAMIC AMENORRHEA; REPRODUCTIVE TECHNOLOGY ART; IN-VITRO FERTILIZATION; QUALITY-OF-LIFE; UNITED-STATES; WOMEN; EFFICACY; OUTCOMES; SUPEROVULATION; GONADOTROPIN AB Objective: To identify baseline characteristics of couples that are likely to predict conception, clinical pregnancy, and live birth after up to four cycles of ovarian stimulation with IUI in couples with unexplained infertility. Design: Secondary analyses of data from a prospective, randomized, multicenter clinical trial investigating pregnancy, live birth, and multiple pregnancy rates after ovarian stimulation-IUI with clomiphene citrate, letrozole, or gonadotropins. Setting: Outpatient clinical units. Patient(s): Nine-hundred couples with unexplained infertility who participated in the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation clinical trial. Intervention(s): As part of the clinical trial, treatment was randomized equally to one of three arms and continued for up to four cycles or until pregnancy was achieved. Main Outcome Measure(s): Conception, clinical pregnancy, and live-birth rates. Result(s): In a multivariable logistic regression analysis, after adjustment for other covariates, age, waist circumference, income level, duration of infertility, and a history of prior pregnancy loss were significantly associated with at least one pregnancy outcome. Other baseline demographic and lifestyle characteristics including smoking, alcohol use, and serum levels of antimilllerian hormone were not significantly associated with pregnancy outcomes. Conclusion(s): While age duration of infertility were significant independent ofrace and educationreflect. differences in the underlying etiologie plained infertility or cOOldrevealdmispayarities in access to fertility and/or obstetrical care. Clinical Trial Registration.. NCT01044862. (Fertil Steril 2016,105:1575_83. (C) 2016 byAni ican Society for Reproductive Medicine.) C1 [Hansen, Karl R.; Wild, Robert A.] Univ Oklahoma, Hlth Sci Ctr, Dept Obstet & Gynecol, 920 Stanton L Young Blvd,WP 2410, Oklahoma City, OK 73104 USA. [He, Amy Linnea W.; Huang, Hao; Zhang, Heping] Yale Univ, Dept Biostat, Sch Publ Hlth, New Haven, CT USA. [Styer, Aaron K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA USA. [Butts, Samantha; Coutifaris, Christos] Univ Penn, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Engmann, Lawrence] Univ Connecticut, Sch Med, Dept Obstet & Gynecol, Farmington, CT USA. [Diamond, Michael P.] Georgia Regents Univ, Dept Obstet & Gynecol, Augusta, GA USA. [Legro, Richard S.] Penn State Univ, Dept Obstet & Gynecol, Hershey, PA USA. [Alvero, Ruben; Santoro, Nanette] Univ Colorado Denver, Dept Obstet & Gynecol, Aurora, CO USA. [Robinson, Randal D.] Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, San Antonio, TX 78229 USA. [Casson, Peter] Univ Vermont, Dept Obstet & Gynecol, Burlington, VT USA. [Christman, Gregory M.] Univ Florida, Shands Hosp, Dept Obstet & Gynecol, Gainesville, FL USA. [Eisenberg, Esther] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. RP Hansen, KR (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Obstet & Gynecol, 920 Stanton L Young Blvd,WP 2410, Oklahoma City, OK 73104 USA. EM karl-hansen@ouhsc.edu OI Alvero, Ruben/0000-0001-6542-710X; Diamond, Michael/0000-0001-6353-4489 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936, U10HD055925, U10HD077680]; American Recovery and Reinvestment Act FX This study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) grants for Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation: U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936, U10HD055925, and U10HD077680. This research was made possible by the funding by American Recovery and Reinvestment Act. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NICHD or the National Institutes of Health. NR 38 TC 2 Z9 2 U1 4 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD JUN PY 2016 VL 105 IS 6 BP 1575 EP U262 DI 10.1016/j.fertnstert.2016.02.020 PG 11 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA DN7WM UT WOS:000377290900032 PM 26949110 ER PT J AU Lau, KHW Chen, ST Wang, X Mohan, S Wergedal, JE Kesavan, C Srivastava, AK Gridley, DS Hall, SL AF Lau, K-H W. Chen, S-T Wang, X. Mohan, S. Wergedal, J. E. Kesavan, C. Srivastava, A. K. Gridley, D. S. Hall, S. L. TI Opposing effects of Sca-1(+) cell-based systemic FGF2 gene transfer strategy on lumbar versus caudal vertebrae in the mouse SO GENE THERAPY LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; AGED OVARIECTOMIZED RATS; ENDOSTEAL BONE-FORMATION; HEMATOPOIETIC STEM-CELLS; PARATHYROID-HORMONE; IN-VIVO; OSTEOCLAST FORMATION; MARROW CULTURES; OSTEOPENIC RATS; FATTY MARROW AB Our previous work showed that a Sca-1(+) cell-based FGF2 therapy was capable of promoting robust increases in trabecular bone formation and connectivity on the endosteum of long bones. Past work reported that administration of FGF2 protein promoted bone formation in red marrow but not in yellow marrow. The issue as to whether the Sca-1(+) cell-based FGF2 therapy is effective in yellow marrow is highly relevant to its clinical potential for osteoporosis, as most red marrows in a person of an advanced age are converted to yellow marrows. Accordingly, this study sought to compare the osteogenic effects of this stem cell-based FGF2 therapy on red marrow-filled lumbar vertebrae with those on yellow marrow-filled caudal vertebrae of young adult W-41/W-41 mice. The Sca-1(+) cell-based FGF2 therapy drastically increased trabecular bone formation in lumbar vertebrae, but the therapy not only did not promote bone formation but instead caused substantial loss of trabecular bone in caudal vertebrae. The lack of an osteogenic response was not due to insufficient engraftment of FGF2-expressing Sca-1(+) cells or inadequate FGF2 expression in caudal vertebrae. Previous studies have demonstrated that recipient mice of this stem cell-based FGF2 therapy developed secondary hyperparathyroidism and increased bone resorption. Thus, the loss of bone mass in caudal vertebrae might in part be due to an increase in resorption without a corresponding increase in bone formation. In conclusion, the Sca-1(+) cell-based FGF2 therapy is osteogenic in red marrow but not in yellow marrow. C1 [Lau, K-H W.; Chen, S-T; Wang, X.; Mohan, S.; Wergedal, J. E.; Kesavan, C.; Hall, S. L.] Jerry L Pettis Mem VA Med Ctr, Musculoskeletal Dis Ctr, 11201 Benton St, Loma Linda, CA 92357 USA. [Srivastava, A. K.] Frederick Natl Lab Canc Res, SAIC Frederick, Appl Dev Res Directorate, Lab Human Toxicol,Pharmacol, Frederick, MD USA. [Gridley, D. S.] Loma Linda Univ, Sch Med, Dept Radiat Med, Loma Linda, CA USA. RP Hall, SL (reprint author), Jerry L Pettis Mem VA Med Ctr, Musculoskeletal Dis Ctr, 11201 Benton St, Loma Linda, CA 92357 USA. EM Susan.Hall1@va.gov RI Gridley, Daila/P-7711-2015 FU Merit Review Entry Program grant from the Department of Veterans Affair Medical Research program FX This work was supported in part by a Merit Review Entry Program grant from the Department of Veterans Affair Medical Research program. All work, except the irradiation procedure, was performed in facilities provided by the Department of Veterans Affairs. NR 47 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 EI 1476-5462 J9 GENE THER JI Gene Ther. PD JUN PY 2016 VL 23 IS 6 BP 500 EP 509 DI 10.1038/gt.2016.21 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DO0VO UT WOS:000377496600003 PM 26934099 ER PT J AU Li, HQ Edie, S Klinedinst, D Jeong, JS Blackshaw, S Maslen, CL Reeves, RH AF Li, Huiqing Edie, Sarah Klinedinst, Donna Jeong, Jun Seop Blackshaw, Seth Maslen, Cheryl L. Reeves, Roger H. TI Penetrance of Congenital Heart Disease in a Mouse Model of Down Syndrome Depends on a Trisomic Potentiator of a Disomic Modifier SO GENETICS LA English DT Article DE trisomic potentiator; disomic modifier; congenital heart disease; Down syndrome ID ATRIOVENTRICULAR SEPTAL-DEFECTS; CARDIAC DEVELOPMENT; TS65DN MICE; CRELD1; MUTATIONS; REGION; RISK AB Down syndrome (DS) is a significant risk factor for congenital heart disease (CHD), increasing the incidence 50 times over the general population. However, half of people with DS have a normal heart and thus trisomy 21 is not sufficient to cause CHD by itself. Ts65Dn mice are trisomic for orthologs of >100 Hsa21 genes, and their heart defect frequency is significantly higher than their euploid littermates. Introduction of a null allele of Creld1 into Ts65Dn increases the penetrance of heart defects significantly. However, this increase was not seen when the Creld1 null allele was introduced into Ts1Cje, a mouse that is trisomic for about two thirds of the Hsa21 orthologs that are triplicated in Ts65Dn. Among the 23 genes present in three copies in Ts65Dn but not Ts1Cje, we identified Jam2 as necessary for the increased penetrance of Creld1-mediated septal defects in Ts65Dn. Thus, overexpression of the trisomic gene, Jam2, is a necessary potentiator of the disomic genetic modifier, Creld1. No direct physical interaction between Jam2 and Creld1 was identified by several methods. Regions of Hsa21 containing genes that are risk factors of CHD have been identified, but Jam2 (and its environs) has not been linked to heart formation previously. The complexity of this interaction may be more representative of the clinical situation in people than consideration of simple single-gene models. C1 [Li, Huiqing; Edie, Sarah; Klinedinst, Donna; Reeves, Roger H.] Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA. [Li, Huiqing; Edie, Sarah; Klinedinst, Donna; Reeves, Roger H.] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD 21205 USA. [Jeong, Jun Seop] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Jeong, Jun Seop] Johns Hopkins Univ, Sch Med, High Throughput Biol Ctr, Baltimore, MD 21205 USA. [Blackshaw, Seth] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Blackshaw, Seth] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Blackshaw, Seth] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Blackshaw, Seth] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD 21205 USA. [Maslen, Cheryl L.] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, Portland, OR 97239 USA. [Li, Huiqing] NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Edie, Sarah] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. RP Reeves, RH (reprint author), Johns Hopkins Univ, Sch Med, Biophys 201, 725 N Wolfe St, Baltimore, MD 21205 USA. EM rreeves@jhmi.edu FU American Heart Association [14GRNT20380202, 12POST11940039]; [HL083300]; [HD038384] FX We thank Akihiko Okuda of the Saitama Medical University in Japan for generously providing Jam2-/- mice. This work was supported in part by HL083300 and HD038384 (R.H.R.), American Heart Association grant-in-aid 14GRNT20380202 (C.L.M.), and the American Heart Association fellowship no. 12POST11940039 (H.L.). NR 28 TC 3 Z9 3 U1 0 U2 1 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 JUN PY 2016 VL 203 IS 2 BP 763 EP + DI 10.1534/genetics.116.188045 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA DO0IO UT WOS:000377462800015 PM 27029737 ER PT J AU Baker, JL Dunn, KA Mingrone, J Wood, BA Karpinski, BA Sherwood, CC Wildman, DE Maynard, TM Bielawski, JP AF Baker, Jennifer L. Dunn, Katherine A. Mingrone, Joseph Wood, Bernard A. Karpinski, Beverly A. Sherwood, Chet C. Wildman, Derek E. Maynard, Thomas M. Bielawski, Joseph P. TI Functional Divergence of the Nuclear Receptor NR2C1 as a Modulator of Pluripotentiality During Hominid Evolution SO GENETICS LA English DT Article DE ancestral gene reconstruction (AGR); codon models; hominid evolutionary survey; nuclear receptors; NR2C1; testicular receptor 2 (TR2); pluripotentiality ID EMBRYONIC STEM-CELLS; DETECTING POSITIVE SELECTION; CODON-SUBSTITUTION MODELS; WIDE ASSOCIATION SCAN; LIKELIHOOD RATIO TEST; PROTEIN-CODING GENES; TR2 ORPHAN RECEPTOR; AMINO-ACID SITES; MAXIMUM-LIKELIHOOD; PHOSPHOENOLPYRUVATE CARBOXYKINASE AB Genes encoding nuclear receptors (NRs) are attractive as candidates for investigating the evolution of gene regulation because they (1) have a direct effect on gene expression and (2) modulate many cellular processes that underlie development. We employed a three-phase investigation linking NR molecular evolution among primates with direct experimental assessment of NR function. Phase 1 was an analysis of NR domain evolution and the results were used to guide the design of phase 2, a codon-model-based survey for alterations of natural selection within the hominids. By using a series of reliability and robustness analyses we selected a single gene, NR2C1, as the best candidate for experimental assessment. We carried out assays to determine whether changes between the ancestral and extant NR2C1s could have impacted stem cell pluripotency (phase 3). We evaluated human, chimpanzee, and ancestral NR2C1 for transcriptional modulation of Oct4 and Nanog (key regulators of pluripotency and cell lineage commitment), promoter activity for Pepck (a proxy for differentiation in numerous cell types), and average size of embryological stem cell colonies (a proxy for the self-renewal capacity of pluripotent cells). Results supported the signal for alteration of natural selection identified in phase 2. We suggest that adaptive evolution of gene regulation has impacted several aspects of pluripotentiality within primates. Our study illustrates that the combination of targeted evolutionary surveys and experimental analysis is an effective strategy for investigating the evolution of gene regulation with respect to developmental phenotypes. C1 [Baker, Jennifer L.; Wood, Bernard A.; Sherwood, Chet C.] George Washington Univ, Ctr Adv Study Human Paleobiol, Washington, DC 20052 USA. [Baker, Jennifer L.; Sherwood, Chet C.; Maynard, Thomas M.] George Washington Univ, George Washington Inst Neurosci, Washington, DC 20052 USA. [Wood, Bernard A.] George Washington Univ, Dept Anat & Regenerat Biol, Washington, DC 20052 USA. [Maynard, Thomas M.] George Washington Univ, Dept Physiol & Pharmacol, Washington, DC 20052 USA. [Baker, Jennifer L.] NHGRI, Ctr Res Genom & Global Hlth, NIH, 12 South Dr, Bethesda, MD 20892 USA. [Dunn, Katherine A.; Bielawski, Joseph P.] Dalhousie Univ, Dept Biol, 1355 Oxford St, Halifax, NS B3H 4R2, Canada. [Mingrone, Joseph; Bielawski, Joseph P.] Dalhousie Univ, Dept Math & Stat, Halifax, NS B3H 4R2, Canada. [Wood, Bernard A.] Smithsonian Inst, Natl Museum Nat Hist, Human Origins Program, Washington, DC 20560 USA. [Wildman, Derek E.] Univ Illinois, Dept Mol & Integrat Physiol, Champaign, IL 61801 USA. [Wildman, Derek E.] Univ Illinois, Inst Genom Biol, Champaign, IL 61801 USA. RP Baker, JL (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, 12 South Dr, Bethesda, MD 20892 USA.; Bielawski, JP (reprint author), Dalhousie Univ, Dept Biol, 1355 Oxford St, Halifax, NS B3H 4R2, Canada. EM JenniferLBaker7@gmail.com; J.Bielawski@dal.ca RI Maynard, Thomas/I-9039-2012; OI Maynard, Thomas/0000-0001-6976-3936; Baker, Jennifer/0000-0002-5192-2377 FU National Science Foundation (NSF) doctoral dissertation research improvement grant [BSC-1455625]; Wenner-Gren Foundation dissertation fieldwork grant [8735]; NSF Integrative Graduate Education and Research traineeship grant [DGE-0801634]; NSF-Human Origins Moving in New Directions (HOMINID) grant [BCS-0827546]; James S. McDonnell Foundation [220020293]; George Washington (GW) Office of the Vice President for Research; GW Institute of Neuroscience Biomarker Core Facility, National Institutes of Health grant [DC-001534]; Natural Sciences and Engineering Research Council of Canada [DG298394]; Centre for Comparative Genomics and Evolutionary Bioinformatics - Tula Foundation; Canadian Institutes of Health Research [CMF-108026] FX The work described here was supported by a National Science Foundation (NSF) doctoral dissertation research improvement grant (BSC-1455625), a Wenner-Gren Foundation dissertation fieldwork grant (8735), an NSF Integrative Graduate Education and Research traineeship grant (DGE-0801634), an NSF-Human Origins Moving in New Directions (HOMINID) grant (BCS-0827546), a grant from the James S. McDonnell Foundation (220020293), George Washington (GW) Office of the Vice President for Research and the GW School of Medicine for the GW Institute of Neuroscience Biomarker Core Facility, National Institutes of Health grant (DC-001534), Natural Sciences and Engineering Research Council of Canada (DG298394), Centre for Comparative Genomics and Evolutionary Bioinformatics (funded by the Tula Foundation), and Canadian Institutes of Health Research (CMF-108026). NR 121 TC 1 Z9 1 U1 1 U2 1 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 JUN PY 2016 VL 203 IS 2 BP 905 EP + DI 10.1534/genetics.115.183889 PG 53 WC Genetics & Heredity SC Genetics & Heredity GA DO0IO UT WOS:000377462800025 PM 27075724 ER PT J AU Thaysen-Andersen, M Chertova, E Bergamaschi, C Moh, ESX Chertov, O Roser, J Sowder, R Bear, J Lifson, J Packer, NH Felber, BK Pavlakis, GN AF Thaysen-Andersen, M. Chertova, E. Bergamaschi, C. Moh, E. S. X. Chertov, O. Roser, J. Sowder, R. Bear, J. Lifson, J. Packer, N. H. Felber, B. K. Pavlakis, G. N. TI Recombinant human heterodimeric IL-15 complex displays extensive and reproducible N- and O-linked glycosylation SO GLYCOCONJUGATE JOURNAL LA English DT Article DE N-glycosylation; O-glycosylation; LC-MS/MS; Glycoprotein; IL-15; IL-15R alpha ID NATURAL-KILLER-CELLS; CD8(+) T-CELLS; HAMSTER OVARY CELLS; IN-VIVO; CIRCULATORY RESIDENCE; SOLUBLE IL-15R-ALPHA; MASS-SPECTROMETRY; RECEPTOR-ALPHA; GLYCAN; EXPRESSION AB Human interleukin 15 (IL-15) circulates in blood as a stable molecular complex with the soluble IL-15 receptor alpha (sIL-15R alpha). This heterodimeric IL-15:sIL-15R alpha complex (hetIL-15) shows therapeutic potential by promoting the growth, mobilization and activation of lymphocytes and is currently evaluated in clinical trials. Favorable pharmacokinetic properties are associated with the heterodimeric formation and the glycosylation of hetIL-15, which, however, remains largely uncharacterized. We report the site-specific N- and O-glycosylation of two clinically relevant large-scale preparations of HEK293-derived recombinant human hetIL-15. Intact IL-15 and sIL-15R alpha and derived glycans and glycopeptides were separately profiled using multiple LC-MS/MS strategies. IL-15 Asn79 and sIL-15R alpha Asn107 carried the same repertoire of biosynthetically-related N-glycans covering mostly alpha 1-6-core-fucosylated and beta-GlcNAc-terminating complex-type structures. The two potential IL-15 N-glycosylation sites (Asn71 and Asn112) located at the IL-2 receptor interface were unoccupied. Mass analysis of intact IL-15 confirmed its N-glycosylation and suggested that Asn79-glycosylation partially prevents Asn77-deamidation. IL-15 contained no O-glycans, whereas sIL-15R alpha was heavily O-glycosylated with partially sialylated core 1 and 2-type mono- to hexasaccharides on Thr2, Thr81, Thr86, Thr156, Ser158, and Ser160. The sialoglycans displayed alpha 2-3- and alpha 2-6-NeuAc-type sialylation. Non-human, potentially immunogenic glycoepitopes (e.g. N-glycolylneuraminic acid and alpha-galactosylation) were not displayed by hetIL-15. Highly reproducible glycosylation of IL-15 and sIL-15R alpha of two batches of hetIL-15 demonstrated consistent manufacturing and purification. In conclusion, we document the heterogeneous and reproducible N- and O-glycosylation of large-scale preparations of the therapeutic candidate hetIL-15. Site-specific mapping of these molecular features is important to evaluate the consistent large-scale production and clinical efficacy of hetIL-15. C1 [Thaysen-Andersen, M.; Moh, E. S. X.; Packer, N. H.] Macquarie Univ, Dept Chem & Biomol Sci, Sydney, NSW 2109, Australia. [Chertova, E.; Roser, J.; Sowder, R.; Lifson, J.] Leidos Biomed Res Inc, Frederick Natl Lab, AIDS & Canc Virus Program, Frederick, MD 21702 USA. [Bergamaschi, C.; Pavlakis, G. N.] NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Bergamaschi, C.; Bear, J.; Felber, B. K.] NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Chertov, O.] Leidos Biomed Inc, Frederick Natl Lab, Canc Res Technol Program, Frederick, MD 21702 USA. RP Thaysen-Andersen, M (reprint author), Macquarie Univ, Dept Chem & Biomol Sci, Sydney, NSW 2109, Australia. EM morten.andersen@mq.edu.au FU international Macquarie University Research Scholarship (iMQRES); Cancer Institute, NSW, Australia; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH) FX This research was facilitated through access to the Australian Proteomics Analysis Facility (APAF). ESXM was supported by an international Macquarie University Research Scholarship (iMQRES). M.T.-A. was supported by an Early Career Fellowship from the Cancer Institute, NSW, Australia. This project was funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E and by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. We thank Admune Therapeutics for supplying hetIL-15 preparations. NR 70 TC 2 Z9 2 U1 2 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0282-0080 EI 1573-4986 J9 GLYCOCONJUGATE J JI Glycoconjugate J. PD JUN PY 2016 VL 33 IS 3 BP 417 EP 433 DI 10.1007/s10719-015-9627-1 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DO2JG UT WOS:000377605400013 PM 26563299 ER PT J AU Castinetti, F Daly, AF Stratakis, CA Caberg, JH Castermans, E Trivellin, G Rostomyan, L Saveanu, A Jullien, N Reynaud, R Barlier, A Bours, V Brue, T Beckers, A AF Castinetti, F. Daly, A. F. Stratakis, C. A. Caberg, J. -H. Castermans, E. Trivellin, G. Rostomyan, L. Saveanu, A. Jullien, N. Reynaud, R. Barlier, A. Bours, V. Brue, T. Beckers, A. TI GPR101 Mutations are not a Frequent Cause of Congenital Isolated Growth Hormone Deficiency SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE hypopituitarism; gigantism; X-LAG syndrome; growth hormone deficiency; congenital hypopituitarism ID PROTEIN-COUPLED RECEPTOR; GIGANTISM; DISCOVERY; MATRIX; GENE; GHD AB Patients with Xq26.3 microduplication present with X-linked acrogigantism (X-LAG) syndrome, an early-childhood form of gigantism due to marked growth hormone (GH) hypersecretion from mixed GH-PRL adenomas and hyperplasia. The microduplication includes GPR101, which is upregulated in patients' tumor tissue. The GPR101 gene codes for an orphan G protein coupled receptor that is normally highly expressed in the hypothalamus. Our aim was to determine whether GPR101 loss of function mutations or deletions could be involved in patients with congenital isolated GH deficiency (GHD). Taking advantage of the cohort of patients from the GENHYPOPIT network, we studied 41 patients with unexplained isolated GHD. All patients had Sanger sequencing of the GPR101 gene and array comparative genome hybridization (aCGH) to look for deletions. Functional studies (cell culture with GH secretion measurements, cAMP response) were performed. One novel GPR101 variant, c.589 G> T (p.V197L), was seen in the heterozygous state in a patient with isolated GHD. In silico analysis suggested that this variant could be deleterious. Functional studies did not show any significant difference in comparison with wild type for GH secretion and cAMP response. No truncating, frameshift, or small insertion-deletion (indel) GPR101 mutations were seen in the 41 patients. No deletion or other copy number variation at chromosome Xq26.3 was found on aCGH. We found a novel GPR101 variant of unknown significance, in a patient with isolated GH deficiency. Our study did not identify GPR101 abnormalities as a frequent cause of GH deficiency. C1 [Castinetti, F.; Saveanu, A.; Jullien, N.; Reynaud, R.; Barlier, A.; Brue, T.] CNRS, CRN2M, Fac Med, UMR7286, Marseille, France. [Castinetti, F.; Saveanu, A.; Jullien, N.; Reynaud, R.; Barlier, A.; Brue, T.] Aix Marseille Univ, La Concept Hosp, Assistance Publ Hop Marseille, Reference Ctr Rare Pituitary Dis DEFHY, Marseille, France. [Daly, A. F.; Rostomyan, L.; Beckers, A.] Univ Liege, Ctr Hosp Univ Liege, Dept Endocrinol, Domaine Univ Sart Tilman, B-4000 Liege, Belgium. [Stratakis, C. A.; Trivellin, G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet PDEGEN, NIH, Bethesda, MD USA. [Stratakis, C. A.; Trivellin, G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Endocrinol Interinst Training Program, NIH, Bethesda, MD USA. [Caberg, J. -H.; Castermans, E.; Bours, V.] Univ Liege, Ctr Hosp Univ Liege, Dept Human Genet, Domaine Univ Sart Tilman, B-4000 Liege, Belgium. [Saveanu, A.; Barlier, A.] La Concept Hosp, Assistance Publ Hop Marseille, Mol Endocrinol Lab, Marseille, France. RP Beckers, A (reprint author), Univ Liege, Ctr Hosp Univ Liege, Domaine Univ Sart Tilman, B-4000 Liege, Belgium. EM albert.beckers@chu.ulg.ac.be RI Jullien, Nicolas/O-1947-2015; Trivellin, Giampaolo/J-6583-2016; Daly, Adrian /E-2178-2011; OI Jullien, Nicolas/0000-0001-8273-2106; Trivellin, Giampaolo/0000-0003-2384-4153; Daly, Adrian /0000-0001-6130-2975; Castinetti, Frederic/0000-0002-1808-8800 FU Fonds d'Investissement de Recherche Scientifique of the Centre Hospitalier Universitaire de Liege; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [Z01-HD008920] FX This research was supported by funding from the Fonds d'Investissement de Recherche Scientifique of the Centre Hospitalier Universitaire de Liege and by a grant from the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (Z01-HD008920). The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about. The authors would like to thank all the clinicians who sent DNA samples of patients with congenital pituitary hormone deficiency in the GENHYPOPIT network. NR 22 TC 5 Z9 5 U1 2 U2 2 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 EI 1439-4286 J9 HORM METAB RES JI Horm. Metab. Res. PD JUN PY 2016 VL 48 IS 6 BP 389 EP 393 DI 10.1055/s-0042-100733 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DO0DF UT WOS:000377448900006 PM 26797872 ER PT J AU Azizi, S Imani, F Ghavidel, S Tahmasebi, A Kwak, JT Xu, S Turkbey, B Choyke, P Pinto, P Wood, B Mousavi, P Abolmaesumi, P AF Azizi, Shekoofeh Imani, Farhad Ghavidel, Sahar Tahmasebi, Amir Kwak, Jin Tae Xu, Sheng Turkbey, Baris Choyke, Peter Pinto, Peter Wood, Bradford Mousavi, Parvin Abolmaesumi, Purang TI Detection of prostate cancer using temporal sequences of ultrasound data: a large clinical feasibility study SO INTERNATIONAL JOURNAL OF COMPUTER ASSISTED RADIOLOGY AND SURGERY LA English DT Article; Proceedings Paper CT 7th International Conference on Information Processing in Computer-Assisted Interventions (IPCAI) CY JUN 21-22, 2016 CL Heidelberg, GERMANY DE Temporal ultrasound data; Deep learning; Deep belief network; Cancer diagnosis; Prostate cancer ID GLEASON SCORE; BIOPSY; FUSION; MRI; ELASTOGRAPHY; GUIDANCE AB This paper presents the results of a large study involving fusion prostate biopsies to demonstrate that temporal ultrasound can be used to accurately classify tissue labels identified in multi-parametric magnetic resonance imaging (mp-MRI) as suspicious for cancer. We use deep learning to analyze temporal ultrasound data obtained from 255 cancer foci identified in mp-MRI. Each target is sampled in axial and sagittal planes. A deep belief network is trained to automatically learn the high-level latent features of temporal ultrasound data. A support vector machine classifier is then applied to differentiate cancerous versus benign tissue, verified by histopathology. Data from 32 targets are used for the training, while the remaining 223 targets are used for testing. Our results indicate that the distance between the biopsy target and the prostate boundary, and the agreement between axial and sagittal histopathology of each target impact the classification accuracy. In 84 test cores that are 5 mm or farther to the prostate boundary, and have consistent pathology outcomes in axial and sagittal biopsy planes, we achieve an area under the curve of 0.80. In contrast, all of these targets were labeled as moderately suspicious in mp-MR. Using temporal ultrasound data in a fusion prostate biopsy study, we achieved a high classification accuracy specifically for moderately scored mp-MRI targets. These targets are clinically common and contribute to the high false-positive rates associated with mp-MRI for prostate cancer detection. Temporal ultrasound data combined with mp-MRI have the potential to reduce the number of unnecessary biopsies in fusion biopsy settings. C1 [Azizi, Shekoofeh; Imani, Farhad; Abolmaesumi, Purang] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Ghavidel, Sahar; Mousavi, Parvin] Queens Univ, Kingston, ON, Canada. [Tahmasebi, Amir] Philips Res North Amer, Cambridge, MA USA. [Kwak, Jin Tae; Xu, Sheng; Turkbey, Baris; Choyke, Peter; Pinto, Peter; Wood, Bradford] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Azizi, S (reprint author), Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. EM shazizi@ece.ubc.ca NR 31 TC 0 Z9 0 U1 2 U2 7 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 JUN PY 2016 VL 11 IS 6 SI SI BP 947 EP 956 DI 10.1007/s11548-016-1395-2 PG 10 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging; Surgery SC Engineering; Radiology, Nuclear Medicine & Medical Imaging; Surgery GA DO0DG UT WOS:000377449000012 PM 27059021 ER PT J AU Joseph, J Claggett, BC Anand, IS Fleg, JL Huynh, T Desai, AS Solomon, SD O'Meara, E Mckinlay, S Pitt, B Pfeffer, MA Lewis, EF AF Joseph, Jacob Claggett, Brian C. Anand, Inder S. Fleg, Jerome L. Huynh, Thao Desai, Akshay S. Solomon, Scott D. O'Meara, Eileen Mckinlay, Sonja Pitt, Bertram Pfeffer, Marc A. Lewis, Eldrin F. TI QRS Duration Is a Predictor of Adverse Outcomes in Heart Failure With Preserved Ejection Fraction SO JACC-HEART FAILURE LA English DT Article DE dyssynchrony; electrocardiogram; heart failure with preserved ejection fraction; outcomes ID BUNDLE-BRANCH BLOCK; PROGNOSTIC-SIGNIFICANCE; VENTRICULAR FUNCTION; ATRIAL-FIBRILLATION; TRIAL; SPIRONOLACTONE; DYSSYNCHRONY; PREVALENCE; MORTALITY; THERAPY AB OBJECTIVES This study examined the relationship between baseline QRS duration and clinical outcomes in subjects enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial. BACKGROUND Heart failure with preserved ejection fraction (HFPEF) is a heterogeneous clinical syndrome. Whether QRS duration identifies HFPEF subjects at an increased risk of adverse outcomes has not been well studied. METHODS QRS duration was analyzed as a dichotomous variable (>= 120 ms or <120 ms) and as a continuous variable to determine its relation to the primary outcome (composite of cardiovascular death, aborted cardiac arrest, or HF hospitalization [HFH]) and to each component of the primary outcome. Multivariate analyses were conducted in the entire study cohort as well as in separate analyses for subjects enrolled only from North and South America, or from Russia and Georgia. RESULTS The QRS duration of >= 120 ms was independently associated with an increased risk of the primary outcome (p = 0.009) and HFH (p = 0.003) in the entire study cohort and in the subset enrolled in the Americas. There was a linear relation of QRS duration with risk of the primary outcome and HFH. No interaction was observed between treatment with spironolactone and QRS duration. The risk of adverse outcomes was increased independently of the type of conduction abnormality underlying prolonged QRS duration. CONCLUSIONS This post hoc analysis demonstrated that prolonged QRS duration identifies HFPEF subjects at a higher risk of adverse clinical outcomes and that spironolactone had a similar effect on outcomes independent of QRS duration. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302) (C) 2016 by the American College of Cardiology Foundation. C1 [Joseph, Jacob; Claggett, Brian C.; Desai, Akshay S.; Solomon, Scott D.; Pfeffer, Marc A.; Lewis, Eldrin F.] Brigham & Womens Hosp, Dept Med, 77 Ave Louis Pasteur,New Res Bldg,Room 630, Boston, MA 02115 USA. [Joseph, Jacob] Vet Affairs Boston Healthcare Syst, Boston, MA USA. [Anand, Inder S.] Univ Minnesota, Minneapolis, MN USA. [Fleg, Jerome L.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Huynh, Thao] Montreal Gen Hosp, Montreal, PQ H3G 1A4, Canada. [O'Meara, Eileen] Inst Cardiol Montreal, Montreal, PQ, Canada. [Mckinlay, Sonja] New England Res Inst, 9 Galen St, Watertown, MA 02172 USA. [Pitt, Bertram] Univ Michigan, Ann Arbor, MI 48109 USA. RP Joseph, J (reprint author), Brigham & Womens Hosp, Dept Med, 77 Ave Louis Pasteur,New Res Bldg,Room 630, Boston, MA 02115 USA. EM jjoseph16@partners.org NR 35 TC 1 Z9 1 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD JUN PY 2016 VL 4 IS 6 BP 477 EP 486 DI 10.1016/j.jchf.2016.02.013 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DN9TP UT WOS:000377423900010 PM 27039126 ER PT J AU Tsao, CW Lyass, A Larson, MG Cheng, S Lam, CSP Aragam, JR Benjamin, EJ Vasan, RS AF Tsao, Connie W. Lyass, Asya Larson, Martin G. Cheng, Susan Lam, Carolyn S. P. Aragam, Jayashri R. Benjamin, Emelia J. Vasan, Ramachandran S. TI Prognosis of Adults With Borderline Left Ventricular Ejection Fraction SO JACC-HEART FAILURE LA English DT Article DE echocardiography; epidemiology; heart failure; left ventricular function ID CHRONIC HEART-FAILURE; M-MODE ECHOCARDIOGRAPHY; CARDIOVASCULAR HEALTH; SYSTOLIC DYSFUNCTION; CLINICAL-IMPLICATIONS; EUROPEAN-SOCIETY; NATURAL-HISTORY; POPULATION; FRAMINGHAM; RECOMMENDATIONS AB OBJECTIVES This study sought to examine the association of a borderline left ventricular ejection fraction (LVEF) of 50% to 55% with cardiovascular morbidity and mortality in a community-based cohort. BACKGROUND Guidelines stipulate a LVEF >55% as normal, but the optimal threshold, if any, remains uncertain. The prognosis of a "borderline" LVEF, 50% to 55%, is unknown. METHODS This study evaluated Framingham Heart Study participants who underwent echocardiography between 1979 and 2008 (n = 10,270 person-observations, mean age 60 years, 57% women). Using pooled data with up to 12 years of follow-up and multivariable Cox regression, we evaluated the associations of borderline LVEF and continuous LVEF with the risk of developing a composite outcome (heart failure [HF] or death; primary outcome) and incident HF (secondary outcome). RESULTS During follow-up (median 7.9 years), HF developed in 355 participants, and 1,070 died. Among participants with an LVEF of 50% to 55% (prevalence 3.5%), rates of the composite outcome and HF were 0.24 and 0.13 per 10 years of follow-up, respectively, versus 0.16 and 0.05 in participants having a normal LVEF. In multivariable-adjusted analyses, LVEF of 50% to 55% was associated with increased risk of the composite outcome (hazard ratio [HR]: 1.37; 95% confidence interval [CI]: 1.05 to 1.80) and HF (HR: 2.15; 95% CI: 1.41 to 3.28). There was a linear inverse relationship of continuous LVEF with the composite outcome (HR per 5 LVEF% decrement: 1.12; 95% CI: 1.07 to 1.16) and HF (HR per 5 LVEF% decrement: 1.23; 95% CI: 1.15 to 1.32). CONCLUSIONS Persons with an LVEF of 50% to 55% in the community have greater risk for morbidity and mortality relative to persons with an LVEF >55%. Additional studies are warranted to elucidate the optimal management of these individuals. (C) 2016 by the American College of Cardiology Foundation. C1 [Tsao, Connie W.] Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc, Boston, MA 02215 USA. [Tsao, Connie W.] Harvard Univ, Sch Med, Boston, MA USA. [Tsao, Connie W.; Lyass, Asya; Larson, Martin G.; Cheng, Susan; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Tsao, Connie W.; Lyass, Asya; Larson, Martin G.; Cheng, Susan; Benjamin, Emelia J.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Lyass, Asya; Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Cheng, Susan; Aragam, Jayashri R.] Brigham & Womens Hosp, Dept Med, Div Cardiol, Boston, MA USA. [Lam, Carolyn S. P.] Natl Univ Hlth Ctr, Dept Med, Div Cardiol, Singapore, Singapore. [Aragam, Jayashri R.; Vasan, Ramachandran S.] Vet Affairs Boston Healthcare Syst, Dept Med, Div Cardiol, Boston, MA USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Cardiol Med, Boston, MA 02118 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med, Boston, MA 02118 USA. RP Tsao, CW (reprint author), Beth Israel Deaconess Med Ctr, Cardiovasc Div, 330 Brookline Ave, Boston, MA 02215 USA. EM ctsaol@bidmc.harvard.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [N01HC25195, K23 HL118529, K99 HL107642, R01 HL080124, R01 HL093328]; NINDS NIH HHS [R01 NS017950] NR 31 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD JUN PY 2016 VL 4 IS 6 BP 502 EP 510 DI 10.1016/j.jchf.2016.03.003 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DN9TP UT WOS:000377423900014 PM 27256754 ER PT J AU Moore, SC Lee, IM Weiderpass, E Campbell, PT Sampson, JN Kitahara, CM Keadle, SK Arem, H de Gonzalez, AB Hartge, P Adami, HO Blair, CK Borch, KB Boyd, E Check, DP Fournier, A Freedman, ND Gunter, M Johannson, M Khaw, KT Linet, MS Orsini, N Park, Y Riboli, E Robien, K Schairer, C Sesso, H Spriggs, M Van Dusen, R Wolk, A Matthews, CE Patel, AV AF Moore, Steven C. Lee, I-Min Weiderpass, Elisabete Campbell, Peter T. Sampson, Joshua N. Kitahara, Cari M. Keadle, Sarah K. Arem, Hannah de Gonzalez, Amy Berrington Hartge, Patricia Adami, Hans-Olov Blair, Cindy K. Borch, Kristin B. Boyd, Eric Check, David P. Fournier, Agness Freedman, Neal D. Gunter, Marc Johannson, Mattias Khaw, Kay-Tee Linet, Martha S. Orsini, Nicola Park, Yikyung Riboli, Elio Robien, Kim Schairer, Catherine Sesso, Howard Spriggs, Michael Van Dusen, Roy Wolk, Alicja Matthews, Charles E. Patel, Alpa V. TI Association of Leisure-Time Physical Activity With Risk of 26 Types of Cancer in 1.44 Million Adults SO JAMA INTERNAL MEDICINE LA English DT Article ID POSTMENOPAUSAL BREAST-CANCER; RANDOMIZED CONTROLLED-TRIAL; BODY-MASS INDEX; NIH-AARP DIET; UNITED-STATES; SEX-HORMONES; LUNG-CANCER; WEIGHT-GAIN; METAANALYSIS; WOMEN AB IMPORTANCE Leisure-time physical activity has been associated with lower risk of heart-disease and all-cause mortality, but its association with risk of cancer is not well understood. OBJECTIVE To determine the association of leisure-time physical activity with incidence of common types of cancer and whether associations vary by body size and/or smoking. DESIGN, SETTING, AND PARTICIPANTS We pooled data from 12 prospective US and European cohorts with self-reported physical activity (baseline, 1987-2004). We used multivariable Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals for associations of leisure-time physical activity with incidence of 26 types of cancer. Leisure-time physical activity levels were modeled as cohort-specific percentiles on a continuous basis and cohort-specific results were synthesized by random-effects meta-analysis. Hazard ratios for high vs low levels of activity are based on a comparison of risk at the 90th vs 10th percentiles of activity. The data analysis was performed from January 1, 2014, to June 1, 2015. EXPOSURES Leisure-time physical activity of a moderate to vigorous intensity. MAIN OUTCOMES AND MEASURES Incident cancer during follow-up. RESULTS A total of 1.44 million participants (median [range] age, 59 [19-98] years; 57% female) and 186 932 cancers were included. High vs low levels of leisure-time physical activity were associated with lower risks of 13 cancers: esophageal adenocarcinoma (HR, 0.58; 95% CI, 0.37-0.89), liver (HR, 0.73; 95% CI, 0.55-0.98), lung (HR, 0.74; 95% CI, 0.71-0.77), kidney (HR, 0.77; 95% CI, 0.70-0.85), gastric cardia (HR, 0.78; 95% CI, 0.64-0.95), endometrial (HR, 0.79; 95% CI, 0.68-0.92), myeloid leukemia (HR, 0.80; 95% CI, 0.70-0.92), myeloma (HR, 0.83; 95% CI, 0.72-0.95), colon (HR, 0.84; 95% CI, 0.77-0.91), head and neck (HR, 0.85; 95% CI, 0.78-0.93), rectal (HR, 0.87; 95% CI, 0.80-0.95), bladder (HR, 0.87; 95% CI, 0.82-0.92), and breast (HR, 0.90; 95% CI, 0.87-0.93). Body mass index adjustment modestly attenuated associations for several cancers, but 10 of 13 inverse associations remained statistically significant after this adjustment. Leisure-time physical activity was associated with higher risks of malignant melanoma (HR, 1.27; 95% CI, 1.16-1.40) and prostate cancer (HR, 1.05; 95% CI, 1.03-1.08). Associations were generally similar between overweight/obese and normal-weight individuals. Smoking status modified the association for lung cancer but not other smoking-related cancers. CONCLUSIONS AND RELEVANCE Leisure-time physical activity was associated with lower risks of many cancer types. Health care professionals counseling inactive adults should emphasize that most of these associations were evident regardless of body size or smoking history, supporting broad generalizability of findings. C1 [Moore, Steven C.; Sampson, Joshua N.; Kitahara, Cari M.; Keadle, Sarah K.; Arem, Hannah; de Gonzalez, Amy Berrington; Hartge, Patricia; Check, David P.; Freedman, Neal D.; Linet, Martha S.; Schairer, Catherine; Matthews, Charles E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lee, I-Min; Sesso, Howard] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Weiderpass, Elisabete; Adami, Hans-Olov] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Weiderpass, Elisabete; Borch, Kristin B.] Univ Tromso, Arctic Univ Norway, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki, Finland. [Weiderpass, Elisabete] Canc Registry Norway, Inst Populat Based Canc Res, Dept Res, Oslo, Norway. [Campbell, Peter T.; Patel, Alpa V.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Arem, Hannah] USAID Bur Global Hlth, Washington, DC USA. [Adami, Hans-Olov] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Blair, Cindy K.] Univ New Mexico, Div Epidemiol Biostat & Prevent Med, Albuquerque, NM 87131 USA. [Boyd, Eric; Spriggs, Michael; Van Dusen, Roy] Information Management Serv Inc, Rockville, MD USA. [Fournier, Agness] Inst Gustave Roussy, Ctr Res Epidemiol & Populat Hlth, Villejuif, France. [Gunter, Marc; Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Gunter, Marc] Int Agcy Res Canc, Sect Nutr & Metab, 150 Cours Albert Thomas, F-69372 Lyon, France. [Johannson, Mattias] Int Agcy Res Canc, Genet Epidemiol Grp, 150 Cours Albert Thomas, F-69372 Lyon, France. [Johannson, Mattias] Umea Univ, Dept Biobank Res, Umea, Sweden. [Khaw, Kay-Tee] Univ Cambridge, Cambridge Inst Publ Hlth, Cambridge, England. [Orsini, Nicola; Wolk, Alicja] Karolinska Inst, Inst Environm Med, Unit Nutr Epidemiol, S-10401 Stockholm, Sweden. [Park, Yikyung] Washington Univ, Sch Med, Div Publ Hlth Sci, St Louis, MO USA. [Robien, Kim] George Washington Univ, Sch Publ Hlth, Milken Inst, Dept Exercise & Nutr Sci, Washington, DC USA. RP Moore, SC (reprint author), Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM moorest@mail.nih.gov RI Weiderpass, Elisabete/M-4029-2016; Kitahara, Cari/R-8267-2016; Moore, Steven/D-8760-2016; OI Weiderpass, Elisabete/0000-0003-2237-0128; Moore, Steven/0000-0002-8169-1661; Robien, Kim/0000-0002-2120-2280 FU Intramural Research Program of the National Institutes of Health (NIH) FX This study was supported by the Intramural Research Program of the National Institutes of Health (NIH). Details regarding funding for the individual studies are listed in the eAcknowledgments in the Supplement. NR 45 TC 16 Z9 16 U1 9 U2 11 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 JUN PY 2016 VL 176 IS 6 BP 816 EP 825 DI 10.1001/jamainternmed.2016.1548 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DN6KU UT WOS:000377184000022 PM 27183032 ER PT J AU Desai, A Jung, MY Olivera, A Gilfillan, AM Prussin, C Kirshenbaum, AS Beaven, MA Metcalfe, DD AF Desai, Avanti Jung, Mi-Yeon Olivera, Ana Gilfillan, Alasdair M. Prussin, Calman Kirshenbaum, Arnold S. Beaven, Michael A. Metcalfe, Dean D. TI IL-6 promotes an increase in human mast cell numbers and reactivity through suppression of suppressor of cytokine signaling 3 SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE cells; signal transducer and activator of transcription 3; suppressor of cytokine signaling 3; stem cell factor; IL-6; mastocytosis ID FC-EPSILON-RI; SOLUBLE INTERLEUKIN-6 RECEPTOR; PERIPHERAL-BLOOD; COLORECTAL-CANCER; EXPRESSION; GROWTH; SOCS3; DISEASE; GENE; HYPERMETHYLATION AB Background: IL-6, levels of which are reported to be increased in association with mastocytosis, asthma, and urticaria, is used in conjunction with stem cell factor to generate CD34(+) cell-derived primary human mast cell (HuMC) cultures. Despite these associations, the effects on and mechanisms by which prolonged exposure to IL-6 alters HuMC numbers and function are not well understood. Objectives: We sought to study the effect of IL-6 on HuMC function, the mechanisms by which IL-6 exerts its effects, and the relationship of these findings to mastocytosis. Methods: HuMCs were cultured in stem cell factor with or without IL-6. Responses to FceRI aggregation and expression of proteases and receptors, including the soluble IL-6 receptor (sIL-6R), were then quantitated. Epigenetic changes in suppressor of cytokine signaling 3 (SOCS3) were determined by using methylation-specific PCR. Serum samples from healthy control subjects and patients with mastocytosis were assayed for IL-6, tryptase, and sIL-6R. Results: IL-6 enhanced mast cell (MC) proliferation, maturation, and reactivity after FceRI aggregation. IL-6 reduced expression of SOCS3, which correlated with methylation of the SOCS3 promoter and increased expression and activation of signal transducer and activator of transcription 3. IL-6 also suppressed constitutive production of sIL-6R, and serum levels of sIL-6R were similarly reduced in patients with mastocytosis. Conclusion: IL-6 increases MC proliferation and formation of a more reactive phenotype enabled by suppressing proteolytic cleavage of sIL-6R from IL-6R and downregulation of the SOCS3 autoinhibitory pathway. We suggest IL-6 blockade might ameliorate MC-related symptoms and pathology in patients with MC-related diseases associated with increased IL-6 levels, including mastocytosis. C1 [Desai, Avanti; Jung, Mi-Yeon; Olivera, Ana; Gilfillan, Alasdair M.; Prussin, Calman; Kirshenbaum, Arnold S.; Metcalfe, Dean D.] NIAID, Lab Allerg Dis, NIH, Rm 11C208,Bldg 10, Bethesda, MD 20892 USA. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Desai, A (reprint author), NIAID, Lab Allerg Dis, NIH, Rm 11C208,Bldg 10, Bethesda, MD 20892 USA. EM avanti.desai@nih.gov FU Division of Intramural Research Programs of the National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute, National Institutes of Health FX Supported by the Division of Intramural Research Programs of the National Institute of Allergy and Infectious Diseases and the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 64 TC 2 Z9 2 U1 1 U2 1 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 JUN PY 2016 VL 137 IS 6 BP 1863 EP + DI 10.1016/j.jaci.2015.09.059 PG 15 WC Allergy; Immunology SC Allergy; Immunology GA DO1GT UT WOS:000377527200028 PM 26774658 ER PT J AU Happel, CS Stone, KD Freeman, AF Shah, NN Wang, A Lyons, JJ Guerrerio, PA Hickstein, DD Su, HC AF Happel, Corinne S. Stone, Kelly D. Freeman, Alexandra F. Shah, Nirali N. Wang, Angela Lyons, Jonathan J. Guerrerio, Pamela A. Hickstein, Dennis D. Su, Helen C. TI Food allergies can persist after myeloablative hematopoietic stem cell transplantation in dedicator of cytokinesis 8-deficient patients SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID BONE-MARROW-TRANSPLANTATION; FARM MILK CONSUMPTION; HYPER-IGE SYNDROME; DOCK8 DEFICIENCY; CHILDHOOD ASTHMA; MICRORNAS; LONG; IMMUNODEFICIENCY; ASSOCIATION; EXPRESSION C1 [Happel, Corinne S.; Su, Helen C.] NIAID, Lab Host Defenses, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Stone, Kelly D.; Lyons, Jonathan J.; Guerrerio, Pamela A.] NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Freeman, Alexandra F.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Shah, Nirali N.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Wang, Angela] Frederick Natl Lab Canc Res, Clin Res Directorate, Clin Monitoring Res Program, Leidos Biomed Res, Frederick, MD USA. RP Su, HC (reprint author), NIAID, Lab Host Defenses, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hsu@niaid.nih.gov OI Lyons, Jonathan/0000-0002-2346-8189 FU CCR NIH HHS [HHSN261200800001C]; Intramural NIH HHS [ZIA AI001193-02]; NCI NIH HHS [HHSN261200800001E] NR 42 TC 1 Z9 1 U1 6 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 JUN PY 2016 VL 137 IS 6 BP 1895 EP + DI 10.1016/j.jaci.2015.11.017 PG 17 WC Allergy; Immunology SC Allergy; Immunology GA DO1GT UT WOS:000377527200036 PM 26827248 ER PT J AU Azizollahi, S Aflatoonian, R Gilani, MAS Behnam, B Tajik, N Asghari-Jafarabadi, M Asgari, HR Koruji, M AF Azizollahi, Saeid Aflatoonian, Reza Gilani, Mohammad Ali Sadighi Behnam, Babak Tajik, Nader Asghari-Jafarabadi, Mohammad Asgari, Hamid Reza Koruji, Morteza TI Alteration of spermatogenesis following spermatogonial stem cells transplantation in testicular torsion-detorsion mice SO JOURNAL OF ASSISTED REPRODUCTION AND GENETICS LA English DT Article DE SSCs transplantation; Pre- and post-meiotic genes; Testicular torsion ID IN-VITRO CULTURE; MALE GERM-CELLS; A SPERMATOGONIA; MOUSE TESTIS; RECIPIENT PREPARATION; SELF-RENEWAL; C-KIT; PROLIFERATION; DIFFERENTIATION; GDNF AB Testicular ischemia is the main consequence of testicular torsion, in both clinical and experimental aspects. Preservation and auto-transplantation of spermatogonial stem cells (SSCs) could be a new treatment for infertility in testicular ischemia following testicular torsion. To apply the idea in this study, animals were randomly divided into four groups of control, sham, with torsion, and with torsion followed by transplantation (TT). Isolated SSCs from neonatal mice were cultured and identified by flow cytometry (C-KIT-, INTEGRIN beta(1) (+)) and RT-PCR (Reverse transcription polymerase chain reaction) for specific spermatogonial cell markers (Oct4, Gfr alpha-1, Plzf, Vasa, Itg alpha (6) , and Itg beta (1) ). SSCs were transplanted upon a 2-h testicular torsion in the TT group. Cultured cells were transplanted into ischemia reperfusion testicle 2 weeks post-testicular torsion. Eight weeks after SSCs transplantation, the SSCs-transplanted testes and epididymis were removed for sperm analysis, weight and histopathological evaluation, and pre- and post-meiotic gene expression assessment by qRT-PCR. Our findings indicated that all evaluated parameters (epididymal sperm profile, Johnsen score, Plzf, Gfr alpha-1, Scp-1, Tekt-1 expressions, and histopathological profile) were significantly decreased following testicular torsion (group 3) when compared to the control group (p a parts per thousand currency sign 0.05). However, all abovementioned parameters showed a significant increase/improvement in torsion-transplantation group compared to torsion group. However, these parameters in the TT group were significantly lower in the sham and control groups (p a parts per thousand currency sign 0.05). SSCs transplantation could up-regulate the expression of pre- and post-meiotic genes in testicular ischemia, which resulted in improvement of both testicular function and structure after testicular torsion. C1 [Azizollahi, Saeid; Asgari, Hamid Reza; Koruji, Morteza] Iran Univ Med Sci, Sch Med, Dept Anat Sci, Tehran, Iran. [Aflatoonian, Reza] ACECR, Royan Inst Reprod Biomed, Reprod Biomed Res Ctr, Dept Endocrinol & Female Infertil, Tehran, Iran. [Gilani, Mohammad Ali Sadighi] Univ Tehran Med Sci, Sch Med, Dept Urol, Tehran, Iran. [Gilani, Mohammad Ali Sadighi] ACECR, Royan Inst Reprod Biomed, Reprod Biomed Res Ctr, Dept Androl, Tehran, Iran. [Behnam, Babak] Iran Univ Med Sci, Sch Med, Dept Med Genet & Mol Biol, Tehran, Iran. [Behnam, Babak] NIH, Undiagnosed Dis Program, Off Director, Bethesda, MD 20892 USA. [Behnam, Babak] NHGRI, NIH, Bethesda, MD 20892 USA. [Behnam, Babak; Koruji, Morteza] IUMS, Cellular & Mol Res Ctr, Hemmat Highway,POB 14155-5983, Tehran, Iran. [Tajik, Nader] Iran Univ Med Sci, Sch Med, Dept Immunol, Tehran, Iran. [Asghari-Jafarabadi, Mohammad] Tabriz Univ Med Sci, Rd Traff Injury Res Ctr, Tabriz, Iran. RP Koruji, M (reprint author), Iran Univ Med Sci, Sch Med, Dept Anat Sci, Tehran, Iran.; Koruji, M (reprint author), IUMS, Cellular & Mol Res Ctr, Hemmat Highway,POB 14155-5983, Tehran, Iran. EM koruji.m@iums.ac.ir RI Asghari Jafarabadi, Mohammmad/A-7478-2017 OI Asghari Jafarabadi, Mohammmad/0000-0003-3284-9749 FU Iran University of Medical Sciences (IUMS) [90-04-30-14879] FX This study was funded by a grant from Iran University of Medical Sciences (IUMS) (Number: 90-04-30-14879) for PhD student thesis, and all experiments have been performed at Cellular and Molecular Research Center, IUMS, Tehran, Iran. NR 71 TC 0 Z9 0 U1 1 U2 4 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 JUN PY 2016 VL 33 IS 6 BP 771 EP 781 DI 10.1007/s10815-016-0708-2 PG 11 WC Genetics & Heredity; Obstetrics & Gynecology; Reproductive Biology SC Genetics & Heredity; Obstetrics & Gynecology; Reproductive Biology GA DN7FZ UT WOS:000377242000012 PM 27052833 ER PT J AU Lu, XY Fukumoto, S Yamada, Y Evans, CA Diekwisch, TGH Luan, XH AF Lu, Xuanyu Fukumoto, Satoshi Yamada, Yoshihiko Evans, Carla A. Diekwisch, Thomas G. H. Luan, Xianghong TI Ameloblastin, an Extracellular Matrix Protein, Affects Long Bone Growth and Mineralization SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE AMELOBLASTIN; IGF1; BMP7; BONE DEVELOPMENT; MESENCHYMAL CELLS ID MULTIFUNCTIONAL COMPLEX ORGAN.; EPITHELIAL ROOT SHEATH; MESENCHYMAL STEM-CELLS; MORPHOGENETIC PROTEIN-7; CALCIUM-BINDING; IN-VITRO; GENE; DIFFERENTIATION; EXPRESSION; CARTILAGE AB Matrix molecules such as the enamel-related calcium-binding phosphoprotein ameloblastin (AMBN) are expressed in multiple tissues, including teeth, bones, and cartilage. Here we have asked whether AMBN is of functional importance for timely long bone development and, if so, how it exerts its function related to osteogenesis. Adolescent AMBN-deficient mice (AMBN(5-6)) suffered from a 33% to 38% reduction in femur length and an 8.4% shorter trunk spinal column when compared with WT controls, whereas there was no difference between adult animals. On a cellular level, AMBN truncation resulted in a shortened growth plate and a 41% to 49% reduction in the number of proliferating tibia chondrocytes and osteoblasts. Bone marrow stromal cells (BMSCs) isolated from AMBN mutant mice displayed defects in proliferation and differentiation potential as well as cytoskeleton organization. Osteogenesis-related growth factors, such as insulin-like growth factor 1 (IGF1) and BMP7, were also significantly (46% to 73%) reduced in AMBN-deficient BMSCs. Addition of exogenous AMBN restored cytoskeleton structures in AMBN mutant BMSCs and resulted in a dramatic 400% to 600% increase in BMP2, BMP7, and Col1A expression. Block of RhoA diminished the effect of AMBN on osteogenic growth factor and matrix protein gene expression. Addition of exogenous BMP7 and IGF1 rescued the proliferation and differentiation potential of AMBN-deficient BMSCs. Confirming the effects of AMBN on long bone growth, back-crossing of mutant mice with full-length AMBN overexpressors resulted in a complete rescue of AMBN(5-6) bone defects. Together, these data indicate that AMBN affects extracellular matrix production and cell adhesion properties in the long bone growth plate, resulting in altered cytoskeletal dynamics, increased osteogenesis-related gene expression, as well as osteoblast and chondrocyte proliferation. We propose that AMBN facilitates rapid long bone growth and an important growth spurt during the skeletogenesis of adolescent tooth-bearing vertebrates. (c) 2016 American Society for Bone and Mineral Research. C1 [Lu, Xuanyu; Diekwisch, Thomas G. H.; Luan, Xianghong] Univ Illinois, Coll Dent, Dept Oral Biol, Brodie Lab Craniofacial Genet, 801 South Paulina, Chicago, IL 60612 USA. [Fukumoto, Satoshi; Yamada, Yoshihiko] Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD USA. [Evans, Carla A.; Luan, Xianghong] Univ Illinois, Coll Dent, Dept Orthodont, Brodie Lab Craniofacial Genet, Chicago, IL 60612 USA. RP Luan, XH (reprint author), Univ Illinois, Coll Dent, Dept Oral Biol, Brodie Lab Craniofacial Genet, 801 South Paulina, Chicago, IL 60612 USA.; Diekwisch, TGH (reprint author), Texas A&M Univ, Baylor Coll Dent, Dept Periodont, 3302 Gaston Ave, Dallas, TX 75246 USA.; Diekwisch, TGH (reprint author), Texas A&M Univ, Baylor Coll Dent, Ctr Craniofacial Res & Diag, 3302 Gaston Ave, Dallas, TX 75246 USA. EM diekwisch@bcd.tamhsc.edu; luan@uic.edu FU NIDCR [DE18057, DE19155] FX This study has been generously supported by grants DE18057 and DE19155 from the NIDCR. The authors thank two anonymous reviewers for their guidance with improving the quality and depth of our manuscript. We also appreciate the help of Dr Yoshihiro Ito for maintaining the mouse models employed in the current study. NR 49 TC 3 Z9 3 U1 4 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD JUN PY 2016 VL 31 IS 6 BP 1235 EP 1246 DI 10.1002/jbmr.2788 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DN7PL UT WOS:000377269200014 PM 26766111 ER PT J AU Jou, JD Jain, S Georgiev, IS Donald, BR AF Jou, Jonathan D. Jain, Swati Georgiev, Ivelin S. Donald, Bruce R. TI BWM: A Novel, Provable, Ensemble-based Dynamic Programming Algorithm for Sparse Approximations of Computational Protein Design SO JOURNAL OF COMPUTATIONAL BIOLOGY LA English DT Article DE protein design; sparse residue interaction graphs; provable algorithms; branch-decomposition; dynamic programming; ensemble-based algorithms; OSPREY ID DEAD-END ELIMINATION; SIDE-CHAIN; GRAMICIDIN SYNTHETASE; BACKBONE FLEXIBILITY; SEARCH ALGORITHM; PREDICTION; REDESIGN; ENZYME; OPTIMIZATION; CONFORMATION AB Sparse energy functions that ignore long range interactions between residue pairs are frequently used by protein design algorithms to reduce computational cost. Current dynamic programming algorithms that fully exploit the optimal substructure produced by these energy functions only compute the GMEC. This disproportionately favors the sequence of a single, static conformation and overlooks better binding sequences with multiple low-energy conformations. Provable, ensemble-based algorithms such as A* avoid this problem, but A* cannot guarantee better performance than exhaustive enumeration. We propose a novel, provable, dynamic programming algorithm called Branch-Width Minimization* (BWM*) to enumerate a gap-free ensemble of conformations in order of increasing energy. Given a branch-decomposition of branch-width w for an n-residue protein design with at most q discrete side-chain conformations per residue, BWM* returns the sparse GMEC in O(nw(2) q(3/2w)) time and enumerates each additional conformation in merely O(n log q) time. We define a new measure, Total Effective Search Space (TESS), which can be computed efficiently a priori before BWM* or A* is run. We ran BWM* on 67 protein design problems and found that TESS discriminated between BWM*-efficient and A*-efficient cases with 100% accuracy. As predicted by TESS and validated experimentally, BWM* outperforms A* in 73% of the cases and computes the full ensemble or a close approximation faster than A*, enumerating each additional conformation in milliseconds. Unlike A*, the performance of BWM* can be predicted in polynomial time before running the algorithm, which gives protein designers the power to choose the most efficient algorithm for their particular design problem. C1 [Jou, Jonathan D.; Jain, Swati; Georgiev, Ivelin S.; Donald, Bruce R.] Duke Univ, Dept Comp Sci, Durham, NC 27708 USA. [Jain, Swati; Donald, Bruce R.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27708 USA. [Jain, Swati] Duke Univ, Dept Computat Biol, Durham, NC 27708 USA. [Jain, Swati] Duke Univ, Bioinformat Program, Durham, NC 27708 USA. [Donald, Bruce R.] Duke Univ, Dept Chem, Durham, NC 27708 USA. [Georgiev, Ivelin S.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Donald, BR (reprint author), Duke Univ, Med Ctr, Dept Biochem, Dept Comp Sci, Durham, NC 27708 USA. EM brd+jcb15@cs.duke.edu FU National Institutes of Health [R01-GM-78031, R01-GM073919, R01-GM073930] FX We thank all members of the Donald lab, and Prof. Jane Richardson and Prof. David Richardson for helpful discussion and comments. This work is supported by the following grants from the National Institutes of Health: R01-GM-78031 to B.R.D, R01-GM073919 and R01-GM073930 to D.C.R. NR 49 TC 1 Z9 1 U1 1 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1066-5277 EI 1557-8666 J9 J COMPUT BIOL JI J. Comput. Biol. PD JUN PY 2016 VL 23 IS 6 BP 413 EP 424 DI 10.1089/cmb.2015.0194 PG 12 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA DN9WX UT WOS:000377432500001 PM 26744898 ER PT J AU Michlmayr, D Bardina, SV Rodriguez, CA Pletnev, AG Lim, JK AF Michlmayr, Daniela Bardina, Susana V. Rodriguez, Carlos A. Pletnev, Alexander G. Lim, Jean K. TI Dual Function of Ccr5 during Langat Virus Encephalitis: Reduction in Neutrophil-Mediated Central Nervous System Inflammation and Increase in T Cell-Mediated Viral Clearance SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TICK-BORNE ENCEPHALITIS; WEST-NILE-VIRUS; CHEMOKINE RECEPTOR CCR5; JAPANESE ENCEPHALITIS; IMMUNODEFICIENT MICE; CCR5-DEFICIENT MICE; INFECTION; EXPRESSION; FLAVIVIRUSES; PATHOGENESIS AB Tick-borne encephalitis virus (TBEV) is a vector-transmitted flavivirus that causes potentially fatal neurologic infection. There are thousands of cases reported annually, and despite the availability of an effective vaccine, the incidence of TBEV is increasing worldwide. Importantly, up to 30% of affected individuals develop long-term neurologic sequelae. We investigated the role of chemokine receptor Ccr5 in a mouse model of TBEV infection using the naturally attenuated tick-borne flavivirus Langat virus (LGTV). Ccr5-deficient mice presented with an increase in viral replication within the CNS and decreased survival during LGTV encephalitis compared with wild-type controls. This enhanced susceptibility was due to the temporal lag in lymphocyte migration into the CNS. Adoptive transfer of wild-type T cells, but not Ccr5-deficient T cells, significantly improved survival outcome in LGTV-infected Ccr5-deficient mice. Concomitantly, a significant increase in neutrophil migration into the CNS in LGTV-infected Ccr5(-/-) mice was documented at the late stage of infection. Ab-mediated depletion of neutrophils in Ccr5(-/-) mice resulted in a significant improvement in mortality, a decrease in viral load, and a decrease in overall tissue damage in the CNS compared with isotype control-treated mice. Ccr5 is crucial in directing T cells toward the LGTV-infected brain, as well as in suppressing neutrophil-mediated inflammation within the CNS. C1 [Michlmayr, Daniela; Bardina, Susana V.; Rodriguez, Carlos A.; Lim, Jean K.] Icahn Sch Med Mt Sinai, Dept Microbiol, One Gustave L Levy Pl,Box 1124, New York, NY 10029 USA. [Pletnev, Alexander G.] NIAID, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Lim, JK (reprint author), Icahn Sch Med Mt Sinai, Dept Microbiol, One Gustave L Levy Pl,Box 1124, New York, NY 10029 USA. EM jean.lim@mssm.edu FU National Institute of Allergy and Infectious Diseases [R01AI108715, F31AI110071]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Institutes of Health [T32AI007647] FX This work was supported by National Institute of Allergy and Infectious Diseases Grant R01AI108715 and in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. S.V.B. was supported in part by National Institutes of Health Research Training Award T32AI007647 and National Institute of Allergy and Infectious Diseases Fellowship F31AI110071. NR 66 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2016 VL 196 IS 11 BP 4622 EP 4631 DI 10.4049/jimmunol.1502452 PG 10 WC Immunology SC Immunology GA DO3IU UT WOS:000377676000022 PM 27183602 ER PT J AU Blatt, AZ Saggu, G Kulkarni, KV Cortes, C Thurman, JM Ricklin, D Lambris, JD Valenzuela, JG Ferreira, VP AF Blatt, Adam Z. Saggu, Gurpanna Kulkarni, Koustubh V. Cortes, Claudio Thurman, Joshua M. Ricklin, Daniel Lambris, John D. Valenzuela, Jesus G. Ferreira, Viviana P. TI Properdin-Mediated C5a Production Enhances Stable Binding of Platelets to Granulocytes in Human Whole Blood SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HEMOLYTIC-UREMIC SYNDROME; COMPLEMENT ACTIVATION; FACTOR-H; TISSUE FACTOR; P-SELECTIN; POLYMORPHONUCLEAR LEUKOCYTES; LUTZOMYIA-LONGIPALPIS; ALTERNATIVE PATHWAY; SALIVARY PROTEIN; SHEAR-STRESS AB Enhanced levels of platelet/granulocyte aggregates (PGAs) are found in patients suffering from many different inflammatory vascular diseases, and their formation in animal models of vascular disease is associated with increased thromboinflammation and worsened outcomes. The complement system, a part of the innate immune system, influences PGA formation, but the mechanisms for its effects are unknown. In this study, we have defined complement-mediated mechanisms that enhance PGA formation in human whole blood stimulated with thrombin receptor-activating peptide (TRAP) using ex vivo flow cytometry assays. We demonstrate that physiological properdin, a positive regulator of complement alternative pathway activity, increases PGA formation when added to TRAP-stimulated blood. All physiological properdin forms increase PGA formation, but properdin tetramers are the most efficient at increasing complement activity and PGA formation. Inhibition of endogenous properdin, either circulating in the blood or produced locally by leukocytes, impairs TRAP-mediated PGA formation to the same level as specific inhibition of either the alternative or classical pathway. Additionally, blocking the interaction of C5a with its cellular receptor prevents properdin-mediated increases in PGA formation. Adding either properdin tetramers or C5a to whole blood increases CD11b expression on granulocytes, and this increase is prevented by blockade of the C5a-C5a receptor axis. Finally, we demonstrate that the effects of properdin on PGA formation are tightly regulated by Factor H. Cumulatively, our data indicate that properdin enhances PGA formation via increased production of C5a, and that inhibition of properdin function has therapeutic potential to limit thrombo-inflammation in diseases characterized by increased PGA formation. C1 [Blatt, Adam Z.; Saggu, Gurpanna; Kulkarni, Koustubh V.; Ferreira, Viviana P.] Univ Toledo, Coll Med & Life Sci, Dept Med Microbiol & Immunol, 3000 Arlington Ave,Mail Stop 1021, Toledo, OH 43614 USA. [Cortes, Claudio] Oakland Univ, William Beaumont Sch Med, Dept Biomed Sci, Rochester, MI 48309 USA. [Thurman, Joshua M.] Univ Colorado, Sch Med, Dept Med, Aurora, CO 80045 USA. [Ricklin, Daniel; Lambris, John D.] Univ Penn, Perelman Sch Med, Pathol & Lab Med, Philadelphia, PA 19104 USA. [Valenzuela, Jesus G.] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Ferreira, VP (reprint author), Univ Toledo, Coll Med & Life Sci, Dept Med Microbiol & Immunol, 3000 Arlington Ave,Mail Stop 1021, Toledo, OH 43614 USA. EM viviana.ferreira@utoledo.edu OI Ferreira, Viviana/0000-0001-8923-5671; Ricklin, Daniel/0000-0001-6140-0233; Cortes, Claudio/0000-0003-2870-0028 FU National Institutes of Health [R01HL112937, R01DK076690, P01AI068730]; American Heart Association [15PRE25230012] FX This work was supported by National Institutes of Health Grants R01HL112937 (to V.P.F.), R01DK076690 (to J.M.T.), and P01AI068730 (to J.D.L.), as well as by American Heart Association Predoctoral Fellowship 15PRE25230012 (to A.Z.B.). NR 76 TC 3 Z9 3 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2016 VL 196 IS 11 BP 4671 EP 4680 DI 10.4049/jimmunol.1600040 PG 10 WC Immunology SC Immunology GA DO3IU UT WOS:000377676000027 PM 27183616 ER PT J AU Payne, RO Milne, KH Elias, SC Edwards, NJ Douglas, AD Brown, RE Silk, SE Biswas, S Miura, K Roberts, R Rampling, TW Venkatraman, N Hodgson, SH Labbe, GM Halstead, FD Poulton, ID Nugent, FL de Graaf, H Sukhtankar, P Williams, NC Ockenhouse, CF Kathcart, AK Qabar, AN Waters, NC Soisson, LA Birkett, AJ Cooke, GS Faust, SN Woods, C Ivinson, K McCarthy, JS Diggs, CL Vekemans, J Long, CA Hill, AVS Lawrie, AM Dutta, S Draper, SJ AF Payne, Ruth O. Milne, Kathryn H. Elias, Sean C. Edwards, Nick J. Douglas, Alexander D. Brown, Rebecca E. Silk, Sarah E. Biswas, Sumi Miura, Kazutoyo Roberts, Rachel Rampling, Thomas W. Venkatraman, Navin Hodgson, Susanne H. Labbe, Genevieve M. Halstead, Fenella D. Poulton, Ian D. Nugent, Fay L. de Graaf, Hans Sukhtankar, Priya Williams, Nicola C. Ockenhouse, Christian F. Kathcart, April K. Qabar, Aziz N. Waters, Norman C. Soisson, Lorraine A. Birkett, Ashley J. Cooke, Graham S. Faust, Saul N. Woods, Colleen Ivinson, Karen McCarthy, James S. Diggs, Carter L. Vekemans, Johan Long, Carole A. Hill, Adrian V. S. Lawrie, Alison M. Dutta, Sheetij Draper, Simon J. TI Demonstration of the Blood-Stage Plasmodium falciparum Controlled Human Malaria Infection Model to Assess Efficacy of the P. falciparum Apical Membrane Antigen 1 Vaccine, FMP2.1/AS01 SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE malaria; AMA1; vaccine; blood stage; CHMI ID PARASITE MULTIPLICATION RATES; RANDOMIZED CONTROLLED-TRIAL; CLINICAL-TRIAL; IMMUNOGENICITY; ANTIBODY; SAFETY; SPOROZOITES; VOLUNTEERS; CHALLENGE; PROTEIN AB Background. Models of controlled human malaria infection (CHMI) initiated by mosquito bite have been widely used to assess efficacy of preerythrocytic vaccine candidates in small proof-of-concept phase 2a clinical trials. Efficacy testing of blood-stage malaria parasite vaccines, however, has generally relied on larger-scale phase 2b field trials in malaria-endemic populations. We report the use of a blood-stage P. falciparum CHMI model to assess blood-stage vaccine candidates, using their impact on the parasite multiplication rate (PMR) as the primary efficacy end point. Methods. Fifteen healthy United Kingdom adult volunteers were vaccinated with FMP2.1, a protein vaccine that is based on the 3D7 clone sequence of apical membrane antigen 1 (AMA1) and formulated in Adjuvant System 01 (AS01). Twelve vaccinees and 15 infectivity controls subsequently underwent blood-stage CHMI. Parasitemia was monitored by quantitative real-time polymerase chain reaction (PCR) analysis, and PMR was modeled from these data. Results. FMP2.1/AS01 elicited anti-AMA1 T-cell and serum antibody responses. Analysis of purified immunoglobulin G showed functional growth inhibitory activity against P. falciparum in vitro. There were no vaccine-or CHMI-related safety concerns. All volunteers developed blood-stage parasitemia, with no impact of the vaccine on PMR. Conclusions. FMP2.1/AS01 demonstrated no efficacy after blood-stage CHMI. However, the model induced highly reproducible infection in all volunteers and will accelerate proof-of-concept testing of future blood-stage vaccine candidates. C1 [Payne, Ruth O.; Milne, Kathryn H.; Elias, Sean C.; Edwards, Nick J.; Douglas, Alexander D.; Brown, Rebecca E.; Silk, Sarah E.; Biswas, Sumi; Rampling, Thomas W.; Venkatraman, Navin; Hodgson, Susanne H.; Labbe, Genevieve M.; Halstead, Fenella D.; Nugent, Fay L.; Hill, Adrian V. S.; Draper, Simon J.] Univ Oxford, Jenner Inst Labs, Oxford OX1 2JD, England. [Payne, Ruth O.; Roberts, Rachel; Rampling, Thomas W.; Venkatraman, Navin; Hodgson, Susanne H.; Poulton, Ian D.; Lawrie, Alison M.] Univ Oxford, Ctr Clin Vaccinol & Trop Med, Oxford OX1 2JD, England. [Williams, Nicola C.] Univ Oxford, Ctr Stat Med, Oxford OX1 2JD, England. [Williams, Nicola C.] Univ Oxford, Botnar Res Ctr, Oxford OX1 2JD, England. [de Graaf, Hans; Sukhtankar, Priya; Faust, Saul N.] Univ Hosp Southampton Natl Hlth Serv NHS Fdn Trus, Natl Inst Hlth Res NIHR Wellcome Trust Clin Res F, Southampton, Hants, England. [de Graaf, Hans; Sukhtankar, Priya; Faust, Saul N.] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England. [Cooke, Graham S.] Imperial Coll Healthcare NHS Trust, NIHR Wellcome Trust Clin Res Facil, London, England. [Miura, Kazutoyo; Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ockenhouse, Christian F.; Kathcart, April K.; Qabar, Aziz N.; Waters, Norman C.; Dutta, Sheetij] Walter Reed Army Inst Res, Mil Malaria Res Program, Silver Spring, MD USA. [Ockenhouse, Christian F.; Birkett, Ashley J.; Woods, Colleen; Ivinson, Karen] PATH Malaria Vaccine Initiat, Washington, DC USA. [Soisson, Lorraine A.; Diggs, Carter L.] US Agcy Int Dev, Washington, DC 20523 USA. [McCarthy, James S.] QIMR Berghofer Med Res Inst, Herston, Qld, Australia. [Vekemans, Johan] GlaxoSmithKline Vaccines, Rixensart, Belgium. RP Payne, RO (reprint author), Churchill Hosp, CCVTM, Old Rd, Oxford OX3 7LE, England. EM ruth.payne@ndm.ox.ac.uk FU PATH Malaria Vaccine Initiative (MVI), through the Infectious Disease Division, Bureau for Global Health, US Agency for International Development [GHS-A-00-04-00016-00]; National Institute of Allergy and Infectious Diseases, National Institutes of Health; United Kingdom National Institute of Health Research (NIHR) infrastructure, through the NIHR Oxford Biomedical Research Centre; United Kingdom National Institute of Health Research (NIHR) infrastructure, through Southampton NIHR Wellcome Trust Clinical Research Facility; United Kingdom National Institute of Health Research (NIHR) infrastructure, through Imperial College NIHR Wellcome Trust Clinical Research Facility; Wellcome Trust [089455/2/09/Z, 097940/Z/11/Z]; St Catherine's College, Oxford University; Nuffield Department of Medicine; Jenner Institute; Lister Institute; United Kingdom Medical Research Council (MRC); Department for International Development (DFID); EDCTP2 program; European Union (MRC) [G1000527] FX This work was supported by the PATH Malaria Vaccine Initiative (MVI), through the Infectious Disease Division, Bureau for Global Health, US Agency for International Development (under cooperative agreement GHS-A-00-04-00016-00); by the Intramural Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; by the United Kingdom National Institute of Health Research (NIHR) infrastructure, through the NIHR Oxford Biomedical Research Centre, the Southampton NIHR Wellcome Trust Clinical Research Facility, and the Imperial College NIHR Wellcome Trust Clinical Research Facility; by the Wellcome Trust (research training fellowships 089455/2/09/Z [to A. D. D.] and 097940/Z/11/Z [to S. H. H.]); by St Catherine's College, Oxford University (junior research fellowship to S. B.) and Nuffield Department of Medicine leadership fellowship (to S. B.); by the Jenner Institute (Jenner Investigator appointments to A. V. S. H. and S. J. D.); by the Lister Institute (research prize fellowship to S. J. D.); and, jointly, by the United Kingdom Medical Research Council (MRC) and Department for International Development (DFID), under the MRC/DFID Concordat agreement, and by the EDCTP2 program, supported by the European Union (MRC career development fellowship G1000527 to S. J. D.). NR 44 TC 7 Z9 7 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 1 PY 2016 VL 213 IS 11 BP 1743 EP 1751 DI 10.1093/infdis/jiw039 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DO0BC UT WOS:000377443400011 PM 26908756 ER PT J AU Aslan, H Oliveira, F Meneses, C Castrovinci, P Gomes, R Teixeira, C Derenge, CA Orandle, M Gradoni, L Oliva, G Fischer, L Valenzuela, JG Kamhawi, S AF Aslan, Hamide Oliveira, Fabiano Meneses, Claudio Castrovinci, Philip Gomes, Regis Teixeira, Clarissa Derenge, Candace A. Orandle, Marlene Gradoni, Luigi Oliva, Gaetano Fischer, Laurent Valenzuela, Jesus G. Kamhawi, Shaden TI New Insights Into the Transmissibility of Leishmania infantum From Dogs to Sand Flies: Experimental Vector-Transmission Reveals Persistent Parasite Depots at Bite Sites SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE canine leishmaniasis; Leishmania infantum; Lutzomyia longipalpis; dogs; reservoir; vector transmission; skin; bite site; infectivity; parasite-pickup ID CANINE VISCERAL LEISHMANIASIS; CUTANEOUS LEISHMANIASIS; LUTZOMYIA-LONGIPALPIS; ASYMPTOMATIC DOGS; FOLLOW-UP; SKIN; INFECTION; PROMASTIGOTES; PROTECTION; CHAGASI AB Canine leishmaniasis (CanL) is a chronic fatal disease of dogs and a major source of human infection through propagation of parasites in vectors. Here, we infected 8 beagles through multiple experimental vector transmissions with Leishmania infantum-infected Lutzomyia longipalpis. CanL clinical signs varied, although live parasites were recovered from all dog spleens. Splenic parasite burdens correlated positively with Leishmania-specific interleukin 10 levels, negatively with Leishmania-specific interferon gamma and interleukin 2 levels, and negatively with Leishmania skin test reactivity. A key finding was parasite persistence for 6 months in lesions observed at the bite sites in all dogs. These recrudesced following a second transmission performed at a distal site. Notably, sand flies efficiently acquired parasites after feeding on lesions at the primary bite site. In this study, controlled vector transmissions identify a potentially unappreciated role for skin at infectious bite sites in dogs with CanL, providing a new perspective regarding the mechanism of Leishmania transmissibility to vector sand flies. C1 [Aslan, Hamide; Oliveira, Fabiano; Meneses, Claudio; Castrovinci, Philip; Gomes, Regis; Teixeira, Clarissa; Derenge, Candace A.; Valenzuela, Jesus G.; Kamhawi, Shaden] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rm 2E-32D,12735 Twinbrook Pkwy, Rockville, MD 20852 USA. [Orandle, Marlene] NIAID, Comparat Med Branch, NIH, Rockville, MD 20852 USA. [Aslan, Hamide] Selahaddin Eyyubi Univ, Fac Hlth Sci, Diyarbakir, Turkey. [Gomes, Regis; Teixeira, Clarissa] Fundacao Oswaldo Cruz, Escritorio Reg Fiocruz Piau, Teresina, Brazil. [Gradoni, Luigi] Ist Super Sanita, Unit Vector Borne Dis & Int Hlth, Viale Regina Elena 299, I-00161 Rome, Italy. [Oliva, Gaetano] Univ Naples Federico II, Dept Vet Med & Anim Prod, Naples, Italy. [Fischer, Laurent] Merial SAS, R&D, Lab Lyon Gerland, Lyon, France. RP Kamhawi, S (reprint author), NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rm 2E-32D,12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM skamhawi@niaid.nih.gov FU Division of Intramural Research, NIAID, National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Intramural Research, NIAID, National Institutes of Health. NR 45 TC 4 Z9 4 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 1 PY 2016 VL 213 IS 11 BP 1752 EP 1761 DI 10.1093/infdis/jiw022 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DO0BC UT WOS:000377443400012 PM 26768257 ER PT J AU Hotaling, NA Khristov, V Wan, Q Sharma, R Jha, BS Lotfi, M Maminishkis, A Simon, CG Bharti, K AF Hotaling, Nathan A. Khristov, Vladimir Wan, Qin Sharma, Ruchi Jha, Balendu Shekhar Lotfi, Mostafa Maminishkis, Arvydas Simon, Carl G., Jr. Bharti, Kapil TI Nanofiber Scaffold-Based Tissue-Engineered Retinal Pigment Epithelium to Treat Degenerative Eye Diseases SO JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS LA English DT Review ID HUMAN BRUCHS MEMBRANE; POLY(LACTIC ACID) FIBER; PLURIPOTENT STEM-CELLS; IN-VITRO DEGRADATION; AMNIOTIC MEMBRANE; SUBRETINAL SPACE; POLY(EPSILON-CAPROLACTONE) NANOFIBERS; ELECTROSPUN SCAFFOLDS; MACULAR DEGENERATION; FLUID TRANSPORT AB Clinical-grade manufacturing of a functional retinal pigment epithelium (RPE) monolayer requires reproducing, as closely as possible, the natural environment in which RPE grows. In vitro, this can be achieved by a tissue engineering approach, in which the RPE is grown on a nanofibrous biological or synthetic scaffold. Recent research has shown that nanofiber scaffolds perform better for cell growth and transplantability compared with their membrane counterparts and that the success of the scaffold in promoting cell growth/function is not heavily material dependent. With these strides, the field has advanced enough to begin to consider implementation of one, or a combination, of the tissue engineering strategies discussed herein. In this study, we review the current state of tissue engineering research for in vitro culture of RPE/scaffolds and the parameters for optimal scaffold design that have been uncovered during this research. Next, we discuss production methods and manufacturers that are capable of producing the nanofiber scaffolds in such a way that would be biologically, regulatory, clinically, and commercially viable. Then, a discussion of how the scaffolds could be characterized, both morphologically and mechanically, to develop a testing process that is viable for regulatory screening is performed. Finally, an example of a tissue-engineered RPE/scaffold construct is given to provide the reader a framework for understanding how these pieces could fit together to develop a tissue-engineered RPE/scaffold construct that could pass regulatory scrutiny and can be commercially successful. C1 [Hotaling, Nathan A.; Simon, Carl G., Jr.] Natl Inst Stand & Technol, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA. [Hotaling, Nathan A.; Sharma, Ruchi; Jha, Balendu Shekhar; Bharti, Kapil] NEI, Unit Ocular & Stem Cell Translat Res, NIH, 10 Ctr Dr,Bldg 10,Room 10B10, Bethesda, MD 20892 USA. [Khristov, Vladimir; Wan, Qin; Lotfi, Mostafa; Maminishkis, Arvydas] NEI, Sect Epithelial & Retinal Physiol & Dis, NIH, Bethesda, MD 20892 USA. RP Hotaling, NA; Bharti, K (reprint author), NEI, Unit Ocular & Stem Cell Translat Res, NIH, 10 Ctr Dr,Bldg 10,Room 10B10, Bethesda, MD 20892 USA. EM nathan.Hotaling@nih.gov; kapilbharti@nei.nih.gov OI Hotaling, Nathan/0000-0001-8423-6464 FU NEI Intramural Funds; NIH CRM; NIH FX This work was, in part, supported by NEI Intramural Funds, NIH CRM, and NIH Common Fund grants to K. Bharti. The authors would like to thank Kiel Gramley from FibeRio Technology Corporation for giving the SEM image of melt spun fibers in Fig. 3C. This article, a contribution of NIST, is not subject to US copyright. Certain equipment and instruments or materials are identified in the article to adequately specify nanofiber production capabilities. Such identification does not imply recommendation by NIH/NIST, nor does it imply that the materials are necessarily the best available for the purpose. NR 129 TC 1 Z9 1 U1 6 U2 9 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1080-7683 EI 1557-7732 J9 J OCUL PHARMACOL TH JI J. Ocular Pharmacol. Ther. PD JUN PY 2016 VL 32 IS 5 SI SI BP 272 EP 285 DI 10.1089/jop.2015.0157 PG 14 WC Ophthalmology; Pharmacology & Pharmacy SC Ophthalmology; Pharmacology & Pharmacy GA DN9KW UT WOS:000377399500006 PM 27110730 ER PT J AU Gadow, KD Brown, NV Arnold, LE Buchan-Page, KA Bukstein, OG Butter, E Farmer, CA Findling, RL Kolko, DJ Molina, BSG Rice, RR Schneider, J Aman, MG AF Gadow, Kenneth D. Brown, Nicole V. Arnold, L. Eugene Buchan-Page, Kristin A. Bukstein, Oscar G. Butter, Eric Farmer, Cristan A. Findling, Robert L. Kolko, David J. Molina, Brooke S. G. Rice, Robert R., Jr. Schneider, Jayne Aman, Michael G. TI Severely Aggressive Children Receiving Stimulant Medication Versus Stimulant and Risperidone: 12-Month Follow-Up of the TOSCA Trial SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE ADHD; oppositional defiant disorder; conduct disorder; risperidone; methylphenidate ID OPPOSITIONAL DEFIANT DISORDER; MULTIPLE TIC DISORDER; DEFICIT/HYPERACTIVITY DISORDER; RATING-SCALE; ADHD; METHYLPHENIDATE; METAANALYSIS AB Objective: The objective of this study was to evaluate 52-week clinical outcomes of children with co-occurring attention-deficit/hyperactivity disorder (ADHD), disruptive behavior disorder, and serious physical aggression who participated in a prospective, longitudinal study that began with a controlled, 9-week clinical trial comparing the relative efficacy of parent training + stimulant medication + placebo (Basic; n = 84) versus parent training + stimulant + risperidone (Augmented; n = 84). Method: Almost two-thirds (n = 7.08; 64%) of families in the 9-week study participated in week 52 follow-ups (Basic, n = 55; Augmented, n = 53) and were representative of the initial study sample. The assessment battery included caregiver and clinician ratings and laboratory tests. Results: Only 43% of participants in the Augmented group and 36% in the Basic group still adhered to their assigned regimen (not significant [NS]); 23% of those in the Augmented group and 11% in the Basic group were taking no medication (NS). Both randomized groups improved baseline to follow-up, but the 3 primary parent reported behavioral outcomes showed no significant between-group differences. Exploratory analyses indicated that participants in the Augmented group (65%) were more likely (p =.02) to have a Clinical Global Impressions (CGI) severity score of 1 to 3 (i.e., normal to mildly ill) at follow-up than those in the Basic group (42%). Parents rated 45% of children as impaired often or very often from ADHD, noncompliant, or aggressive behavior. The Augmented group had elevated prolactin levels, and the Basic group had decreased weight over time. Findings were generally similar whether groups were defined by randomized assignment or follow-up treatment status. Conclusion: Both treatment strategies were associated with clinical improvement at follow-up, and primary behavioral outcomes did not differ significantly. Many children evidenced lingering mental health concerns, suggesting the need for additional research into more effective interventions. C1 [Gadow, Kenneth D.; Schneider, Jayne] SUNY Stony Brook, Level 10,Room 041 F, Stony Brook, NY 11794 USA. [Brown, Nicole V.] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA. [Arnold, L. Eugene; Buchan-Page, Kristin A.; Butter, Eric; Rice, Robert R., Jr.; Aman, Michael G.] Ohio State Univ, Nisonger Ctr, Columbus, OH 43210 USA. [Farmer, Cristan A.] NIMH, Nisonger Ctr, Bethesda, MD 20892 USA. [Farmer, Cristan A.] NIMH, Pediat & Dev Neurosci Branch, Bethesda, MD 20892 USA. [Bukstein, Oscar G.; Kolko, David J.; Molina, Brooke S. G.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Bukstein, Oscar G.] Boston Childrens Hosp, Boston, MA USA. [Bukstein, Oscar G.] Harvard Univ, Med Sch, Cambridge, MA 02138 USA. [Findling, Robert L.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Findling, Robert L.] Johns Hopkins Univ, Kennedy Krieger Inst, Baltimore, MD USA. RP Gadow, KD (reprint author), SUNY Stony Brook, Ctr Understanding Biol Using Imaging Technol CUBI, Dept Psychiat, Hlth Sci Ctr T 10, Level 10,Room 041 F, Stony Brook, NY 11794 USA. EM kennethgadow@stonybrook.edu FU NIMH [R01 MH077907]; Case Western Reserve University [R01 MH077750]; University of Pittsburgh [R01 MH077676]; Stony Brook University [R01MH 077997]; National Institutes of Health (NIH) General Clinical Research Center grant [M01RR10710]; Clinical and Translational Science Awards from the National Center for Advancing Translational Sciences [8UL1TR000090-05, UL1 RR024153, UL1 TR000005] FX This study was supported by grants from NIMH to The Ohio State University (R01 MH077907), Case Western Reserve University (R01 MH077750), the University of Pittsburgh (R01 MH077676), and Stony Brook University (R01MH 077997) The project was supported by a National Institutes of Health (NIH) General Clinical Research Center grant M01RR10710 (Stony Brook University) and Clinical and Translational Science Awards from the National Center for Advancing Translational Sciences: grants 8UL1TR000090-05 (The Ohio State University) and UL1 RR024153 and UL1 TR000005 (University of Pittsburgh). NR 23 TC 4 Z9 4 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JUN PY 2016 VL 55 IS 6 BP 469 EP 478 DI 10.1016/j.jaac.2016.03.014 PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DN9TT UT WOS:000377424300006 PM 27238065 ER PT J AU Beijers, RJHCG van den Borst, B Newman, AB Yende, S Kritchevsky, SB Cassano, PA Bauer, DC Harris, TB Schols, AMWJ AF Beijers, Rosanne J. H. C. G. van den Borst, Bram Newman, Anne B. Yende, Sachin Kritchevsky, Stephen B. Cassano, Patricia A. Bauer, Douglas C. Harris, Tamara B. Schols, Annemie M. W. J. CA Hlth ABC Study TI A Multidimensional Risk Score to Predict All-Cause Hospitalization in Community-Dwelling Older Individuals With Obstructive Lung Disease SO JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION LA English DT Article DE COPD; pulmonary disease; older age persons; Cox proportional hazards modeling ID PULMONARY-DISEASE; PHYSICAL-ACTIVITY; RANDOMIZED-TRIAL; ELDERLY SUBJECTS; COPD; MORTALITY; PERFORMANCE; COMORBIDITIES; POPULATION; TIOTROPIUM AB Background: Both respiratory and nonrespiratory hospitalizations are common and costly events in older individuals with obstructive lung disease. Prevention of any hospitalization in these individuals is essential. We aimed to construct a prediction model for all-cause hospitalization risk in community-dwelling older individuals with obstructive lung disease. Methods: We studied 268 community-dwelling individuals with obstructive lung disease (defined as FEV1/FVC0.7 to r<0.85), and 3 (20%) high correlation (r >= 0.85) with survival. Conclusions: The use of surrogate end points for drug approval often lacks formal empirical verification of the strength of the surrogate-survival association. (C) 2016 Mayo Foundation for Medical Education and Research C1 [Kim, Chul] NCI, Med Oncol Serv, NIH, Bethesda, MD 20892 USA. [Prasad, Vinay] Oregon Hlth & Sci Univ, Knight Canc Inst, Div Hematol Oncol, Portland, OR 97201 USA. RP Prasad, V (reprint author), Oregon Hlth & Sci Univ, Knight Canc Inst, Div Hematol Oncol, Med, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM prasad@ohsu.edu NR 77 TC 4 Z9 4 U1 1 U2 5 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 JUN PY 2016 VL 91 IS 6 BP 713 EP 725 DI 10.1016/j.mayocp.2016.02.012 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA DN8CG UT WOS:000377306200009 ER PT J AU Shapiro, E Bernstein, J Adams, HR Barbier, AJ Buracchio, T Como, P Delaney, KA Eichler, F Goldsmith, JC Hogan, M Kovacs, S Mink, JW Odenkirchen, J Parisi, MA Skrinar, A Waisbren, SE Mulberg, AE AF Shapiro, Elsa Bernstein, Jessica Adams, Heather R. Barbier, Ann J. Buracchio, Teresa Como, Peter Delaney, Kathleen A. Eichler, Florian Goldsmith, Jonathan C. Hogan, Melissa Kovacs, Sarrit Mink, Jonathan W. Odenkirchen, Joanne Parisi, Melissa A. Skrinar, Alison Waisbren, Susan E. Mulberg, Andrew E. TI Neurocognitive clinical outcome assessments for inborn errors of metabolism and other rare conditions SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Inborn errors; Neurocognitive; Clinical outcome assessment; Natural history studies; Rare diseases; Drug development ID LIPOFUSCINOSIS BATTEN-DISEASE; RATING-SCALE; TRIALS AB Well-defined and reliable clinical outcome assessments are essential for determining whether a drug provides clinically meaningful treatment benefit for patients. In 2015, FDA convened a workshop, "Assessing Neurocognitive Outcomes in Inborn Errors of Metabolism." Topics covered included special challenges of clinical studies of inborn errors of metabolism (IEMs) and other rare diseases; complexities of identifying treatment effects in the context of the dynamic processes of child development and disease progression; and the importance of natural history studies. Clinicians, parents/caregivers, and participants from industry, academia, and government discussed factors to consider when developing measures to assess treatment outcomes, as well as tools and methods that may contribute to standardizing measures. Many issues examined are relevant to the broader field of rare diseases in addition to specifics of IEMs. Published by Elsevier Inc. C1 [Shapiro, Elsa; Delaney, Kathleen A.] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. [Shapiro, Elsa; Delaney, Kathleen A.] Shapiro & Delaney LLC, Mendota Hts, MN USA. [Bernstein, Jessica; Buracchio, Teresa; Goldsmith, Jonathan C.; Kovacs, Sarrit; Mulberg, Andrew E.] US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Adams, Heather R.; Mink, Jonathan W.] Univ Rochester, Med Ctr, Dept Neurol, Div Child Neurol, Rochester, NY 14642 USA. [Barbier, Ann J.] Shire, Lexington, MA USA. [Como, Peter] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Eichler, Florian] Harvard Univ, Sch Med, Dept Neurol, Ctr Rare Neurol Dis,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Hogan, Melissa] Saving Case & Friends Inc, Thompsons Stn, TN USA. [Odenkirchen, Joanne] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Parisi, Melissa A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Skrinar, Alison] Ultragenyx Pharmaceut Inc, Clin Outcomes Res & Evaluat, Novato, CA USA. [Waisbren, Susan E.] Harvard Univ, Sch Med, Metab Program, Div Genet & Genom,Boston Childrens Hosp, Boston, MA 02115 USA. [Barbier, Ann J.] Agios Pharmaceut, Cambridge, MA USA. RP Bernstein, J (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM shapi004@umn.edu; jessica.bemstein@fda.hhs.gov; Heather_Adams@URMC.Rochester.edu; annjbarbier@aol.com; teresa.buracchio@fda.hhs.gov; peter.como@fda.hhs.gov; kate.delaney@shapiroanddelaney.com; feichler@partners.org; jonathan.goldsmith@fda.hhs.gov; melissa@savingcase.com; sarrit.kovacs@fda.hhs.gov; Jonathan_Mink@URMC.Rochester.edu; jo21x@nih.gov; parisima@mail.nih.gov; ASkrinar@ultragenyx.com; Susan.Waisbren@childrens.harvard.edu; andrew.mulberg@fda.hhs.gov OI Hogan, Melissa/0000-0003-1249-2164; Shapiro, Elsa/0000-0003-0276-0276 FU NICHD NIH HHS [U54 HD061221] NR 14 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUN PY 2016 VL 118 IS 2 BP 65 EP 69 DI 10.1016/j.ymgme.2016.04.006 PG 5 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA DN9TJ UT WOS:000377423300001 PM 27132782 ER PT J AU Champaigne, NL Leroy, JG Kishnani, PS Decaestecker, J Steenkiste, E Chaubey, A Li, JR Verslype, C Van Dorpe, J Pollard, L Goldstein, JL Libbrecht, L Basehore, M Chen, NS Hu, HP Wood, T Friez, MJ Huizing, M Stevenson, RE AF Champaigne, Neena L. Leroy, Jules G. Kishnani, Priya S. Decaestecker, Jochen Steenkiste, Edwin Chaubey, Alka Li, Jiarui Verslype, Chris Van Dorpe, Jo Pollard, Laura Goldstein, Jennifer L. Libbrecht, Louis Basehore, Monica Chen, Nansheng Hu, Heping Wood, Tim Friez, Michael J. Huizing, Marjan Stevenson, Roger E. TI New observation of sialuria prompts detection of liver tumor in previously reported patient SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Sialuria; Sialic acids; UDP acetylglucosamine-2-epimerase; Hepatomegaly; Intrahepatic cholangiocarcinoma ID INTRAHEPATIC CHOLANGIOCARCINOMA; GLYCOSYLATION; 2-EPIMERASE; DISEASE AB Sialuria, a rare inborn error of metabolism, was diagnosed in a healthy 12-year-old boy through whole exome sequencing. The patient had experienced mild delays of speech and motor development, as well as persistent hepatomegaly. Identification of the 8th individual with this disorder, prompted follow-up of the mother-son pair of patients diagnosed over 15 years ago. Hepatomegaly was confirmed in the now 19-year-old son, but in the 46-year-old mother a clinically silent liver tumor was detected by ultrasound and MRI. The tumor was characterized as an intrahepatic cholangiocarcinoma (IHCC) and DNA analysis of both tumor and normal liver tissue confirmed the original GNE mutation. As the maternal grandmother in the latter family died at age 49 years of a liver tumor, a retrospective study of the remaining pathology slides was conducted and confirmed it to have been an IHCC as well. The overall observation generated the hypothesis that sialuria may predispose to development of this form of liver cancer. As proof of sialuria in the grandmother could not be obtained, an alternate cause of IHCC cannot be ruled out. In a series of 102 patients with IHCC, not a single instance was found with the allosteric site mutation in the GNE gene. This confirms that sialuria is rare even in a selected group of patients, but does not invalidate the concern that sialuria may be a risk factor for IHCC Synopsis: Sialuria is a rare inborn error of metabolism characterized by excessive synthesis and urinary excretion of free sialic acid with only minimal clinical morbidity in early childhood, but may be a risk factor for intrahepatic cholangiocarcinoma in adulthood. (C) 2016 Elsevier Inc All rights reserved. C1 [Champaigne, Neena L.; Leroy, Jules G.; Chaubey, Alka; Pollard, Laura; Basehore, Monica; Wood, Tim; Friez, Michael J.; Stevenson, Roger E.] Greenwood Genet Ctr, 106 Gregor Mendel Circle, Greenwood, SC 29646 USA. [Kishnani, Priya S.; Goldstein, Jennifer L.] Duke Univ, Med Ctr, Div Med Genet, Durham, NC USA. [Decaestecker, Jochen; Steenkiste, Edwin] Delta Gen Hosp, Dept Gastroenterol & Hepatol, Dept Pathol, Roeselare, Belgium. [Li, Jiarui; Chen, Nansheng] Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC V5A 1S6, Canada. [Verslype, Chris] Univ Hosp Leuven, Dept Hepatol, Leuven, Belgium. [Van Dorpe, Jo; Libbrecht, Louis] Ghent Univ Hosp, Sch Med, N Goormaghtigh Inst Pathol, Ghent, Belgium. [Hu, Heping] Second Mil Med Univ, Dept Hepatobiliary Med, Eastern Hepatobiliary Surg Hosp, Shanghai, Peoples R China. [Huizing, Marjan] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Champaigne, NL (reprint author), Greenwood Genet Ctr, 106 Gregor Mendel Circle, Greenwood, SC 29646 USA. EM neena@ggc.org NR 22 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUN PY 2016 VL 118 IS 2 BP 92 EP 99 DI 10.1016/j.ymgme.2016.04.004 PG 8 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA DN9TJ UT WOS:000377423300005 PM 27142465 ER PT J AU Hanson, RL Leti, F Tsinajinnie, D Kobes, S Puppala, S Curran, JE Almasy, L Lehman, DM Blangero, J Duggirala, R DiStefano, JK AF Hanson, Robert L. Leti, Fatjon Tsinajinnie, Darwin Kobes, Sayuko Puppala, Sobha Curran, Joanne E. Almasy, Laura Lehman, Donna M. Blangero, John Duggirala, Ravindranath DiStefano, Johanna K. TI The Arg59Trp variant in ANGPTL8 (betatrophin) is associated with total and HDL-cholesterol in American Indians and Mexican Americans and differentially affects cleavage of ANGPTL3 SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Cholesterol; Diabetes; Dyslipidemias; Genetics; HDL; Lipasin; Betatrophin; RIFL; C19ORF80; LOC55908 ID GENOME-WIDE ASSOCIATION; ANGIOPOIETIN-LIKE PROTEIN; QUANTITATIVE LIPID TRAITS; TOTAL SERUM-CHOLESTEROL; CORONARY-HEART-DISEASE; CASSETTE TRANSPORTER 1; LIPOPROTEIN-LIPASE; AFRICAN-AMERICANS; TANGIER-DISEASE; RISK-FACTORS AB We previously identified a locus linked to total cholesterol (TC) concentration in Pima Indians on chromosome 19p. To characterize this locus, we genotyped >2000 SNPs in 1838 Pimas and assessed association with log(TC). We observed evidence for association with log(TC) with rs2278426 (3.5% decrease/copy of the T allele; P = 5.045 x 10(-6)) in the ANGPTL8 (angiopoietin-like 8) gene. We replicated this association in 2413 participants of the San Antonio Mexican American Family Study (SAMAFS: 2.0% decrease per copy of the T allele; P = 0.005842). In a meta-analysis of the combined data, we found the strongest estimated effect with rs2278426 (P = 2.563 x 10(-7)). The variant T allele at rs2278426 predicts an Arg59Trp substitution and has previously been associated with LDL-C and HDL-C. In Pimas and SAMAFS participants, the T allele of rs2278426 was associated with reduced HDL-C levels (P = 0.000741 and 0.00002, respectively), and the combined estimated effect for the two cohorts was -3.8% (P = 8.526 x 10(-8)). ANGPTL8 transcript and protein levels increased in response to both glucose and insulin. The variant allele was associated with increased levels of cleaved ANGPTL3. We conclude that individuals with the variant allele may have lower TC and HDL-C levels due to increased activation of ANGPTL3 by ANGPTL8. (C) 2016 Elsevier Inc. All rights reserved. C1 [Hanson, Robert L.; Kobes, Sayuko] NIDDK, Diabet Epidemiol & Clin Res Sect, NIH, 1550 East Indian Sch Rd, Phoenix, AZ 85014 USA. [Leti, Fatjon; DiStefano, Johanna K.] Natl Jewish Hlth, Ctr Genes Environm & Hlth, Dept Biomed Res, 1400 Jackson St, Denver, CO 80206 USA. [Tsinajinnie, Darwin; DiStefano, Johanna K.] Translat Genom Res Inst, Diabet Cardiovasc & Metab Dis Div, 445 Fifth St, Phoenix, AZ 85004 USA. [Puppala, Sobha; Curran, Joanne E.; Almasy, Laura; Blangero, John; Duggirala, Ravindranath] Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Brownsville, TX 78520 USA. [Puppala, Sobha; Curran, Joanne E.; Almasy, Laura; Blangero, John; Duggirala, Ravindranath] 1214 W Schunior St, Edinburg, TX 78541 USA. [Puppala, Sobha; Curran, Joanne E.; Almasy, Laura; Blangero, John; Duggirala, Ravindranath] 3463 Mag Dr, San Antonio, TX 78229 USA. [Lehman, Donna M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. [Lehman, Donna M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. RP DiStefano, JK (reprint author), Natl Jewish Hlth, Ctr Genes Environm & Hlth, Dept Biomed Res, 1400 Jackson St, Denver, CO 80206 USA. EM distefanoj@njhealth.org FU NHLBI NIH HHS [R01 HL093042, R01 HL084439]; NIDDK NIH HHS [R01 DK047482, R01 DK053889] NR 69 TC 1 Z9 1 U1 3 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUN PY 2016 VL 118 IS 2 BP 128 EP 137 DI 10.1016/j.ymgme.2016.04.007 PG 10 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA DN9TJ UT WOS:000377423300009 PM 27117576 ER PT J AU Lowy, D Singer, D DePinho, R Simon, GC Soon-Shiong, P AF Lowy, Douglas Singer, Dinah DePinho, Ron Simon, Gregory C. Soon-Shiong, Patrick TI Cancer moonshot countdown SO NATURE BIOTECHNOLOGY LA English DT Article C1 [Lowy, Douglas; Singer, Dinah] NCI, Div Canc Biol, Bethesda, MD 20892 USA. [DePinho, Ron] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. [Simon, Gregory C.] White House Canc Task Force, Washington, DC USA. [Soon-Shiong, Patrick] NantWorks LLC, Culver City, CA USA. RP Lowy, D (reprint author), NCI, Div Canc Biol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JUN PY 2016 VL 34 IS 6 BP 596 EP 599 PG 4 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DO5TT UT WOS:000377846400021 PM 27281415 ER PT J AU Thomas, E Liang, TJ AF Thomas, Emmanuel Liang, T. Jake TI Experimental models of hepatitis B and C - new insights and progress SO NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY LA English DT Review ID HEPATOMA-CELL LINE; PRIMARY HUMAN HEPATOCYTES; ADULT HUMAN HEPATOCYTES; INNATE IMMUNE-RESPONSE; IN-VITRO INFECTION; VIRUS GENOTYPE 3A; NON-A; LIVER-CELLS; EFFICIENT REPLICATION; DRUG-METABOLISM AB Viral hepatitis is a major cause of morbidity and mortality, affecting hundreds of millions of people worldwide. Hepatitis-causing viruses initiate disease by establishing both acute and chronic infections, and several of these viruses are specifically associated with the development of hepatocellular carcinoma. Consequently, intense research efforts have been focusing on increasing our understanding of hepatitis virus biology and on improving antiviral therapy and vaccination strategies. Although valuable information on viral hepatitis emerged from careful epidemiological studies on sporadic outbreaks in humans, experimental models using cell culture, rodent and non-human primates were essential in advancing the field. Through the use of these experimental models, improvement in both the treatment and prevention of viral hepatitis has progressed rapidly; however, agents of viral hepatitis are still among the most common pathogens infecting humans. In this Review, we describe the important part that these experimental models have played in the study of viral hepatitis and led to monumental advances in our understanding and treatment of these pathogens. Ongoing developments in experimental models are also described. C1 [Thomas, Emmanuel] Schiff Ctr Liver Dis, Room PAP514,Papanicolaou Bldg,1550 NW 10th Ave, Miami, FL 33136 USA. [Thomas, Emmanuel] Sylvester Canc Ctr, Room PAP514,Papanicolaou Bldg,1550 NW 10th Ave, Miami, FL 33136 USA. [Liang, T. Jake] NIH, Liver Dis Branch, Bldg 10-9B16, Bethesda, MD 20892 USA. RP Liang, TJ (reprint author), NIH, Liver Dis Branch, Bldg 10-9B16, Bethesda, MD 20892 USA. EM jliang@nih.gov FU Miami Center for AIDS Research, Leonard M. Miller School of Medicine, USA [P30AI073961]; Miami CTSI KL2 program FX E.T. acknowledges funding support from the Miami Center for AIDS Research, Leonard M. Miller School of Medicine, USA (P30AI073961) and a the Miami CTSI KL2 program. NR 170 TC 1 Z9 1 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5045 EI 1759-5053 J9 NAT REV GASTRO HEPAT JI Nat. Rev. Gastroenterol. Hepatol. PD JUN PY 2016 VL 13 IS 6 BP 362 EP 374 DI 10.1038/nrgastro.2016.37 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DO0SB UT WOS:000377487500008 PM 27075261 ER PT J AU Devaiah, BN Case-Borden, C Gegonne, A Hsu, CH Chen, QR Meerzaman, D Dey, A Ozato, K Singer, DS AF Devaiah, Ballachanda N. Case-Borden, Chanelle Gegonne, Anne Hsu, Chih Hao Chen, Qingrong Meerzaman, Daoud Dey, Anup Ozato, Keiko Singer, Dinah S. TI BRD4 is a histone acetyltransferase that evicts nucleosomes from chromatin SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID BROMODOMAIN PROTEIN BRD4; ACETYLATED CHROMATIN; SELECTIVE-INHIBITION; LATERAL SURFACE; TERMINAL DOMAIN; TRANSCRIPTION; PHOSPHORYLATION; BOOKMARKING; CHROMOSOMES; EXPRESSION AB Bromodomain protein 4 (BRD4) is a chromatin-binding protein implicated in cancer and autoimmune diseases that functions as a scaffold for transcription factors at promoters and super-enhancers. Although chromatin decompaction and transcriptional activation of target genes are associated with BRD4 binding, the mechanisms involved are unknown. We report that BRD4 is a histone acetyltransferase (HAT) that acetylates histones H3 and H4 with a pattern distinct from those of other HATs. Both mouse and human BRD4 have intrinsic HAT activity. Importantly, BRD4 acetylates H3 K122, a residue critical for nucleosome stability, thus resulting in nucleosome eviction and chromatin decompaction. Nucleosome clearance by BRD4 occurs genome wide, including at its targets MYC, FOS and AURKB (Aurora B kinase), resulting in increased transcription. These findings suggest a model wherein BRD4 actively links chromatin structure and transcription: it mediates chromatin decompaction by acetylating and evicting nucleosomes at target genes, thereby activating transcription. C1 [Devaiah, Ballachanda N.; Case-Borden, Chanelle; Gegonne, Anne; Singer, Dinah S.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Hsu, Chih Hao; Chen, Qingrong; Meerzaman, Daoud] NCI, Ctr Biomed Informat & Informat Technol, NIH, Bethesda, MD 20892 USA. [Dey, Anup; Ozato, Keiko] NICHD, Lab Mol Growth Regulat, NIH, Bethesda, MD USA. RP Singer, DS (reprint author), NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. EM dinah.singer@nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank D. Levens, E. Harlow, R. Sen and L. Staudt for critical reading of the manuscript and members of the Singer laboratory for discussions. We are especially grateful to K. Placek and K. Zhao for their technical assistance with the RNA-seq experiments. We thank M. Zhou for the mass spectrometry analysis and the NIH CIT/Biowulf cluster used in the analyses of the ChIP-seq data. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 37 TC 12 Z9 12 U1 3 U2 9 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 JUN PY 2016 VL 23 IS 6 BP 540 EP 548 DI 10.1038/nsmb.3228 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DN9SU UT WOS:000377421800016 PM 27159561 ER PT J AU Liao, J Marinelli, F Lee, C Huang, YH Faraldo-Gomez, JD Jiang, YX AF Liao, Jun Marinelli, Fabrizio Lee, Changkeun Huang, Yihe Faraldo-Gomez, Jose D. Jiang, Youxing TI Mechanism of extracellular ion exchange and binding-site occlusion in a sodium/calcium exchanger SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID SODIUM-CALCIUM EXCHANGE; SARCOLEMMAL NA+-CA2+ EXCHANGER; CARDIAC NA+/CA2+ EXCHANGER; STRUCTURAL BASIS; SQUID AXONS; TRANSPORT; CA2+; NA; STOICHIOMETRY; RESIDUES AB Na+/Ca2+ exchangers use the Na+ electrochemical gradient across the plasma membrane to extrude intracellular Ca2+ and play a central role in Ca2+ homeostasis. Here, we elucidate their mechanisms of extracellular ion recognition and exchange through a structural analysis of the exchanger from Methanococcus jannaschii (NCX_Mj) bound to Na+, Ca2+ or Sr2+ in various occupancies and in an apo state. This analysis defines the binding mode and relative affinity of these ions, establishes the structural basis for the anticipated 3:1 Na+/Ca2+-exchange stoichiometry and reveals the conformational changes at the onset of the alternating-access transport mechanism. An independent analysis of the dynamics and conformational free-energy landscape of NCX_Mj in different ion-occupancy states, based on enhanced-sampling molecular dynamics simulations, demonstrates that the crystal structures reflect mechanistically relevant, interconverting conformations. These calculations also reveal the mechanism by which the outward-to inward transition is controlled by the ion occupancy, thereby explaining the emergence of strictly coupled Na+/Ca2+ antiport. C1 [Liao, Jun] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China. [Marinelli, Fabrizio; Faraldo-Gomez, Jose D.] NHLBI, Theoret Mol Biophys Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. [Lee, Changkeun; Huang, Yihe; Jiang, Youxing] Univ Texas SW Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA. [Lee, Changkeun; Jiang, Youxing] Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA. RP Liao, J (reprint author), ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China.; Faraldo-Gomez, JD (reprint author), NHLBI, Theoret Mol Biophys Sect, NIH, Bldg 10, Bethesda, MD 20892 USA.; Jiang, YX (reprint author), Univ Texas SW Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA.; Jiang, YX (reprint author), Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA. EM liaojun@shanghaitech.edu.cn; jose.faraldo@nih.gov; youxing.jiang@utsouthwestern.edu FU US Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]; Howard Hughes Medical Institute; National Institutes of Health [R01GM079179]; Welch Foundation [I-1578]; General Program of the National Natural Science Foundation of China [31470817]; Division of Intramural Research of the National Heart, Lung and Blood Institute, National Institutes of Health FX The experimental results reported in this article derive from measurements made at the Advanced Photon Source of the Argonne National Laboratory, GM/CA (23ID), which is operated by the University of Chicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research, under contract DE-AC02-06CH11357. We thank the beamline staff for their assistance in data collection. This work was supported in part by the Howard Hughes Medical Institute; by grants from the National Institutes of Health (R01GM079179 to Y.J.) and the Welch Foundation (grant I-1578 to Y.J.); by the General Program of the National Natural Science Foundation of China (project 31470817 to J.L.); and by the Division of Intramural Research of the National Heart, Lung and Blood Institute, National Institutes of Health (to F.M. and J.D.F.-G.). NR 35 TC 2 Z9 2 U1 9 U2 9 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 JUN PY 2016 VL 23 IS 6 BP 590 EP 599 DI 10.1038/nsmb.3230 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DN9SU UT WOS:000377421800022 PM 27183196 ER PT J AU Su, TC Lin, SH Lee, PT Yeh, SH Hsieh, TH Chou, SY Su, TP Hung, JJ Chang, WC Lee, YC Chuang, JY AF Su, Tzu-Chieh Lin, Shu-Hui Lee, Pin-Tse Yeh, Shiu-Hwa Hsieh, Tsun-Hsun Chou, Szu-Yi Su, Tsun-Ping Hung, Jan-Jong Chang, Wen-Chang Lee, Yi-Chao Chuang, Jian-Ying TI The sigma-1 receptor-zinc finger protein 179 pathway protects against hydrogen peroxide-induced cell injury SO NEUROPHARMACOLOGY LA English DT Article DE Sig-1R; Znf179; DHEA/DHEAS; Reactive oxygen species; Hydrogen peroxide ID TRAUMATIC BRAIN-INJURY; NEURODEGENERATIVE DISEASES; OXIDATIVE STRESS; DEHYDROEPIANDROSTERONE DHEA; ALZHEIMERS-DISEASE; NEUROSTEROIDS; BINDING; ZNF179; DIFFERENTIATION; INVOLVEMENT AB The accumulation of reactive oxygen species (ROS) have implicated the pathogenesis of several human diseases including neurodegenerative disorders, stroke, and traumatic brain injury, hence protecting neurons against ROS is very important. In this study, we focused on sigma-1 receptor (Sig-1R), a chaperone at endoplasmic reticulum, and investigated its protective functions. Using hydrogen peroxide (H2O2)-induced ROS accumulation model, we verified that apoptosis-signaling pathways were elicited by H2O2 treatment. However, the Sig-1R agonists, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS), reduced the activation of apoptotic pathways significantly. By performing protein protein interaction assays and shRNA knockdown of Sig-1R, we identified the brain Zinc finger protein 179 (Znf179) as a downstream target of Sig-1R regulation. The neuroprotective effect of Znf179 over expression was similar to that of DHEAS treatment, and likely mediated by affecting the levels of antioxidant enzymes. We also quantified the levels of peroxiredoxin 3 (Prx3) and superoxide dismutase 2 (SOD2) in the hippocampi of wild-type and Znf179 knockout mice, and found both enzymes to be reduced in the knockout versus the wild-type mice. In summary, these results reveal that Znf179 plays a novel role in neuroprotection, and Sig-1R agonists may be therapeutic candidates to prevent ROS-induced damage in neurodegenerative and neurotraumatic diseases. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Su, Tzu-Chieh; Lin, Shu-Hui; Chang, Wen-Chang] Taipei Med Univ, Grad Inst Med Sci, Taipei 110, Taiwan. [Lin, Shu-Hui; Hsieh, Tsun-Hsun; Chou, Szu-Yi; Lee, Yi-Chao; Chuang, Jian-Ying] Taipei Med Univ, Grad Inst Neural Regenerat Med, 250 Wuxing St, Taipei 110, Taiwan. [Lee, Pin-Tse; Yeh, Shiu-Hwa] Natl Hlth Res Inst, Inst Biotechnol & Pharmaceut Res, Zhunan Township, Miaoli County, Taiwan. [Lee, Pin-Tse; Su, Tsun-Ping] NIDA, Cellular Pathobiol Sect, Intramural Res Program, Baltimore, MD USA. [Hung, Jan-Jong] Natl Cheng Kung Univ, Inst Bioinformat & Biosignal Transduct, Tainan 701, Taiwan. [Chang, Wen-Chang; Lee, Yi-Chao; Chuang, Jian-Ying] Taipei Med Univ, Ctr Neurotrauma & Neuroregenerat, Taipei 110, Taiwan. RP Lee, YC; Chuang, JY (reprint author), Taipei Med Univ, Grad Inst Neural Regenerat Med, 250 Wuxing St, Taipei 110, Taiwan. EM yclee@tmu.edu.tw; chuangcy@tmu.edu.tw OI Lee, Yi-Chao/0000-0003-3451-183X FU Ministry of Science and Technology [MOST 103-2320-B-038-046-MY3, MOST 103-2321-B-038-001, MOST 104-2923-B-038-002-MY3]; Taipei Medical University [TMU102-AE1-B25] FX This work was supported by grants from the Ministry of Science and Technology (MOST 103-2320-B-038-046-MY3, MOST 103-2321-B-038-001, and MOST 104-2923-B-038-002-MY3) and Taipei Medical University (TMU102-AE1-B25). NR 37 TC 0 Z9 0 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JUN PY 2016 VL 105 BP 1 EP 9 DI 10.1016/j.neuropharm.2016.01.015 PG 9 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DN8EF UT WOS:000377311300001 PM 26792191 ER PT J AU Doumatey, AP Zhou, J Zhou, M Prieto, D Rotimi, CN Adeyemo, A AF Doumatey, Ayo Priscille Zhou, Jie Zhou, Ming Prieto, DaRue Rotimi, Charles N. Adeyemo, Adebowale TI Proinflammatory and lipid biomarkers mediate metabolically healthy obesity: A proteomics study SO OBESITY LA English DT Article ID APOLIPOPROTEIN A-IV; FETUIN-A; CARDIOVASCULAR-DISEASE; INDIVIDUALS; INFLAMMATION; WEIGHT; IDENTIFICATION; EPIDEMIOLOGY; ASSOCIATION; POPULATION AB ObjectiveThe metabolically healthy obesity (MHO) phenotype is an important obesity subtype in which obesity is not accompanied by any metabolic comorbidity. However, the underlying molecular mechanisms remain elusive. In this study, a shotgun proteomics approach to identify circulating biomolecules and pathways associated with MHO was used. MethodsThe subjects were 20 African-American women: 10 MHO cases and 10 metabolically abnormal individuals with obesity (MAO) controls. Serum proteins were detected and quantified using label-free proteomics. Differential expression of proteins between the two groups was analyzed, and the list of differentially expressed proteins was analyzed to determine enriched biological pathways. ResultsTwenty proteins were differentially expressed between MHO and controls. These proteins included: hemoglobin subunits (HBA1, P=6.00 x 10(-18)), haptoglobin-related protein (HPR, P=1.2 x 10(-15)), apolipoproteins (APOB-100, P=1.50 x 10(-40); APOA4, P=1.1 x 10(-14)), retinol-binding protein 4 (RBP4, P=7.1 x 10(-08)), and CRP (P=2.0 x 10(-04)). MHO was associated with lower levels of proinflammatory and higher levels of anti-inflammatory biomarkers when compared with MAO. Pathway analysis showed enrichment of lipids and inflammatory pathways, including LXR/RXR and FXR/RXR activation, and acute phase response signaling. ConclusionsThese findings suggested that protection from dysregulated inflammatory and lipid processes were primary molecular hallmarks of MHO. The candidate biomarkers (AHSG, RBP4, and APOA4) identified in this study are potential prognostic markers for MHO. C1 [Doumatey, Ayo Priscille; Zhou, Jie; Rotimi, Charles N.; Adeyemo, Adebowale] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Zhou, Ming; Prieto, DaRue] NCI, Lab Prote & Analyt Technol, Leidos Biomed Res Inc, NIH, Frederick, MD 21701 USA. RP Doumatey, AP (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. EM doumateya@mail.nih.gov FU National Institutes of Health (NIH) from the Office of Research on Minority Health [3T37TW00041-03S2]; National Human Genome Research Institute (NHGRI); National Center for Research Resources (NCRR); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK-54001]; Intramural Research Program of the Center for Research on Genomics and Global Health; NHGRI; NIDDK; Center for Information Technology; Office of the Director at the NIH [Z01HG200362] FX Support for this study is provided by National Institutes of Health (NIH) grant No. 3T37TW00041-03S2 from the Office of Research on Minority Health, the National Human Genome Research Institute (NHGRI), the National Center for Research Resources (NCRR), and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant DK-54001. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of the NIH. This research was supported in part by the Intramural Research Program of the Center for Research on Genomics and Global Health. The Center for Research on Genomics and Global Health is supported by the NHGRI, the NIDDK, the Center for Information Technology, and the Office of the Director at the NIH (Z01HG200362). NR 39 TC 1 Z9 1 U1 4 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD JUN PY 2016 VL 24 IS 6 BP 1257 EP 1265 DI 10.1002/oby.21482 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA DO1EK UT WOS:000377521100013 PM 27106679 ER PT J AU Nicastro, HL Belter, CW Lauer, MS Coady, SA Fine, LJ Loria, CM AF Nicastro, Holly L. Belter, Christopher W. Lauer, Michael S. Coady, Sean A. Fine, Lawrence J. Loria, Catherine M. TI The Productivity of NHLBI-Funded Obesity Research, 1983-2013 SO OBESITY LA English DT Article ID CITATION ANALYSIS; IMPACT; ASSOCIATION; PERCENTILES; DISEASE; CLONING; ASTHMA; RISK AB ObjectiveTo describe and elucidate the time trends of the academic productivity of NHLBI's obesity-related research funding via bibliometric analysis of 30 years of NHLBI-supported obesity-related publications. MethodsIn total, 3,545 NHLBI-funded obesity-related publications were identified in the Thomson Reuters InCites database. Shared references in a community detection algorithm were used to identify publication topics. Characteristics of publications and topical communities were analyzed based on citation count and percentile rank. A percentile rank >90 was considered highly cited. ResultsObesity-related publications increased more than 10-fold over 30 years, whereas NHLBI-funded publications only increased twofold NHLBI-funded obesity publications were cited a median of 23 times (IQR 8-55, range 0-2,047, mean 52). Thirty percent of these publications were highly cited compared to the expected ten percent. Six topical communities were present in 1983 compared to 16 in 2013. The most highly cited topical areas were sleep (n=199 publications, 38% highly cited), cardiovascular morbidity and mortality (n=277, 36%), obesity correlates and consequences (n=588, 35%), and asthma and inflammation (n=283, 35%). ConclusionsNHLBI-funded obesity publications have contributed substantially to the obesity literature, with many highly cited. Publications grew in number and topical diversity over 30 years and grew at a faster rate than total NHLBI publications. C1 [Nicastro, Holly L.; Coady, Sean A.; Fine, Lawrence J.; Loria, Catherine M.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Belter, Christopher W.] NIH, NIH Lib, Bldg 10, Bethesda, MD 20892 USA. [Lauer, Michael S.] NIH, Off Extramural Res Act, Bldg 10, Bethesda, MD 20892 USA. RP Nicastro, HL (reprint author), NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. EM holly.nicastro@nih.gov RI Belter, Christopher/L-6487-2013 OI Belter, Christopher/0000-0001-5221-6880 NR 36 TC 0 Z9 0 U1 5 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD JUN PY 2016 VL 24 IS 6 BP 1356 EP 1365 DI 10.1002/oby.21478 PG 10 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA DO1EK UT WOS:000377521100026 PM 27145059 ER PT J AU Eblen, MK Wagner, RM RoyChowdhury, D Patel, KC Pearson, K AF Eblen, Matthew K. Wagner, Robin M. RoyChowdhury, Deepshikha Patel, Katherine C. Pearson, Katrina TI How Criterion Scores Predict the Overall Impact Score and Funding Outcomes for National Institutes of Health Peer-Reviewed Applications SO PLOS ONE LA English DT Article ID GRANT APPLICATIONS AB Understanding the factors associated with successful funding outcomes of research project grant (R01) applications is critical for the biomedical research community. R01 applications are evaluated through the National Institutes of Health (NIH) peer review system, where peer reviewers are asked to evaluate and assign scores to five research criteria when assessing an application's scientific and technical merit. This study examined the relationship of the five research criterion scores to the Overall Impact score and the likelihood of being funded for over 123,700 competing R01 applications for fiscal years 2010 through 2013. The relationships of other application and applicant characteristics, including demo-graphics, to scoring and funding outcomes were studied as well. The analyses showed that the Approach and, to a lesser extent, the Significance criterion scores were the main predictors of an R01 application's Overall Impact score and its likelihood of being funded. Applicants might consider these findings when submitting future R01 applications to NIH. C1 [Eblen, Matthew K.; Wagner, Robin M.; RoyChowdhury, Deepshikha; Patel, Katherine C.; Pearson, Katrina] NIH, Off Extramural Res, Bldg 10, Bethesda, MD 20892 USA. [Eblen, Matthew K.; Wagner, Robin M.] CDC, Off Publ Hlth Sci Serv, Atlanta, GA 30333 USA. RP Eblen, MK (reprint author), NIH, Off Extramural Res, Bldg 10, Bethesda, MD 20892 USA.; Eblen, MK (reprint author), CDC, Off Publ Hlth Sci Serv, Atlanta, GA 30333 USA. EM matteblen@gmail.com NR 19 TC 0 Z9 0 U1 3 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 1 PY 2016 VL 11 IS 6 AR e0155060 DI 10.1371/journal.pone.0155060 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN6KZ UT WOS:000377184700009 PM 27249058 ER PT J AU Lo, YL Pan, WH Hsu, WL Chien, YC Chen, JY Hsu, MM Lou, PJ Chen, IH Hildesheim, A Chen, CJ AF Lo, Yen-Li Pan, Wen-Harn Hsu, Wan-Lun Chien, Yin-Chu Chen, Jen-Yang Hsu, Mow-Ming Lou, Pei-Jen Chen, I-How Hildesheim, Allan Chen, Chien-Jen TI Partial Least Square Discriminant Analysis Discovered a Dietary Pattern Inversely Associated with Nasopharyngeal Carcinoma Risk SO PLOS ONE LA English DT Article ID PRESERVED FOODS; NUTRITIONAL EPIDEMIOLOGY; LOW-CHOLESTEROL; NUTRIENT INTAKE; HEART-DISEASE; CHINESE DIET; CANCER-RISK; FATTY-ACIDS; TAIWAN; CONSUMPTION AB Evidence on the association between dietary component, dietary pattern and nasopharyngeal carcinoma (NPC) is scarce. A major challenge is the high degree of correlation among dietary constituents. We aimed to identify dietary pattern associated with NPC and to illustrate the dose-response relationship between the identified dietary pattern scores and the risk of NPC. Taking advantage of a matched NPC case-control study, data from a total of 319 incident cases and 319 matched controls were analyzed. Dietary pattern was derived employing partial least square discriminant analysis (PLS-DA) performed on energy-adjusted food frequencies derived from a 66-item food-frequency questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with multiple conditional logistic regression models, linking pattern scores and NPC risk. A high score of the PLS-DA derived pattern was characterized by high intakes of fruits, milk, fresh fish, vegetables, tea, and eggs ordered by loading values. We observed that one unit increase in the scores was associated with a significantly lower risk of NPC (ORadj = 0.73, 95% CI = 0.60-0.88) after controlling for potential confounders. Similar results were observed among Epstein-Barr virus seropositive subjects. An NPC protective diet is indicated with more phytonutrient-rich plant foods (fruits, vegetables), milk, other protein-rich foods (in particular fresh fish and eggs), and tea. This information may be used to design potential dietary regimen for NPC prevention. C1 [Lo, Yen-Li; Pan, Wen-Harn] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Hsu, Wan-Lun; Chien, Yin-Chu; Chen, Chien-Jen] Acad Sinica, Genom Res Ctr, Taipei 115, Taiwan. [Chen, Jen-Yang] Natl Hlth Res Inst, Natl Inst Canc Res, Chunan, Taiwan. [Chen, Jen-Yang] Natl Taiwan Univ, Coll Med, Grad Inst Microbiol, Taipei, Taiwan. [Hsu, Mow-Ming; Lou, Pei-Jen] Natl Taiwan Univ Hosp, Dept Otolaryngol, Taipei, Taiwan. [Hsu, Mow-Ming; Lou, Pei-Jen] Natl Taiwan Univ, Coll Med, Taipei, Taiwan. [Chen, I-How] Chang Gung Mem Hosp, Dept Otorhinolaryngol Head & Neck Surg, Taoyuan, Taiwan. [Chen, I-How] Chang Gung Univ, Taoyuan, Taiwan. [Hildesheim, Allan] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Chen, Chien-Jen] Natl Taiwan Univ, Grad Inst Epidemiol & Prevent Med, Coll Publ Hlth, Taipei 10764, Taiwan. RP Pan, WH (reprint author), Acad Sinica, Inst Biomed Sci, Taipei, Taiwan.; Chen, CJ (reprint author), Acad Sinica, Genom Res Ctr, Taipei 115, Taiwan.; Chen, CJ (reprint author), Natl Taiwan Univ, Grad Inst Epidemiol & Prevent Med, Coll Publ Hlth, Taipei 10764, Taiwan. EM pan@ibms.sinica.edu.tw; chencj@gate.sinica.edu.tw FU National Institutes of Health, USA; Institute of Biomedical Sciences, Academia Sinica, Taiwan FX This study was supported from the intramural funds from the National Institutes of Health, USA and from Institute of Biomedical Sciences, Academia Sinica, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 0 Z9 0 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 1 PY 2016 VL 11 IS 6 AR e0155892 DI 10.1371/journal.pone.0155892 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN6KZ UT WOS:000377184700022 PM 27249558 ER PT J AU Sassi, C Ridge, PG Nalls, MA Gibbs, R Ding, JH Lupton, MK Troakes, C Lunnon, K Al-Sarraj, S Brown, KS Medway, C Lord, J Turton, J Morgan, K Powell, JF Kauwe, JS Cruchaga, C Bras, J Goate, AM Singleton, AB Guerreiro, R Hardy, J AF Sassi, Celeste Ridge, Perry G. Nalls, Michael A. Gibbs, Raphael Ding, Jinhui Lupton, Michelle K. Troakes, Claire Lunnon, Katie Al-Sarraj, Safa Brown, Kristelle S. Medway, Christopher Lord, Jenny Turton, James Morgan, Kevin Powell, John F. Kauwe, John S. Cruchaga, Carlos Bras, Jose Goate, Alison M. Singleton, Andrew B. Guerreiro, Rita Hardy, John CA ARUK Consortium TI Influence of Coding Variability in APP-A beta Metabolism Genes in Sporadic Alzheimer's Disease SO PLOS ONE LA English DT Article ID AMYLOID PRECURSOR PROTEIN; GENOME-WIDE ASSOCIATION; IDENTIFIES VARIANTS; MISSENSE MUTATIONS; DEGRADING ENZYMES; COMMON VARIANTS; SEQUENCING DATA; RECEPTOR LR11; SORL1; ABCA7 AB The cerebral deposition of A beta(42), a neurotoxic proteolytic derivate of amyloid precursor protein (APP), is a central event in Alzheimer's disease (AD)(Amyloid hypothesis). Given the key role of APP-A beta metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, A beta degradation and clearance. We then used exome and genome sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effect of coding variants in these genes as potential susceptibility factors for AD, in a cohort composed of 332 sporadic and mainly late-onset AD cases and 676 elderly controls from North America and the UK. Our study shows that common coding variability in these genes does not play a major role for the disease development. In the single-variant association analysis, the main hits, none of which statistically significant after multiple testing correction (1.9e(-4)= 18 years old were interviewed in the National Epidemiologic Survey on Alcohol and Related Conditions-III. Psychiatric and substance use disorders were assessed with the Alcohol Use Disorders and Associated Disabilities Interview Schedule-5. Results: The prevalences of 12-month and lifetime cannabis use disorder were 2.5% and 6.3%. Among those with 12-month and lifetime diagnoses, the mean days of marijuana use per year were 225.3 (SE=5.7) and 274.2 (SE=3.8). The odds of 12-month and lifetime cannabis use disorder were higher for men, Native Americans, unmarried individuals, those with low incomes, and young adults (e.g., among those age 18-24 years versus >= 45: odds ratio for 12-month disorder, 7.2; 95% confidence interval, 5.5-9.5). Cannabis use disorder was associated with other substance use disorders, affective disorders, anxiety, and personality disorders. Twelve-month cannabis use disorder was associated with disability. As disorder severity increased, virtually all associations became stronger. Only 13.2% with lifetime cannabis use disorder participated in 12-step programs or professional treatment. Conclusions: DSM-5 cannabis use disorder is prevalent, associated with comorbidity and disability, and largely untreated. Findings suggest the need to improve prevention and educate the public, professionals, and policy makers about possible harms associated with cannabis use disorders and available interventions. C1 [Saha, Tulshi D.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, Rockville, MD 20852 USA. Columbia Univ, Coll Phys & Surg, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. RP Saha, TD (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, Rockville, MD 20852 USA. EM sahatd@mail.nih.gov FU National Institute on Drug Abuse (NIDA) [R01DA034244-01]; New York State Psychiatric Institute; NIDA [F32DA0364431]; intramural program, National Institute on Alcohol Abuse and Alcoholism (NIAAA); NIAAA; NIDA FX Supported by National Institute on Drug Abuse (NIDA) grant R01DA034244-01 and the New York State Psychiatric Institute (Dr. Hasin), by NIDA grant F32DA0364431 (Dr. Kerridge), and by the intramural program, National Institute on Alcohol Abuse and Alcoholism (NIAAA). The National Epidemiologic Survey on Alcohol and Related Conditions-III was sponsored by NIAAA, with supplemental support from NIDA. Sponsors and funders had no role in the design and conduct of the study; in collection, management, analysis, and interpretation of the data; or in preparation, review, and approval of the manuscript. NR 75 TC 14 Z9 14 U1 10 U2 17 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUN PY 2016 VL 173 IS 6 BP 588 EP 599 DI 10.1176/appi.ajp.2015.15070907 PG 12 WC Psychiatry SC Psychiatry GA DN3FT UT WOS:000376948500010 PM 26940807 ER PT J AU Rosenkrantz, AB Oto, A Turkbey, B Westphalen, AC AF Rosenkrantz, Andrew B. Oto, Aytekin Turkbey, Baris Westphalen, Antonio C. TI Prostate Imaging Reporting and Data System (PI-RADS), Version 2: A Critical Look SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Editorial Material DE guidelines; MRI; PI-RADS; prostate biopsy; prostate cancer; Prostate Imaging Reporting and Data System AB OBJECTIVE. The purpose of this article is to highlight the potential challenges associated with the Prostate Imaging Reporting and Data System, version 2 (PI-RADS v2), and to offer, when possible, suggestions and ideas for improvement. CONCLUSION. PI-RADS v2 offers clear improvements to its earlier version and will greatly benefit the prostate MRI community. Nonetheless, caution remains on the basis of early user experience, and potential ambiguities and gaps of PI-RADS v2 are noted. Continued data-driven clarification and refinement of the guidelines will be invaluable for PI-RADS v2 to achieve its goal of improving patient care. C1 [Rosenkrantz, Andrew B.] NYU, Langone Med Ctr, Sch Med, Dept Radiol,Ctr Biomed Imaging, 660 First Ave,3rd Fl, New York, NY 10016 USA. [Oto, Aytekin] Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. [Turkbey, Baris] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Westphalen, Antonio C.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. RP Rosenkrantz, AB (reprint author), NYU, Langone Med Ctr, Sch Med, Dept Radiol,Ctr Biomed Imaging, 660 First Ave,3rd Fl, New York, NY 10016 USA. EM Andrew.Rosenkrantz@nyumc.org NR 5 TC 7 Z9 7 U1 0 U2 2 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD JUN PY 2016 VL 206 IS 6 BP 1179 EP 1183 DI 10.2214/AJR.15.15765 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DN2XW UT WOS:000376927300017 PM 26913638 ER PT J AU Sheppard, AE Stoesser, N Wilson, DJ Sebra, R Kasarskis, A Anson, LW Giess, A Pankhurst, LJ Vaughan, A Grim, CJ Cox, HL Yeh, AJ Sifri, CD Walker, AS Peto, TE Crook, DW Mathers, AJ AF Sheppard, Anna E. Stoesser, Nicole Wilson, Daniel J. Sebra, Robert Kasarskis, Andrew Anson, Luke W. Giess, Adam Pankhurst, Louise J. Vaughan, Alison Grim, Christopher J. Cox, Heather L. Yeh, Anthony J. Sifri, Costi D. Walker, A. Sarah Peto, Tim E. Crook, Derrick W. Mathers, Amy J. CA MMM Informatics Grp TI Nested Russian Doll-Like Genetic Mobility Drives Rapid Dissemination of the Carbapenem Resistance Gene bla(KPC) SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID SEQUENCE TYPE 258; KLEBSIELLA-PNEUMONIAE ST258; HYDROLYZING BETA-LACTAMASE; NEW-YORK HOSPITALS; ESCHERICHIA-COLI; MOLECULAR EPIDEMIOLOGY; NEW-JERSEY; ACINETOBACTER-BAUMANNII; ANTIBIOTIC-RESISTANCE; UNITED-STATES AB The recent widespread emergence of carbapenem resistance in Enterobacteriaceae is a major public health concern, as carbapenems are a therapy of last resort against this family of common bacterial pathogens. Resistance genes can mobilize via various mechanisms, including conjugation and transposition; however, the importance of this mobility in short-term evolution, such as within nosocomial outbreaks, is unknown. Using a combination of short-and long-read whole-genome sequencing of 281 blaKPC-positive Enterobacteriaceae isolates from a single hospital over 5 years, we demonstrate rapid dissemination of this carbapenem resistance gene to multiple species, strains, and plasmids. Mobility of bla(KPC) occurs at multiple nested genetic levels, with transmission of bla(KPC) strains between individuals, frequent transfer of bla(KPC) plasmids between strains/ species, and frequent transposition of bla(KPC) transposon Tn4401 between plasmids. We also identify a common insertion site for Tn4401 within various Tn2-like elements, suggesting that homologous recombination between Tn2-like elements has enhanced the spread of Tn4401 between different plasmid vectors. Furthermore, while short-read sequencing has known limitations for plasmid assembly, various studies have attempted to overcome this by the use of reference-based methods. We also demonstrate that, as a consequence of the genetic mobility observed in this study, plasmid structures can be extremely dynamic, and therefore these reference- based methods, as well as traditional partial typing methods, can produce very misleading conclusions. Overall, our findings demonstrate that nonclonal resistance gene dissemination can be extremely rapid, presenting significant challenges for public health surveillance and achieving effective control of antibiotic resistance. C1 [Sheppard, Anna E.; Stoesser, Nicole; Wilson, Daniel J.; Anson, Luke W.; Giess, Adam; Pankhurst, Louise J.; Vaughan, Alison; Walker, A. Sarah; Peto, Tim E.; Crook, Derrick W.] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Med, Modernizing Med Microbiol Consortium, Oxford OX3 9DU, England. [Sebra, Robert; Kasarskis, Andrew] Icahn Sch Med, Icahn Inst, New York, NY USA. [Sebra, Robert; Kasarskis, Andrew] Icahn Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Grim, Christopher J.] US FDA, Laurel, MD USA. [Cox, Heather L.; Yeh, Anthony J.; Sifri, Costi D.; Mathers, Amy J.] Univ Virginia Hlth Syst, Dept Med, Div Infect Dis & Int Hlth, Charlottesville, VA USA. [Sifri, Costi D.] Univ Virginia Hlth Syst, Off Hosp Epidemiol, Charlottesville, VA USA. [Crook, Derrick W.] Publ Hlth England, Microbiol Serv, London, England. [Mathers, Amy J.] Univ Virginia Hlth Syst, Dept Pathol, Clin Microbiol, Charlottesville, VA USA. [Giess, Adam] Univ Bergen, Dept Informat, N-5008 Bergen, Norway. [Yeh, Anthony J.] NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Sheppard, AE (reprint author), Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Med, Modernizing Med Microbiol Consortium, Oxford OX3 9DU, England.; Mathers, AJ (reprint author), Univ Virginia Hlth Syst, Dept Med, Div Infect Dis & Int Hlth, Charlottesville, VA USA.; Mathers, AJ (reprint author), Univ Virginia Hlth Syst, Dept Pathol, Clin Microbiol, Charlottesville, VA USA. EM anna.sheppard@ndm.ox.ac.uk; ajm5b@virginia.edu OI Wilson, Daniel/0000-0002-0940-3311; Sheppard, Anna/0000-0002-2913-0920 FU Health Innovation Challenge Fund [HICF-T5-358, WT098615/Z/12/Z]; Department of Health; Wellcome Trust; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and the University of Oxford; NIHR Oxford Health Protection Research Unit on Healthcare Associated Infection and Antimicrobial Resistance [HPRU-2012-10041]; Wellcome Trust [101237/Z/13/Z]; Royal Society [101237/Z/13/Z] FX This publication presents independent research commissioned by the Health Innovation Challenge Fund (grants HICF-T5-358 and WT098615/Z/12/Z), a parallel funding partnership of the Department of Health and Wellcome Trust, the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and the University of Oxford, and the NIHR Oxford Health Protection Research Unit on Healthcare Associated Infection and Antimicrobial Resistance (HPRU-2012-10041). The views expressed in this publication are those of the authors and not necessarily those of the funders. D.W.C. and T.E.P. are NIHR senior investigators. N.S. was supported by a Wellcome Trust University of Oxford research fellowship during this work. D.J.W. is a Sir Henry Dale Fellow jointly funded by the Wellcome Trust and the Royal Society (grant 101237/Z/13/Z). NR 55 TC 10 Z9 11 U1 3 U2 4 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 JUN PY 2016 VL 60 IS 6 BP 3767 EP 3778 DI 10.1128/AAC.00464-16 PG 12 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA DN4PE UT WOS:000377048900060 PM 27067320 ER PT J AU Sandoz, KM Beare, PA Cockrell, DC Heinzen, RA AF Sandoz, Kelsi M. Beare, Paul A. Cockrell, Diane C. Heinzen, Robert A. TI Complementation of Arginine Auxotrophy for Genetic Transformation of Coxiella burnetii by Use of a Defined Axenic Medium (vol 82, pg 3042, 2016) SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Correction C1 [Sandoz, Kelsi M.; Beare, Paul A.; Cockrell, Diane C.; Heinzen, Robert A.] NIAID, Coxiella Pathogenesis Sect, Bacteriol Lab, Rocky Mt Labs,NIH, Hamilton, MT USA. RP Sandoz, KM (reprint author), NIAID, Coxiella Pathogenesis Sect, Bacteriol Lab, Rocky Mt Labs,NIH, Hamilton, MT USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD JUN PY 2016 VL 82 IS 12 BP 3695 EP 3695 DI 10.1128/AEM.01212-16 PG 1 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DN4FI UT WOS:000377018400029 PM 27247311 ER PT J AU Zhang, X Basuli, F Shi, ZD Xu, BY Blackman, B Choyke, PL Swenson, RE AF Zhang, Xiang Basuli, Falguni Shi, Zhen-Dan Xu, Biying Blackman, Burchelle Choyke, Peter L. Swenson, Rolf E. TI Automated synthesis of [F-18](2S,4R)-4-fluoroglutamine on a GE TRACERlab (TM) FX-N Pro module SO APPLIED RADIATION AND ISOTOPES LA English DT Article DE Fluoroglutamine; F-18; Automation; PET imaging; Tumor ID GLUTAMINE-METABOLISM AB Glutamine (Gin) and its analogues may serve as imaging agents for tumor diagnosis using positron emission tomography (PET), especially for tumors with negative [F-18]FDG scan. We report the first automated synthesis of [F-18](2S,4R)-4-fluoroglutamine ([F-18]FGln) on a GE TRACERlab (TM) FX-N Pro module. [F-18]FGln was obtained in 80 +/- 3 min with a radiochemical yield of 21 +/- 3% (n=5, uncorrected). The radiochemical purity was > 98%, and optical purity 90 +/- 5%. The synthesis is highly reproducible with good chemical purity, radiochemical yield, and is suitable for translation to cGMP production. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Zhang, Xiang; Basuli, Falguni; Shi, Zhen-Dan; Xu, Biying; Blackman, Burchelle; Swenson, Rolf E.] NHLBI, Imaging Probe Dev Ctr, NIH, Rockville, MD USA. [Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. RP Swenson, RE (reprint author), NHLBI, Imaging Probe Dev Ctr, NIH, Rockville, MD USA. EM rolf.swenson@nih.gov FU National Cancer Institute, National Institutes of Health, United States [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, United States under Contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 11 TC 0 Z9 0 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0969-8043 J9 APPL RADIAT ISOTOPES JI Appl. Radiat. Isot. PD JUN PY 2016 VL 112 BP 110 EP 114 DI 10.1016/j.apradiso.2016.02.016 PG 5 WC Chemistry, Inorganic & Nuclear; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Chemistry; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA DM9QV UT WOS:000376701700016 PM 27019029 ER PT J AU Sharov, AA AF Sharov, Alexei A. TI Coenzyme world model of the origin of life SO BIOSYSTEMS LA English DT Review DE Coenzyme world; Origin of life; Lipid world; Molecular heredity; Molecular cooperation ID RNA WORLD; SELF-REPLICATION; GENETIC-CODE; EVOLUTIONARY CONSTRAINTS; CARBONACEOUS METEORITES; ACID; EMERGENCE; PARADIGM; CELLS; SETS AB The origin of life means the emergence of heritable and evolvable self-reproduction. However the mechanisms of primordial heredity were different from those in contemporary cells. Here I argue that primordial life had no nucleic acids; instead heritable signs were represented by isolated catalytically active self reproducing molecules, similar to extant coenzymes, which presumably colonized surfaces of oil droplets in water. The model further assumes that coenzyme-like molecules (CLMs) changed surface properties of oil droplets (e.g., by oxidizing terminal carbons), and in this Way created and sustained favorable-conditions for their own self-reproduction. Such niche-dependent self-reproduction is a necessary condition for cooperation between different kinds of CLMs because they have to coexist in the same oil droplets and either succeed or perish together. Additional kinds of hereditary molecules were acquired via coalescence of oil droplets carrying different kinds of CLMs or via modification of already existing CLMs. Eventually, polymerization of CLMs became controlled by other polymers used as templates; and this kind of template-based synthesis eventually resulted in the emergence of RNA-like replicons. Apparently, oil droplets transformed into the outer membrane of cells via engulfing water, stabilization of the surface, and osmoregulation. In result, the metabolism was internalized allowing cells to accumulate free-floating resources (e.g., animoacids, ATP), which was a necessary condition for the development of protein synthesis. Thus, life originated from simple but already functional molecules, and its gradual evolution towards higher complexity was driven by cooperation and natural selection. Published by Elsevier Ireland Ltd. C1 [Sharov, Alexei A.] NIA, Genet Lab, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Sharov, AA (reprint author), NIA, Genet Lab, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM sharov@comcast.net FU National Institute on Aging (NIA/NIH) [Z01 AG000656-13] FX This project was supported entirely by the Intramural Research Program of the National Institute on Aging (NIA/NIH), project Z01 AG000656-13. Funding organization had no involvement in this study. NR 83 TC 1 Z9 1 U1 11 U2 30 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0303-2647 EI 1872-8324 J9 BIOSYSTEMS JI Biosystems PD JUN PY 2016 VL 144 BP 8 EP 17 DI 10.1016/j.biosystems.2016.03.003 PG 10 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA DN7BI UT WOS:000377229900002 PM 26968100 ER PT J AU Kwak, JT Hewitt, SM Kajdacsy-Balla, AA Sinha, S Bhargava, R AF Kwak, Jin Tae Hewitt, Stephen M. Kajdacsy-Balla, Andre Alexander Sinha, Saurabh Bhargava, Rohit TI Automated prostate tissue referencing for cancer detection and diagnosis SO BMC BIOINFORMATICS LA English DT Article DE Prostate cancer; Database; Tissue morphology; Tissue retrieval; Infrared imaging; Decision support ID IMAGE RETRIEVAL-SYSTEM; PATHOLOGICAL IMAGES; HISTOLOGICAL IMAGES; CARCINOMA; CLASSIFICATION; RECURRENCE; FEATURES; PREDICTION; PATTERN; DESIGN AB Background: The current practice of histopathology review is limited in speed and accuracy. The current diagnostic paradigm does not fully describe the complex and complicated patterns of cancer. To address these needs, we develop an automated and objective system that facilitates a comprehensive and easy information management and decision-making. We also develop a tissue similarity measure scheme to broaden our understanding of tissue characteristics. Results: The system includes a database of previously evaluated prostate tissue images, clinical information and a tissue retrieval process. In the system, a tissue is characterized by its morphology. The retrieval process seeks to find the closest matching cases with the tissue of interest. Moreover, we define 9 morphologic criteria by which a pathologist arrives at a histomorphologic diagnosis. Based on the 9 criteria, true tissue similarity is determined and serves as the gold standard of tissue retrieval. Here, we found a minimum of 4 and 3 matching cases, out of 5, for similar to 80 % and similar to 60 % of the queries when a match was defined as the tissue similarity score >= 5 and >= 6, respectively. We were also able to examine the relationship between tissues beyond the Gleason grading system due to the tissue similarity scoring system. Conclusions: Providing the closest matching cases and their clinical information with pathologists will help to conduct consistent and reliable diagnoses. Thus, we expect the system to facilitate quality maintenance and quality improvement of cancer pathology. C1 [Sinha, Saurabh] Univ Illinois, Dept Comp Sci, 2122 Siebel Ctr,201 N Goodwin Ave, Urbana, IL 61801 USA. [Bhargava, Rohit] Univ Illinois, Beckman Inst Adv Sci & Technol, Dept Bioengn, Dept Mech Sci & Engn Elect & Comp Engn Chem & Bio, 4265 Beckman Inst 405 N Mathews Ave, Urbana, IL 61801 USA. [Bhargava, Rohit] Univ Illinois, Univ Illinois, Ctr Canc, 4265 Beckman Inst 405 N Mathews Ave, Urbana, IL 61801 USA. [Kwak, Jin Tae] Sejong Univ, Dept Comp Sci & Engn, Seoul 05006, South Korea. [Hewitt, Stephen M.] NCI, Tissue Array Res Program, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20850 USA. [Kajdacsy-Balla, Andre Alexander] Univ Illinois, Dept Pathol, Chicago, IL 60612 USA. RP Sinha, S (reprint author), Univ Illinois, Dept Comp Sci, 2122 Siebel Ctr,201 N Goodwin Ave, Urbana, IL 61801 USA.; Bhargava, R (reprint author), Univ Illinois, Beckman Inst Adv Sci & Technol, Dept Bioengn, Dept Mech Sci & Engn Elect & Comp Engn Chem & Bio, 4265 Beckman Inst 405 N Mathews Ave, Urbana, IL 61801 USA.; Bhargava, R (reprint author), Univ Illinois, Univ Illinois, Ctr Canc, 4265 Beckman Inst 405 N Mathews Ave, Urbana, IL 61801 USA. EM sinhas@illinois.edu; rxb@illinois.edu OI Hewitt, Stephen/0000-0001-8283-1788; Bhargava, Rohit/0000-0001-7360-994X FU National Institutes of Health - National Cancer Institute [R01CA138882] FX This work was supported by National Institutes of Health - National Cancer Institute via grant R01CA138882. NR 64 TC 0 Z9 0 U1 3 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD JUN 1 PY 2016 VL 17 AR 227 DI 10.1186/s12859-016-1086-6 PG 12 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA DN7NC UT WOS:000377262100001 PM 27247129 ER PT J AU Colombara, DV Manhart, LE Carter, JJ Hawes, SE Weiss, NS Hughes, JP Qiao, YL Taylor, PR Smith, JS Galloway, DA AF Colombara, Danny V. Manhart, Lisa E. Carter, Joseph J. Hawes, Stephen E. Weiss, Noel S. Hughes, James P. Qiao, You-Lin Taylor, Philip R. Smith, Jennifer S. Galloway, Denise A. TI Absence of an association of human polyomavirus and papillomavirus infection with lung cancer in China: a nested case-control study SO BMC CANCER LA English DT Article DE Lung cancer; Human polyomavirus; KI polyomavirus; WU polyomavirus; Merkel cell polyomavirus; Human papillomavirus ID MERKEL CELL POLYOMAVIRUS; POLYMERASE-CHAIN-REACTION; CAUSAL ASSOCIATION; KI POLYOMAVIRUS; CARCINOMA; METAANALYSIS; RISK; HPV; IDENTIFICATION; ANTIBODIES AB Background: Studies of human polyomavirus (HPyV) infection and lung cancer are limited and those regarding the association of human papillomavirus (HPV) infection and lung cancer have produced inconsistent results. Methods: We conducted a nested case-control study to assess the association between incident lung cancer of various histologies and evidence of prior infection with HPyVs and HPVs. We selected serum from 183 cases and 217 frequency matched controls from the Yunnan Tin Miner's Cohort study, which was designed to identify biomarkers for early detection of lung cancer. Using multiplex liquid bead microarray (LBMA) antibody assays, we tested for antibodies to the VP1 structural protein and small T antigen (ST-Ag) of Merkel cell, KI, and WU HPyVs. We also tested for antibodies against HPV L1 structural proteins (high-risk types 16, 18, 31, 33, 52, and 58 and low-risk types 6 and 11) and E6 and E7 oncoproteins (high risk types 16 and 18). Measures of antibody reactivity were log transformed and analyzed using logistic regression. Results: We found no association between KIV, WUV, and MCV antibody levels and incident lung cancer (P-corrected for multiple comparisons >0.10 for all trend tests). We also found no association with HPV-16, 18, 31, 33, 52, and 58 seropositivity (P-corrected for multiple comparisons >0.05 for all). Conclusions: Future studies of infectious etiologies of lung cancer should look beyond HPyVs and HPVs as candidate infectious agents. C1 [Colombara, Danny V.; Manhart, Lisa E.; Hawes, Stephen E.; Weiss, Noel S.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Colombara, Danny V.; Carter, Joseph J.; Weiss, Noel S.; Hughes, James P.; Galloway, Denise A.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Hughes, James P.] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Qiao, You-Lin] Chinese Acad Med Sci, Inst Canc, Dept Canc Epidemiol, Beijing 100021, Peoples R China. [Taylor, Philip R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Smith, Jennifer S.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Colombara, Danny V.] Univ Washington, Inst Hlth Metr & Evaluat, 2301 5th Ave,Suite 600, Seattle, WA 98121 USA. RP Colombara, DV (reprint author), Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA.; Colombara, DV (reprint author), Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA.; Colombara, DV (reprint author), Univ Washington, Inst Hlth Metr & Evaluat, 2301 5th Ave,Suite 600, Seattle, WA 98121 USA. EM dvc2@uw.edu RI Qiao, You-Lin/B-4139-2012 OI Qiao, You-Lin/0000-0001-6380-0871 FU Fogarty International Clinical Research Scholars and Fellows Program at Vanderbilt University [R24 TW007988]; National Cancer Institute [R25 CA094880]; Intramural Research Program of the NIH; National Cancer Institute; Division of Cancer Epidemiology and Genetics FX This work was supported by the Fogarty International Clinical Research Scholars and Fellows Program at Vanderbilt University [R24 TW007988 trainee support to DVC]; the National Cancer Institute [R25 CA094880 trainee support to DVC]; the Intramural Research Program of the NIH, the National Cancer Institute, and the Division of Cancer Epidemiology and Genetics; and the generous support of many individuals through Experiement.com. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JUN 1 PY 2016 VL 16 AR 342 DI 10.1186/s12885-016-2381-3 PG 11 WC Oncology SC Oncology GA DN3MC UT WOS:000376965300001 PM 27246610 ER PT J AU Hu, JP Lee, D Hu, S Zhang, S Chao, H Li, CSR AF Hu, Jianping Lee, Dianne Hu, Sien Zhang, Sheng Chao, Herta Li, Chiang-shan R. TI Individual variation in the neural processes of motor decisions in the stop signal task: the influence of novelty seeking and harm avoidance personality traits SO BRAIN STRUCTURE & FUNCTION LA English DT Article DE Anxiety; Impulsivity; TPQ; Reaction time; No-go ID HUMAN ORBITOFRONTAL CORTEX; IOWA GAMBLING TASK; RISK-TAKING; FUNCTIONAL CONNECTIVITY; COGNITIVE CONTROL; ANXIOUS YOUTH; FMRI; ANALOG; ACTIVATION; BRAIN AB Personality traits contribute to variation in human behavior, including the propensity to take risk. Extant work targeted risk-taking processes with an explicit manipulation of reward, but it remains unclear whether personality traits influence simple decisions such as speeded versus delayed responses during cognitive control. We explored this issue in an fMRI study of the stop signal task, in which participants varied in response time trial by trial, speeding up and risking a stop error or slowing down to avoid errors. Regional brain activations to speeded versus delayed motor responses (risk-taking) were correlated to novelty seeking (NS), harm avoidance (HA) and reward dependence (RD), with age and gender as covariates, in a whole brain regression. At a corrected threshold, the results showed a positive correlation between NS and risk-taking responses in the dorsomedial prefrontal, bilateral orbitofrontal, and frontopolar cortex, and between HA and risk-taking responses in the parahippocampal gyrus and putamen. No regional activations varied with RD. These findings demonstrate that personality traits influence the neural processes of executive control beyond behavioral tasks that involve explicit monetary reward. The results also speak broadly to the importance of characterizing inter-subject variation in studies of cognition and brain functions. C1 [Hu, Jianping; Lee, Dianne; Hu, Sien; Zhang, Sheng; Li, Chiang-shan R.] Yale Univ, Sch Med, Dept Psychiat, 333 Cedar St, New Haven, CT 06519 USA. [Hu, Jianping] S China Normal Univ, Sch Psychol, Guangzhou 510631, Guangdong, Peoples R China. [Lee, Dianne] NIH, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Chao, Herta] Yale Univ, Sch Med, Dept Internal Med, 333 Cedar St, New Haven, CT 06519 USA. [Chao, Herta] VA Connecticut Hlth Care Syst, Med Serv, West Haven, CT 06516 USA. [Li, Chiang-shan R.] Yale Univ, Sch Med, Dept Neurobiol, 333 Cedar St, New Haven, CT 06519 USA. [Li, Chiang-shan R.] Yale Univ, Sch Med, Interdept Neurosci Program, 333 Cedar St, New Haven, CT 06519 USA. [Li, Chiang-shan R.] Connecticut Mental Hlth Ctr, S112,34 Pk St, New Haven, CT 06519 USA. RP Li, CSR (reprint author), Yale Univ, Sch Med, Dept Psychiat, 333 Cedar St, New Haven, CT 06519 USA.; Li, CSR (reprint author), Yale Univ, Sch Med, Dept Neurobiol, 333 Cedar St, New Haven, CT 06519 USA.; Li, CSR (reprint author), Yale Univ, Sch Med, Interdept Neurosci Program, 333 Cedar St, New Haven, CT 06519 USA.; Li, CSR (reprint author), Connecticut Mental Hlth Ctr, S112,34 Pk St, New Haven, CT 06519 USA. EM chiang-shan.li@yale.edu RI Li, Chiang-Shan/J-2813-2016 OI Li, Chiang-Shan/0000-0002-9393-1212 FU NIH [K02DA026990, R01DA023248, R01AA021449]; Scientific Research Foundation of Graduate School of South China Normal University [2013kyjj025] FX This study was supported by NIH grants K02DA026990, R01DA023248, R01AA021449. Jianping Hu was supported by the Scientific Research Foundation of Graduate School of South China Normal University (Grant 2013kyjj025). NR 93 TC 1 Z9 1 U1 4 U2 11 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2653 EI 1863-2661 J9 BRAIN STRUCT FUNCT JI Brain Struct. Funct. PD JUN PY 2016 VL 221 IS 5 BP 2607 EP 2618 DI 10.1007/s00429-015-1061-4 PG 12 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA DN4DB UT WOS:000377012100014 PM 25989852 ER PT J AU Wang, HH Drake, SK Yong, C Gucek, M Tropea, M Rosenberg, AZ Dekker, JP Suffredini, AF AF Wang, Honghui Drake, Steven K. Yong, Chen Gucek, Marjan Tropea, Margaret Rosenberg, Avi Z. Dekker, John P. Suffredini, Anthony F. TI A Novel Peptidomic Approach to Strain Typing of Clinical Acinetobacter baumannii Isolates Using Mass Spectrometry SO CLINICAL CHEMISTRY LA English DT Article ID DESORPTION IONIZATION-TIME; RESISTANCE; IDENTIFICATION AB BACKGROUND: Acinetobacter baumannii is a common nosocomial pathogen and strain-typing methods play an important role in hospital outbreak investigations and epidemiologic surveillance. We describe a method for identifying strain-specific peptide markers based on LC-MS/MS profiling of digested peptides. This method classified a test set of A. baumannii isolates collected from a hospital outbreak with discriminatory performance exceeding that of MALDI-TOF mass spectrometry. METHODS: Following the construction of a species "pan-peptidome" by in silico translation and digestion of whole genome sequences, a hypothetical set of genome-specific peptides for an isolate was constructed from the disjoint set of the pan-peptidome and the isolate's calculated peptidome. The genome-specific peptidome guided selection of highly expressed genome-specific peptides from LC-MS/MS experimental profiles as potential peptide markers. The species specificity of each experimentally identified genome-specific peptide was confirmed through a Unipept lowest common ancestor analysis. RESULTS: Fifteen A. baumannii isolates were analyzed to derive a set of genome- and species-specific peptides that could be used as peptide markers Identified peptides were cross-checked with protein BLAST against a set of 22 A. baumannii whole genome sequences. A subset of these peptide markers was confirmed to be present in the actual peptide profiles generated by multiple reaction monitoring and targeted LC-MS/MS. The experimentally identified peptides separated these isolates into 6 strains that agreed with multilocus sequence typing analysis performed on the same isolates. CONCLUSIONS: This approach may be generalizable to other bacterial species, and the peptides may be useful for rapid MS strain tracking of isolates with broad application to infectious disease diagnosis. (C) 2016 American Association for Clinical Chemistry C1 [Wang, Honghui; Drake, Steven K.; Tropea, Margaret; Suffredini, Anthony F.] NHLBI, Dept Crit Care Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Yong, Chen; Gucek, Marjan] NHLBI, Prote Core Facil, Bldg 10, Bethesda, MD 20892 USA. [Rosenberg, Avi Z.] NIDDK, Kidney Dis Sect, Bethesda, MD 20892 USA. [Dekker, John P.] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Suffredini, AF (reprint author), NIH, Dept Crit Care Med, Ctr Clin, 10 Ctr Dr, Bethesda, MD 20892 USA. EM asuffredini@cc.nih.gov FU Intramural Research Program of the Clinical Center; National Heart, Lung and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; M. Gucek Intramural Research Program, the National Heart, Lung and Blood Institute FX Intramural Research Program of the Clinical Center, the National Heart, Lung and Blood Institute, and the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; M. Gucek Intramural Research Program, the National Heart, Lung and Blood Institute. NR 19 TC 1 Z9 1 U1 5 U2 5 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2016 VL 62 IS 6 BP 866 EP 875 DI 10.1373/clinchem.2015.253468 PG 10 WC Medical Laboratory Technology SC Medical Laboratory Technology GA DN4QI UT WOS:000377051900014 PM 27117471 ER PT J AU Cohen-Fix, O Kutay, U AF Cohen-Fix, Orna Kutay, Ulrike TI Editorial overview: The cell nucleus: Plastic, elastic and fantastic SO CURRENT OPINION IN CELL BIOLOGY LA English DT Editorial Material C1 [Cohen-Fix, Orna] NIDDK, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. [Kutay, Ulrike] ETH, Inst Biochem, Dept Biol, CH-8093 Zurich, Switzerland. RP Cohen-Fix, O (reprint author), NIDDK, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 EI 1879-0410 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD JUN PY 2016 VL 40 BP IV EP V DI 10.1016/j.ceb.2016.05.007 PG 2 WC Cell Biology SC Cell Biology GA DN3XF UT WOS:000376996800001 PM 27242262 ER PT J AU Ebrahimi, H Cooper, JP AF Ebrahimi, Hani Cooper, Julia Promisel TI Finding a place in the SUN: telomere maintenance in a diverse nuclear landscape SO CURRENT OPINION IN CELL BIOLOGY LA English DT Review ID DEPENDENT UBIQUITIN LIGASE; CONTROLS DNA-REPLICATION; PROTEIN PHOSPHATASE 1; FISSION YEAST; BUDDING YEAST; PERIPHERAL HETEROCHROMATIN; SACCHAROMYCES-CEREVISIAE; GENOME ARCHITECTURE; SPINDLE FORMATION; ANCHOR TELOMERES AB Telomeres function in the context of a complex nuclear milieu in which telomeres tend to occupy distinct subnuclear regions. Indeed, regulation of the subnuclear positioning of telomeres is conserved from yeast to human, raising the age-old question: to what extent is location important for function? In mitotically dividing cells, the positioning of telomeres affects their epigenetic state and influences telomere processing and synthesis. In meiotic cells, telomere location is important for homologue pairing, centromere assembly and spindle formation. Here we focus on recent insights into the functions of telomere positioning in maintaining genome integrity. C1 [Ebrahimi, Hani; Cooper, Julia Promisel] NCI, Telomere Biol Sect, LBMB, NIH, Bethesda, MD 20892 USA. RP Cooper, JP (reprint author), NCI, Telomere Biol Sect, LBMB, NIH, Bethesda, MD 20892 USA. EM julie.cooper@nih.gov FU National Cancer Institute FX We thank our lab members for discussion. Research in our laboratory is funded by the National Cancer Institute. NR 69 TC 1 Z9 1 U1 3 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 EI 1879-0410 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD JUN PY 2016 VL 40 BP 145 EP 152 DI 10.1016/j.ceb.2016.03.011 PG 8 WC Cell Biology SC Cell Biology GA DN3XF UT WOS:000376996800020 PM 27064212 ER PT J AU Deng, XH Wu, DK AF Deng, Xiaohong Wu, Doris K. TI Temporal coupling between specifications of neuronal and macular fates of the inner ear SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Transplantation; Fate determination; Inner ear development; Lineage; Neuronal fate; Sensory fate; Vestibular ganglion; Auditory ganglion; Utricular macula; Saccular macula ID VESTIBULAR NEURONS; OTIC VESICLE; EXPRESSION; GATA3; CLOSURE; CELLS AB The inner ear is a complex organ comprised of various specialized sensory organs for detecting sound and head movements. The timing of specification for these sensory organs, however, is not clear. Previous fate mapping results of the inner ear indicate that vestibular and auditory ganglia and two of the vestibular sensory organs, the utricular macula (UM) and saccular macula (SM), are lineage related. Based on the medial-lateral relationship where respective auditory and vestibular neuroblasts exit from the otic epithelium and the subsequent formation of the medial SM and lateral UM in these regions, we hypothesized that specification of the two lateral structures, the vestibular ganglion and the UM are coupled and likewise for the two medial structures, the auditory ganglion and the SM. We tested this hypothesis by surgically inverting the primary axes of the otic cup in ovo and investigating the fate of the vestibular neurogenic region, which had been spotted with a lipophilic dye. Our results showed that the laterally-positioned, dye-associated, vestibular ganglion and UM were largely normal in transplanted ears, whereas both auditory ganglion and SM showed abnormalities suggesting the lateral but not the medial-derived structures were mostly specified at the time of transplantation. Both of these results are consistent with a temporal coupling between neuronal and macular fate specifications. Published by Elsevier Inc. C1 [Deng, Xiaohong; Wu, Doris K.] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. [Deng, Xiaohong] Univ Maryland, Sch Med, Dept Otorhinolaryngol Head & Neck Surg, Baltimore, MD 21201 USA. RP Wu, DK (reprint author), NIDCD, 35A Convent Dr,Rm 1D824, Bethesda, MD 20892 USA. EM wud@nidcd.nih.gov FU United States National Institute on Deafness and Other Communication Disorders Intramural program [ZIA DC000021-22] FX The authors would like to thank Eric Yi for conducting 3D reconstructions, Drs. Lisa Cunningham and Elizabeth Driver for critical reading of the manuscript, The work was supported by United States National Institute on Deafness and Other Communication Disorders Intramural program awarded to D.K.W. (Grant number: ZIA DC000021-22). We thank NIH Medical Arts for illustrating Figure 1. NR 20 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2016 VL 414 IS 1 BP 21 EP 33 DI 10.1016/j.ydbio.2016.04.008 PG 13 WC Developmental Biology SC Developmental Biology GA DN1FT UT WOS:000376812400005 PM 27083418 ER PT J AU Aviles-Santa, ML Hsu, LL Arredondo, M Menke, A Werner, E Thyagarajan, B Heiss, G Teng, YP Schneiderman, N Giachello, AL Gallo, LC Talavera, GA Cowie, CC AF Aviles-Santa, M. Larissa Hsu, Lucy L. Arredondo, Mario Menke, Andy Werner, Ellen Thyagarajan, Bharat Heiss, Gerardo Teng, Yanping Schneiderman, Neil Giachello, Aida L. Gallo, Linda C. Talavera, Gregory A. Cowie, Catherine C. TI Differences in Hemoglobin A(1c) Between Hispanics/Latinos and Non-Hispanic Whites: An Analysis of the Hispanic Community Health Study/Study of Latinos and the 2007-2012 National Health and Nutrition Examination Survey SO DIABETES CARE LA English DT Article ID GLYCATED HEMOGLOBIN; DIABETES-MELLITUS; CARDIOVASCULAR RISK; ETHNIC-DIFFERENCES; PLASMA-GLUCOSE; HBA1C LEVELS; A1C LEVELS; ASSOCIATION; ADULTS; DIAGNOSIS AB OBJECTIVETo determine whether, after adjustment for glycemia and other selected covariates, hemoglobin A(1c) (HbA(1c)) differed among adults from six Hispanic/Latino heritage groups (Central American, Cuban, Dominican, Mexican, Puerto Rican, and South American) and between Hispanic/Latino and non-Hispanic white adults without self-reported diabetes.RESEARCH DESIGN AND METHODSWe performed a cross-sectional analysis of data from 13,083 individuals without self-reported diabetes from six Hispanic/Latino heritage groups, enrolled from 2008 to 2011 in the Hispanic Community Health Study/Study of Latinos, and 2,242 non-Hispanic white adults enrolled during the 2007-2012 cycles of the National Health and Nutrition Examination Survey. We compared HbA(1c) levels among Hispanics/Latinos and between Hispanics/Latinos and non-Hispanic whites before and after adjustment for age, sex, fasting (FPG) and 2-h post-oral glucose tolerance test (2hPG) glucose, anthropometric measurements, and selected biochemical and hematologic variables and after stratification by diabetes status: unrecognized diabetes (FPG 7.1 mmol/L or 2hPG 11.2 mmol/L), prediabetes (FPG 5.6-7.0 mmol/L or 2hPG 7.8-11.1 mmol/L), and normal glucose tolerance (FPG <5.6 mmol/L and 2hPG <7.8 mmol/L).RESULTSAdjusted mean HbA(1c) differed significantly across all seven groups (P < 0.001). Non-Hispanic whites had significantly lower HbA(1c) (P < 0.05) than each individual Hispanic/Latino heritage group. Upon stratification by diabetes status, statistically significant differences (P < 0.001) in adjusted mean HbA(1c) persisted across all seven groups.CONCLUSIONSHbA(1c) differs among Hispanics/Latinos of diverse heritage groups and between non-Hispanic whites and Hispanics/Latinos after adjustment for glycemia and other covariates. The clinical significance of these differences is unknown. C1 [Aviles-Santa, M. Larissa; Hsu, Lucy L.] NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Arredondo, Mario] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Menke, Andy] Social & Sci Syst Inc, Silver Spring, MD USA. [Werner, Ellen] NHLBI, Div Blood Dis & Resources, NIH, Bldg 10, Bethesda, MD 20892 USA. [Thyagarajan, Bharat] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Heiss, Gerardo; Teng, Yanping] Univ N Carolina, Collaborat Studies Coordinating Ctr, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Schneiderman, Neil] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Giachello, Aida L.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Gallo, Linda C.] San Diego State Univ, Dept Psychol, San Diego, CA 92182 USA. [Talavera, Gregory A.] San Diego State Univ, Inst Behav & Community Hlth, Grad Sch Publ Hlth, San Diego, CA 92182 USA. [Cowie, Catherine C.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Aviles-Santa, ML (reprint author), NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. EM avilessantal@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute [N01-HC65233, N01-HC65234, N01-HC65235, N01-HC65236, N01-HC65237]; NIH, National Institute on Minority Health and Health Disparities; NIH, National Institute on Deafness and Other Communication Disorders; NIH, National Institute of Dental and Craniofacial Research; NIH, National Institute of Diabetes and Digestive and Kidney Diseases; NIH, National Institute of Neurological Disorders and Stroke; NIH Office of Dietary Supplements FX The first phase of the HCHS/SOL was carried out as a collaborative study, supported by contracts from the National Heart, Lung, and Blood Institute, to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The collaborative and co-funded NIH institutes, centers, and offices for the study include the National Institute on Minority Health and Health Disparities, the National Institute on Deafness and Other Communication Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the NIH Office of Dietary Supplements. NR 40 TC 2 Z9 2 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD JUN PY 2016 VL 39 IS 6 BP 1010 EP 1017 DI 10.2337/dc15-2579 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DN3RJ UT WOS:000376980500028 PM 27208330 ER PT J AU Boyle, KD Keyes-Elstein, L Ehlers, MR McNamara, J Rigby, MR Gitelman, SE Weiner, LJ Much, KL Herold, KC AF Boyle, Karen D. Keyes-Elstein, Lynette Ehlers, Mario R. McNamara, James Rigby, Mark R. Gitelman, Stephen E. Weiner, Lia J. Much, Kristen L. Herold, Kevan C. TI Two- and Four-Hour Tests Differ in Capture of C-Peptide Responses to a Mixed Meal in Type 1 Diabetes SO DIABETES CARE LA English DT Letter ID PHASE-2 TRIAL C1 [Boyle, Karen D.; Keyes-Elstein, Lynette; Weiner, Lia J.; Much, Kristen L.] Rho Fed Syst Div, Chapel Hill, NC USA. [Ehlers, Mario R.] Immune Tolerance Network, San Francisco, CA USA. [McNamara, James] NIAID, Rockville, MD USA. [Rigby, Mark R.] Pharmaceut Co Johnson & Johnson, Janssen Res & Dev, Spring House, PA USA. [Gitelman, Stephen E.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA. [Herold, Kevan C.] Yale Univ, Dept Immunobiol & Internal Med, New Haven, CT USA. RP Boyle, KD (reprint author), Rho Fed Syst Div, Chapel Hill, NC USA. EM karen_boyle@rhoworld.com FU NCATS NIH HHS [UL1 TR000004]; NIAID NIH HHS [UM1 AI109565, HHSN272200800029C, N01AI15416, UM2 AI117870]; NIDDK NIH HHS [P30 DK045735] NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD JUN PY 2016 VL 39 IS 6 BP E76 EP E78 DI 10.2337/dc15-2077 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DN3RJ UT WOS:000376980500002 PM 27208317 ER PT J AU Smith, MT Guyton, KZ Gibbons, CF Fritz, JM Portier, CJ Rusyn, I DeMarini, DM Caldwell, JC Kavlock, RJ Lambert, PF Hecht, SS Bucher, JR Stewart, BW Baan, RA Cogliano, VJ Straif, K AF Smith, Martyn T. Guyton, Kathryn Z. Gibbons, Catherine F. Fritz, Jason M. Portier, Christopher J. Rusyn, Ivan DeMarini, David M. Caldwell, Jane C. Kavlock, Robert J. Lambert, Paul F. Hecht, Stephen S. Bucher, John R. Stewart, Bernard W. Baan, Robert A. Cogliano, Vincent J. Straif, Kurt TI Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review ID BENZENE-INDUCED LEUKEMIA; LOW-DOSE EXPOSURES; EPIGENETIC MECHANISMS; MOLECULAR-MECHANISMS; GENOMIC INSTABILITY; SIGNALING PATHWAYS; CHEMICAL-MIXTURES; NUCLEAR RECEPTORS; DRUG-METABOLISM; CANCER HALLMARK AB BACKGROUND: A recent review by the International Agency for Research on Cancer (IARC) updated the assessments of the > 100 agents classified as Group 1, carcinogenic to humans (IARC Monographs Volume 100, parts A-F). This exercise was complicated by the absence of a broadly accepted, systematic method for evaluating mechanistic data to support conclusions regarding human hazard from exposure to carcinogens. OBJECTIVES AND METHODS: IARC therefore convened two workshops in which an international Working Group of experts identified 10 key characteristics, one or more of which are commonly exhibited by established human carcinogens. DISCUSSION: These characteristics provide the basis for an objective approach to identifying and organizing results from pertinent mechanistic studies. The 10 characteristics are the abilities of an agent to 1) act as an electrophile either directly or after metabolic activation; 2) be genotoxic; 3) alter DNA repair or cause genomic instability; 4) induce epigenetic alterations; 5) induce oxidative stress; 6) induce chronic inflammation; 7) be immunosuppressive; 8) modulate -receptor-mediated effects; 9) cause immortalization; and 10) alter cell proliferation, cell death, or nutrient supply. CONCLUSION: We describe the use of the 10 key characteristics to conduct a systematic literature search focused on relevant end points and construct a graphical representation of the identified mechanistic information. Next, we use benzene and polychlorinated biphenyls as examples to illustrate how this approach may work in practice. The approach described is similar in many respects to those currently being implemented by the U.S. EPA's Integrated Risk Information System Program and the U.S. National Toxicology Program. C1 [Smith, Martyn T.] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Room 386, Berkeley, CA 94720 USA. [Guyton, Kathryn Z.; Baan, Robert A.; Straif, Kurt] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France. [Gibbons, Catherine F.; Fritz, Jason M.; DeMarini, David M.; Caldwell, Jane C.; Kavlock, Robert J.; Cogliano, Vincent J.] US EPA, Off Res & Dev, Washington, DC 20460 USA. [Gibbons, Catherine F.; Fritz, Jason M.; DeMarini, David M.; Caldwell, Jane C.; Kavlock, Robert J.; Cogliano, Vincent J.] US EPA, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Portier, Christopher J.] Environm Def Fund, Washington, DC USA. [Rusyn, Ivan] Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX USA. [Lambert, Paul F.] Univ Wisconsin, Sch Med & Publ Hlth, McArdle Lab Canc Res, Madison, WI USA. [Hecht, Stephen S.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA. [Bucher, John R.] NIEHS, Natl Toxicol Program, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Stewart, Bernard W.] Univ New S Wales, Fac Med, Sydney, NSW, Australia. RP Smith, MT (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Li Ka Shing Ctr, Room 386, Berkeley, CA 94720 USA. EM martynts@berkeley.edu RI Fritz, Jason/K-1439-2013; Rusyn, Ivan/S-2426-2016 FU National Institutes of Health, National Institute of Environmental Health Sciences [P42ES004705]; attorneys FX M.T.S. was supported by National Institutes of Health, National Institute of Environmental Health Sciences grant P42ES004705.; M. T. S. has received consulting fees from attorneys representing plaintiffs and defense in cases involving exposure to benzene and other chemical agents. The other authors declare they have no actual or potential competing financial interests. NR 73 TC 12 Z9 12 U1 8 U2 22 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 JUN PY 2016 VL 124 IS 6 BP 713 EP 721 DI 10.1289/ehp.1509912 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DN5BO UT WOS:000377081300013 PM 26600562 ER PT J AU Upson, K Harmon, QE Baird, DD AF Upson, Kristen Harmon, Quaker E. Baird, Donna D. TI Soy-Based Infant Formula Feeding and Ultrasound-Detected Uterine Fibroids among Young African-American Women with No Prior Clinical Diagnosis of Fibroids SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID DISEASE SUSCEPTIBILITY; RISK-FACTORS; BLACK-WOMEN; EXPOSURE; LEIOMYOMATA; AGE; PREVALENCE; ADULTHOOD AB BACKGROUND: Early-life soy phytoestrogen exposure has been shown in Eker rats to increase uterine fibroid incidence in adulthood. Two large epidemiologic cohorts have provided some support for increased fibroid risk with infant soy formula feeding in women, but both cohorts relied on self-report of clinically diagnosed fibroids. OBJECTIVE: We evaluated the relationship between infant soy formula feeding and ultrasound-detected fibroids. METHODS: The Study of Environment, Lifestyle & Fibroids (SELF) is an ongoing cohort study of 1,696 African-American women ages 23-34 years with baseline ultrasound screening to detect and measure fibroids >= 0.5 cm in diameter. Questionnaire data on soy formula feeding during infancy was ascertained for 1,553 participants (89% based on mother's report), of whom 345 were found to have fibroids. We estimated the association between soy formula feeding and fibroid prevalence and tumor number using log-binomial regression. Among those with fibroids, we compared fibroid size between soy formula-exposed and unexposed women using multivariable linear regression. RESULTS: We did not observe an association between soy formula feeding and fibroid prevalence [adjusted prevalence ratio (aPR) 0.9, 95% CI: 0.7, 1.3]. Nor were exposed women with fibroids more likely to have >= 2 tumors than unexposed women with fibroids (aPR 1.0, 95% CI: 0.7, 1.6). However, exposed women with fibroids had significantly larger fibroids than unexposed women with fibroids. On average, soy formula feeding was associated with a 32% increase in the diameter of the largest fibroid (95% CI: 6%, 65%) and a 127% increase in total tumor volume (95% CI: 12%, 358%). CONCLUSIONS: Our observation that women fed soy formula as infants have larger fibroids than unexposed women provides further support for persistent effects of early life phytoestrogen exposure on the uterus. C1 [Upson, Kristen; Harmon, Quaker E.; Baird, Donna D.] NIEHS, Epidemiol Branch, NIH, US Dept HHS, 111 TW Alexander Dr,Rall Bldg 101,MD A3-05, Res Triangle Pk, NC 27709 USA. RP Upson, K (reprint author), NIEHS, Epidemiol Branch, NIH, 111 TW Alexander Dr,Rall Bldg 101,MD A3-05, Res Triangle Pk, NC 27709 USA. EM kristen.upson@nih.gov RI Upson, Kristen/D-4504-2017; Baird, Donna/D-5214-2017 OI Upson, Kristen/0000-0001-9598-8776; Baird, Donna/0000-0002-5544-2653 FU Intramural Research Program of the National Institutes of Health; Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [1ZIA ES049013-19] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (1ZIA ES049013-19). NR 36 TC 1 Z9 1 U1 1 U2 5 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 JUN PY 2016 VL 124 IS 6 BP 769 EP 775 DI 10.1289/ehp.1510082 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DN5BO UT WOS:000377081300020 PM 26565393 ER PT J AU Gorodetsky, E Carli, V Sarchiapone, M Roy, A Goldman, D Enoch, MA AF Gorodetsky, E. Carli, V. Sarchiapone, M. Roy, A. Goldman, D. Enoch, M-A. TI Predictors for self-directed aggression in Italian prisoners include externalizing behaviors, childhood trauma and the serotonin transporter gene polymorphism 5-HTTLPR SO GENES BRAIN AND BEHAVIOR LA English DT Article DE 5-HTTLPR genotype; BGHA; childhood trauma; CTQ; externalizing behaviors; extraversion; prisoners; self-directed aggression; self-mutilators; serotonin transporter gene polymorphism; suicide attempters ID FLUID AMINE METABOLITES; SUICIDE ATTEMPTS; CEREBROSPINAL-FLUID; PERSONALITY-DISORDER; FOLLOW-UP; PSYCHIATRIC-INPATIENTS; BORDERLINE PERSONALITY; INJURIOUS-BEHAVIOR; MENTAL-DISORDER; RATING-SCALE AB Suicidal behavior and self-mutilation can be regarded as the expression of self-directed aggression and both are common in prison populations. We investigated the influence of externalizing behaviors, depressive symptoms, childhood trauma, 5-HTTLPR variants on self-directed aggression (N=145) in a group of 702 male Italian prisoners. Participants were comprehensively evaluated, including for psychiatric disorders, impulsive traits, lifetime aggressive behavior [Brown-Goodwin Lifetime History of Aggression (BGHA)], hostility, violent behavior during incarceration, depressive symptomatology [Hamilton Depression Rating Scale (HDRS)], childhood trauma [Childhood Trauma Questionnaire (CTQ)]. Logistic regression analysis showed false discovery rate corrected independent main effects of externalizing behaviors: BGHA (P=0.001), violent behavior in jail (P=0.007), extraversion (P=0.015); HDRS (P=0.0004), Axis I disorders (P=0.015), CTQ (P=0.004) and 5-HTTLPR genotype (P=0.02). Carriers of 5-HTTLPR high (LALA), intermediate (LALG, SLA) activity variants were more likely to have exhibited self-directed aggression relative to the low activity (LGLG, SLG, SS) variant: high/low: odds ratio (OR)=2.3, 95% confidence interval (CI) 1.27-4.68, P=0.007; intermediate/low: OR=1.96, 95% CI 1.09-3.68, P=0.025. The CTQ main effect was driven by physical abuse. There was no interactive effect of 5-HTTLPR and CTQ. Secondary logistic regression analyses in (1) all suicide attempters (N=88) and (2) all self-mutilators (N=104), compared with controls showed that in both groups, childhood trauma (P=0.008-0.01), depression (P=0.0004-0.001) were strong predictors. BGHA, violent behavior in jail predicted self-mutilation (P=0.002) but not suicide attempts (P=0.1). This study was able to distinguish differing influences on self-directed aggression between groups of closely related predictor variables within the externalizing behavioral domain. 5-HTTLPR had an independent, variant dosage effect. C1 [Gorodetsky, E.; Goldman, D.; Enoch, M-A.] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. [Carli, V.; Sarchiapone, M.] Univ Molise, Dept Med & Hlth Sci, Campobasso, Italy. [Carli, V.] Karolinska Inst, Natl Ctr Suicide Res & Prevent Mental Hlth NASP 3, Stockholm, Sweden. [Sarchiapone, M.] Natl Inst Hlth Migrat & Poverty, Rome, Italy. [Roy, A.] Vet Affairs Med Ctr, Psychiat Serv, E Orange, NJ USA. RP Gorodetsky, E (reprint author), NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. EM egorod@mail.nih.gov RI Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; Sarchiapone, Marco/0000-0001-9583-3117 FU Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health [AA000306-10] FX This research was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health AA000306-10. None of the authors have any disclosures or conflicts of interest to declare. NR 79 TC 1 Z9 1 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1601-1848 EI 1601-183X J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD JUN PY 2016 VL 15 IS 5 BP 465 EP 473 DI 10.1111/gbb.12293 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DN6VV UT WOS:000377215500003 PM 27062586 ER PT J AU Corral-Frias, NS Pizzagalli, DA Carre, JM Michalski, LJ Nikolova, YS Perlis, RH Fagerness, J Lee, MR Conley, ED Lancaster, TM Haddad, S Wolf, A Smoller, JW Hariri, AR Bogdan, R AF Corral-Frias, N. S. Pizzagalli, D. A. Carre, J. M. Michalski, L. J. Nikolova, Y. S. Perlis, R. H. Fagerness, J. Lee, M. R. Conley, E. Drabant Lancaster, T. M. Haddad, S. Wolf, A. Smoller, J. W. Hariri, A. R. Bogdan, R. TI COMT Val(158)Met genotype is associated with reward learning: a replication study and meta-analysis SO GENES BRAIN AND BEHAVIOR LA English DT Article DE Anhedonia; COMT; dopamine; meta-analysis; response bias; reward ID METHYLTRANSFERASE VAL(108/158)MET POLYMORPHISM; VENTRAL STRIATUM REACTIVITY; MAJOR DEPRESSIVE DISORDER; GENETIC ASSOCIATION; TREATMENT RESPONSE; PREFRONTAL CORTEX; HUMAN BRAIN; VAL158MET POLYMORPHISM; MIDBRAIN DOPAMINE; NUCLEUS-ACCUMBENS AB Identifying mechanisms through which individual differences in reward learning emerge offers an opportunity to understand both a fundamental form of adaptive responding as well as etiological pathways through which aberrant reward learning may contribute to maladaptive behaviors and psychopathology. One candidate mechanism through which individual differences in reward learning may emerge is variability in dopaminergic reinforcement signaling. A common functional polymorphism within the catechol-O-methyl transferase gene (COMT; rs4680, Val(158)Met) has been linked to reward learning, where homozygosity for the Met allele (linked to heightened prefrontal dopamine function and decreased dopamine synthesis in the midbrain) has been associated with relatively increased reward learning. Here, we used a probabilistic reward learning task to asses response bias, a behavioral form of reward learning, across three separate samples that were combined for analyses (age: 21.80 +/- 3.95; n = 392; 268 female; European-American: n = 208). We replicate prior reports that COMT rs4680 Met allele homozygosity is associated with increased reward learning in European-American participants ( = 0.20, t = 2.75, P < 0.01; R-2 = 0.04). Moreover, a meta-analysis of 4 studies, including the current one, confirmed the association between COMT rs4680 genotype and reward learning (95% CI -0.11 to -0.03; z = 3.2; P < 0.01). These results suggest that variability in dopamine signaling associated with COMT rs4680 influences individual differences in reward which may potentially contribute to psychopathology characterized by reward dysfunction. C1 [Corral-Frias, N. S.] Washington Univ, Dept Psychiat, St Louis, MO USA. [Corral-Frias, N. S.; Michalski, L. J.; Bogdan, R.] Washington Univ, Dept Psychol, BRAIN Lab, St Louis, MO 63130 USA. [Pizzagalli, D. A.] McLean Hosp, Ctr Depress Anxiety & Stress Res, 115 Mill St, Belmont, MA 02178 USA. [Pizzagalli, D. A.] McLean Hosp, Neuroimaging Ctr, 115 Mill St, Belmont, MA 02178 USA. [Pizzagalli, D. A.] Harvard Univ, Sch Med, Belmont, MA 02178 USA. [Carre, J. M.] Nipissing Univ, North Bay, ON, Canada. [Nikolova, Y. S.] Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Perlis, R. H.; Smoller, J. W.] Massachusetts Gen Hosp, Cambridge, MA USA. [Perlis, R. H.; Smoller, J. W.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Perlis, R. H.; Fagerness, J.; Haddad, S.; Smoller, J. W.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Lee, M. R.] NIDA, Intramural Res Program, Baltimore, MD USA. [Conley, E. Drabant] 23 & Me, Cardiff, S Glam, Wales. [Lancaster, T. M.] Cardiff Univ, Neurosci & Mental Hlth Res Inst, Cardiff CF10 3AX, S Glam, Wales. [Wolf, A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Wolf, A.] Harvard Univ, Sch Med, Boston, MA USA. [Hariri, A. R.] Duke Univ, Neurogenet Lab, Dept Psychol & Neurosci, Durham, NC USA. [Bogdan, R.] Washington Univ, Div Biol & Biomed Sci, St Louis, MO USA. RP Corral-Frias, NS (reprint author), Washington Univ, Campus Box 1125,Psychol Bldg,One Brookings Dr, St Louis, MO 63130 USA. EM corraln@psychiatry.wustl.edu FU NIMH [R01-MH068376, MH101521, T32-MH014677]; Sackler Scholar in Psychobiology; Duke University; National Institutes of Health [NIDA R01-DA033369, NIDA R01-DA031579, NIA R01-AG045231, T32-GM081739]; Klingenstein Third Generation Foundation; Otsuka America Pharmaceutical; Pfizer FX We are thankful to the Duke Neurogenetics Study (DNS) and Center for Depression, Anxiety and Stress Research (CDASR) participants and staff. Studies conducted at Harvard University were supported by NIMH Grant R01-MH068376 (awarded to D.A.P.), and a Sackler Scholar in Psychobiology (awarded to R.B.). D.A.P. was also partially supported by NIMH grant MH101521. The Duke Neurogenetics Study is supported by Duke University and the National Institutes of Health (NIDA R01-DA033369). A.R.H. receives additional support from the National Institutes of Health (NIDA R01-DA031579). N.C.S. was supported by NIMH (T32-MH014677). R.B. was supported by the Klingenstein Third Generation Foundation and receives additional support from the National Institutes of Health (NIA R01-AG045231). L.J.M. was supported by the National Institutes of Health (T32-GM081739). In the past three years, Dr. Pizzagalli has received honoraria/consulting fees from Otsuka America Pharmaceutical and Pfizer for activities unrelated to this project. All other authors report no conflict of interest. NR 91 TC 2 Z9 2 U1 3 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1601-1848 EI 1601-183X J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD JUN PY 2016 VL 15 IS 5 BP 503 EP 513 DI 10.1111/gbb.12296 PG 11 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DN6VV UT WOS:000377215500006 PM 27138112 ER PT J AU Kukurba, KR Parsana, P Balliu, B Smith, KS Zappala, Z Knowles, DA Fave, MJ Davis, JR Li, X Zhu, XW Potash, JB Weissman, MM Shi, JX Kundaje, A Levinson, DF Awadalla, P Mostafavi, S Battle, A Montgomery, SB AF Kukurba, Kimberly R. Parsana, Princy Balliu, Brunilda Smith, Kevin S. Zappala, Zachary Knowles, David A. Fave, Marie-Julie Davis, Joe R. Li, Xin Zhu, Xiaowei Potash, James B. Weissman, Myrna M. Shi, Jianxin Kundaje, Anshul Levinson, Douglas F. Awadalla, Philip Mostafavi, Sara Battle, Alexis Montgomery, Stephen B. TI Impact of the X Chromosome and sex on regulatory variation SO GENOME RESEARCH LA English DT Article ID GENE-EXPRESSION VARIATION; GENOME-WIDE ASSOCIATION; GENDER-DIFFERENCES; CELL-DEATH; OPEN CHROMATIN; SAMPLE-SIZE; DISEASE; POPULATION; TRANSCRIPTOME; ARCHITECTURE AB The X Chromosome, with its unique mode of inheritance, contributes to differences between the sexes at a molecular level, including sex-specific gene expression and sex-specific impact of genetic variation. Improving our understanding of these differences offers to elucidate the molecular mechanisms underlying sex-specific traits and diseases. However, to date, most studies have either ignored the X Chromosome or had insufficient power to test for the sex-specific impact of genetic variation. By analyzing whole blood transcriptomes of 922 individuals, we have conducted the first large-scale, genome-wide analysis of the impact of both sex and genetic variation on patterns of gene expression, including comparison between the X Chromosome and autosomes. We identified a depletion of expression quantitative trait loci (eQTL) on the X Chromosome, especially among genes under high selective constraint. In contrast, we discovered an enrichment of sex-specific regulatory variants on the X Chromosome. To resolve the molecular mechanisms underlying such effects, we generated chromatin accessibility data through ATAC-sequencing to connect sex-specific chromatin accessibility to sex-specific patterns of expression and regulatory variation. As sex-specific regulatory variants discovered in our study can inform sex differences in heritable disease prevalence, we integrated our data with genome-wide association study data for multiple immune traits identifying several traits with significant sex biases in genetic susceptibilities. Together, our study provides genome-wide insight into how genetic variation, the X Chromosome, and sex shape human gene regulation and disease. C1 [Kukurba, Kimberly R.; Balliu, Brunilda; Smith, Kevin S.; Zappala, Zachary; Davis, Joe R.; Li, Xin; Montgomery, Stephen B.] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Kukurba, Kimberly R.; Zappala, Zachary; Davis, Joe R.; Kundaje, Anshul; Montgomery, Stephen B.] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. [Parsana, Princy; Knowles, David A.; Battle, Alexis] Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21218 USA. [Fave, Marie-Julie; Awadalla, Philip] Univ Montreal, Dept Pediat, St Justine Univ Hosp, Res Ctr, Montreal, PQ H3T 1J4, Canada. [Zhu, Xiaowei; Levinson, Douglas F.] Stanford Univ, Dept Psychiat, Sch Med, Stanford, CA 94305 USA. [Potash, James B.] Univ Iowa Hosp & Clin, Dept Psychiat, Iowa City, IA 52242 USA. [Weissman, Myrna M.] Columbia Univ, Dept Psychiat, New York, NY 10032 USA. [Weissman, Myrna M.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Shi, Jianxin] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kundaje, Anshul; Montgomery, Stephen B.] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Mostafavi, Sara] Univ British Columbia, Dept Stat, Vancouver, BC V6T 1Z4, Canada. RP Montgomery, SB (reprint author), Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA.; Montgomery, SB (reprint author), Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA.; Battle, A (reprint author), Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21218 USA.; Montgomery, SB (reprint author), Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. EM ajbattle@cs.jhu.edu; smontgom@stanford.edu FU DoD, Air Force Office of Scientific Research, National Defense Science and Engineering Graduate (NDSEQ) Fellowship [32 CFR 168a]; Edward Mallinckrodt Jr. Foundation; NIH (Office of the Director) [R01MH101814]; NIH (National Human Genome Research Institute) [R01HG008150] FX We thank Stephen J. Galli for critical review of the manuscript. K. R. K. is supported by DoD, Air Force Office of Scientific Research, National Defense Science and Engineering Graduate (NDSEQ) Fellowship, 32 CFR 168a. S. B. M. is supported by the Edward Mallinckrodt Jr. Foundation. A. B. and S. B. M. are supported by the NIH (Office of the Director, R01MH101814; and National Human Genome Research Institute, R01HG008150). NR 74 TC 4 Z9 4 U1 5 U2 6 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD JUN PY 2016 VL 26 IS 6 BP 768 EP 777 DI 10.1101/gr.197897.115 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA DN5EY UT WOS:000377090400005 PM 27197214 ER PT J AU Gage, JC Joste, N Ronnett, BM Stoler, M Hunt, WC Schiffman, M Wheeler, CM AF Gage, Julia C. Joste, Nancy Ronnett, Brigitte M. Stoler, Mark Hunt, William C. Schiffman, Mark Wheeler, Cosette M. TI A comparison of cervical histopathology variability using whole slide digitized images versus glass slides: experience with a statewide registry (vol 44, pg 2542, 2013) SO HUMAN PATHOLOGY LA English DT Correction C1 [Gage, Julia C.; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20850 USA. [Joste, Nancy; Hunt, William C.; Wheeler, Cosette M.] Univ New Mexico, Hlth Sci Ctr, Ctr HPV Prevent, Dept Pathol, Albuquerque, NM 87131 USA. [Ronnett, Brigitte M.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Ronnett, Brigitte M.] Johns Hopkins Univ, Sch Med, Dept Gynecol & Obstet, Baltimore, MD 21205 USA. [Stoler, Mark] Univ Virginia, Dept Pathol, Charlottesville, VA 22908 USA. RP Wheeler, CM (reprint author), Univ New Mexico, Hlth Sci Ctr, Dept Pathol, House Prevent Epidemiol HOPE, Albuquerque, NM 87131 USA. EM cwheeler@salud.unm.edu FU NCI NIH HHS [R01 CA134779] NR 1 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0046-8177 EI 1532-8392 J9 HUM PATHOL JI Hum. Pathol. PD JUN PY 2016 VL 52 BP 201 EP 201 DI 10.1016/j.humpath.2016.04.001 PG 1 WC Pathology SC Pathology GA DN4TB UT WOS:000377059000027 PM 27141825 ER PT J AU Deplanche, M Alekseeva, L Semenovskaya, K Fu, CL Dessauge, F Finot, L Petzl, W Zerbe, H Le Loir, Y Rainard, P Smith, DGE Germon, P Otto, M Berkova, N AF Deplanche, Martine Alekseeva, Ludmila Semenovskaya, Ksenia Fu, Chih-Lung Dessauge, Frederic Finot, Laurence Petzl, Wolfram Zerbe, Holm Le Loir, Yves Rainard, Pascal Smith, David G. E. Germon, Pierre Otto, Michael Berkova, Nadia TI Staphylococcus aureus Phenol-Soluble Modulins Impair Interleukin Expression in Bovine Mammary Epithelial Cells SO INFECTION AND IMMUNITY LA English DT Article ID INNATE IMMUNE-RESPONSES; ESCHERICHIA-COLI; HUMAN NEUTROPHILS; DENDRITIC CELLS; IL-6 PRODUCTION; DAIRY-COWS; RECEPTOR; INFLAMMATION; INFECTION; PEPTIDES AB The role of the recently described interleukin-32 (IL-32) in Staphylococcus aureus-induced mastitis, an inflammation of the mammary gland, is unclear. We determined expression of IL-32, IL-6, and IL-8 in S. aureus-and Escherichia coli-infected bovine mammary gland epithelial cells. Using live bacteria, we found that in S. aureus-infected cells, induction of IL-6 and IL-8 expression was less pronounced than in E. coli-infected cells. Notably, IL-32 expression was decreased in S. aureus-infected cells, while it was increased in E. coli-infected cells. We identified the staphylococcal phenol-soluble modulin (PSM) peptides as key contributors to these effects, as IL-32, IL-6, and IL-8 expression by epithelial cells exposed to psm mutant strains was significantly increased compared to that in cells exposed to the isogenic S. aureus wild-type strain, indicating that PSMs inhibit the production of these interleukins. The use of genetically complemented strains confirmed this observation. Inasmuch as the decreased expression of IL-32, which is involved in dendritic cell maturation, impairs immune responses, our results support a PSM-dependent mechanism that allows for the development of chronic S. aureus-related mastitis. C1 [Deplanche, Martine; Alekseeva, Ludmila; Semenovskaya, Ksenia; Le Loir, Yves; Berkova, Nadia] INRA, STLO, UMR1253, F-35042 Rennes, France. [Deplanche, Martine; Alekseeva, Ludmila; Semenovskaya, Ksenia; Le Loir, Yves; Berkova, Nadia] Agrocampus Ouest, STLO, UMR1253, Rennes, France. [Alekseeva, Ludmila] Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow, Russia. [Fu, Chih-Lung; Otto, Michael] NIH, Bacteriol Lab, Bldg 10, Bethesda, MD 20892 USA. [Dessauge, Frederic; Finot, Laurence] INRA, PEGASE, UMR1348, St Gilles, France. [Petzl, Wolfram; Zerbe, Holm] Univ Munich, Clin Ruminants, Ctr Clin Vet Med, Munich, Germany. [Rainard, Pascal; Germon, Pierre] INRA, Infect & Sante Publ, UMR1282, F-37380 Nouzilly, France. [Rainard, Pascal; Germon, Pierre] Univ Tours, Infect & Sante Publ, UMR1282, Tours, France. [Smith, David G. E.] Univ Glasgow, Inst Infect Immun & Inflammat, Glasgow, Lanark, Scotland. [Smith, David G. E.] Heriot Watt Univ, Sch Life Sci, Edinburgh, Midlothian, Scotland. RP Berkova, N (reprint author), INRA, STLO, UMR1253, F-35042 Rennes, France.; Berkova, N (reprint author), Agrocampus Ouest, STLO, UMR1253, Rennes, France. EM nadia.berkova@rennes.inra.fr OI Smith, David/0000-0002-2484-2603; Zerbe, Holm/0000-0002-7972-4858 FU French National Institute for Agricultural Research (INRA), GISA [Ruminflame P10552]; ERA NET ANIHWA (KOLIMASTIR Convention) [ANR-13-ANWA-0003-06]; NIH (Intramural Research Program) FX This work, including the efforts of Martine Deplanche, Yves Le Loir, Pascal Rainard, Pierre GERMON, and Nadia Berkova, was funded by French National Institute for Agricultural Research (INRA), GISA (Ruminflame P10552). This work, including the efforts of Ludmila Alekseeva, Ksenia Semenovskaya, Pascal Rainard, David G. E. Smith, Pierre GERMON, and Nadia Berkova, was funded by ERA NET ANIHWA (KOLIMASTIR Convention ANR-13-ANWA-0003-06). This work, including the efforts of Michael Otto, was funded by NIH (Intramural Research Program). NR 48 TC 0 Z9 0 U1 3 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD JUN PY 2016 VL 84 IS 6 BP 1682 EP 1692 DI 10.1128/IAI.01330-15 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DN5KW UT WOS:000377106900002 PM 27001539 ER PT J AU Wang, XW Shaw, DK Sakhon, OS Snyder, GA Sundberg, EJ Santambrogio, L Sutterwala, FS Dumler, JS Shirey, KA Perkins, DJ Richard, K Chagas, AC Calvo, E Kopecky, J Kotsyfakis, M Pedra, JHF AF Wang, Xiaowei Shaw, Dana K. Sakhon, Olivia S. Snyder, Greg A. Sundberg, Eric J. Santambrogio, Laura Sutterwala, Fayyaz S. Dumler, J. Stephen Shirey, Kari Ann Perkins, Darren J. Richard, Katharina Chagas, Andrezza C. Calvo, Eric Kopecky, Jan Kotsyfakis, Michail Pedra, Joao H. F. TI The Tick Protein Sialostatin L2 Binds to Annexin A2 and Inhibits NLRC4-Mediated Inflammasome Activation SO INFECTION AND IMMUNITY LA English DT Article ID ANAPLASMA-PHAGOCYTOPHILUM INFECTION; HUMAN GRANULOCYTIC ANAPLASMOSIS; NAIP/NLRC4 INFLAMMASOMES; BACTERIAL LIGANDS; BORNE PATHOGENS; NEEDLE PROTEIN; RECOGNITION; DOCKING; SYSTEM; SERVER AB Tick saliva contains a number of effector molecules that inhibit host immunity and facilitate pathogen transmission. How tick proteins regulate immune signaling, however, is incompletely understood. Here, we describe that loop 2 of sialostatin L2, an anti-inflammatory tick protein, binds to annexin A2 and impairs the formation of the NLRC4 inflammasome during infection with the rickettsial agent Anaplasma phagocytophilum. Macrophages deficient in annexin A2 secreted significantly smaller amounts of interleukin-1 beta (IL-1 beta) and IL-18 and had a defect in NLRC4 inflammasome oligomerization and caspase-1 activation. Accordingly, Annexin a2-deficient mice were more susceptible to A. phagocytophilum infection and showed splenomegaly, thrombocytopenia, and monocytopenia. Providing translational support to our findings, better binding of annexin A2 to sialostatin L2 in sera from 21 out of 23 infected patients than in sera from control individuals was also demonstrated. Overall, we establish a unique mode of inflammasome evasion by a pathogen, centered on a blood-feeding arthropod. C1 [Wang, Xiaowei; Shaw, Dana K.; Sakhon, Olivia S.; Sundberg, Eric J.; Dumler, J. Stephen; Shirey, Kari Ann; Perkins, Darren J.; Richard, Katharina; Pedra, Joao H. F.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Snyder, Greg A.; Sundberg, Eric J.] Univ Maryland, Sch Med, Inst Human Virol, Dept Med, Baltimore, MD 21201 USA. [Santambrogio, Laura] Yeshiva Univ, Albert Einstein Coll Med, Dept Pathol, Dept Microbiol & Immunol, Bronx, NY USA. [Santambrogio, Laura] Yeshiva Univ, Albert Einstein Coll Med, Dept Orthoped Surg, Bronx, NY USA. [Sutterwala, Fayyaz S.] Univ Iowa, Dept Internal Med, Inflammat Program, Iowa City, IA 52242 USA. [Sutterwala, Fayyaz S.] Univ Iowa, Dept Internal Med, Div Infect Dis, Iowa City, IA 52242 USA. [Dumler, J. Stephen] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Chagas, Andrezza C.; Calvo, Eric] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Kopecky, Jan] Univ South Bohemia Ceske Budejovice, Fac Sci, Budweis, Czech Republic. [Kotsyfakis, Michail] Acad Sci Czech Republic, Ctr Biol, Inst Parasitol, Budweis, Czech Republic. [Sakhon, Olivia S.] Univ Calif Riverside, Sch Med, Div Biomed Sci, Riverside, CA 92521 USA. RP Pedra, JHF (reprint author), Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. EM jpedra@som.umaryland.edu RI Kotsyfakis, Michail/G-9525-2014; OI Kotsyfakis, Michail/0000-0002-7526-1876; Shaw, Dana/0000-0002-5212-2494; Calvo, Eric/0000-0001-7880-2730; Pedra, Joao/0000-0001-8740-2667 FU HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [R01 AI093653, R01 AI116523] FX This work, including the efforts of Joao H. F. Pedra, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (R01 AI093653). This work, including the efforts of Joao H. F. Pedra, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (R01 AI116523). NR 29 TC 2 Z9 2 U1 2 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD JUN PY 2016 VL 84 IS 6 BP 1796 EP 1805 DI 10.1128/IAI.01526-15 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DN5KW UT WOS:000377106900013 PM 27045038 ER PT J AU Boghossian, NS McDonald, SA Bell, EF Carlo, WA Brumbaugh, JE Stoll, BJ Laptook, AR Shankaran, S Walsh, MC Das, A Higgins, RD AF Boghossian, Nansi S. McDonald, Scott A. Bell, Edward F. Carlo, Waldemar A. Brumbaugh, Jane E. Stoll, Barbara J. Laptook, Abbot R. Shankaran, Seetha Walsh, Michele C. Das, Abhik Higgins, Rosemary D. CA Eunice Kennedy Shriver Natl Inst Human Dev Neonatal Res Network TI Association of Antenatal Corticosteroids With Mortality, Morbidity, and Neurodevelopmental Outcomes in Extremely Preterm Multiple Gestation Infants SO JAMA PEDIATRICS LA English DT Article ID RESPIRATORY-DISTRESS-SYNDROME; TWIN PREGNANCIES; GROWTH; BETAMETHASONE; BIRTH; SINGLETON; THERAPY AB IMPORTANCE Little is known about the effects of antenatal corticosteroids (ANS) on extremely preterm multiples. OBJECTIVE To examine if use of ANS is associated with improvement in major outcomes in extremely preterm multiples. DESIGN, SETTING, AND PARTICIPANTS Infants with a gestational age between 22 and 28 weeks born at a National Institute of Child Health and Human Development Neonatal Research Network center were studied between January 1998 and December 2013. Generalized estimating equation models were used to generate adjusted relative risks (aRR) controlling for important maternal and neonatal variables. EXPOSURE Antenatal corticosteroids. MAIN OUTCOMES AND MEASURES In-hospital mortality and the composite outcome of neurodevelopmental impairment at 18 to 22 months' corrected age or death before assessment. RESULTS A total of 6925 multiple-birth infants were studied; 5775 of 6925 (83.4%) were twins, and 4276 (61.7%) were white. Of the total study population, 6094 (88%) were born to women who received ANS. In-hospital mortality was lower among infants with exposure to ANS vs no exposure (aRR = 0.87; 95% CI, 0.78-0.96). Neurodevelopmental impairment or death was not significantly lower among those exposed to ANS vs no exposure (aRR = 0.93; 95% CI, 0.84-1.03). Other adverse outcomes that occurred less frequently among infants of women receiving ANS included severe intraventricular hemorrhage (aRR = 0.68; 95% CI, 0.58-0.78) and the combined outcomes of necrotizing enterocolitis or death and severe intraventricular hemorrhage or death. Subgroup analyses indicated that exposure to ANS was associated with a lower risk of mortality and a lower composite of neurodevelopmental impairment or mortality among nonsmall for gestational age multiples (aRR = 0.82; 95% CI, 0.74-0.92; and aRR = 0.89; 95% CI, 0.80-0.98, respectively) and a higher risk among small for gestational age multiples (aRR = 1.40; 95% CI, 1.02-1.93; and aRR = 1.62; 95% CI, 1.22-2.16, respectively). Antenatal corticosteroids were associated with higher neurodevelopmental impairment or mortality among multiple-birth infants of mothers with diabetes (aRR = 1.55; 95% CI, 1.00-2.38) but not among infants of mothers without diabetes (aRR = 0.91; 95% CI, 0.83-1.01). CONCLUSIONS AND RELEVANCE Compared with no exposure, exposure to ANS was associated with a lower risk of mortality in extremely preterm multiples, with no significant differences in the composite of neurodevelopmental impairment or death. Future research should investigate the increased risks of mortality and the composite of neurodevelopmental impairment or death associated with exposure to corticosteroids among small for gestational age multiples. C1 [Boghossian, Nansi S.] Univ S Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. [McDonald, Scott A.] RTI Int, Res Triangle Pk, NC USA. [Bell, Edward F.; Brumbaugh, Jane E.] Univ Iowa, Dept Pediat, 200 Hawkins Dr, Iowa City, IA 52242 USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Stoll, Barbara J.] Univ Texas Hlth Sci Ctr Houston, Dept Pediat, Houston, TX 77030 USA. [Laptook, Abbot R.] Brown Univ, Dept Pediat, Warren Alpert Med Sch, Providence, RI 02912 USA. [Laptook, Abbot R.] Women & Infants Hosp Rhode Isl, Providence, RI 02908 USA. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Walsh, Michele C.] Case Western Reserve Univ, Dept Pediat, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Das, Abhik] RTI Int, Rockville, MD USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Bell, EF (reprint author), Univ Iowa, Dept Pediat, 200 Hawkins Dr, Iowa City, IA 52242 USA. EM edward-bell@uiowa.edu FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Center for Research Resources; National Center for Advancing Translational Sciences FX The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Center for Research Resources, and the National Center for Advancing Translational Sciences provided grant support for the Neonatal Research Network Generic Database and Follow-up Studies through cooperative agreements. NR 24 TC 1 Z9 1 U1 0 U2 2 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 JUN PY 2016 VL 170 IS 6 BP 593 EP 601 DI 10.1001/jamapediatrics.2016.0104 PG 9 WC Pediatrics SC Pediatrics GA DN6LC UT WOS:000377185000019 PM 27088897 ER PT J AU Williams, A Hayashi, T Wolozny, D Yin, BJ Su, TC Betenbaugh, MJ Su, TP AF Williams, Abasha Hayashi, Teruo Wolozny, Daniel Yin, Bojiao Su, Tzu-Chieh Betenbaugh, Michael J. Su, Tsung-Ping TI The non-apoptotic action of Bcl-x(L): regulating Ca2+ signaling and bioenergetics at the ER-mitochondrion interface SO JOURNAL OF BIOENERGETICS AND BIOMEMBRANES LA English DT Article DE Bcl-x(L); Bioenergetics; Calicum signaling; Mitochondria; ER; MAM; IP(3)R3 ID HAMSTER OVARY CELLS; ENDOPLASMIC-RETICULUM; INOSITOL 1,4,5-TRISPHOSPHATE; CALCIUM; BCL-2; RECEPTORS; PROTEIN; METABOLISM; MODULATION; EXPRESSION AB Bcl-2 family proteins are known to competitively regulate Ca2+; however, the specific inter-organelle signaling pathways and related cellular functions are not fully elucidated. In this study, a portion of Bcl-x(L) was detected at the ER-mitochondrion interface or MAM (mitochondria-associated ER membrane) in association with type 3 inositol 1,4,5-trisphosphate receptors (IP(3)R3); an association facilitated by the BH4 and transmembrane domains of Bcl-x(L). Moreover, increasing Bcl-x(L) expression enhanced transient mitochondrial Ca2+ levels upon ER Ca2+ depletion induced by short-term, non-apoptotic incubation with thapsigargin (Tg), while concomitantly reducing cytosolic Ca2+ release. These mitochondrial changes appear to be IP(3)R3-dependent and resulted in decreased NAD/NADH ratios and higher electron transport chain oxidase activity. Interestingly, extended Tg exposure stimulated ER stress, but not apoptosis, and further enhanced TCA cycling. Indeed, confocal analysis indicated that Bcl-x(L) translocated to the MAM and increased its interaction with IP(3)R3 following extended Tg treatment. Thus, the MAM is a critical cell-signaling junction whereby Bcl-x(L) dynamically interacts with IP(3)R3 to coordinate mitochondrial Ca2+ transfer and alters cellular metabolism in order to increase the cells' bioenergetic capacity, particularly during periods of stress. C1 [Williams, Abasha; Hayashi, Teruo; Su, Tzu-Chieh; Su, Tsung-Ping] NIDA, Cellular Pathobiol Sect, IRP, NIH,DHHS, 333 Cassell Dr, Baltimore, MD 21224 USA. [Williams, Abasha; Wolozny, Daniel; Yin, Bojiao; Betenbaugh, Michael J.] Johns Hopkins Univ, Dept Biomol & Chem Engn, 3400 North Charles St, Baltimore, MD 21218 USA. [Williams, Abasha] FDA CDER OPS OBP, Div Biotechnol Review & Res 2, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Hayashi, Teruo] Seiwakai Nishikawa Hosp, 293-2 Minato Machi, Hamada, Shimane 6970052, Japan. RP Su, TP (reprint author), NIDA, Cellular Pathobiol Sect, IRP, NIH,DHHS, 333 Cassell Dr, Baltimore, MD 21224 USA.; Betenbaugh, MJ (reprint author), Johns Hopkins Univ, Dept Biomol & Chem Engn, 3400 North Charles St, Baltimore, MD 21218 USA. EM beten@jhu.edu; tsu@intra.nida.nih.gov FU NSF; Intramural Research Program, National Institute of Drug Abuse, NIH, DHHS FX The authors would like to thank R.Y. Tsien (University of California, San Diego, CA) for generously providing D1ER Ca2+ cameleon. We additionally thank J.M. Hardwick (Johns Hopkins University, Baltimore, MD) for providing Bcl-xL Delta BH4 and Bcl-xL Delta TM constructs, and Biolog, Inc. for providing the use of its Omnilog microarray system. This work is supported by the NSF and the Intramural Research Program, National Institute of Drug Abuse, NIH, DHHS. NR 81 TC 2 Z9 2 U1 1 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0145-479X EI 1573-6881 J9 J BIOENERG BIOMEMBR JI J. Bioenerg. Biomembr. PD JUN PY 2016 VL 48 IS 3 BP 211 EP 225 DI 10.1007/s10863-016-9664-x PG 15 WC Biophysics; Cell Biology SC Biophysics; Cell Biology GA DN4GT UT WOS:000377022700004 PM 27155879 ER PT J AU Fenerty, KE Patronas, NJ Heery, CR Gulley, JL Folio, LR AF Fenerty, Kathleen E. Patronas, Nicholas J. Heery, Christopher R. Gulley, James L. Folio, Les R. TI Resources Required for Semi-Automatic Volumetric Measurements in Metastatic Chordoma: Is Potentially Improved Tumor Burden Assessment Worth the Time Burden? SO JOURNAL OF DIGITAL IMAGING LA English DT Article DE Radiology workflow; Segmentation; Clinical oncology; Efficiency; PACS ID SOLID TUMORS; CT; INFORMATICS; EFFICIENCY; CRITERIA; THERAPY; LESIONS; PACS AB The Response Evaluation Criteria in Solid Tumors (RECIST) is the current standard for assessing therapy response in patients with malignant solid tumors; however, volumetric assessments are thought to be more representative of actual tumor size and hence superior in predicting patient outcomes. We segmented all primary and metastatic lesions in 21 chordoma patients for comparison to RECIST. Primary tumors were segmented on MR and validated by a neuroradiologist. Metastatic lesions were segmented on CT and validated by a general radiologist. We estimated times for a research assistant to segment all primary and metastatic chordoma lesions using semi-automated volumetric segmentation tools available within our PACS (v12.0, Carestream, Rochester, NY), as well as time required for radiologists to validate the segmentations. We also report success rates of semi-automatic segmentation in metastatic lesions on CT and time required to export data. Furthermore, we discuss the feasibility of volumetric segmentation workflow in research and clinical settings. The research assistant spent approximately 65 h segmenting 435 lesions in 21 patients. This resulted in 1349 total segmentations (average 2.89 min per lesion) and over 13,000 data points. Combined time for the neuroradiologist and general radiologist to validate segmentations was 45.7 min per patient. Exportation time for all patients totaled only 6 h, providing time-saving opportunities for data managers and oncologists. Perhaps cost-neutral resource reallocation can help acquire volumes paralleling our example workflow. Our results will provide researchers with benchmark resources required for volumetric assessments within PACS and help prepare institutions for future volumetric assessment criteria. C1 [Fenerty, Kathleen E.; Heery, Christopher R.] NCI, Lab Tumor Immunol & Biol, CCR, NIH, Bethesda, MD 20892 USA. [Patronas, Nicholas J.; Folio, Les R.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Gulley, James L.] NCI, Genitourinary Malignancies Branch, CCR, NIH, Bethesda, MD 20892 USA. RP Fenerty, KE (reprint author), NCI, Lab Tumor Immunol & Biol, CCR, NIH, Bethesda, MD 20892 USA. EM kfenerty@iupui.edu; npatronas@cc.nih.gov; heerycr@mail.nih.gov; gulleyj@mail.nih.gov; les.folio@nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU Intramural Research Program, National Institutes of Health Clinical Center FX Supported by Intramural Research Program, National Institutes of Health Clinical Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 18 TC 1 Z9 1 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0897-1889 EI 1618-727X J9 J DIGIT IMAGING JI J. Digit. Imaging PD JUN PY 2016 VL 29 IS 3 BP 357 EP 364 DI 10.1007/s10278-015-9846-9 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DN3AG UT WOS:000376933800013 PM 26596767 ER PT J AU Arcaz, AC Huestis, DL Dao, A Yaro, AS Diallo, M Andersen, J Blomquist, GJ Lehmann, T AF Arcaz, Arthur C. Huestis, Diana L. Dao, Adama Yaro, Alpha S. Diallo, Moussa Andersen, John Blomquist, Gary J. Lehmann, Tovi TI Desiccation tolerance in Anopheles coluzzii: the effects of spiracle size and cuticular hydrocarbons SO JOURNAL OF EXPERIMENTAL BIOLOGY LA English DT Article DE Mosquito; Aestivation; Anopheles gambiae; Desiccation resistance; Water balance; Dry season ID FASO WEST-AFRICA; MOLECULAR-FORMS; DROSOPHILA-MELANOGASTER; GAMBIAE COMPLEX; BURKINA-FASO; DRY-SEASON; WATER CONSERVATION; MALARIA MOSQUITO; METABOLIC-RATE; CULEX-PIPIENS AB The African malaria mosquitoes Anopheles gambiae and Anopheles coluzzii range over forests and arid areas, where they withstand dry spells and months-long dry seasons, suggesting variation in their desiccation tolerance. We subjected a laboratory colony (G3) and wild Sahelian mosquitoes during the rainy and dry seasons to desiccation assays. The thoracic spiracles and amount and composition of cuticular hydrocarbons (CHCs) of individual mosquitoes were measured to determine the effects of these traits on desiccation tolerance. The relative humidity of the assay, body water available, rate of water loss and water content at death accounted for 88% of the variation in desiccation tolerance. Spiracle size did not affect the rate of water loss or desiccation tolerance of the colony mosquitoes, as was the case for the total CHCs. However, six CHCs accounted for 71% of the variation in desiccation tolerance and three accounted for 72% of the variation in the rate of water loss. Wild A. coluzzii exhibited elevated desiccation tolerance during the dry season. During that time, relative thorax and spiracle sizes were smaller than during the rainy season. A smaller spiracle size appeared to increase A. coluzzii's desiccation tolerance, but was not statistically significant. Seasonal changes in CHC composition were detected in Sahelian A. coluzzii. Stepwise regression models suggested the effect of particular CHCs on desiccation tolerance. In conclusion, the combination of particular CHCs along with the total amount of CHCs is a primary mechanism conferring desiccation tolerance in A. coluzzii, while variation in spiracle size might be a secondary mechanism. C1 [Arcaz, Arthur C.; Huestis, Diana L.; Andersen, John; Lehmann, Tovi] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Dao, Adama; Yaro, Alpha S.; Diallo, Moussa] Malaria Res & Training Ctr, Fac Med Pharm & Odontostomatol, BP 1805, Bamako, Mali. [Blomquist, Gary J.] Univ Nevada, Dept Biochem & Mol Biol, Reno, NV 89557 USA. [Huestis, Diana L.] US Dept State, Off US Global AIDS Coordinator & Hlth Diplomacy, Washington, DC 20520 USA. RP Lehmann, T (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM TLehmann@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences [P20GM103440] FX This study was supported (in part) by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases; and by a grant from the National Institute of General Medical Sciences (P20GM103440). Deposited in PMC for immediate release. NR 66 TC 1 Z9 1 U1 6 U2 10 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0022-0949 EI 1477-9145 J9 J EXP BIOL JI J. Exp. Biol. PD JUN PY 2016 VL 219 IS 11 BP 1675 EP 1688 DI 10.1242/jeb.135665 PG 14 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DN2EX UT WOS:000376878000018 PM 27207644 ER PT J AU Ma, C Greten, TF AF Ma, Chi Greten, Tim F. TI "Invisible" MDSC in tumor-bearing individuals after antibody depletion: fact or fiction? SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Editorial Material ID SUPPRESSOR-CELLS; NEUTROPHILS; MARKER C1 [Ma, Chi; Greten, Tim F.] NCI, Gastrointestinal Malignancy Sect, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Greten, TF (reprint author), NCI, NIH, CCR, Bldg 10,Rm 3B43,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tim.greten@nih.gov NR 10 TC 1 Z9 1 U1 6 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 JUN PY 2016 VL 99 IS 6 BP 794 EP 796 DI 10.1189/jlb.5CE0116-047R PG 3 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA DN2IN UT WOS:000376887400002 PM 27252522 ER PT J AU Whibley, N Tritto, E Traggiai, E Kolbinger, F Moulin, P Brees, D Coleman, BM Mamo, AJ Garg, AV Jaycox, JR Siebenlist, U Kammuller, M Gaffen, SL AF Whibley, Natasha Tritto, Elaine Traggiai, Elisabetta Kolbinger, Frank Moulin, Pierre Brees, Dominique Coleman, Bianca M. Mamo, Anna J. Garg, Abhishek V. Jaycox, Jillian R. Siebenlist, Ulrich Kammuller, Michael Gaffen, Sarah L. TI Antibody blockade of IL-17 family cytokines in immunity to acute murine oral mucosal candidiasis SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article ID CHRONIC MUCOCUTANEOUS CANDIDIASIS; HYPER-IGE SYNDROME; TUMOR-NECROSIS-FACTOR; HOST-DEFENSE; OROPHARYNGEAL CANDIDIASIS; CUTTING EDGE; TH17 CELLS; PRIMARY IMMUNODEFICIENCY; HETERODIMERIC CYTOKINE; FUNGAL-INFECTION AB Antibodies targeting IL-17A or its receptor, IL-17RA, are approved to treat psoriasis and are being evaluated for other autoimmune conditions. Conversely, IL-17 signaling is critical for immunity to opportunistic mucosal infections caused by the commensal fungus Candida albicans, as mice and humans lacking the IL-17R experience chronic mucosal candidiasis. IL-17A, IL-17F, and IL-17AF bind the IL-17RA-IL-17RC heterodimeric complex and deliver qualitatively similar signals through the adaptor Act1. Here, we used a mouse model of acute oropharyngeal candidiasis to assess the impact of blocking IL-17 family cytokines compared with specific IL-17 cytokine gene knockout mice. Anti-IL-17A antibodies, which neutralize IL-17A and IL-17AF, caused elevated oral fungal loads, whereas antiI-L-17AF and anti-IL-17F antibodies did not. Notably, there was a cooperative effect of blocking IL-17A, IL-17AF, and IL-17F together. Termination of anti-IL-17A treatment was associated with rapid C. albicans clearance. IL-17F deficient mice were fully resistant to oropharyngeal candidiasis, consistent with antibody blockade. However, IL-17A-deficient mice had lower fungal burdens than anti IL-17A-treated mice. Act1-deficient mice were much more susceptible to oropharyngeal candidiasis than anti-IL-17A antibody -treated mice, yet anti -IL-17A and anti-IL-17RA treatment caused equivalent susceptibilities. Based on microarray analyses of the oral mucosa during infection, only a limited number of genes were associated with oropharyngeal candidiasis susceptibility. In sum, we conclude that IL-17A is the main cytokine mediator of immunity in murine oropharyngeal candidiasis, but a cooperative relationship among IL-17A, IL-17AF, and IL-17F exists in vivo. Susceptibility displays the following hierarchy: IL-17RA- or Act1-deficiency > anti-IL-17A + anti-IL-17F antibodies > anti -IL-17A or anti-IL-17RA antibodies > IL-17A deficiency. C1 [Whibley, Natasha; Coleman, Bianca M.; Mamo, Anna J.; Garg, Abhishek V.; Jaycox, Jillian R.; Gaffen, Sarah L.] Univ Pittsburgh, Dept Med, Div Rheumatol & Clin Immunol, BST S702,200 Lothrop St, Pittsburgh, PA 15261 USA. [Tritto, Elaine; Traggiai, Elisabetta; Kolbinger, Frank; Moulin, Pierre; Brees, Dominique; Kammuller, Michael] Novartis Inst Biomed Res, Klybeckstr 141, CH-4057 Basel, Switzerland. [Siebenlist, Ulrich] NIAID, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Gaffen, SL (reprint author), Univ Pittsburgh, Dept Med, Div Rheumatol & Clin Immunol, BST S702,200 Lothrop St, Pittsburgh, PA 15261 USA.; Kammuller, M (reprint author), Novartis Inst Biomed Res, Klybeckstr 141, CH-4057 Basel, Switzerland. EM michael.kammueller@novartis.com; sarah.gaffen@pitt.edu FU U.S. National Institutes of Health (NIH) [DE022550, DE023815, AI107825]; Novartis; Intramural Research Program of National Institute of Allergy and Infectious Diseases, NIH FX S.L.G. was supported by the U.S. National Institutes of Health (NIH; Grants DE022550, DE023815, and AI107825) and a grant from Novartis. U.S. was supported by the Intramural Research Program of National Institute of Allergy and Infectious Diseases, NIH. The authors thank Dr. Y. Iwakura, University of Tokyo, for kindly providing IL-17A-/- and IL-17F-/- mice and Drs. M. McGeachy, J. Kolls, A. Waisman, and P. Biswas for helpful suggestions. NR 74 TC 3 Z9 3 U1 3 U2 3 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 JUN PY 2016 VL 99 IS 6 BP 1153 EP 1164 DI 10.1189/jlb.4A0915-42812 PG 12 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA DN2IN UT WOS:000376887400033 PM 26729813 ER PT J AU Aas, S Delmas, C AF Aas, Sean Delmas, Candice TI The ethics of sexual reorientation: what should clinicians and researchers do? SO JOURNAL OF MEDICAL ETHICS LA English DT Article ID DUAL-USE RESEARCH; ORIENTATION; WITNESSES; SCIENCES AB Technological measures meant to change sexual orientation are, we have argued elsewhere, deeply alarming, even and indeed especially if they are safe and effective. Here we point out that this in part because they produce a distinctive kind of 'clinical collective action problem', a sort of dilemma for individual clinicians and researchers: a treatment which evidently relieves the suffering of particular patients, but in the process contributes to a practice that substantially worsens the conditions that produce this suffering in the first place. We argue that the role obligations of clinicians to relieve the suffering of their patients put them in a poor position to solve this problem, though they can take measures to avoid complicity in the harms that would result from widespread use of individually safe and effective reorientation biotechnology. But in the end the medical community as a whole still seems obligated to provide these measures, if they become technologically feasible. Medical researchers are in a better position to prevent the harms that would result if reorientation techniques were safe, effective and widely available. We argue that the harms attendant on the development of safe and effective re-orientation techniques give researchers reason to avoid 'applied' research aimed at developing these techniques, and to be careful in the conduct of basic orientation research which might be applied in this way. C1 [Aas, Sean] NIH, Dept Bioeth, 10 Ctr Dr,Room 1C118, Bethesda, MD 20892 USA. [Delmas, Candice] Northeastern Univ, Dept Philosophy & Polit Sci, Boston, MA 02115 USA. RP Aas, S (reprint author), NIH, Dept Bioeth, 10 Ctr Dr,Room 1C118, Bethesda, MD 20892 USA. EM sean.aas@gmail.com NR 35 TC 0 Z9 0 U1 2 U2 2 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 JUN PY 2016 VL 42 IS 6 BP 340 EP 347 DI 10.1136/medethics-2016-103562 PG 8 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA DN5MJ UT WOS:000377112300002 PM 27145812 ER PT J AU Apolo, AB Lindenberg, L Shih, JH Mena, E Kim, JW Park, JC Alikhani, A McKinney, YY Weaver, J Turkbey, B Parnes, HL Wood, LV Madan, RA Gulley, JL Dahut, WL Kurdziel, KA Choyke, PL AF Apolo, Andrea B. Lindenberg, Liza Shih, Joanna H. Mena, Esther Kim, Joseph W. Park, Jong C. Alikhani, Anna McKinney, Yolanda Y. Weaver, Juanita Turkbey, Baris Parnes, Howard L. Wood, Lauren V. Madan, Ravi A. Gulley, James L. Dahut, William L. Kurdziel, Karen A. Choyke, Peter L. TI Prospective Study Evaluating (NaF)-F-18 PET/CT in Predicting Clinical Outcomes and Survival in Advanced Prostate Cancer SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE prostate cancer; NaF PET/CT; sodium fluoride; bone metastases; nuclear imaging in prostate cancer ID POSITRON-EMISSION-TOMOGRAPHY; PLANAR BONE-SCINTIGRAPHY; F-18-FLUORIDE PET; END-POINTS; METASTASES; STATISTICS; FLUORIDE; TECHNOLOGY; PATTERNS; ACCURATE AB This prospective pilot study evaluated the ability of (NaF)-F-18 PET/CT to detect and monitor bone metastases over time and its correlation with clinical outcomes and survival in advanced prostate cancer. Methods: Sixty prostate cancer patients, including 30 with and 30 without known bone metastases by conventional imaging, underwent (NaF)-F-18 PET/CT at baseline, 6 mo, and 12 mo. Positive lesions were verified on follow-up scans. Changes in SUVs and lesion number were correlated with prostate-specific antigen change, clinical impression, and overall survival. Results: Significant associations included the following: SUV and prostate-specific antigen percentage change at 6 mo (P = 0.014) and 12 mo (P = 0.0005); SUV maximal percentage change from baseline and clinical impression at 6 mo (P = 0.0147) and 6-12 mo (P = 0.0053); SUV change at 6 mo and overall survival (P = 0.018); number of lesions on (NaF)-F-18 PET/CT and clinical impression at baseline (P < 0.0001), 6 mo (P = 0.0078), and 12 mo (P = 0.0029); and number of lesions on (NaF)-F-18 PET/CT per patient at baseline and overall survival (P = 0.017). In an exploratory analysis, paired 99mTc-methylene diphosphonate bone scans (Tc-99m-BS) were available for 35 patients at baseline, 19 at 6 mo, and 14 at 12 mo (68 scans). Malignant lesions on (NaF)-F-18 PET/CT (n = 57) were classified on 99mTc-BS as malignant 65% of the time, indeterminate 25% of the time, and negative 10% of the time. Additionally, 69% of paired scans showed more lesions on (NaF)-F-18 PET/CT than on 99mTc-BS. Conclusion: The baseline number of malignant lesions and changes in SUV on follow-up (NaF)-F-18 PET/CT significantly correlate with clinical impression and overall survival. (NaF)-F-18 PET/CT detects more bone metastases earlier than 99mTc-BS and enhances detection of new bone disease in high-risk patients. C1 [Apolo, Andrea B.; Kim, Joseph W.; Park, Jong C.; Parnes, Howard L.; Madan, Ravi A.; Gulley, James L.; Dahut, William L.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, 10 Ctr Dr,12N226,MSC 1906, Bethesda, MD 20892 USA. [Lindenberg, Liza; Mena, Esther; Alikhani, Anna; McKinney, Yolanda Y.; Weaver, Juanita; Turkbey, Baris; Kurdziel, Karen A.; Choyke, Peter L.] NCI, Mol Imaging Program, Ctr Canc Res, NIH, 10 Ctr Dr,12N226,MSC 1906, Bethesda, MD 20892 USA. [Shih, Joanna H.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, 10 Ctr Dr,12N226,MSC 1906, Bethesda, MD 20892 USA. [Weaver, Juanita] Frederick Natl Lab Canc Res, Clin Res Directorate, Clin Monitoring Res Program, Leidos Biomed Res Inc, Frederick, MD USA. [Wood, Lauren V.] NCI, Vaccine Branch, Clin Trials Team, Ctr Canc Res,NIH, 10 Ctr Dr,12N226,MSC 1906, Bethesda, MD 20892 USA. RP Apolo, AB (reprint author), NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, 10 Ctr Dr,12N226,MSC 1906, Bethesda, MD 20892 USA. EM andrea.apolo@nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] 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 project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. No other potential conflict of interest relevant to this article was reported. NR 23 TC 5 Z9 5 U1 1 U2 2 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 JUN PY 2016 VL 57 IS 6 BP 886 EP 892 DI 10.2967/jnumed.115.166512 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DN4QN UT WOS:000377052400038 PM 26795292 ER PT J AU Beydoun, MA Fanelli-Kuczmarski, MT Shaked, D Dore, GA Beydoun, HA Rostant, OS Evans, MK Zonderman, AB AF Beydoun, May A. Fanelli-Kuczmarski, Marie T. Shaked, Danielle Dore, Greg A. Beydoun, Hind A. Rostant, Ola S. Evans, Michele K. Zonderman, Alan B. TI Alternative Pathway Analyses Indicate Bidirectional Relations between Depressive Symptoms, Diet Quality, and Central Adiposity in a Sample of Urban US Adults SO JOURNAL OF NUTRITION LA English DT Article DE depression; dietary quality; central adiposity; socioeconomic status; urban adults ID BODY-MASS INDEX; SOCIOECONOMIC-STATUS; LONGITUDINAL ASSOCIATIONS; PHYSICAL-ACTIVITY; HYPERCORTISOLEMIC DEPRESSION; WAIST CIRCUMFERENCE; ABDOMINAL OBESITY; MOOD DISORDERS; ENERGY-DENSITY; OLDER-ADULTS AB Background: Temporality between socioeconomic status (SES), depressive symptoms (DS), dietary quality (DO), and central adiposity (CA) is underexplored. Objectives: Alternative pathways linking SES to DQ, DS, and CA were tested and models compared, stratified by race and sex. Methods: With the use of data from the Healthy Aging in Neighborhoods of Diversity across the Life Span (baseline age: 30-64 y; 2 visits; mean follow-up: 4.9 y), 12 structural equation models (SM) were conducted and compared. Time dependent factors included the Center for Epidemiologic Studies-Depression [CES-D total score, baseline or visit 1 (v1), follow-up or visit 2 (v2), mean across visits (m), and annual rate of change (Delta)], 2010 Healthy Eating Index (HEI) (same notation), and central adiposity principal components' analysis score of waist circumference and trunk fat (kg) (Adip(cent)) (same notation). Sample sizes were white women (WW, n = 236), white men (WM, n = 159), African American women (AAW, n = 395), and African American men (AAM, n = 274), and a multigroup analysis within the SM framework was also conducted. Results: In the best-fitting model, overall,similar to 31% of the total effect of SES -> Adip(cent)(v2) (alpha +/- SE:-0.10 +/- 0.03, P < 0.05) was mediated through a combination of CES-D(v1) and AHEI. Two dominant pathways contributed to the indirect effect: SES ->(-)CES-D(v1)-> (+)Adip(cent)(v2) (-0.015) and SES -> (+) Delta HEI ->(-)Adip(cent)(v2) (-0.017), with a total indirect effect of-0.031 (P < 0.05). In a second best-fitting model, SES independently predicted Adip(cent)(v1,-0.069), Delta HEI(+0.037) and CES-D(v2,-2.70) (P< 0.05), with Adip(cent)(v1) marginally predicting Delta HEI(-0.014) and CES-D(v2, +0.67) (P< 0.10). These findings were indicative of DS's and CA's marginally significant bidirectional association (P < 0.10). Although best-fit selected models were consistent across race x sex categories, path coefficients differed significantly between groups. Specifically, SES -> Adip(cent)[v1(+0.11), v2(+0.14)] was positive.among AAM (P< 0 05), and the overall positive association of Adip(cent)(v1)-CES-D(v2) was specific to AAW (+0.97, P < 0.10). Conclusions: Despite consistent model fit, pathways linking SES to DQ, DS, and CA differed markedly among the race x sex groups. Our findings can inform the potential effectiveness of various mental health and dietary interventions. C1 [Beydoun, May A.; Shaked, Danielle; Dore, Greg A.; Rostant, Ola S.; Evans, Michele K.; Zonderman, Alan B.] NIA, Lab Epidemiol & Populat Sci, NIH, Intramural Res Program, Baltimore, MD 21224 USA. [Fanelli-Kuczmarski, Marie T.] Univ Delaware, Dept Hlth Nutr & Exercise Sci, Newark, DE USA. [Shaked, Danielle] Univ Maryland Baltimore Cty, Dept Psychol, Baltimore, MD 21228 USA. [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. RP Beydoun, MA (reprint author), NIA, Lab Epidemiol & Populat Sci, NIH, Intramural Res Program, Baltimore, MD 21224 USA. EM baydounm@mail.nih.gov OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institute on Aging, Intramural Research Program FX Supported by the National Institute on Aging, Intramural Research Program. NR 68 TC 1 Z9 1 U1 1 U2 7 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 JUN PY 2016 VL 146 IS 6 BP 1241 EP 1249 DI 10.3945/jn.115.229054 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DN4RI UT WOS:000377054500013 PM 27146916 ER PT J AU Jee, YH Baron, J AF Jee, Youn Hee Baron, Jeffrey TI The Biology of Stature SO JOURNAL OF PEDIATRICS LA English DT Editorial Material ID GROWTH-PLATE SENESCENCE; CATCH-UP GROWTH; LONGITUDINAL BONE-GROWTH; IDIOPATHIC SHORT STATURE; BODY-MASS INDEX; EPIPHYSEAL FUSION; FACTOR-I; HORMONE DEFICIENCY; DELAYED PUBERTY; GENE-EXPRESSION C1 [Jee, Youn Hee; Baron, Jeffrey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Dev, NIH, Bethesda, MD USA. RP Baron, J (reprint author), NIH, CRC, Room 1-3330,10 Ctr Dr MSC 1103, Bethesda, MD 20892 USA. EM jeffrey.baron@nih.gov FU Intramural NIH HHS [Z01 HD000640-13] NR 70 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 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JUN PY 2016 VL 173 BP 32 EP 38 DI 10.1016/j.jpeds.2016.02.068 PG 7 WC Pediatrics SC Pediatrics GA DN0QZ UT WOS:000376770200010 PM 27025909 ER PT J AU Kuban, KCK Joseph, RM O'Shea, TM Allred, EN Heeren, T Douglass, L Stafstrom, CE Jara, H Frazier, JA Hirtz, D Leviton, A AF Kuban, Karl C. K. Joseph, Robert M. O'Shea, Thomas M. Allred, Elizabeth N. Heeren, Timothy Douglass, Laurie Stafstrom, Carl E. Jara, Hernan Frazier, Jean A. Hirtz, Deborah Leviton, Alan CA Extremely Low Gestational Age Newb TI Girls and Boys Born before 28 Weeks Gestation: Risks of Cognitive, Behavioral, and Neurologic Outcomes at Age 10 Years SO JOURNAL OF PEDIATRICS LA English DT Article ID EXTREMELY PRETERM CHILDREN; INFLAMMATION-RELATED PROTEINS; NEONATAL HYPOXIA-ISCHEMIA; AUTISM SPECTRUM DISORDER; LOW-BIRTH-WEIGHT; SEX-DIFFERENCES; INFANTS; EPICURE; IMPACT; BLOOD AB Objectives To compare the prevalence of cognitive, neurologic, and behavioral outcomes at 10 years of age in 428 girls and 446 boys who were born extremely preterm. Study design A total of 889 of 966 eligible children previously enrolled in the multicenter Extremely Low Gestational Age Newborns Study from 2002-2004 were evaluated at 10 years of age. Children underwent a neuropsychological battery and testing for autism spectrum disorder (ASD), and parents reported on their child's behavior, development, and seizures. Results Of the children, 28% of boys and 21% of girls exhibited moderate to severe impairment on summary measures of cognitive abilities. Boys had a higher prevalence of impairment than girls in nearly all measures of cognition, were more than twice as likely to have microcephaly (15% in boys, 8% in girls), and require more often assistive devices to ambulate (6% in boys, 4% in girls). In contrast, boys and girls had comparable risk for a history of seizure (identified in 10% of the cohort) or epilepsy (identified in 7% of the cohort). The boy-to-girl ratio of ASD (9% in boys, 5% in girls) was lower than expected compared with the overall US autism population. Conclusions In this contemporary cohort of children born extremely premature and evaluated at school age, boys had higher prevalence of cognitive, neurologic, and behavioral deficits than girls. The ratio of boys to girls among those with ASD deserves further study as does the perinatal environmental-genetic interactions that might contribute to male preponderance of deficits in this high-risk sample. C1 [Kuban, Karl C. K.; Douglass, Laurie] Boston Med Ctr, Dept Pediat, 1 Boston Med Ctr Pl Dowling Bldg,3 South, Boston, MA 02118 USA. [Joseph, Robert M.] Boston Univ, Dept Anat & Neuroanat, Boston, MA 02215 USA. [O'Shea, Thomas M.] Univ N Carolina, Dept Pediat, Div Neonatal Perinatal Med, Chapel Hill, NC USA. [Allred, Elizabeth N.; Leviton, Alan] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Allred, Elizabeth N.; Leviton, Alan] Boston Childrens Hosp, Neuroepidemiol Unit, Dept Neurol, Boston, MA USA. [Heeren, Timothy] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Stafstrom, Carl E.] Johns Hopkins Univ Hosp, Dept Neurol, Div Pediat Neurol, Baltimore, MD 21287 USA. [Jara, Hernan] Boston Univ, Boston Med Ctr, Dept Radiol, Boston, MA 02215 USA. [Frazier, Jean A.] Univ Massachusetts, Sch Med, Univ Massachusetts Mem Hlth Care, Dept Psychiat, Worcester, MA USA. [Hirtz, Deborah] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Kuban, KCK (reprint author), Boston Med Ctr, Dept Pediat, 1 Boston Med Ctr Pl Dowling Bldg,3 South, Boston, MA 02118 USA. EM karl.kuban@bmc.org RI Hunter, Scott/S-7866-2016 OI Hunter, Scott/0000-0001-7434-2327 FU National Institute of Neurological Disorders and Stroke [5U01NS040069-05, 2R01NS040069-09]; National Institute of Child Health and Human Development [5P30HD018655-28]; Alcobra; Forest Pharmaceuticals; Janssen Research and Development; Pfizer, Inc.; Neuren; Roche; Seaside Therapeutics; SyneuRX International FX Supported by the National Institute of Neurological Disorders and Stroke ( 5U01NS040069-05 and 2R01NS040069-09) and the National Institute of Child Health and Human Development ( 5P30HD018655-28). J. F. receives grant and research support from Alcobra, Forest Pharmaceuticals, Janssen Research and Development, Pfizer, Inc., Neuren, Roche, Seaside Therapeutics, and SyneuRX International, and sits on a Data Safety Board for an adolescent clinical trial supported by Forest Pharmaceuticals. The authors declare no conflicts of interest. NR 54 TC 4 Z9 4 U1 7 U2 13 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 JUN PY 2016 VL 173 BP 69 EP + DI 10.1016/j.jpeds.2016.02.048 PG 8 WC Pediatrics SC Pediatrics GA DN0QZ UT WOS:000376770200017 PM 27004675 ER PT J AU Parascandola, M Bloch, M AF Parascandola, Mark Bloch, Michele TI The Global Laboratory of Tobacco Control: Research to Advance Tobacco Cessation in LMICs SO JOURNAL OF SMOKING CESSATION LA English DT Article ID MIDDLE-INCOME COUNTRIES; SMOKING PREVALENCE; OUTLET DENSITY; HEALTH; DEPENDENCE; POVERTY; POLICY; REDUCTION; EPIDEMIC; EXPOSURE AB For over half a century, the U.S. National Cancer Institute (NCI) has supported research on tobacco and health, which has contributed to reductions in tobacco-caused morbidity and mortality in the U.S. But while tobacco use has been slowly declining in most high-income nations, including the US, it has continued to increase in other parts of the globe. Of the 800 million adult men who currently smoke cigarettes, over 80% are in low-and middle-income countries ( LMICs), and these countries will bear an increasing share of the health and economic burden of tobacco use. At the same time, there are additional challenges to implementing tobacco control programs in LMICs, including a diversity of tobacco products, limited capacity and resources for tobacco control, and competing health priorities. While a large body of evidence has been generated around tobacco dependence treatment and other measures in high-income countries, this work is only partly applicable to many LMICs. In this paper we focus on research needs and opportunities around tobacco cessation interventions for LMICs, highlighting four areas: understanding diverse tobacco products, development of low-cost cessation interventions, integrating tobacco cessation into health systems, and understanding tobacco use behaviors across different contexts. Expanding tobacco control research and research capacity in LMICs is crucial to reducing tobacco use and cancer rates worldwide. Furthermore, research conducted in countries around the world can yield important insights for understanding tobacco use behaviors and the effectiveness of tobacco control interventions in the US. C1 [Parascandola, Mark; Bloch, Michele] NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 3E125, Bethesda, MD 20892 USA. RP Parascandola, M (reprint author), NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 3E125, Bethesda, MD 20892 USA. EM paramark@mail.nih.gov NR 76 TC 2 Z9 2 U1 1 U2 1 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1834-2612 J9 J SMOK CESS JI J. Smok. Cess. PD JUN PY 2016 VL 11 IS 2 BP 70 EP 77 DI 10.1017/jsc.2015.22 PG 8 WC Substance Abuse SC Substance Abuse GA DN3XV UT WOS:000376998500004 ER PT J AU Chertow, GM Levin, NW Beck, GJ Daugirdas, JT Eggers, PW Kliger, AS Larive, B Rocco, MV Greene, T AF Chertow, Glenn M. Levin, Nathan W. Beck, Gerald J. Daugirdas, John T. Eggers, Paul W. Kliger, Alan S. Larive, Brett Rocco, Michael V. Greene, Tom CA Frequent Hemodial Network FHN TI Long-Term Effects of Frequent In-Center Hemodialysis SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID FHN RANDOMIZED-TRIALS; QUALITY-OF-LIFE; MEMBRANE FLUX; 3 TIMES; HEALTH AB The Frequent Hemodialysis Network Daily Trial randomized 245 patients to receive six (frequent) or three (conventional) in-center hemodialysis sessions per week for 12 months. As reported previously, frequent in center hemodialysis yielded favorable effects on the coprimary composite outcomes of death or change in left ventricular mass and death or change in self-reported physical health. Here, we determined the long-term effects of the 12-month frequent in-center hemodialysis intervention. We determined the vital status of patients over a median of 3.6 years (10%-90% range, 1.5-5.3 years) after randomization. Using an intention to treat analysis, we compared the mortality hazard in randomized groups. In a subset of patients from both groups, we reassessed left ventricular mass and self-reported physical health a year or more after completion of the intervention; 20 of 125 patients (16%) randomized to frequent hemodialysis died during the combined trial and post-trial observation periods in contrast to 34 of 120 patients (28%) randomized to conventional hemodialysis. The relative mortality hazard for frequent versus conventional hemodialysis was 0.54 (95% confidence interval, 0.31 to 0.93); with censoring of time after kidney transplantation, the relative hazard was 0.56 (95% confidence interval, 0.32 to 0.99). Bayesian analysis suggested a relatively high probability of clinically significant benefit and a very low probability of harm with frequent hemodialysis. In conclusion, a 12-month frequent in-center hemodialysis intervention significantly reduced long-term mortality, suggesting that frequent hemodialysis may benefit selected patients with ESRD. C1 [Chertow, Glenn M.] Stanford Univ, Dept Med, Palo Alto, CA 93034 USA. [Levin, Nathan W.] Renal Res Inst, New York, NY USA. [Beck, Gerald J.; Larive, Brett; Greene, Tom] Cleveland Clin Fdn, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Daugirdas, John T.] Univ Illinois, Chicago, IL USA. [Eggers, Paul W.] NIDDK, Bethesda, MD 20892 USA. [Kliger, Alan S.] Yale Univ, New Haven, CT USA. [Rocco, Michael V.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Greene, Tom] Univ Utah, Salt Lake City, UT USA. RP Chertow, GM (reprint author), Stanford Univ, Sch Med, 1070 Arastradero Rd,Suite 313, Palo Alto, CA 93034 USA. EM gchertow@stanford.edu FU National Institutes of Health (NIH); National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK); Center for Medicare and Medical Services; NIH Research Foundation; NIDDK through the American Recovery and Reinvestment Act; Amgen, Inc.; Baxter, Inc.; Dialysis Clinics, Inc. FX The Frequent Hemodialysis Network (FHN) Trials were sponsored by the National Institutes of Health (NIH), the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), the Center for Medicare and Medical Services, and the NIH Research Foundation. Additional funds were provided by the NIDDK through the American Recovery and Reinvestment Act. Contributors to the NIH Foundation in support of the FHN Trials included Amgen, Inc.; Baxter, Inc.; and Dialysis Clinics, Inc. NR 25 TC 6 Z9 6 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUN PY 2016 VL 27 IS 6 BP 1830 EP 1836 DI 10.1681/ASN.2015040426 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA DN1NY UT WOS:000376833900028 PM 26467779 ER PT J AU Alfadhli, A Mack, A Ritchie, C Cylinder, I Harper, L Tedbury, PR Freed, EO Barklis, E AF Alfadhli, Ayna Mack, Andrew Ritchie, Christopher Cylinder, Isabel Harper, Logan Tedbury, Philip R. Freed, Eric O. Barklis, Eric TI Trimer Enhancement Mutation Effects on HIV-1 Matrix Protein Binding Activities SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ENVELOPE GLYCOPROTEIN INCORPORATION; GAG MEMBRANE-BINDING; PLASMA-MEMBRANE; LIPID RAFTS; CRYOELECTRON MICROSCOPY; CRYSTAL-STRUCTURES; CYTOPLASMIC TAIL; MEDIATED DAMAGE; RNA AB The HIV-1 matrix (MA) protein is the amino-terminal domain of the HIV-1 precursor Gag (Pr55Gag) protein. MA binds to membranes and RNAs, helps transport Pr55Gag proteins to virus assembly sites at the plasma membranes of infected cells, and facilitates the incorporation of HIV-1 envelope (Env) proteins into virions by virtue of an interaction with the Env protein cytoplasmic tails (CTs). MA has been shown to crystallize as a trimer and to organize on membranes in hexamer lattices. MA mutations that localize to residues near the ends of trimer spokes have been observed to impair Env protein assembly into virus particles, and several of these are suppressed by the 62QR mutation at the hubs of trimer interfaces. We have examined the binding activities of wild-type (WT) MA and 62QR MA variants and found that the 62QR mutation stabilized MA trimers but did not alter the way MA proteins organized on membranes. Relative to WT MA, the 62QR protein showed small effects on membrane and RNA binding. However, 62QR proteins bound significantly better to Env CTs than their WT counterparts, and CT binding efficiencies correlated with trimerization efficiencies. Our data suggest a model in which multivalent binding of trimeric HIV-1 Env proteins to MA trimers contributes to the process of Env virion incorporation. IMPORTANCE The HIV-1 Env proteins assemble as trimers, and incorporation of the proteins into virus particles requires an interaction of Env CT domains with the MA domains of the viral precursor Gag proteins. Despite this knowledge, little is known about the mechanisms by which MA facilitates the virion incorporation of Env proteins. To help elucidate this process, we examined the binding activities of an MA mutant that stabilizes MA trimers. We found that the mutant proteins organized similarly to WT proteins on membranes, and that mutant and WT proteins revealed only slight differences in their binding to RNAs or lipids. However, the mutant proteins showed better binding to Env CTs than the WT proteins, and CT binding correlated with MA trimerization. Our results suggest that multivalent binding of trimeric HIV-1 Env proteins to MA trimers contributes to the process of Env virion incorporation. C1 [Alfadhli, Ayna; Mack, Andrew; Ritchie, Christopher; Cylinder, Isabel; Harper, Logan; Barklis, Eric] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. [Tedbury, Philip R.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Barklis, E (reprint author), Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. EM barklis@ohsu.edu OI Tedbury, Philip/0000-0001-8151-4967 FU HHS \ NIH \ National Institute of General Medical Sciences (NIGMS) [R01 GM060170, R01 GM101983] FX This work, including the efforts of Eric Barklis, was funded by HHS vertical bar NIH vertical bar National Institute of General Medical Sciences (NIGMS) (R01 GM060170 and R01 GM101983). NR 56 TC 0 Z9 0 U1 2 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUN PY 2016 VL 90 IS 12 BP 5657 EP 5664 DI 10.1128/JVI.00509-16 PG 8 WC Virology SC Virology GA DN7AL UT WOS:000377227600013 PM 27030269 ER PT J AU Mudd, JC Perkins, MR DiNapoli, SR Hirsch, VM Brenchley, JM AF Mudd, Joseph C. Perkins, Molly R. DiNapoli, Sarah R. Hirsch, Vanessa M. Brenchley, Jason M. TI Interleukin-2 Therapy Induces CD4 Downregulation, Which Decreases Circulating CD4 T Cell Counts, in African Green Monkeys SO JOURNAL OF VIROLOGY LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; SIVAGM INFECTION; HIV-INFECTION; LYMPHOCYTES; MACAQUES; VIREMIA; PATHOGENICITY; EXPRESSION; RESISTANCE; INDUCTION AB African green monkeys (AGMs) are natural hosts of simian immunodeficiency virus (SIVAGM). Because these animals do not develop simian AIDS despite maintaining high viral loads, there is considerable interest in determining how these animals have evolved to avoid SIV disease progression. Unlike nonnatural hosts of SIV, adult AGMs maintain low levels of CD4(+) T cells at steady states and also have a large population of virus-resistant CD8 alpha alpha T cells that lack CD4 expression despite maintaining T helper cell functionalities. In recent work, we have shown that homeostatic cytokines can induce CD4 downregulation in AGM T cells in vitro. Through administering therapeutic doses of recombinant human interleukin-2 (IL-2) to AGMs, we show here that this mechanism is operative in vivo. IL-2 therapy induced transient yet robust proliferation in all major T cell subsets. Within the CD4(+) T cell population, those that were induced into cycle by IL-2 exhibited characteristics of CD4-to-CD8 alpha alpha conversion. In all animals receiving IL-2, circulating CD4(+) T cell counts and proportions tended to be lower and CD4(+) CD8 alpha alpha(+) T cell counts tended to be higher. Despite reductions in circulating target cells, the viral load was unaffected over the course of study. IMPORTANCE The data in this study identify that homeostatic cytokines can downregulate CD4 in vivo and, when given therapeutically, can induce AGMs to sustain very low levels of circulating CD4(+) T cells without showing signs of immunodeficiency. C1 [Mudd, Joseph C.; DiNapoli, Sarah R.; Hirsch, Vanessa M.; Brenchley, Jason M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Perkins, Molly R.] Bluebird Bio, Cambridge, MA USA. [Mudd, Joseph C.; DiNapoli, Sarah R.; Brenchley, Jason M.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Brenchley, JM (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM Jbrenchl@mail.nih.gov OI DiNapoli, Sarah/0000-0002-3675-9030 FU Division of Intramural Research/NIAID/NIH FX Funding for this study was provided in part by the Division of Intramural Research/NIAID/NIH. NR 31 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUN PY 2016 VL 90 IS 12 BP 5750 EP 5758 DI 10.1128/JVI.00057-16 PG 9 WC Virology SC Virology GA DN7AL UT WOS:000377227600021 PM 27053558 ER PT J AU Thomas, A Teicher, BA Hassan, RT AF Thomas, Anish Teicher, Beverly A. Hassan, Raffi T. TI Antibody-drug conjugates for cancer therapy SO LANCET ONCOLOGY LA English DT Review ID BRENTUXIMAB VEDOTIN SGN-35; ACUTE MYELOID-LEUKEMIA; ADO-TRASTUZUMAB EMTANSINE; METASTATIC BREAST-CANCER; LARGE-CELL LYMPHOMA; PHASE-II; INOTUZUMAB-OZOGAMICIN; GLEMBATUMUMAB VEDOTIN; HEMATOLOGICAL MALIGNANCIES; SACITUZUMAB GOVITECAN AB Antibody-drug conjugates are monoclonal antibodies conjugated to cytotoxic agents. They use antibodies that are specific to tumour cell-surface proteins and, thus, have tumour specificity and potency not achievable with traditional drugs. Design of effective antibody-drug conjugates for cancer therapy requires selection of an appropriate target, a monoclonal antibody against the target, potent cytotoxic effector molecules, and conjugation of the monoclonal antibody to cytotoxic agents. Substantial advances in all these aspects in the past decade have resulted in regulatory approval of ado-trastuzumab emtansine and brentuximab vedotin for clinical use. Several promising antibody-drug conjugates are now in late-phase clinical testing. Ongoing efforts are focused on identifying better targets, more effective cytotoxic payloads, and further improvements in antibody-drug linker technology. Improved understanding of the mechanistic basis of antibody-drug conjugate activity will enable design of rational combination therapies with other agents, including immunotherapy. C1 [Thomas, Anish; Hassan, Raffi T.] NCI, Thorac & GI Oncol Branch, Bethesda, MD 20892 USA. [Teicher, Beverly A.] NCI, Mol Pharmacol Branch DCTD, Bethesda, MD 20892 USA. RP Hassan, RT (reprint author), NCI, Thorac & GI Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM hassanr@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (USA) FX We thank the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (USA) for support. NR 72 TC 12 Z9 12 U1 20 U2 50 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD JUN PY 2016 VL 17 IS 6 BP E254 EP E262 PG 9 WC Oncology SC Oncology GA DN4VX UT WOS:000377066400025 PM 27299281 ER PT J AU Pirbhoy, PS Farris, S Steward, O AF Pirbhoy, Patricia Salgado Farris, Shannon Steward, Oswald TI Synaptic activation of ribosomal protein S6 phosphorylation occurs locally in activated dendritic domains SO LEARNING & MEMORY LA English DT Article ID LONG-TERM POTENTIATION; IMMEDIATE-EARLY GENE; ARC MESSENGER-RNA; ELONGATION-FACTOR 1A; GYRUS IN-VIVO; DENTATE GYRUS; TRANSLATIONAL CONTROL; RAPAMYCIN PATHWAY; MAMMALIAN TARGET; RAT HIPPOCAMPUS AB Previous studies have shown that induction of long-term potentiation (LTP) induces phosphorylation of ribosomal protein S6 (rpS6) in postsynaptic neurons, but the functional significance of rpS6 phosphorylation is poorly understood. Here, we show that synaptic stimulation that induces perforant path LTP triggers phosphorylation of rpS6 (p-rpS6) locally near active synapses. Using antibodies specific for phosphorylation at different sites (ser235/236 versus ser240/244), we show that strong synaptic activation led to dramatic increases in immunostaining throughout postsynaptic neurons with selectively higher staining for p-ser235/236 in the activated dendritic lamina. Following LTP induction, phosphorylation at ser235/236 was detectable by 5 min, peaked at 30 min, and was maintained for hours. Phosphorylation at both sites was completely blocked by local infusion of the NMDA receptor antagonist, APV. Despite robust induction of p-rpS6 following high frequency stimulation, assessment of protein synthesis by autoradiography revealed no detectable increases. Exploration of a novel environment led to increases in the number of p-rpS6-positive neurons throughout the forebrain in a pattern reminiscent of immediate early gene induction and many individual neurons that were p-rpS6-positive coexpressed Arc protein. Our results constrain hypotheses about the possible role of rpS6 phosphorylation in regulating postsynaptic protein synthesis during induction of synaptic plasticity. C1 [Pirbhoy, Patricia Salgado; Farris, Shannon; Steward, Oswald] Univ Calif Irvine, Reeve Irvine Res Ctr, Irvine, CA 92697 USA. [Pirbhoy, Patricia Salgado; Farris, Shannon; Steward, Oswald] Univ Calif Irvine, Dept Neurobiol & Behav, Ctr Neurobiol Learning & Memory, Irvine, CA 92697 USA. [Farris, Shannon; Steward, Oswald] Univ Calif Irvine, Dept Anat & Neurobiol, Irvine, CA 92697 USA. [Steward, Oswald] Univ Calif Irvine, Dept Neurosurg, Irvine, CA 92697 USA. [Farris, Shannon] NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Steward, O (reprint author), Univ Calif Irvine, Reeve Irvine Res Ctr, Irvine, CA 92697 USA.; Steward, O (reprint author), Univ Calif Irvine, Dept Neurobiol & Behav, Ctr Neurobiol Learning & Memory, Irvine, CA 92697 USA.; Steward, O (reprint author), Univ Calif Irvine, Dept Anat & Neurobiol, Irvine, CA 92697 USA.; Steward, O (reprint author), Univ Calif Irvine, Dept Neurosurg, Irvine, CA 92697 USA. EM osteward@uci.edu OI Steward, Oswald/0000-0001-7069-8756; Farris, Shannon/0000-0003-4473-1684; Pirbhoy, Patricia/0000-0001-8733-7447 FU National Institutes of Health (NIH) [NS12333]; NIH MBRS-IMSD [GM055246, 5T32 NS045540, F31 NS083349] FX Supported by National Institutes of Health (NIH) grant NS12333 (O.S.); P.S.P. was the recipient of fellowship support from NIH MBRS-IMSD GM055246, 5T32 NS045540, F31 NS083349. NR 91 TC 0 Z9 0 U1 1 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1072-0502 EI 1549-5485 J9 LEARN MEMORY JI Learn. Mem. PD JUN PY 2016 VL 23 IS 6 BP 255 EP 269 DI 10.1101/lm.041947.116 PG 15 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA DN3EX UT WOS:000376946300002 PM 27194793 ER PT J AU Fayer, S Yu, Q Kim, J Moussette, S Camerini-Otero, RD Naumova, AK AF Fayer, Shawn Yu, Qi Kim, Joongbaek Moussette, Sanny Camerini-Otero, R. Daniel Naumova, Anna K. TI Robertsonian translocations modify genomic distribution of gamma H2AFX and H3.3 in mouse germ cells SO MAMMALIAN GENOME LA English DT Article ID SEX-CHROMOSOME INACTIVATION; TRANSMISSION RATIO DISTORTION; DOUBLE-STRAND BREAKS; MAMMALIAN MEIOSIS; X-CHROMOSOME; CHROMATIN; MICE; SPERMATOCYTES; RECOMBINATION; ASYNAPSIS AB Heterozygosity for Robertsonian translocations hampers pairing and synapsis between the translocated chromosome and its normal homologs during meiotic prophase I. This causes meiotic silencing of unsynapsed chromatin in pericentromeric regions. Several lines of evidence suggest that autosomal asynapsis leads to meiotic arrest in males and two underlying mechanisms have been proposed: (1) reactivation of the X and Y chromosomes due to competition for silencing factors and (2) meiotic silencing of genes that are located in the unsynapsed regions and are essential for meiotic progression. The latter mechanism requires that asynapsis and meiotic silencing spread beyond the p-arms of the normal homologs into gene-rich regions. We used chromatin immunoprecipitation assays to determine whether histones gamma H2AFX and H3.3, both marks of asynapsis and meiotic silencing, are enriched in gene-rich regions of the translocated chromosomes and their homologs in the spermatocytes of heterozygous carriers of Robertsonian translocations. We also asked if gamma H2AFX and H3.3 enrichment was reduced at the X chromosome and if gamma H2AFX and H3.3 enrichment was higher on the normal homolog. Our data show that gamma H2AFX enrichment extends as far as 9-15 Mb of the annotated genomic sequence of the q-arms of the translocated chromosomal trivalents and that both gamma H2AFX and H3.3 levels are reduced over the X chromosome. Our data are also suggestive of an asymmetry in gamma H2AFX and H3.3 enrichment with a bias toward the non-translocated homolog. C1 [Fayer, Shawn; Naumova, Anna K.] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Yu, Qi; Kim, Joongbaek; Camerini-Otero, R. Daniel] NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. [Moussette, Sanny; Naumova, Anna K.] McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ, Canada. [Naumova, Anna K.] McGill Univ, Dept Obstet & Gynecol, Montreal, PQ H3A 2T5, Canada. RP Naumova, AK (reprint author), McGill Univ, Dept Human Genet, Montreal, PQ, Canada.; Naumova, AK (reprint author), McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ, Canada.; Naumova, AK (reprint author), McGill Univ, Dept Obstet & Gynecol, Montreal, PQ H3A 2T5, Canada. EM anna.naoumova@mcgill.ca FU NSERC; Center for Studies in Reproduction (CSR) of McGill University; CSR of McGill University; Department of Human Genetics FX The authors are grateful to Florencia Pratto for advice in conducting ChIP assays, to Teruko Taketo for critical reading of the manuscript, and Yuri Chang for assistance. This work was supported by funds from the NSERC and the Center for Studies in Reproduction (CSR) of McGill University (to A.N.). S.F was supported by scholarships from the CSR of McGill University and the Department of Human Genetics. NR 50 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-8990 EI 1432-1777 J9 MAMM GENOME JI Mamm. Genome PD JUN PY 2016 VL 27 IS 5-6 BP 225 EP 236 DI 10.1007/s00335-016-9630-2 PG 12 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA DN3VX UT WOS:000376993300006 PM 27090237 ER PT J AU Willis, WT Jackman, MR Messer, JI Kuzmiak-Glancy, S Glancy, B AF Willis, Wayne T. Jackman, Matthew R. Messer, Jeffrey I. Kuzmiak-Glancy, Sarah Glancy, Brian TI A Simple Hydraulic Analog Model of Oxidative Phosphorylation SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE MITOCHONDRIA; ENERGY TRANSDUCTION; GIBBS FREE ENERGY; NONEQUILIBRIUM THERMODYNAMICS ID SKELETAL-MUSCLE MITOCHONDRIA; ENZYME-CATALYZED REACTIONS; METABOLIC-CONTROL ANALYSIS; PROBES ACTOMYOSIN STATES; RAT-LIVER MITOCHONDRIA; OXYGEN-UPTAKE KINETICS; CREATINE-KINASE; LINEAR RELATION; NONEQUILIBRIUM THERMODYNAMICS; BIOCHEMICAL ADAPTATIONS AB Mitochondrial oxidative phosphorylation is the primary source of cellular energy transduction in mammals. This energy conversion involves dozens of enzymatic reactions, energetic intermediates, and the dynamic interactions among them. With the goal of providing greater insight into the complex thermodynamics and kinetics (thermokinetics) of mitochondrial energy transduction, a simple hydraulic analog model of oxidative phosphorylation is presented. In the hydraulic model, water tanks represent the forward and back pressures exerted by thermodynamic driving forces: the matrix redox potential (G(redox)), the electrochemical potential for protons across the mitochondrial inner membrane (G(H)(+)), and the free energy of adenosine 5-triphosphate (ATP) (G(ATP)). Net water flow proceeds from tanks with higher water pressure to tanks with lower pressure through enzyme pipes whose diameters represent the conductances (effective activities) of the proteins that catalyze the energy transfer. These enzyme pipes include the reactions of dehydrogenase enzymes, the electron transport chain (ETC), and the combined action of ATP synthase plus the ATP-adenosine 5-diphosphate exchanger that spans the inner membrane. In addition, reactive oxygen species production is included in the model as a leak that is driven out of the ETC pipe by high pressure (high G(redox)) and a proton leak dependent on the G(H)(+) for both its driving force and the conductance of the leak pathway. Model water pressures and flows are shown to simulate thermodynamic forces and metabolic fluxes that have been experimentally observed in mammalian skeletal muscle in response to acute exercise, chronic endurance training, and reduced substrate availability, as well as account for the thermokinetic behavior of mitochondria from fast- and slow-twitch skeletal muscle and the metabolic capacitance of the creatine kinase reaction. C1 [Willis, Wayne T.] Arizona State Univ, Mayo Clin, Ctr Metab & Vasc Biol, Scottsdale, AZ USA. [Jackman, Matthew R.] Univ Colorado, Dept Med, Div Endocrinol, Anschutz Med Campus, Aurora, CO USA. [Messer, Jeffrey I.] Mesa Community Coll, Exercise Sci Dept, Mesa, AZ USA. [Kuzmiak-Glancy, Sarah] George Washington Univ, Dept Biomed Engn, Washington, DC USA. [Glancy, Brian] NHLBI, Lab Cardiac Energet, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Willis, WT (reprint author), Arizona State Univ, Mayo Clin, Ctr Metab & Vasc Biol, CRB 2 228, Mail Code 3020,13208 E Shea Blvd, Scottsdale, AZ 85259 USA. EM waynewillis@asu.edu RI Glancy, Brian/P-3163-2016 OI Glancy, Brian/0000-0002-8571-244X FU National Science Foundation [IBN-0116997] FX This work was supported by the National Science Foundation (grant no. IBN-0116997). The authors declare no conflicts of interest. NR 68 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD JUN PY 2016 VL 48 IS 6 BP 990 EP 1000 DI 10.1249/MSS.0000000000000884 PG 11 WC Sport Sciences SC Sport Sciences GA DM8MO UT WOS:000376617900004 PM 26807634 ER PT J AU Liu, ZJ Liu, SK Yao, J Bao, LS Zhang, JR Li, Y Jiang, C Sun, LY Wang, RJ Zhang, Y Zhou, T Zeng, QF Fu, Q Gao, S Li, N Koren, S Jiang, YL Zimin, A Xu, P Phillippy, AM Geng, X Song, L Sun, FY Li, C Wang, XZ Chen, AL Jin, YL Yuan, ZH Yang, YJ Tan, SX Peatman, E Lu, JG Qin, ZK Dunham, R Li, ZX Sonstegard, T Feng, JB Danzmann, RG Schroeder, S Scheffler, B Duke, MV Ballard, L Kucuktas, H Kaltenboeck, L Liu, HX Armbruster, J Xie, YJ Kirby, ML Tian, Y Flanagan, ME Mu, WJ Waldbieser, GC AF Liu, Zhanjiang Liu, Shikai Yao, Jun Bao, Lisui Zhang, Jiaren Li, Yun Jiang, Chen Sun, Luyang Wang, Ruijia Zhang, Yu Zhou, Tao Zeng, Qifan Fu, Qiang Gao, Sen Li, Ning Koren, Sergey Jiang, Yanliang Zimin, Aleksey Xu, Peng Phillippy, Adam M. Geng, Xin Song, Lin Sun, Fanyue Li, Chao Wang, Xiaozhu Chen, Ailu Jin, Yulin Yuan, Zihao Yang, Yujia Tan, Suxu Peatman, Eric Lu, Jianguo Qin, Zhenkui Dunham, Rex Li, Zhaoxia Sonstegard, Tad Feng, Jianbin Danzmann, Roy G. Schroeder, Steven Scheffler, Brian Duke, Mary V. Ballard, Linda Kucuktas, Huseyin Kaltenboeck, Ludmilla Liu, Haixia Armbruster, Jonathan Xie, Yangjie Kirby, Mona L. Tian, Yi Flanagan, Mary Elizabeth Mu, Weijie Waldbieser, Geoffrey C. TI The channel catfish genome sequence provides insights into the evolution of scale formation in teleosts SO NATURE COMMUNICATIONS LA English DT Article ID SECRETORY CALCIUM-BINDING; SCPP GENE EVOLUTION; ICTALURUS-PUNCTATUS; TISSUE MINERALIZATION; PHYSICAL MAP; HIGH-DENSITY; ZEBRAFISH; FISH; DUPLICATION; RECEPTOR AB Catfish represent 12% of teleost or 6.3% of all vertebrate species, and are of enormous economic value. Here we report a high-quality reference genome sequence of channel catfish (Ictalurus punctatus), the major aquaculture species in the US. The reference genome sequence was validated by genetic mapping of 54,000 SNPs, and annotated with 26,661 predicted protein-coding genes. Through comparative analysis of genomes and transcriptomes of scaled and scaleless fish and scale regeneration experiments, we address the genomic basis for the most striking physical characteristic of catfish, the evolutionary loss of scales and provide evidence that lack of secretory calcium-binding phosphoproteins accounts for the evolutionary loss of scales in catfish. The channel catfish reference genome sequence, along with two additional genome sequences and transcriptomes of scaled catfishes, provide crucial resources for evolutionary and biological studies. This work also demonstrates the power of comparative subtraction of candidate genes for traits of structural significance. C1 [Liu, Zhanjiang; Liu, Shikai; Yao, Jun; Bao, Lisui; Zhang, Jiaren; Li, Yun; Jiang, Chen; Sun, Luyang; Wang, Ruijia; Zhang, Yu; Zhou, Tao; Zeng, Qifan; Fu, Qiang; Gao, Sen; Li, Ning; Jiang, Yanliang; Xu, Peng; Geng, Xin; Song, Lin; Sun, Fanyue; Li, Chao; Wang, Xiaozhu; Chen, Ailu; Jin, Yulin; Yuan, Zihao; Yang, Yujia; Tan, Suxu; Peatman, Eric; Lu, Jianguo; Qin, Zhenkui; Dunham, Rex; Li, Zhaoxia; Feng, Jianbin; Kucuktas, Huseyin; Kaltenboeck, Ludmilla; Liu, Haixia; Xie, Yangjie; Tian, Yi; Mu, Weijie] Auburn Univ, Fish Mol Genet & Biotechnol Lab, Sch Fisheries Aquaculture & Aquat Sci, Auburn, AL 36849 USA. [Liu, Zhanjiang; Liu, Shikai; Yao, Jun; Bao, Lisui; Zhang, Jiaren; Li, Yun; Jiang, Chen; Sun, Luyang; Wang, Ruijia; Zhang, Yu; Zhou, Tao; Zeng, Qifan; Fu, Qiang; Gao, Sen; Li, Ning; Jiang, Yanliang; Xu, Peng; Geng, Xin; Song, Lin; Sun, Fanyue; Li, Chao; Wang, Xiaozhu; Chen, Ailu; Jin, Yulin; Yuan, Zihao; Yang, Yujia; Tan, Suxu; Peatman, Eric; Lu, Jianguo; Qin, Zhenkui; Dunham, Rex; Li, Zhaoxia; Feng, Jianbin; Kucuktas, Huseyin; Kaltenboeck, Ludmilla; Liu, Haixia; Xie, Yangjie; Tian, Yi; Mu, Weijie] Auburn Univ, Program Cell & Mol Biosci, Auburn, AL 36849 USA. [Koren, Sergey; Phillippy, Adam M.] Natl Ctr Biodefense Anal, 110 Thomas Johnson Dr, Ft Detrick, MD 21702 USA. [Koren, Sergey; Phillippy, Adam M.] Countermeasures Ctr, 110 Thomas Johnson Dr, Ft Detrick, MD 21702 USA. [Zimin, Aleksey] Univ Maryland, Inst Phys Sci & Technol, College Pk, MD 20742 USA. [Sonstegard, Tad; Schroeder, Steven] ARS, Bovine Funct Genom Lab, USDA, 10300 Baltimore Ave, Beltsville, MD 20705 USA. [Danzmann, Roy G.] Univ Guelph, Dept Integrat Biol, Guelph, ON N1G 2W1, Canada. [Scheffler, Brian; Duke, Mary V.; Ballard, Linda] ARS, USDA, Genom & Bioinformat Res Unit, POB 38, Stoneville, MS 38776 USA. [Armbruster, Jonathan] Auburn Univ, Dept Biol Sci, Auburn, AL 36849 USA. [Kirby, Mona L.; Flanagan, Mary Elizabeth; Waldbieser, Geoffrey C.] USDA ARS Warmwater Aquaculture Res Unit, POB 38,141 Expt Stn Rd, Stoneville, MS 38776 USA. [Koren, Sergey; Phillippy, Adam M.] NHGRI, NIH, Bethesda, MD 20892 USA. [Sonstegard, Tad] Recombinetics Inc, 1246 Univ Ave W 301, St Paul, MN 55104 USA. RP Liu, ZJ (reprint author), Auburn Univ, Fish Mol Genet & Biotechnol Lab, Sch Fisheries Aquaculture & Aquat Sci, Auburn, AL 36849 USA.; Liu, ZJ (reprint author), Auburn Univ, Program Cell & Mol Biosci, Auburn, AL 36849 USA. EM liuzhan@auburn.edu RI Xu, Peng/J-4018-2012; OI Schroeder, Steven/0000-0001-9103-5150; Scheffler, Brian/0000-0003-1968-8952 FU Agriculture and Food Research Initiative (AFRI) [2009-35205-05101, 2010-65205-20356, 2012-67015-19410]; USDA National Institute of Food and Agriculture (NIFA) Animal Genomics, Genetics, and Breeding Program [2015-67015-22907]; USDA Agricultural Research Service [CRIS 6402-31000-009-00D]; Department of Homeland Security Science and Technology Directorate (DHS/ST) [HSHQDC-07-C-00020] FX This project was supported by Agriculture and Food Research Initiative (AFRI) Competitive Grants 2009-35205-05101, 2010-65205-20356 and 2012-67015-19410, and partially by Competitive Grant no. 2015-67015-22907 from the USDA National Institute of Food and Agriculture (NIFA) Animal Genomics, Genetics, and Breeding Program and CRIS 6402-31000-009-00D of the USDA Agricultural Research Service. Mention of trade names or commercial products in this publication is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the U.S. Department of Agriculture. USDA is an equal opportunity provider and employer. The contributions of SK and AMP were funded under Agreement No. HSHQDC-07-C-00020 awarded by the Department of Homeland Security Science and Technology Directorate (DHS/S&T) for the management and operation of the National Biodefense Analysis and Countermeasures Center (NBACC), a Federally Funded Research and Development Center. The views and conclusions contained in this document are those of the authors and should not be interpreted as necessarily representing the official policies, either expressed or implied, of the U.S. Department of Homeland Security. In no event shall the DHS, NBACC or Battelle National Biodefense Institute (BNBI) have any responsibility or liability for any use, misuse, inability to use or reliance on the information contained herein. The Department of Homeland Security does not endorse any products or commercial services mentioned in this publication. We thank Renee Beam and Karen Veverica for their support in production and maintenance of experimental fish, and to thank Brian Walenz, Jason Miller and Steven Salzberg for their discussions regarding genome assembly. NR 68 TC 19 Z9 19 U1 13 U2 33 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 JUN PY 2016 VL 7 AR 11757 DI 10.1038/ncomms11757 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN5XC UT WOS:000377144000001 PM 27249958 ER PT J AU Ishizuka, AS Lyke, KE DeZure, A Berry, AA Richie, TL Mendoza, FH Enama, ME Gordon, IJ Chang, LJ Sarwar, UN Zephir, KL Holman, LA James, ER Billingsley, PF Gunasekera, A Chakravarty, S Manoj, A Li, ML Ruben, AJ Li, T Eappen, AG Stafford, RE Natasha, KC Murshedkar, T DeCederfelt, H Plummer, SH Hendel, CS Novik, L Costner, PJM Saunders, JG Laurens, MB Plowe, CV Flynn, B Whalen, WR Todd, JP Noor, J Rao, S Sierra-Davidson, K Lynn, GM Epstein, JE Kemp, MA Fahle, GA Mikolajczak, SA Fishbaugher, M Sack, BK Kappe, SHI Davidson, SA Garver, LS Bjorkstrom, NK Nason, MC Graham, BS Roederer, M Sim, BKL Hoffman, SL Ledgerwood, JE Seder, RA AF Ishizuka, Andrew S. Lyke, Kirsten E. DeZure, Adam Berry, Andrea A. Richie, Thomas L. Mendoza, Floreliz H. Enama, Mary E. Gordon, Ingelise J. Chang, Lee-Jah Sarwar, Uzma N. Zephir, Kathryn L. Holman, LaSonji A. James, Eric R. Billingsley, Peter F. Gunasekera, Anusha Chakravarty, Sumana Manoj, Anita Li, MingLin Ruben, Adam J. Li, Tao Eappen, Abraham G. Stafford, Richard E. Natasha, K. C. Murshedkar, Tooba DeCederfelt, Hope Plummer, Sarah H. Hendel, Cynthia S. Novik, Laura Costner, Pamela J. M. Saunders, Jamie G. Laurens, Matthew B. Plowe, Christopher V. Flynn, Barbara Whalen, William R. Todd, J. P. Noor, Jay Rao, Srinivas Sierra-Davidson, Kailan Lynn, Geoffrey M. Epstein, Judith E. Kemp, Margaret A. Fahle, Gary A. Mikolajczak, Sebastian A. Fishbaugher, Matthew Sack, Brandon K. Kappe, Stefan H. I. Davidson, Silas A. Garver, Lindsey S. Bjorkstrom, Niklas K. Nason, Martha C. Graham, Barney S. Roederer, Mario Sim, B. Kim Lee Hoffman, Stephen L. Ledgerwood, Julie E. Seder, Robert A. CA VRC 312& VRC Study Teams TI Protection against malaria at 1 year and immune correlates following PfSPZ vaccination SO NATURE MEDICINE LA English DT Article ID DELTA-T-CELLS; NONREPLICATING SPOROZOITE VACCINE; PLASMODIUM-FALCIPARUM; MONOCLONAL-ANTIBODIES; LIVER STAGES; IMMUNIZATION; MICE; EFFICACY; BERGHEI; MEMORY AB An attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine, PfSPZ Vaccine, is highly protective against controlled human malaria infection (CHMI) 3 weeks after immunization, but the durability of protection is unknown. We assessed how vaccine dosage, regimen, and route of administration affected durable protection in malaria-naive adults. After four intravenous immunizations with 2.7 x 10(5) PfSPZ, 6/11 (55%) vaccinated subjects remained without parasitemia following CHMI 21 weeks after immunization. Five non-parasitemic subjects from this dosage group underwent repeat CHMI at 59 weeks, and none developed parasitemia. Although Pf-specific serum antibody levels correlated with protection up to 21-25 weeks after immunization, antibody levels waned substantially by 59 weeks. Pf-specific T cell responses also declined in blood by 59 weeks. To determine whether T cell responses in blood reflected responses in liver, we vaccinated nonhuman primates with PfSPZ Vaccine. Pf-specific interferon-g-producing CD8 T cells were present at similar to 100-fold higher frequencies in liver than in blood. Our findings suggest that PfSPZ Vaccine conferred durable protection to malaria through long-lived tissue-resident T cells and that administration of higher doses may further enhance protection. C1 [Ishizuka, Andrew S.; DeZure, Adam; Mendoza, Floreliz H.; Enama, Mary E.; Gordon, Ingelise J.; Chang, Lee-Jah; Sarwar, Uzma N.; Zephir, Kathryn L.; Holman, LaSonji A.; Plummer, Sarah H.; Hendel, Cynthia S.; Novik, Laura; Costner, Pamela J. M.; Saunders, Jamie G.; Flynn, Barbara; Whalen, William R.; Todd, J. P.; Noor, Jay; Rao, Srinivas; Sierra-Davidson, Kailan; Lynn, Geoffrey M.; Graham, Barney S.; Roederer, Mario; Ledgerwood, Julie E.; Seder, Robert A.] NIAID, VRC, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lyke, Kirsten E.; Berry, Andrea A.; Laurens, Matthew B.; Plowe, Christopher V.] Univ Maryland, Sch Med, Inst Global Hlth, Ctr Vaccine Dev, Baltimore, MD 21201 USA. [Lyke, Kirsten E.; Berry, Andrea A.; Laurens, Matthew B.; Plowe, Christopher V.] Univ Maryland, Sch Med, Div Malaria Res, Baltimore, MD 21201 USA. [Richie, Thomas L.; James, Eric R.; Billingsley, Peter F.; Gunasekera, Anusha; Chakravarty, Sumana; Manoj, Anita; Li, MingLin; Ruben, Adam J.; Li, Tao; Eappen, Abraham G.; Stafford, Richard E.; Natasha, K. C.; Murshedkar, Tooba; Sim, B. Kim Lee; Hoffman, Stephen L.] Sanaria Inc, Rockville, MD USA. [Li, MingLin; Stafford, Richard E.; Natasha, K. C.; Sim, B. Kim Lee] Prot Potential LLC, Rockville, MD USA. [DeCederfelt, Hope] NIH, Ctr Clin, Pharmaceut Dev Sect, Bethesda, MD 20892 USA. [Epstein, Judith E.] NMRC, Malaria Dept, Silver Spring, MD USA. [Kemp, Margaret A.; Fahle, Gary A.] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. [Mikolajczak, Sebastian A.; Fishbaugher, Matthew; Sack, Brandon K.; Kappe, Stefan H. I.] Ctr Infect Dis Res, Seattle, WA USA. [Davidson, Silas A.; Garver, Lindsey S.] Walter Reed Army Inst Res, Entomol Branch, Silver Spring, MD USA. [Bjorkstrom, Niklas K.] Karolinska Inst, Karolinska Univ Hosp, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden. [Nason, Martha C.] NIAID, Biostat Res Branch, Div Clin Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Chang, Lee-Jah] Sanofi, Swiftwater, PA USA. [Sarwar, Uzma N.] Montefiore Med Ctr, Albert Einstein Coll Med, New York, NY USA. [Rao, Srinivas] Sanofi, Cambridge, MA USA. RP Seder, RA (reprint author), NIAID, VRC, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rseder@mail.nih.gov RI Laurens, Matthew/E-7293-2013; OI Laurens, Matthew/0000-0003-3874-581X; Ishizuka, Andrew/0000-0002-3024-7536; Bjorkstrom, Niklas/0000-0002-0967-076X; Mikolajczak, Sebastian/0000-0003-1996-9703 FU VRC, NIAID, NIH; NIAID [5R44AI055229-11, 5R44AI058499-08, 5R44AI058375-08]; Bill and Melinda Gates Foundation [24922]; [6000.RADI.F.A0309] FX The authors thank the vaccine trials participants for their contribution and commitment to vaccine research. We acknowledge the contributions of: our US National Institutes of Health (NIH) Clinical Center (CC) and National Institute of Allergy and Infectious Diseases (NIAID) colleagues, especially J. Stein, J. Pierson, R. Eckes, P. Driscoll, L. Ediger, and the nursing staff of the 5NW, SCSU, 5SE-S, and 5SE-N units; our VRC colleagues, especially A. Mittelman, H. Harvey, M. Young, C. Artis, R. Hicks, P. Darrah, and T. Abram; our Sanaria and Protein Potential colleagues, especially Y. Abebe, J. Jackson, A. Awe, M. King, H. Huang, A. Patil, S. Matheny, J. Overby, Y. Wen, K. Nelson, V. Pich, M. Orozco, D. Padilla, E. Saverino, B. Jiang, L. Gao, R. Xu, E. Fomumbod, M. Laskowski, T. T. Wai, F. Beams, R. Thompson, and A. Hoffman for administrative, operations, and legal support, and T. Luke for insight and inspiration; the EMMES Corporation; the NIAID Institutional Review Board; the NIAID Office of Communications and Government Relations; the NIH CC Department of Laboratory Medicine; the NIH CC IND Pharmacy, and the NIH CC Patient Recruitment and Public Liaison Office. We appreciate the expert reviews of the Safety Monitoring Committee (A. Durbin, K. Kester, and A. Cross) and the assistance from the US Military Malaria Vaccine Program, the Walter Reed Army Institute of Research Entomology Branch, and the Naval Medical Research Center (NMRC), especially A. Reyes, Y. Alcorta, G. Banania, C. Fedders, M. Dowler, T. Savransky, D. Patel, C. Brando, K. Kobylinski, and K. Walker. This work was supported by the intramural research program of the VRC, NIAID, NIH. Production and characterization of the PfSPZ Vaccine were supported in part by NIAID Small Business Innovation Research grants 5R44AI055229-11 (S. L. H.), 5R44AI058499-08 (S. L. H.), and 5R44AI058375-08 (S. L. H.). The humanized mouse experiments reported here were funded by the Bill and Melinda Gates Foundation (Investment ID: 24922; to S. H. I. K.). The findings and conclusions in this report are those of the authors and do not necessarily reflect the views of the funding agency or collaborators. The views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, the Department of the Army, the Department of Defense, or the US Government. This work was supported in part by work unit number 6000.RADI.F.A0309 to NMRC. J. E. E. and S. A. D. are military service members, and this work was prepared as part of their official duties. Title 17 U.S.C. $101 defines a US Government work as a work prepared by a military service member or employee of the US Government as part of that person's official duties. NR 49 TC 17 Z9 17 U1 4 U2 8 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 JUN PY 2016 VL 22 IS 6 BP 614 EP + DI 10.1038/nm.4110 PG 13 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DO0NQ UT WOS:000377476000014 PM 27158907 ER PT J AU Zanusso, G Monaco, S Pocchiari, M Caughey, B AF Zanusso, Gianluigi Monaco, Salvatore Pocchiari, Maurizio Caughey, Byron TI Advanced tests for early and accurate diagnosis of Creutzfeldt-Jakob disease SO NATURE REVIEWS NEUROLOGY LA English DT Review ID PATHOLOGICAL PRION PROTEIN; QUAKING-INDUCED CONVERSION; FATAL FAMILIAL INSOMNIA; CEREBROSPINAL-FLUID; BETA OLIGOMERS; VARIANT; BLOOD; CJD; VCJD; CLASSIFICATION AB Early and accurate diagnosis of Creutzfeldt-Jakob disease (CJD) is a necessary to distinguish this untreatable disease from treatable rapidly progressive dementias, and to prevent iatrogenic transmission. Currently, definitive diagnosis of CJD requires detection of the abnormally folded, CJD-specific form of protease-resistant prion protein (PrPCJD) in brain tissue obtained postmortem or via biopsy; therefore, diagnosis of sporadic CJD in clinical practice is often challenging. Supporting investigations, including MRI, EEG and conventional analyses of cerebrospinal fluid (CSF) biomarkers, are helpful in the diagnostic work-up, but do not allow definitive diagnosis. Recently, novel ultrasensitive seeding assays, based on the amplified detection of PrPCJD, have improved the diagnostic process; for example, real-time quaking-induced conversion (RT-QuIC) is a sensitive method to detect prion-seeding activity in brain homogenate from humans with any subtype of sporadic CJD. RT-QuIC can also be used for in vivo diagnosis of CJD: its diagnostic sensitivity in detecting PrPCJD in CSF samples is 96%, and its specificity is 100%. Recently, we provided evidence that RT-QuIC of olfactory mucosa brushings is a 97% sensitive and 100% specific for sporadic CJD. These assays provide a basis for definitive antemortem diagnosis of prion diseases and, in doing so, improve prospects for reducing the risk of prion transmission. Moreover, they can be used to evaluate outcome measures in therapeutic trials for these as yet untreatable infections. C1 [Zanusso, Gianluigi; Monaco, Salvatore] Univ Verona, Dept Neurosci Biomed & Movement Sci, Policlin GB Rossi, Piazzale LA Scuro 10, I-37134 Verona, Italy. [Pocchiari, Maurizio] Ist Super Sanita, Dept Cell Biol & Neurosci, Viale Regina Elena 299, I-00161 Rome, Italy. [Caughey, Byron] NIAID, Lab Persistent Viral Dis, Rocky Mt Labs, NIH, 903 4th St, Hamilton, MT 59840 USA. RP Zanusso, G (reprint author), Univ Verona, Dept Neurosci Biomed & Movement Sci, Policlin GB Rossi, Piazzale LA Scuro 10, I-37134 Verona, Italy. EM gianluigi.zanusso@univr.it FU Joint Programming Neurodegenerative Disease BIOMARKPD; Fondazione Cariverona "Biomarcatori predittivi e diagnostici in patologie neoplastiche, infiammatorie e neurodegenerative"; Intramural Research Program of the NIAID FX We thank the E-learning facility of the University of Verona for producing the olfactory brushing video. This work was funded in part by Joint Programming Neurodegenerative Disease BIOMARKPD (G.Z.), Fondazione Cariverona "Biomarcatori predittivi e diagnostici in patologie neoplastiche, infiammatorie e neurodegenerative" (G.Z., S.M.) and the Intramural Research Program of the NIAID (B.C.). NR 73 TC 8 Z9 8 U1 7 U2 17 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4758 EI 1759-4766 J9 NAT REV NEUROL JI Nat. Rev. Neurol. PD JUN PY 2016 VL 12 IS 6 BP 325 EP 333 DI 10.1038/nrneurol.2016.65 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DN1LR UT WOS:000376827800007 PM 27174240 ER PT J AU Absinta, M Sati, P Reich, DS AF Absinta, Martina Sati, Pascal Reich, Daniel S. TI Advanced MRI and staging of multiple sclerosis lesions SO NATURE REVIEWS NEUROLOGY LA English DT Review ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; BLOOD-BRAIN-BARRIER; APPEARING WHITE-MATTER; INFLAMMATORY CORTICAL DEMYELINATION; COMMON MARMOSET MONKEY; CENTRAL-NERVOUS-SYSTEM; MS LESIONS; 7 TESLA; MENINGEAL INFLAMMATION; IN-VIVO AB Over the past few decades, MRI-based visualization of demyelinated CNS lesions has become pivotal to the diagnosis and monitoring of multiple sclerosis (MS). In this Review, we outline current efforts to correlate imaging findings with the pathology of lesion development in MS, and the pitfalls that are being encountered in this research. Multimodal imaging at high and ultra-high magnetic field strengths is yielding biologically relevant insights into the pathophysiology of blood-brain barrier dynamics and both active and chronic inflammation, as well as mechanisms of lesion healing and remyelination. Here, we parallel the results in humans with advances in imaging of a primate model of MS - experimental autoimmune encephalomyelitis (EAE) in the common marmoset - in which demyelinated lesions resemble their human counterparts far more closely than do EAE lesions in the rodent. This approach holds promise for the identification of innovative biological markers, and for next-generation clinical trials that will focus more on tissue protection and repair. C1 [Absinta, Martina; Sati, Pascal; Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, NIH, 10 Ctr Dr,MSC 1400,Bldg 10,Room 5C103, Rockville, MD 20852 USA. [Absinta, Martina] Univ Vita Salute San Raffaele, San Raffaele Sci Inst, Inst Expt Neurol, Div Neurosci, Via Olgettina 60, I-20132 Milan, Italy. RP Reich, DS (reprint author), NINDS, Translat Neuroradiol Unit, NIH, 10 Ctr Dr,MSC 1400,Bldg 10,Room 5C103, Rockville, MD 20852 USA. EM reichds@ninds.nih.gov RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke, USA; Vertex Pharmaceuticals; Myelin Repair Foundation FX The authors acknowledge financial support from the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, USA. D.S.R. has received research support from Vertex Pharmaceuticals and the Myelin Repair Foundation. This funding is not a competing interest in the context of the current article. NR 145 TC 1 Z9 1 U1 1 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4758 EI 1759-4766 J9 NAT REV NEUROL JI Nat. Rev. Neurol. PD JUN PY 2016 VL 12 IS 6 BP 358 EP 368 DI 10.1038/nrneurol.2016.59 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA DN1LR UT WOS:000376827800010 PM 27125632 ER PT J AU Kassis, H Shehadah, A Li, C Zhang, Y Cui, YS Roberts, C Sadry, N Liu, XS Chopp, M Zhang, ZG AF Kassis, Haifa Shehadah, Amjad Li, Chao Zhang, Yi Cui, Yisheng Roberts, Cynthia Sadry, Neema Liu, Xianshuang Chopp, Michael Zhang, Zheng Gang TI Class IIa histone deacetylases affect neuronal remodeling and functional outcome after stroke SO NEUROCHEMISTRY INTERNATIONAL LA English DT Article DE Epigenetics; Stroke; Neuronal repair ID FOCAL CEREBRAL-ISCHEMIA; GENE-EXPRESSION; HDAC INHIBITOR; BRAIN-INJURY; MOUSE-BRAIN; RAT; TRANSCRIPTION; RECOVERY; CELLS; MODEL AB We have previously demonstrated that stroke induces nuclear shuttling of class IIa histone deacetylase 4 (HDAC4). Stroke-induced nuclear shuttling of HDAC4 is positively and significantly correlated with improved indices of neuronal remodeling in the pert-infarct cortex. In this study, using a rat model for middle cerebral artery occlusion (MCAO), we tested the effects of selective inhibition of class IIa HDACs on functional recovery and neuronal remodeling when administered 24hr after stroke. Adult male Wistar rats (n = 15-17/group) were subjected to 2 h MCAO and orally gavaged with MC1568 (a selective class IIa HDAC inhibitor), SAHA (a non-selective HDAC inhibitor), or vehicle-control for 7 days starting 24 h after MCAO. A battery of behavioral tests was performed. Lesion volume measurement and immunohistochemistry were performed 28 days after MCAO. We found that stroke increased total HDAC activity in the ipsilateral hemisphere compared to the contralateral hemisphere. Stroke-increased HDAC activity was significantly decreased by the administration of SAHA as well as by MC1568. However, SAHA significantly improved functional outcome compared to vehicle control, whereas selective class Ha inhibition with MC1568 increased mortality and lesion volume and did not improve functional outcome. In addition, MC1568 decreased microtubule associated protein 2 (MAP2, dendrites), phosphorylated neurofilament heavy chain (pNFH, axons) and myelin basic protein (MBP, myelination) immunoreactivity in the peri-infarct cortex. Quantitative RT-PCR of cortical neurons isolated by laser capture microdissection revealed that MC1568, but not SAHA, downregulated CREB and c-fos expression. Additionally, MC1568 decreased the expression of phosphorylated CREB (active) in neurons. Taken together, these findings demonstrate that selective inhibition of class Ha HDACs impairs neuronal remodeling and neurological outcome. Inactivation of CREB and c-fos by MC1568 likely contributes to this detrimental effect. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Kassis, Haifa; Shehadah, Amjad; Li, Chao; Zhang, Yi; Cui, Yisheng; Roberts, Cynthia; Sadry, Neema; Liu, Xianshuang; Chopp, Michael; Zhang, Zheng Gang] Henry Ford Hlth Syst, Dept Neurol, Detroit, MI 48202 USA. [Chopp, Michael] Oakland Univ, Dept Phys, Rochester, MI 48309 USA. [Kassis, Haifa] Uniformed Serv Univ Hlth Sci, Dept Pharmacol & Mol Therapeut, Bethesda, MD 20814 USA. [Shehadah, Amjad] Natl Inst Neurol Disorders & Stroke, Sect Stroke Diagnost & Therapeut, Bethesda, MD 20892 USA. RP Zhang, ZG (reprint author), Henry Ford Hosp, Dept Neurol, 2799 W Grand Blvd, Detroit, MI 48202 USA. EM zhazh@neuro.hfh.edu FU NIH [RO1 NS088656, RO1 NS075156] FX This work was supported by NIH grants RO1 NS088656 (MC) and RO1 NS075156 (ZGZ). NR 47 TC 1 Z9 1 U1 3 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0197-0186 EI 1872-9754 J9 NEUROCHEM INT JI Neurochem. Int. PD JUN PY 2016 VL 96 BP 24 EP 31 DI 10.1016/j.neuint.2016.04.006 PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DN1DO UT WOS:000376806700003 PM 27103167 ER PT J AU Larsen, GY Schober, M Fabio, A Wisniewski, SR Grant, MJC Shafi, N Bennett, TD Hirtz, D Bell, MJ AF Larsen, Gitte Y. Schober, Michelle Fabio, Anthony Wisniewski, Stephen R. Grant, Mary Jo C. Shafi, Nadeem Bennett, Tellen D. Hirtz, Deborah Bell, Michael J. TI Structure, Process, and Culture Differences of Pediatric Trauma Centers Participating in an International Comparative Effectiveness Study of Children with Severe Traumatic Brain Injury SO NEUROCRITICAL CARE LA English DT Article DE Pediatric traumatic brain injury; Secondary injuries; Comparative effectiveness research; Pediatric neurocritical care; Quality of care ID INTENSIVE-CARE UNITS; QUALITY; SAFETY; HYPOTHERMIA AB Traumatic brain injury (TBI) is an important worldwide cause of death and disability for children. The Approaches and Decisions for Acute Pediatric TBI (ADAPT) Trial is an observational, cohort study to compare the effectiveness of six aspects of TBI care. Understanding the differences between clinical sites-including their structure, clinical processes, and culture differences-will be necessary to assess differences in outcome from the study and can inform the overall community regarding differences across academic centers. We developed a survey and queried ADAPT site principal investigators with a focus on six domains: (i) hospital, (ii) pediatric intensive care unit (PICU), (iii) medical staff characteristics, (iv) quality of care, (v) medication safety, and (vi) safety culture. Summary statistics were used to describe differences between centers. ADAPT clinical sites that enrolled a subject within the first year (32 US-based, 11 international) were studied. A wide variation in site characteristics was observed in hospital and ICU characteristics, including an almost sevenfold range in ICU size (8-55 beds) and more than fivefold range of overall ICU admissions (537-2623). Nursing staffing (predominantly 1:1 or 1:2) and the presence of pharmacists within the ICU (79 %) were less variable, and most sites "strongly agreed" or "agreed" that Neurosurgery and Critical Care teams worked well together (81.4 %). However, a minority of sites (46 %) used an explicit protocol for treatment of children with severe TBI care. We found a variety of inter-center structure, process, and culture differences. These intrinsic differences between sites may begin to explain why interventional studies have failed to prove efficacy of experimental therapies. Understanding these differences may be an important factor in analyzing future ADAPT trial results and in determining best practices for pediatric severe TBI. C1 [Larsen, Gitte Y.; Schober, Michelle] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [Grant, Mary Jo C.] Univ Utah, Dept Nursing, Salt Lake City, UT USA. [Fabio, Anthony; Wisniewski, Stephen R.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Bell, Michael J.] Univ Pittsburgh, Dept Crit Care Med Neurol Surg & Pediat, 3434 Fifth Ave, Pittsburgh, PA 15260 USA. [Shafi, Nadeem] Univ Tennessee, Dept Pediat, Memphis, TN USA. [Bennett, Tellen D.] Univ Colorado, Dept Pediat, Aurora, CO USA. [Hirtz, Deborah] NINDS, Div Extramural Res, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Bell, MJ (reprint author), Univ Pittsburgh, Dept Crit Care Med Neurol Surg & Pediat, 3434 Fifth Ave, Pittsburgh, PA 15260 USA. EM bellmj4@upmc.edu OI Bennett, Tellen/0000-0003-1483-4236; Wisniewski, Stephen/0000-0002-3877-9860; Fabio, Anthony/0000-0002-6808-4939 FU NIH [U01 NS081041] FX This study was funded by an NIH Grant (U01 NS081041). NR 18 TC 0 Z9 1 U1 3 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1541-6933 EI 1556-0961 J9 NEUROCRIT CARE JI Neurocrit. Care PD JUN PY 2016 VL 24 IS 3 BP 353 EP 360 DI 10.1007/s12028-015-0218-6 PG 8 WC Critical Care Medicine; Clinical Neurology SC General & Internal Medicine; Neurosciences & Neurology GA DN2ZP UT WOS:000376932100005 PM 26627225 ER PT J AU Trefler, A Sadeghi, N Thomas, AG Pierpaoli, C Baker, CI Thomas, C AF Trefler, Aaron Sadeghi, Neda Thomas, Adam G. Pierpaoli, Carlo Baker, Chris I. Thomas, Cibu TI Impact of time-of-day on brain morphometric measures derived from T-1-weighted magnetic resonance imaging SO NEUROIMAGE LA English DT Article ID VOXEL-BASED MORPHOMETRY; HUMAN CEREBRAL-CORTEX; CEREBROSPINAL-FLUID PRODUCTION; SURFACE-BASED ANALYSIS; CORTICAL THICKNESS; MRI; VOLUME; SEGMENTATION; DEHYDRATION; SYSTEM AB Measures of brainmorphometry derived from T-1-weighted (T1W) magnetic resonance imaging (MRI) arewidely used to elucidate the relation between brain structure and function. However, the computation of T1W morphometric measures can be confounded by subject-related factors such as head motion and level of hydration. A recent study reported subtle yet significant changes in brain volume from morning to evening in a large group of patient populations as well as in healthy elderly individuals. In addition, there is a growing recognition that factors such as circadian rhythm can impact MRI measures of brain function and structure. Here, we provide a comprehensive assessment of the impact of time-of-day (TOD) on widely used measures of brain morphometry in a group of 19 healthy young adults. Our results show that (a) even in a small group of healthy adult volunteers, a highly significant reduction in apparent brain volume, from morning to evening, could be detected; (b) the apparent volume of all three major tissue compartments-gray matter, white matter, and cerebrospinal fluid were influenced by TOD, and the magnitude of the TOD effect varied across the tissue compartments; (c) measures of cortical thickness, cortical surface area, and gray matter density computed with widely used neuroimaging software suites (i.e., FreeSurfer, FSL-VBM) were all affected by TOD, while other measures, such as curvature indices and sulcal depth, were not; and (d) the effect of TOD appeared to have a greater impact on morphometric measures of the frontal and temporal lobe than on other major lobes of the brain. Our results suggest that the TOD effect is a physiological phenomenon and that controlling for the effect of TOD is crucial for proper interpretation of apparent structural differences measured with T1W morphometry. (C) 2016 Elsevier Inc. All rights reserved. C1 [Trefler, Aaron; Baker, Chris I.] NIMH, Sect Learning & Plast, Rockville, MD USA. [Thomas, Adam G.] NIMH, Sect Funct Imaging Methods, Rockville, MD USA. [Sadeghi, Neda; Pierpaoli, Carlo; Thomas, Cibu] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Quantitat Imaging & Tissue Sci, Bethesda, MD USA. [Thomas, Cibu] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. RP Thomas, C (reprint author), NIH, 13 South Dr,Room 3W16, Bethesda, MD 20892 USA. EM cibu.thomas@nih.gov FU Intramural Research Programs of the National Institute of Child Health and Human Development; National Institute of Mental Health [MH002909-07]; Department of Defense in the Center for Neuroscience and Regenerative Medicine FX This work was supported by the Intramural Research Programs of the National Institute of Child Health and Human Development and the National Institute of Mental Health (Grant Number MH002909-07). Salary support for CT was provided by funding from the Department of Defense in the Center for Neuroscience and Regenerative Medicine. We thank Drs. Joelle Sarlls, Elizabeth Hutchinson and Alexandru Avram for useful comments and discussion. Special thanks to Beth Aguila and Marcie King for help with data acquisition. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Maryland (biowulf.nih.gov). NR 62 TC 2 Z9 2 U1 4 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JUN PY 2016 VL 133 BP 41 EP 52 DI 10.1016/j.neuroimage.2016.02.034 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DN4PB UT WOS:000377048600005 PM 26921714 ER PT J AU Vandekar, SN Shinohara, RT Raznahan, A Hopson, RD Roalf, DR Ruparel, K Gur, RC Gur, RE Satterthwaite, TD AF Vandekar, Simon N. Shinohara, Russell T. Raznahan, Armin Hopson, Ryan D. Roalf, David R. Ruparel, Kosha Gur, Ruben C. Gur, Raquel E. Satterthwaite, Theodore D. TI Subject-level measurement of local cortical coupling SO NEUROIMAGE LA English DT Article DE MRI; Development; Adolescence; Gyrification; Cortex; Folding; Cortical thickness ID HUMAN CEREBRAL-CORTEX; PHILADELPHIA NEURODEVELOPMENTAL COHORT; SURFACE-BASED ANALYSIS; WHITE-MATTER; GENDER-DIFFERENCE; BRAIN-DEVELOPMENT; SCHIZOPHRENIA; THICKNESS; ABNORMALITIES; SYSTEM AB The human cortex is highly folded to allow for a massive expansion of surface area. Notably, the thickness of the cortex strongly depends on cortical topology, with gyral cortex sometimes twice as thick as sulcal cortex. We recently demonstrated that global differences in thickness between gyral and sulcal cortex continue to evolve throughout adolescence. However, human cortical development is spatially heterogeneous, and global comparisons lack power to detect localized differences in development or psychopathology. Here we extend previous work by proposing a new measure - local cortical coupling - that is sensitive to differences in the localized topological relationship between cortical thickness and sulcal depth. After estimation, subject-level coupling maps can be analyzed using standard neuroimaging analysis tools. Capitalizing on a large cross-sectional sample (n = 932) of youth imaged as part of the Philadelphia Neurodevelopmental Cohort, we demonstrate that local coupling is spatially heterogeneous and exhibits nonlinear development-related trajectories. Moreover, we uncover sex differences in coupling that indicate divergent patterns of cortical topology. Developmental changes and sex differences in coupling support its potential as a neuroimaging phenotype for investigating neuropsychiatric disorders that are increasingly conceptualized as disorders of brain development. R code to estimate subject-level coupling maps from any two cortical surfaces generated by FreeSurfer is made publicly available along with this manuscript. (C) 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license. C1 [Vandekar, Simon N.; Hopson, Ryan D.; Roalf, David R.; Ruparel, Kosha; Gur, Ruben C.; Gur, Raquel E.; Satterthwaite, Theodore D.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Vandekar, Simon N.; Shinohara, Russell T.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Raznahan, Armin] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Gur, Ruben C.; Gur, Raquel E.] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Gur, Ruben C.] Philadelphia Vet Adm Med Ctr, Philadelphia, PA 19104 USA. RP Vandekar, SN (reprint author), Univ Penn, Dept Biostat & Epidemiol, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, 504 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM simonv@mail.med.upenn.edu FU RC2 grants from the National Institute of Mental Health [MH089983, MH089924]; Center for Biomedical Computing and Image Analysis (CBICA) at Penn; Dowshen Program for Neuroscience; [K23MH098130]; [R01MH107703]; [R01NS085211]; [K01MH10260]; [T32MH065218-11] FX Thanks for the assistance with data processing (Madhura Ingalhalikar, Alex Smith, Nicholas DeLeo, and Ragini Verma); the PNC acquisition and recruitment team (Monica Calkins, Jeff Valdez, Ryan Hopson, Raphael Gerraty, Marisa Riley, Jack Keefe, Elliott Yodh, and Rosetta Chiavacci); data management (Chad Jackson); help with hypothesis testing in general additive models (Fabian Scheipl); and advice on implementation of the general additive model (Aaron Alexander-Bloch and Phil Reiss). The authors declare no competing financial interests. REG served on the Advisory Board Member for Otsuka Pharmaceuticals. This study was supported by RC2 grants from the National Institute of Mental Health (MH089983 and MH089924). Support for developing statistical analyses (SNV, RTS, TDS) was provided by a seed grant by the Center for Biomedical Computing and Image Analysis (CBICA) at Penn. TDS was supported by K23MH098130 and R01MH107703; RTS was supported by R01NS085211; DRR was supported by K01MH10260; and SNV was supported by T32MH065218-11. Additional support was provided by the Dowshen Program for Neuroscience. NR 47 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JUN PY 2016 VL 133 BP 88 EP 97 DI 10.1016/j.neuroimage.2016.03.002 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DN4PB UT WOS:000377048600009 PM 26956908 ER PT J AU Mejia, AF Sweeney, EM Dewey, B Nair, G Sati, P Shea, C Reich, DS Shinohara, RT AF Mejia, Amanda F. Sweeney, Elizabeth M. Dewey, Blake Nair, Govind Sati, Pascal Shea, Colin Reich, Daniel S. Shinohara, Russell T. TI Statistical estimation of T-1 relaxation times using conventional magnetic resonance imaging SO NEUROIMAGE LA English DT Article DE T1 relaxation time; Magnetic resonance imaging; Multiple sclerosis; Image synthesis ID REMITTING MULTIPLE-SCLEROSIS; DEEP GRAY-MATTER; GENERALIZED LINEAR-MODELS; APPEARING WHITE-MATTER; RESTING-STATE FMRI; T2 HYPOINTENSITY; COGNITIVE IMPAIRMENT; BRAIN; T1; MRI AB Quantitative T-1 maps estimate T-1 relaxation times and can be used to assess diffuse tissue abnormalities within normal-appearing tissue. T-1 maps are popular for studying the progression and treatment of multiple sclerosis (MS). However, their inclusion in standard imaging protocols remains limited due to the additional scanning time and expert calibration required and susceptibility to bias and noise. Here, we propose a new method of estimating T-1 maps using four conventional MR images, which are intensity-normalized using cerebellar gray matter as a reference tissue and related to T-1 using a smooth regression model. Using cross-validation, we generate statistical T-1 maps for 61 subjects with MS. The statistical maps are less noisy than the acquired maps and show similar reproducibility. Tests of group differences in normal-appearing white matter across MS subtypes give similar results using both methods. (C) 2015 Elsevier Inc. All rights reserved. C1 [Mejia, Amanda F.; Sweeney, Elizabeth M.; Reich, Daniel S.] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Sweeney, Elizabeth M.; Dewey, Blake; Nair, Govind; Sati, Pascal; Shea, Colin; Reich, Daniel S.] NINDS, Translat lNeuroradiol Unit, Div Neuroimmunol & Neurovirol, NIH, Bethesda, MD 20892 USA. [Shinohara, Russell T.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. RP Shinohara, RT (reprint author), 514 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM rshi@upenn.edu RI Reich, Daniel/E-5701-2010; OI Reich, Daniel/0000-0002-2628-4334; Dewey, Blake/0000-0003-4554-5058 FU NIH from the National Institute of Neurological Disorders and Stroke (NINDS) [R01 NS085211]; National Science Foundation Graduate Research Fellowship Program [DGE-1,232,825]; NIH/NINDS [R01 NS060910]; NIH/NIA [T32AG021334]; Intramural Research Program of NINDS FX Mejia, Sweeney, and Shinohara are partially funded by the NIH grant R01 NS085211 from the National Institute of Neurological Disorders and Stroke (NINDS). Mejia is partially funded by the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE-1,232,825. Sweeney is partially funded by NIH/NINDS R01 NS060910 and NIH/NIA T32AG021334. The study was supported in part by the Intramural Research Program of NINDS. We acknowledge the contribution of the NINDS Neuroimmunology Clinic and the NIH Functional MRI Facility. This work represents the opinions of the researchers and not necessarily that of the granting organizations. NR 58 TC 1 Z9 1 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JUN PY 2016 VL 133 BP 176 EP 188 DI 10.1016/j.neuroimage.2015.12.037 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DN4PB UT WOS:000377048600016 PM 26732403 ER PT J AU Schliep, KC Mumford, SL Sjaarda, LA Schisterman, EF AF Schliep, Karen C. Mumford, Sunni L. Sjaarda, Lindsey A. Schisterman, Enrique F. TI Trying to Conceive After an Early Pregnancy Loss: An Assessment on How Long Couples Should Wait Reply SO OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 [Schliep, Karen C.] Univ Utah, Hlth Sci Ctr, Dept Family & Prevent Med, Div Publ Hlth, Salt Lake City, UT USA. [Mumford, Sunni L.; Sjaarda, Lindsey A.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Bethesda, MD USA. RP Schliep, KC (reprint author), Univ Utah, Hlth Sci Ctr, Dept Family & Prevent Med, Div Publ Hlth, Salt Lake City, UT USA. NR 1 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUN PY 2016 VL 127 IS 6 BP 1171 EP 1171 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DN3CH UT WOS:000376939500030 PM 27214178 ER PT J AU Brouwer, M Schinasi, L Freeman, LEB Baldi, I Lebailly, P Ferro, G Nordby, KC Schuz, J Leon, ME Kromhout, H AF Brouwer, Maartje Schinasi, Leah Freeman, Laura E. Beane Baldi, Isabelle Lebailly, Pierre Ferro, Gilles Nordby, Karl-Christian Schuz, Joachim Leon, Maria E. Kromhout, Hans TI Assessment of occupational exposure to pesticides in a pooled analysis of agricultural cohorts within the AGRICOH consortium SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID CANCER INCIDENCE; HEALTH; MATRIX; CROP; NETHERLANDS; HERBICIDES; FARMERS; DISEASE; RISK AB Background This paper describes methods developed to assess occupational exposure to pesticide active ingredients and chemical groups, harmonised across cohort studies included in the first AGRICOH pooling project, focused on the risk of lymph-haematological malignancies. Methods Three prospective agricultural cohort studies were included: US Agricultural Health Study (AHS), French Agriculture and Cancer Study (AGRICAN) and Cancer in the Norwegian Agricultural Population (CNAP). Self-reported pesticide use was collected in AHS. Crop-exposure matrices (CEMs) were developed for AGRICAN and CNAP. We explored the potential impact of these differences in exposure assessment by comparing a CEM approach estimating exposure in AHS with self-reported pesticide use. Results In AHS, 99% of participants were considered exposed to pesticides, 68% in AGRICAN and 63% in CNAP. For all cohorts combined (n=316 270), prevalence of exposure ranged from 19% to 59% for 14 chemical groups examined, and from 13% to 46% for 33 active ingredients. Exposures were highly correlated within AGRICAN and CNAP where CEMs were applied; they were less correlated in AHS. Poor agreement was found between self-reported pesticide use and assigned exposure in AHS using a CEM approach resembling the assessment for AGRICAN (kappa -0.00 to 0.33) and CNAP (kappa -0.01 to 0.14). Conclusions We developed country-specific CEMs to assign occupational exposure to pesticides in cohorts lacking self-reported data on the use of specific pesticides. The different exposure assessment methods applied may overestimate or underestimate actual exposure prevalence, and additional work is needed to better estimate how far the exposure estimates deviate from reality. C1 [Brouwer, Maartje; Kromhout, Hans] Univ Utrecht, Inst Risk Assessment Sci, Div Environm Epidemiol, POB 80-178, NL-3584 TD Utrecht, Netherlands. [Schinasi, Leah; Ferro, Gilles; Schuz, Joachim; Leon, Maria E.] Int Agcy Res Canc, Sect Environm & Radiat, 150 Cours Albert Thomas, F-69372 Lyon, France. [Freeman, Laura E. Beane] NCI, Occupat & Environm Epidemiol Branch, Bethesda, MD 20892 USA. [Baldi, Isabelle] Univ Bordeaux, ISPED, Lab St Travail Environm, Bordeaux, France. [Baldi, Isabelle] INSERM, ISPED, Ctr INSERM Epidemiol Biostat U897, Bordeaux, France. [Baldi, Isabelle] CHU Bordeaux, Serv Med Travail, Bordeaux, France. [Lebailly, Pierre] INSERM, Canc & Prevent UMR1086, Caen, France. [Lebailly, Pierre] Univ Caen Basse Normandie, ICORE IFR146, Canc & Prevent, Caen, France. [Lebailly, Pierre] Ctr Lutte Contre Canc Francois Baclesse, Caen, France. [Nordby, Karl-Christian] Natl Inst Occupat Hlth, Dept Occupat Med & Epidemiol, Oslo, Norway. RP Kromhout, H (reprint author), Univ Utrecht, Inst Risk Assessment Sci, Div Environm Epidemiol, POB 80-178, NL-3584 TD Utrecht, Netherlands. EM h.kromhout@uu.nl RI Beane Freeman, Laura/C-4468-2015 OI Beane Freeman, Laura/0000-0003-1294-4124 FU Office National de l'Eau et des Milieux Aquatique (ONEMA), Plan d'action national ECOPHYTO, Axe 3, Volet 4, France; Intramural Research Program of the National Cancer Institute, National Institutes of Health [Z01-CP010119]; Ammodo van Gogh travel grant [VGP.14/20] FX This study was funded by a grant from the Office National de l'Eau et des Milieux Aquatique (ONEMA), Plan d'action national ECOPHYTO 2018, Axe 3, Volet 4, France. In addition, this work was funded, in part, by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (Z01-CP010119) and the Ammodo van Gogh travel grant VGP.14/20. We used the following AHS data releases for this analysis: P1REL201209.0 and P2REL201209. NR 34 TC 2 Z9 2 U1 1 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 EI 1470-7926 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD JUN PY 2016 VL 73 IS 6 BP 359 EP 367 DI 10.1136/oemed-2015-103319 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DN0NL UT WOS:000376760500002 PM 27009271 ER PT J AU Russ, DE Ho, KY Colt, JS Armenti, KR Baris, D Chow, WH Davis, F Johnson, A Purdue, MP Karagas, MR Schwartz, K Schwenn, M Silverman, DT Johnson, CA Friesen, MC AF Russ, Daniel E. Ho, Kwan-Yuet Colt, Joanne S. Armenti, Karla R. Baris, Dalsu Chow, Wong-Ho Davis, Faith Johnson, Alison Purdue, Mark P. Karagas, Margaret R. Schwartz, Kendra Schwenn, Molly Silverman, Debra T. Johnson, Calvin A. Friesen, Melissa C. TI Computer-based coding of free-text job descriptions to efficiently identify occupations in epidemiological studies SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID RENAL-CELL CARCINOMA; EXPOSURE ASSESSMENT; UNITED-STATES; RISK-FACTORS; CANCER; SYSTEMS; WHITE; WOMEN AB Background Mapping job titles to standardised occupation classification (SOC) codes is an important step in identifying occupational risk factors in epidemiological studies. Because manual coding is time-consuming and has moderate reliability, we developed an algorithm called SOCcer (Standardized Occupation Coding for Computer-assisted Epidemiologic Research) to assign SOC-2010 codes based on free-text job description components. Methods Job title and task-based classifiers were developed by comparing job descriptions to multiple sources linking job and task descriptions to SOC codes. An industry-based classifier was developed based on the SOC prevalence within an industry. These classifiers were used in a logistic model trained using 14 983 jobs with expert-assigned SOC codes to obtain empirical weights for an algorithm that scored each SOC/job description. We assigned the highest scoring SOC code to each job. SOCcer was validated in 2 occupational data sources by comparing SOC codes obtained from SOCcer to expert assigned SOC codes and lead exposure estimates obtained by linking SOC codes to a job-exposure matrix. Results For 11 991 case-control study jobs, SOCcer-assigned codes agreed with 44.5% and 76.3% of manually assigned codes at the 6-digit and 2-digit level, respectively. Agreement increased with the score, providing a mechanism to identify assignments needing review. Good agreement was observed between lead estimates based on SOCcer and manual SOC assignments (kappa 0.6-0.8). Poorer performance was observed for inspection job descriptions, which included abbreviations and worksite-specific terminology. Conclusions Although some manual coding will remain necessary, using SOCcer may improve the efficiency of incorporating occupation into large-scale epidemiological studies. C1 [Russ, Daniel E.; Ho, Kwan-Yuet; Johnson, Calvin A.] NIH, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. [Colt, Joanne S.; Baris, Dalsu; Purdue, Mark P.; Silverman, Debra T.; Friesen, Melissa C.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Armenti, Karla R.] Bur Publ Hlth Stat & Informat, Div Publ Hlth Serv, New Hampshire Dept Hlth & Human Serv, Concord, NH USA. [Chow, Wong-Ho] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Davis, Faith] Univ Alberta, Dept Publ Hlth Sci, Edmonton, AB, Canada. [Johnson, Alison] Vermont Canc Registry, Burlington, VT USA. [Karagas, Margaret R.] Geisel Sch Med Dartmouth, Hanover, NH USA. [Schwartz, Kendra] Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI USA. [Schwenn, Molly] Maine Canc Registry, Augusta, ME USA. RP Russ, DE (reprint author), NIH, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM druss@mail.nih.gov RI Friesen, Melissa/A-5362-2009; OI Russ, Daniel/0000-0003-4040-4416 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; Intramural Research Program, Center for Information Technology, National Institutes Of Health FX Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; Intramural Research Program, Center for Information Technology, National Institutes Of Health. NR 30 TC 1 Z9 1 U1 3 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 EI 1470-7926 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD JUN PY 2016 VL 73 IS 6 BP 417 EP 424 DI 10.1136/oemed-2015-103152 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DN0NL UT WOS:000376760500009 PM 27102331 ER PT J AU Olivieri, L Cross, R O'Brien, KJ Xue, H Kellman, P Hansen, MS AF Olivieri, Laura Cross, Russell O'Brien, Kendall J. Xue, Hui Kellman, Peter Hansen, Michael S. TI Free-breathing motion-corrected late-gadolinium-enhancement imaging improves image quality in children SO PEDIATRIC RADIOLOGY LA English DT Article DE Children; Free breathing; Heart; Late gadolinium enhancement; Magnetic resonance imaging ID CARDIOVASCULAR MAGNETIC-RESONANCE; MYOCARDIAL-INFARCTION; POPULATION; TRUEFISP; RISK AB The value of late-gadolinium-enhancement (LGE) imaging in the diagnosis and management of pediatric and congenital heart disease is clear; however current acquisition techniques are susceptible to error and artifacts when performed in children because of children's higher heart rates, higher prevalence of sinus arrhythmia, and inability to breath-hold. Commonly used techniques in pediatric LGE imaging include breath-held segmented FLASH (segFLASH) and steady-state free precession-based (segSSFP) imaging. More recently, single-shot SSFP techniques with respiratory motion-corrected averaging have emerged. This study tested and compared single-shot free-breathing LGE techniques with standard segmented breath-held techniques in children undergoing LGE imaging. Thirty-two consecutive children underwent clinically indicated late-enhancement imaging using intravenous gadobutrol 0.15 mmol/kg. Breath-held segSSFP, breath-held segFLASH, and free-breathing single-shot SSFP LGE sequences were performed in consecutive series in each child. Two blinded reviewers evaluated the quality of the images and rated them on a scale of 1-5 (1 = poor, 5 = superior) based on blood pool-myocardial definition, presence of cardiac motion, presence of respiratory motion artifacts, and image acquisition artifact. We used analysis of variance (ANOVA) to compare groups. Patients ranged in age from 9 months to 18 years, with a mean +/- standard deviation (SD) of 13.3 +/- 4.8 years. R-R interval at the time of acquisition ranged 366-1,265 milliseconds (ms) (47-164 beats per minute [bpm]), mean +/- SD of 843+/-231 ms (72+/-21 bpm). Mean +/- SD quality ratings for long-axis imaging for segFLASH, segSSFP and single-shot SSFP were 3.1+/-0.9, 3.4+/-0.9 and 4.0+/-0.9, respectively (P < 0.01 by ANOVA). Mean +/- SD quality ratings for short-axis imaging for segFLASH, segSSFP and single-shot SSFP were 3.4+/-1, 3.8+/-0.9 and 4.3+/-0.7, respectively (P < 0.01 by ANOVA). Single-shot late-enhancement imaging with motion-corrected averaging is feasible in children, robust at high heart rates and with variable R-R intervals, and can be performed without breath-holding with higher image quality ratings than standard breath-held techniques. Use of free-breathing single-shot motion-corrected technique does not compromise LGE image quality in children who can hold their breath, and it can significantly improve image quality in children who cannot hold their breath or who have significant arrhythmia. C1 [Olivieri, Laura; Cross, Russell; O'Brien, Kendall J.] Childrens Natl Hlth Syst, Div Cardiol, W3-200,111 Michigan Ave NW, Washington, DC 20010 USA. [Olivieri, Laura; O'Brien, Kendall J.; Xue, Hui; Kellman, Peter; Hansen, Michael S.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Olivieri, L (reprint author), Childrens Natl Hlth Syst, Div Cardiol, W3-200,111 Michigan Ave NW, Washington, DC 20010 USA.; Olivieri, L (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM lolivier@childrensnational.org RI Hansen, Michael/J-5391-2015 OI Hansen, Michael/0000-0002-8087-8731 FU National Institutes of Health, National Heart, Lung, and Blood Institute; NHLBI [HHSN268201500001C] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute, and through NHLBI contract award HHSN268201500001C. NR 16 TC 1 Z9 1 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-0449 EI 1432-1998 J9 PEDIATR RADIOL JI Pediatr. Radiol. PD JUN PY 2016 VL 46 IS 7 BP 983 EP 990 DI 10.1007/s00247-016-3553-7 PG 8 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA DN4FX UT WOS:000377020100004 PM 26886912 ER PT J AU Burke, AB Boyce, AM Collins, MT AF Burke, Andrea B. Boyce, Alison M. Collins, Michael T. TI Fibrous Dysplasia: Management of the Optic Canal SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Letter ID MCCUNE-ALBRIGHT SYNDROME C1 [Burke, Andrea B.; Boyce, Alison M.; Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Sect, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Burke, AB (reprint author), Natl Inst Dent & Craniofacial Res, NIH, 30 Convent Dr,Bldg 30,Room 228,MSC 4320, Bethesda, MD 20892 USA. EM andrea.burke@nih.gov FU Intramural NIH HHS [Z99 DE999999] NR 5 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0032-1052 EI 1529-4242 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD JUN PY 2016 VL 137 IS 6 BP 1060E EP 1061E DI 10.1097/PRS.0000000000002210 PG 3 WC Surgery SC Surgery GA DN5HV UT WOS:000377098100030 PM 26890512 ER PT J AU Boyce, AM Burke, A Peck, CC DuFresne, CR Lee, JS Collins, MT AF Boyce, Alison M. Burke, Andrea Peck, Carolee Cutler DuFresne, Craig R. Lee, Janice S. Collins, Michael T. TI Surgical Management of Polyostotic Craniofacial Fibrous Dysplasia: Long-Term Outcomes and Predictors for Postoperative Regrowth SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID MCCUNE-ALBRIGHT-SYNDROME; BONE; CHILDREN; SURGERY; REGION; SKULL AB Background: The mainstay of treatment for craniofacial fibrous dysplasia is surgical; however, optimal indications and techniques are poorly understood, particularly in polyostotic disease and McCune-Albright syndrome. This study investigated surgical indications and risk factors for recurrence in a large cohort. Methods: One hundred thirty-three craniofacial fibrous dysplasia subjects in a natural history study were evaluated. Radiographic studies, operative reports, and clinical records were reviewed. Results: Thirty-six subjects underwent 103 craniofacial procedures (mean, 2.8 operations per subject), with 13.5 +/- 10.5-year follow-up (range, 0 to 39 years). The most common indication was craniofacial deformity (n = 61 operations), including 36 initial operations (59 percent) and 26 reoperations (41 percent). Mean time to reoperation was 3.4 +/- 3.2 years (range, 0.3 to 13.3 years). Regrowth occurred after 42 operations (68 percent), and was more frequent after operations in subjects with McCune-Albright syndrome growth hormone excess [22 of 25 operations (88 percent)] than without growth hormone excess [15 of 36 operations (58 percent); p = 0.02]. Of 11 subjects with growth hormone excess, nine (82 percent) were undiagnosed at the time of their initial operation. Regrowth was more frequent after debulking procedures [31 of 38 (82 percent)] than after more aggressive reconstructions [nine of 20 (45 percent); p = 0.007]. Eleven subjects underwent treatment for aneurysmal bone cysts, with recurrence in one subject. Eleven subjects underwent biopsies and none had complications or regrowth. Conclusions: Craniofacial fibrous dysplasia regrowth and reoperation are common, particularly after debulking procedures. Outcomes are favorable for aneurysmal bone cysts and biopsies. McCune-Albright syndrome growth hormone excess is a risk factor for regrowth, and may be underdiagnosed in surgical patients. Surgeons should be aware of appropriate screening for endocrinopathies in fibrous dysplasia. These findings highlight the importance of a multidisciplinary approach to craniofacial fibrous dysplasia, and individualized care with long-term follow-up. C1 Georgetown Univ & Med Ctr, Skeletal Clin Studies Unit,Dept Plast Surg, Craniofacial & Skeletal Dis Branch,Natl Inst Hlth, Natl Inst Dent & Craniofacial Res,Off Clin Direct, Washington, DC USA. Childrens Natl Hlth Syst, Div Orthopaed & Sports Med, Bone Hlth Program, Div Endocrinol & Diabet, Washington, DC USA. SouthEast Eye Specialists PLLC, Knoxville, TN USA. RP Boyce, AM (reprint author), NIH, 30 Convent Dr,Room 228 MSC 4320, Bethesda, MD 20892 USA. EM boyceam@mail.nih.gov FU National Institutes of Health, National Institute of Dental and Craniofacial Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research. The authors are grateful to the patients and their families for participation in the research, and the efforts of the trainees of the National Institutes of Health Endocrine Training Program for the care they provide to our research subjects at the National Institutes of Health. Mark O. Hatfield Clinical Research Center. NR 25 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0032-1052 EI 1529-4242 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD JUN PY 2016 VL 137 IS 6 BP 1833 EP 1839 DI 10.1097/PRS.0000000000002151 PG 7 WC Surgery SC Surgery GA DN5HV UT WOS:000377098100064 PM 27219238 ER PT J AU Dew, MA DiMartini, AF Ladner, DP Simpson, MA Pomfret, EA Gillespie, BW Merion, RM Zee, J Smith, AR Holtzman, S Sherker, AH Weinrieb, R Fisher, RA Emond, JC Freise, CE Burton, JR Butt, Z AF Dew, Mary Amanda DiMartini, Andrea F. Ladner, Daniela P. Simpson, Mary Ann Pomfret, Elizabeth A. Gillespie, Brenda W. Merion, Robert M. Zee, Jarcy Smith, Abigail R. Holtzman, Susan Sherker, Averell H. Weinrieb, Robert Fisher, Robert A. Emond, Jean C. Freise, Chris E. Burton, James R., Jr. Butt, Zeeshan TI Psychosocial Outcomes 3 to 10 Years After Donation in the Adult to Adult Living Donor Liver Transplantation Cohort Study SO TRANSPLANTATION LA English DT Article ID QUALITY-OF-LIFE; POSTTRAUMATIC GROWTH; ORGAN DONATION; KIDNEY DONORS; BONE-MARROW; VANCOUVER FORUM; UNITED-STATES; FOLLOW-UP; COMPLICATIONS; IMPACT AB Background. Studies of liver donors' psychosocial outcomes focus on the short term and rely largely on quality-of-life measures not specific to donation. We sought to examine long-term donation effects on 3 psychosocial domains: perceived physical, emotional, and socioeconomic outcomes. Methods. Individuals donating 3 to 10 years previously at 9 centers were eligible for telephone surveys. Survey responses were examined descriptively. Cluster analysis was used to identify distinct donor groups based on response profiles across psychosocial domains. Potential predictors of response profiles were evaluated with regression analysis. Results. Five hundred seventeen donors (66%) participated (M = 5.8 years postdonation, SD = 1.9). Fifteen percent to 48% of donors endorsed current donation-related physical health problems and concerns, and 7%-60% reported socioeconomic concerns (eg, insurance difficulties, financial expenditures). However, on average, donors experienced high psychological growth, and 90% felt positively about donation. Cluster analysis revealed 5 donor groups. One group showed high psychological benefit, with little endorsement of physical or socioeconomic concerns (15% of donors). Four groups showed less favorable profiles, with varying combinations of difficulties. The largest such group showed high endorsement of physical concerns and financial expenditures, and only modest psychological benefit (31% of donors). Men and nonHispanic whites were most likely to have unfavorable response profiles (Ps < 0.01). Compared with donors aged 19 to 30 years, older donors were less likely to have unfavorable profiles; these differences were significant for donors in the > 40 to 50 year age group (Ps < 0.008). Conclusions. Even many years postdonation, donors report adverse physical and socioeconomic effects, but positive emotional effects as well. Identification of response profiles and predictors may improve targeting of postdonation surveillance and care. C1 [Dew, Mary Amanda; DiMartini, Andrea F.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15213 USA. [Dew, Mary Amanda] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15213 USA. [Dew, Mary Amanda] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Dew, Mary Amanda] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15213 USA. [DiMartini, Andrea F.] Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15213 USA. [Ladner, Daniela P.; Butt, Zeeshan] Northwestern Univ, Transplant Outcomes Res Collaborat, Chicago, IL 60611 USA. [Ladner, Daniela P.; Butt, Zeeshan] Northwestern Univ, Comprehens Transplant Ctr, Chicago, IL 60611 USA. [Simpson, Mary Ann] Lahey Hosp & Med Ctr Clin Res & Educ, Burlington, MA USA. [Simpson, Mary Ann; Pomfret, Elizabeth A.] Lahey Hosp & Med Ctr, Dept Transplantat, Burlington, MA USA. [Gillespie, Brenda W.; Smith, Abigail R.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Merion, Robert M.] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA. [Merion, Robert M.; Zee, Jarcy; Smith, Abigail R.] Arbor Res Collaborat Hlth, Ann Arbor, MI USA. [Holtzman, Susan] Univ British Columbia, Dept Psychol, Kelowna, BC, Canada. [Sherker, Averell H.] NIDDK, Liver Dis Res Branch, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. [Weinrieb, Robert] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Fisher, Robert A.] Virginia Commonwealth Univ, Dept Transplant Surg, Richmond, VA USA. [Emond, Jean C.] Columbia Univ, Med Ctr, Dept Surg, New York, NY USA. [Freise, Chris E.] Univ Calif San Francisco, Dept Surg, San Francisco, CA USA. [Burton, James R., Jr.] Univ Colorado Anschutz Med Campus, Dept Med, Aurora, CO USA. [Butt, Zeeshan] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [Butt, Zeeshan] Northwestern Univ, Feinberg Sch Med, Inst Publ Hlth & Med, Chicago, IL 60611 USA. RP Dew, MA (reprint author), Univ Pittsburgh, Sch Med, Dept Psychiat, 3811 OHara St, Pittsburgh, PA 15213 USA.; Dew, MA (reprint author), Univ Pittsburgh, Med Ctr, 3811 OHara St, Pittsburgh, PA 15213 USA. EM dewma@upmc.edu OI Smith, Abigail/0000-0001-5496-4460 FU National Institute of Diabetes and Digestive and Kidney Diseases [U01-DK62444, U01-DK62467, U01-DK62483, U01-DK62494, U01-DK62498, U01-DK62531, U01-DK62536, U01-DK85515, U01-DK85563, U01-DK85587] FX This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases through cooperative agreements (grants U01-DK62444, U01-DK62467, U01-DK62483, U01-DK62494, U01-DK62498, U01-DK62531, U01-DK62536, U01-DK85515, U01-DK85563, and U01-DK85587). NR 75 TC 1 Z9 1 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUN PY 2016 VL 100 IS 6 BP 1257 EP 1269 DI 10.1097/TP.0000000000001144 PG 13 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DN5QZ UT WOS:000377126600018 PM 27152918 ER PT J AU McDermott, MM Kibbe, M Guralnik, J Ferrucci, L Polonsky, T Tian, L Zhao, LH Gao, Y Criqui, M AF McDermott, Mary M. Kibbe, Melina Guralnik, Jack Ferrucci, Luigi Polonsky, Tammy Tian, Lu Zhao, Lihui Gao, Ying Criqui, Michael TI Racial Differences in Mobility Loss in Peripheral Artery Disease SO VASCULAR MEDICINE LA English DT Meeting Abstract C1 [McDermott, Mary M.; Kibbe, Melina; Zhao, Lihui; Gao, Ying] Northwestern Feinberg Sch Med, Chicago, IL USA. [Guralnik, Jack] Univ Maryland, Sch Med, College Pk, MD USA. [Ferrucci, Luigi] NIA, Bethesda, MD 20892 USA. [Polonsky, Tammy] Univ Chicago Med, Chicago, IL USA. [Tian, Lu] Stanford Univ, Stanford, CA 94305 USA. [Criqui, Michael] Univ Calif San Diego, La Jolla, CA 92093 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X EI 1477-0377 J9 VASC MED JI Vasc. Med. PD JUN PY 2016 VL 21 IS 3 MA 2 BP 292 EP 292 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DN5IW UT WOS:000377101000020 ER PT J AU Iacovazzo, D Caswell, R Bunce, B Jose, S Yuan, B Hernandez-Ramirez, LC Kapur, S Caimari, F Evanson, J Ferrau, F Dang, MN Gabrovska, P Larkin, SJ Ansorge, O Rodd, C Vance, ML Ramirez-Renteria, C Mercado, M Goldstone, AP Buchfelder, M Burren, CP Gurlek, A Dutta, P Choong, CS Cheetham, T Trivellin, G Stratakis, CA Lopes, MB Grossman, AB Trouillas, J Lupski, JR Ellard, S Sampson, JR Roncaroli, F Korbonits, M AF Iacovazzo, Donato Caswell, Richard Bunce, Benjamin Jose, Sian Yuan, Bo Hernandez-Ramirez, Laura C. Kapur, Sonal Caimari, Francisca Evanson, Jane Ferrau, Francesco Dang, Mary N. Gabrovska, Plamena Larkin, Sarah J. Ansorge, Olaf Rodd, Celia Vance, Mary L. Ramirez-Renteria, Claudia Mercado, Moises Goldstone, Anthony P. Buchfelder, Michael Burren, Christine P. Gurlek, Alper Dutta, Pinaki Choong, Catherine S. Cheetham, Timothy Trivellin, Giampaolo Stratakis, Constantine A. Lopes, Maria-Beatriz Grossman, Ashley B. Trouillas, Jacqueline Lupski, James R. Ellard, Sian Sampson, Julian R. Roncaroli, Federico Korbonits, Marta TI Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study SO ACTA NEUROPATHOLOGICA COMMUNICATIONS LA English DT Article DE XLAG; Gigantism; GPR101; CNV mutation; Pituitary ID HORMONE-RELEASING-HORMONE; SPORADIC PITUITARY-ADENOMAS; INTERACTING PROTEIN GENE; GROWTH-HORMONE; THERAPEUTIC RESPONSES; AIP MUTATIONS; GIGANTISM; HYPERPLASIA; CELL; TRANSFORMATION AB Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly. We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants. We identified 12 patients (10 females and 2 males; 7.8 %) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases. In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing. C1 [Iacovazzo, Donato; Hernandez-Ramirez, Laura C.; Kapur, Sonal; Caimari, Francisca; Ferrau, Francesco; Dang, Mary N.; Gabrovska, Plamena; Korbonits, Marta] Barts & London Queen Marys Sch Med & Dent, Ctr Endocrinol, London EC1M 6BQ, England. [Caswell, Richard; Bunce, Benjamin; Ellard, Sian] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter EX2 5DW, Devon, England. [Jose, Sian; Sampson, Julian R.] Cardiff Univ, Inst Med Genet, Cardiff CF14 4XN, Wales. [Yuan, Bo; Lupski, James R.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Hernandez-Ramirez, Laura C.; Trivellin, Giampaolo; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Bethesda, MD 20892 USA. [Evanson, Jane] Barts Hlth NHS Trust, Dept Radiol, London EC1A 7BE, England. [Larkin, Sarah J.; Ansorge, Olaf] Univ Oxford, Nuffield Dept Clin Neurosci, Dept Neuropathol, Oxford OX1 2JD, England. [Rodd, Celia] Univ Manitoba, Dept Pediat & Child Hlth, Winnipeg, MB R3T 2N2, Canada. [Vance, Mary L.] Univ Virginia, Dept Endocrinol, Charlottesville, VA 22908 USA. [Ramirez-Renteria, Claudia; Mercado, Moises] Univ Nacl Autonoma Mexico, IMSS, Hosp Especialidades Ctr Med Nacl Siglo XXI, Endocrinol Serv & Expt Endocrinol Unit, Mexico City 06720, DF, Mexico. [Goldstone, Anthony P.] Imperial Coll Healthcare NHS Trust, Imperial Ctr Endocrinol, London W12 0HS, England. [Buchfelder, Michael] Univ Duisburg Essen, Dept Neurosurg, D-45141 Essen, Germany. [Burren, Christine P.] Univ Hosp Bristol NHS Fdn Trust, Dept Paediat Endocrinol, Bristol BS2 8HW, Avon, England. [Gurlek, Alper] Hacettepe Univ, Fac Med, Dept Endocrinol & Metab, TR-06100 Ankara, Turkey. [Dutta, Pinaki] PGIMER, Dept Endocrinol, Chandigarh 160012, India. [Choong, Catherine S.] Princess Margaret Hosp Children, Dept Pediat Endocrinol, Subiaco, WA 6008, Australia. [Cheetham, Timothy] Newcastle Univ, Dept Paediat Endocrinol, Royal Victoria Infirm, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. [Lopes, Maria-Beatriz] Univ Virginia, Dept Pathol, Charlottesville, VA 22908 USA. [Grossman, Ashley B.] Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX1 2JD, England. [Trouillas, Jacqueline] Hosp Civils Lyon, Dept Pathol Groupement Hosp Est, F-69500 Bron, France. [Lupski, James R.] Baylor Coll Med Houston, Dept Pediat, Houston, TX 77030 USA. [Lupski, James R.] Baylor Coll Med Houston, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Lupski, James R.] Texas Childrens Hosp, Houston, TX 77030 USA. [Roncaroli, Federico] Univ Manchester, Inst Brain Behav & Mental Hlth, Manchester M13 9PL, Lancs, England. RP Korbonits, M (reprint author), Barts & London Queen Marys Sch Med & Dent, Ctr Endocrinol, London EC1M 6BQ, England. EM m.korbonits@qmul.ac.uk RI Trivellin, Giampaolo/J-6583-2016; Ferrao, Francesco/P-8852-2015; OI Trivellin, Giampaolo/0000-0003-2384-4153; Ferrao, Francesco/0000-0002-7472-6598; Caswell, Richard/0000-0003-0713-4602; Hernandez-Ramirez, Laura C./0000-0002-6599-6406 FU Medical Research Council [MR/L022656/1]; NHGRI NIH HHS [U54 HG006542]; NINDS NIH HHS [R01 NS058529] NR 40 TC 9 Z9 9 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-5960 J9 ACTA NEUROPATHOL COM JI Acta Neuropathol. Commun. PD JUN 1 PY 2016 VL 4 AR 56 DI 10.1186/s40478-016-0328-1 PG 12 WC Neurosciences SC Neurosciences & Neurology GA DM9XK UT WOS:000376718800001 PM 27245663 ER PT J AU Walsh, S Ludlow, AT Metter, EJ Ferrucci, L Roth, SM AF Walsh, Sean Ludlow, Andrew T. Metter, E. Jeffrey Ferrucci, Luigi Roth, Stephen M. TI Replication study of the vitamin D receptor (VDR) genotype association with skeletal muscle traits and sarcopenia SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Genetics; Muscle strength; Sex differences; Haplotype; Muscle mass ID BONE-MINERAL DENSITY; FAT-FREE MASS; HAPLOTYPE RECONSTRUCTION; GENETIC INFLUENCES; JAPANESE WOMEN; GRIP STRENGTH; ELDERLY-MEN; AGE; POLYMORPHISMS; TISSUE AB Polymorphisms in the vitamin D receptor (VDR) gene are some of the most studied in relation to skeletal muscle traits and significant associations have been observed by multiple groups. One such paper by our group provided the first evidence of a genetic association with sarcopenia in men, but that finding has yet to be replicated in an independent cohort. In the present study, we examined multiple VDR polymorphisms in relation to skeletal muscle traits and sarcopenia in 864 men and women across the adult age span. In addition to VDR genotypes and haplotypes, measurements of skeletal muscle strength and fat-free mass (FFM) were determined in all subjects and a measure of sarcopenia was calculated. We observed significant associations between Fok1 and Bsm1 genotypes and skeletal muscle strength in men and women, though these associations were modest and no significant associations were observed for these polymorphisms and muscle mass traits nor for Bsm1-Taq1 haplotype with muscle strength. Fok1 FF genotype was associated with an increased the risk of sarcopenia in older women compared to f-allele carriers (1.3-fold higher risk). These results support previous findings that VDR genetic variation appears to impact skeletal muscle strength and risk for sarcopenia but the influence is modest. C1 [Walsh, Sean] Cent Connecticut State Univ, Sch Educ & Profess Studies, Dept Phys Educ & Human Performance, New Britain, CT 06050 USA. [Ludlow, Andrew T.; Roth, Stephen M.] Univ Maryland, Dept Kinesiol, Sch Publ Hlth, 2153 SPH Bldg, College Pk, MD 20742 USA. [Metter, E. Jeffrey; Ferrucci, Luigi] NIA, Clin Res Branch, Harbor Hosp, Baltimore, MD 21225 USA. RP Roth, SM (reprint author), Univ Maryland, Dept Kinesiol, Sch Publ Hlth, 2153 SPH Bldg, College Pk, MD 20742 USA. EM sroth1@umd.edu OI Roth, Stephen/0000-0002-7841-3695 FU National Institutes of Health [AG021500, AG022791]; NIH pre-doctoral training grant [AG000268] FX The BLSA research was conducted as a component of the Intramural Research Program of the National Institute on Aging. This work was further sponsored by grants AG021500 and AG022791 from the National Institutes of Health. A. Ludlow was supported by an NIH pre-doctoral training grant AG000268. NR 45 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1594-0667 EI 1720-8319 J9 AGING CLIN EXP RES JI Aging Clin. Exp. Res. PD JUN PY 2016 VL 28 IS 3 BP 435 EP 442 DI 10.1007/s40520-015-0447-8 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA DM9KC UT WOS:000376683700009 PM 26415498 ER PT J AU Lawman, HG Troiano, RP Perna, FM Wang, CY Fryar, CD Ogden, CL AF Lawman, Hannah G. Troiano, Richard P. Perna, Frank M. Wang, Chia-Yih Fryar, Cheryl D. Ogden, Cynthia L. TI Associations of Relative Handgrip Strength and Cardiovascular Disease Biomarkers in US Adults, 2011-2012 SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID REGRESSION-ANALYSES CONSIDERATIONS; BODY-MASS INDEX; GRIP STRENGTH; MUSCLE STRENGTH; PHYSICAL-ACTIVITY; EVALUATING RELATIONSHIPS; RESISTANCE EXERCISE; METABOLIC SYNDROME; MUSCULAR STRENGTH; HEART-FAILURE AB Introduction: Although decline in muscle mass and quality and resulting declines in muscle strength are associated with aging, more research is needed in general populations to assess the utility of handgrip strength as an indicator of muscle strength and cardiovascular disease risk. Methods: Data from 4,221 participants aged >= 20 years in the 2011-2012 cycle of National Health and Nutrition Examination Survey were analyzed during 2014-2015. Standing isometric relative handgrip strength (calculated as maximal absolute handgrip strength from both hands divided by BMI) was used to predict cardiovascular biomarkers, including blood pressure (measured systolic and diastolic blood pressure); serum lipids (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides); and plasma insulin and glucose. Results: Results from regression analyses showed that higher relative grip strength was significantly associated with lower systolic blood pressure, triglycerides, and plasma insulin and glucose, and higher high-density lipoprotein cholesterol in male and female participants (p<0.05 for all). Secondary descriptive analyses found that absolute handgrip strength increased significantly with increasing weight status, but relative handgrip strength decreased significantly with increasing weight status. Conclusions: Results suggest that increased relative handgrip strength may be associated with a better profile of cardiovascular health biomarkers among U.S. adults. Relative grip strength, which both adjusts for the confounding of mass and assesses concomitant health risks of increased body size and low muscle strength, may be a useful public health measure of muscle strength. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Lawman, Hannah G.; Wang, Chia-Yih; Fryar, Cheryl D.; Ogden, Cynthia L.] CDC, Natl Ctr Hlth Stat, Hyattsville, MD USA. [Troiano, Richard P.; Perna, Frank M.] NCI, Bethesda, MD 20892 USA. RP Lawman, HG (reprint author), 3311 Toledo Rd, Hyattsville, MD 20782 USA. EM hlawman@cdc.gov NR 30 TC 5 Z9 5 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD JUN PY 2016 VL 50 IS 6 BP 677 EP 683 DI 10.1016/j.amepre.2015.10.022 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DM7CD UT WOS:000376509900005 PM 26689977 ER PT J AU Brown, TM Fee, E Healey, MN AF Brown, Theodore M. Fee, Elizabeth Healey, Michael N. TI Quentin Young (1923-2016): Advocate, Activist, and "Rebel Without a Pause" SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Brown, Theodore M.] Univ Rochester, Dept Hist, Rochester, NY 14627 USA. [Brown, Theodore M.] Univ Rochester, Dept Publ Hlth Sci, Rochester, NY 14627 USA. [Fee, Elizabeth] NIH, Natl Lib Med, Hist Med Div, Bldg 10, Bethesda, MD 20892 USA. [Healey, Michael N.] Univ Rochester, Rochester, NY 14627 USA. RP Brown, TM (reprint author), Univ Rochester, Dept Hist, Rochester, NY 14627 USA. EM Theodore_Brown@urmc.rochester.edu NR 2 TC 1 Z9 1 U1 1 U2 2 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUN PY 2016 VL 106 IS 6 BP 1025 EP 1027 DI 10.2105/AJPH.2016.303219 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DM7DZ UT WOS:000376517100038 PM 27153020 ER PT J AU Yu, T Wang, YT Zhang, HZ Johnson, CH Jiang, YM Li, XJ Wu, ZM Liu, T Krausz, KW Yu, AM Gonzalez, FJ Huang, M Bi, HC AF Yu, Tao Wang, Yongtao Zhang, Huizhen Johnson, Caroline H. Jiang, Yiming Li, Xiangjun Wu, Zeming Liu, Tian Krausz, Kristopher W. Yu, Aiming Gonzalez, Frank J. Huang, Min Bi, Huichang TI Metabolomics reveals mycoplasma contamination interferes with the metabolism of PANC-1 cells SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Mycoplasma contamination; Metabolomics; Cellular metabolism; PANC-1 cells; Cell culture ID TRICARBOXYLIC-ACID CYCLE; MYCOIDES SUBSP-MYCOIDES; HOST-CELLS; IN-VITRO; CULTURES; INFECTION; CANCER; BIOSYNTHESIS; PREVENTION; FERMENTANS AB Mycoplasma contamination is a common problem in cell culture and can alter cellular functions. Since cell metabolism is either directly or indirectly involved in every aspect of cell function, it is important to detect changes to the cellular metabolome after mycoplasma infection. In this study, liquid chromatography mass spectrometry (LC/MS)-based metabolomics was used to investigate the effect of mycoplasma contamination on the cellular metabolism of human pancreatic carcinoma cells (PANC-1). Multivariate analysis demonstrated that mycoplasma contamination induced significant metabolic changes in PANC-1 cells. Twenty-three metabolites were identified and found to be involved in arginine and purine metabolism and energy supply. This study demonstrates that mycoplasma contamination significantly alters cellular metabolite levels, confirming the compelling need for routine checking of cell cultures for mycoplasma contamination, particularly when used for metabolomics studies. C1 [Yu, Tao; Wang, Yongtao; Zhang, Huizhen; Jiang, Yiming; Huang, Min; Bi, Huichang] Sun Yat Sen Univ, Sch Pharmaceut Sci, 132 Waihuandong Rd, Guangzhou 510006, Guangdong, Peoples R China. [Johnson, Caroline H.] Yale Univ, Dept Environm Hlth Sci, Sch Publ Hlth, 60 Coll St, New Haven, CT 06520 USA. [Li, Xiangjun; Wu, Zeming; Liu, Tian] Thermo Fisher Sci, Xin Jinqiao Rd, Shanghai 201206, Peoples R China. [Krausz, Kristopher W.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yu, Aiming] Univ Calif Davis, Med Ctr, Dept Biochem & Mol Med, Sacramento, CA 95817 USA. RP Bi, HC (reprint author), Sun Yat Sen Univ, Sch Pharmaceut Sci, 132 Waihuandong Rd, Guangzhou 510006, Guangdong, Peoples R China. EM bihchang@mail.sysu.edu.cn FU Natural Science Foundation of China [81522047, 81573489, 81373470, 81320108027]; Natural Science Foundation of Guangdong Province [2015A030313124]; Guangzhou Health Care Collaborative Innovation Program [201508020250] FX This work was financially supported by the Natural Science Foundation of China (Grants 81522047, 81573489, 81373470, 81320108027), the Natural Science Foundation of Guangdong Province (Grant 2015A030313124), and the Guangzhou Health Care Collaborative Innovation Program (Grant 201508020250). NR 36 TC 0 Z9 0 U1 6 U2 17 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD JUN PY 2016 VL 408 IS 16 BP 4267 EP 4273 DI 10.1007/s00216-016-9525-9 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DM6IX UT WOS:000376456300007 PM 27074779 ER PT J AU Tu, TW Williams, RA Lescher, JD Jikaria, N Turtzo, LC Frank, JA AF Tu, Tsang-Wei Williams, Rashida A. Lescher, Jacob D. Jikaria, Neekita Turtzo, L. Christine Frank, Joseph A. TI Radiological-Pathological Correlation of Diffusion Tensor and Magnetization Transfer Imaging in a Closed Head Traumatic Brain Injury Model SO ANNALS OF NEUROLOGY LA English DT Article ID FINITE-ELEMENT-ANALYSIS; AXONAL INJURY; MULTIPLE-SCLEROSIS; SPINAL-CORD; MOUSE MODEL; RAT-BRAIN; REMYELINATION; DEMYELINATION; ANISOTROPY; DISEASE AB Objective: Metrics of diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) can detect diffuse axonal injury in traumatic brain injury (TBI). The relationship between the changes in these imaging measures and the underlying pathologies is still relatively unknown. This study investigated the radiological-pathological correlation between these imaging techniques and immunohistochemistry using a closed head rat model of TBI. Methods: TBI was performed on female rats followed longitudinally by magnetic resonance imaging (MRI) out to 30 days postinjury, with a subset of animals selected for histopathological analyses. A MRI-based finite element analysis was generated to characterize the pattern of the mechanical insult and estimate the extent of brain injury to direct the pathological correlation with imaging findings. Results: DTI axial diffusivity and fractional anisotropy (FA) were sensitive to axonal integrity, whereas radial diffusivity showed significant correlation to the myelin compactness. FA was correlated with astrogliosis in the gray matter, whereas mean diffusivity was correlated with increased cellularity. Secondary inflammatory responses also partly affected the changes of these DTI metrics. The magnetization transfer ratio (MTR) at 3.5ppm demonstrated a strong correlation with both axon and myelin integrity. Decrease in MTR at 20ppm correlated with the extent of astrogliosis in both gray and white matter. Interpretation: Although conventional T2-weighted MRI did not detect abnormalities following TBI, DTI and MTI afforded complementary insight into the underlying pathologies reflecting varying injury states over time, and thus may substitute for histology to reveal diffusive axonal injury pathologies in vivo. This correlation of MRI and histology furthers understanding of the microscopic pathology underlying DTI and MTI changes in TBI. C1 [Tu, Tsang-Wei; Williams, Rashida A.; Lescher, Jacob D.; Jikaria, Neekita; Turtzo, L. Christine; Frank, Joseph A.] NIH, Frank Lab, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Turtzo, L. Christine] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. RP Tu, TW (reprint author), NIH, Radiol & Imaging Sci, Ctr Clin, Bldg 10,RM B1N256,10 Ctr Dr MSC 1074, Bethesda, MD 20892 USA. EM tut@cc.nih.gov FU Department of Defense through the Center for Neuroscience and Regenerative Medicine (Henry M. Jackson Foundation) [300604-8.01-60855, 305500-8.01-60855]; Intramural Research Programs of the NIH Clinical Center; National Institute of Biomedical Imaging and Bioengineering FX This work was supported by funding from the Department of Defense through the Center for Neuroscience and Regenerative Medicine (Henry M. Jackson Foundation Award 300604-8.01-60855, J.A.F.; 305500-8.01-60855, L.C.T.) and from the Intramural Research Programs of the NIH Clinical Center and National Institute of Biomedical Imaging and Bioengineering. NR 61 TC 3 Z9 3 U1 5 U2 8 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 JUN PY 2016 VL 79 IS 6 BP 907 EP 920 DI 10.1002/ana.24641 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DN0ST UT WOS:000376775400005 PM 27230970 ER PT J AU de Winter, JM Joureau, B Lee, EJ Kiss, B Yuen, M Gupta, VA Pappas, CT Gregorio, CC Stienen, GJM Edvardson, S Wallgren-Pettersson, C Lehtokari, VL Pelin, K Malfatti, E Romero, NB van Engelen, BG Voermans, NC Donkervoort, S Bonnemann, CG Clarke, NF Beggs, AH Granzier, H Ottenheijm, CAC AF de Winter, Josine M. Joureau, Barbara Lee, Eun-Jeong Kiss, Balazs Yuen, Michaela Gupta, Vandana A. Pappas, Christopher T. Gregorio, Carol C. Stienen, Ger J. M. Edvardson, Simon Wallgren-Pettersson, Carina Lehtokari, Vilma-Lotta Pelin, Katarina Malfatti, Edoardo Romero, Norma B. van Engelen, Baziel G. Voermans, Nicol C. Donkervoort, Sandra Bonnemann, C. G. Clarke, Nigel F. Beggs, Alan H. Granzier, Henk Ottenheijm, Coen A. C. TI Mutation-Specific Effects on Thin Filament Length in Thin Filament Myopathy SO ANNALS OF NEUROLOGY LA English DT Article ID NEMALINE MYOPATHY; SKELETAL-MUSCLE; NEBULIN DEFICIENCY; SARCOMERE LENGTH; WEAKNESS; GENE; CONTRACTILITY; MOUSE; DISRUPTION; PROTEINS AB Objective: Thin filament myopathies are among the most common nondystrophic congenital muscular disorders, and are caused by mutations in genes encoding proteins that are associated with the skeletal muscle thin filament. Mechanisms underlying muscle weakness are poorly understood, but might involve the length of the thin filament, an important determinant of force generation. Methods: We investigated the sarcomere length-dependence of force, a functional assay that provides insights into the contractile strength of muscle fibers as well as the length of the thin filaments, in muscle fibers from 51 patients with thin filament myopathy caused by mutations in NEB, ACTA1, TPM2, TPM3, TNNT1, KBTBD13, KLHL40, and KLHL41. Results: Lower force generation was observed in muscle fibers from patients of all genotypes. In a subset of patients who harbor mutations in NEB and ACTA1, the lower force was associated with downward shifted force-sarcomere length relations, indicative of shorter thin filaments. Confocal microscopy confirmed shorter thin filaments in muscle fibers of these patients. A conditional Neb knockout mouse model, which recapitulates thin filament myopathy, revealed a compensatory mechanism; the lower force generation that was associated with shorter thin filaments was compensated for by increasing the number of sarcomeres in series. This allowed muscle fibers to operate at a shorter sarcomere length and maintain optimal thin-thick filament overlap. Interpretation: These findings might provide a novel direction for the development of therapeutic strategies for thin filament myopathy patients with shortened thin filament lengths. C1 [de Winter, Josine M.; Joureau, Barbara; Stienen, Ger J. M.; Ottenheijm, Coen A. C.] Vrije Univ Amsterdam Med Ctr, Dept Physiol, NL-1081 BT Amsterdam, Netherlands. [Lee, Eun-Jeong; Kiss, Balazs; Pappas, Christopher T.; Gregorio, Carol C.; Granzier, Henk; Ottenheijm, Coen A. C.] Univ Arizona, Dept Cellular & Mol Med, Tucson, AZ USA. [Yuen, Michaela; Clarke, Nigel F.] Childrens Hosp Westmead, Inst Neurosci & Muscle Res, Westmead, NSW, Australia. [Yuen, Michaela; Clarke, Nigel F.] Univ Sydney, Discipline Paediat & Child Hlth, Sydney, NSW 2006, Australia. [Gupta, Vandana A.; Beggs, Alan H.] Harvard Univ, Sch Med, Boston Childrens Hosp, Manton Ctr Orphan Dis Res,Div Genet & Genom, Boston, MA 02115 USA. [Stienen, Ger J. M.] Vrije Univ Amsterdam, Dept Phys & Astron, Amsterdam, Netherlands. [Edvardson, Simon] Hadassah Univ Hosp, Pediat Neurol Unit, IL-91120 Jerusalem, Israel. [Wallgren-Pettersson, Carina; Lehtokari, Vilma-Lotta] Univ Helsinki, Haartman Inst, Dept Med & Clin Genet, Helsinki, Finland. [Wallgren-Pettersson, Carina; Lehtokari, Vilma-Lotta; Pelin, Katarina] Biomedicum Helsinki, Folkhaelsan Inst Genet, Helsinki, Finland. [Pelin, Katarina] Univ Helsinki, Dept Biosci, Div Genet, Helsinki, Finland. [Malfatti, Edoardo; Romero, Norma B.] Grp Hosp Pitie Salpetriere, Ctr Res Myol, F-75634 Paris, France. [van Engelen, Baziel G.; Voermans, Nicol C.] Radboud Univ Nijmegen, Dept Neurol, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Donkervoort, Sandra; Bonnemann, C. G.] NIH, Neuromuscular & Neurogenet Disorders Childhood Se, Bldg 10, Bethesda, MD 20892 USA. RP Ottenheijm, CAC (reprint author), Vrije Univ Amsterdam Med Ctr, Dept Physiol, NL-1081 BT Amsterdam, Netherlands. EM c.ottenheijm@vumc.nl OI Pelin, Katarina/0000-0002-7040-7266 FU EU-FP7-IRSES SarcoSi; NWO-VIDI [016.126.319]; NIH National Institute of Child Health and Human Development [R01 HD075802]; Foundation Building Strength; AUism Charitable Foundation; NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases [5R01AR053897, K01 AR062601, R01 AR044345]; Charles H. Hood Foundation; National Health & Medical Research Council of Australia [1026933, 1022707, 1031893, 1035828]; Australian Postgraduate Award; University of Sydney FX This work was supported by EU-FP7-IRSES SarcoSi (C.A.C.O.), NWO-VIDI (016.126.319, C.A.C.O.), the NIH National Institute of Child Health and Human Development (R01 HD075802, A.H.B.), A Foundation Building Strength (A.H.B.), the AUism Charitable Foundation (A.H.B.), the NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases (5R01AR053897, H.G.; K01 AR062601, V.A.G.; R01 AR044345, A.H.B.), the Charles H. Hood Foundation (V.A.G.), the National Health & Medical Research Council of Australia (1026933, 1022707, 1031893 and 1035828, N.F.C), and an Australian Postgraduate Award and International Postgraduate Research Scholarship from the University of Sydney (M.Y.). NR 37 TC 1 Z9 1 U1 0 U2 1 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 JUN PY 2016 VL 79 IS 6 BP 959 EP 969 DI 10.1002/ana.24654 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DN0ST UT WOS:000376775400010 ER PT J AU Bettencourt, C Hensman-Moss, D Flower, M Wiethoff, S Brice, A Goizet, C Stevanin, G Koutsis, G Karadima, G Panas, M Yescas-Gomes, P Garcia-Velazquez, LE Alonso-Vilatela, ME Lima, M Raposo, M Traynor, B Sweeney, M Wood, N Giunti, P Durr, A Holmans, P Houlden, H Tabrizi, SJ Jones, L AF Bettencourt, Conceicao Hensman-Moss, Davina Flower, Michael Wiethoff, Sarah Brice, Alexis Goizet, Cyril Stevanin, Giovanni Koutsis, Georgios Karadima, Georgia Panas, Marios Yescas-Gomes, Petra Esmeralda Garcia-Velazquez, Lizbeth Elisa Alonso-Vilatela, Maria Lima, Manuela Raposo, Mafalda Traynor, Bryan Sweeney, Mary Wood, Nicholas Giunti, Paola Durr, Alexandra Holmans, Peter Houlden, Henry Tabrizi, Sarah J. Jones, Lesley CA SPATAX Network TI DNA Repair Pathways Underlie a Common Genetic Mechanism Modulating Onset in Polyglutamine Diseases SO ANNALS OF NEUROLOGY LA English DT Article ID HUNTINGTONS-DISEASE; REPEAT INSTABILITY; SPINOCEREBELLAR ATAXIA; MISMATCH REPAIR; EARLIER AGE; CAG REPEAT; EXPANSION; DAMAGE; MUTATIONS; GENOME AB Objective: The polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome-wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases. Methods: We assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single-nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study. Results: In the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 x 10(-5)). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 x 10(-5)) and all SCAs (p = 2.22 x 10(-4)) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 x 10(-5)), all in the same direction as in the HD GWAS. Interpretation: We show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. C1 [Bettencourt, Conceicao; Wiethoff, Sarah; Wood, Nicholas; Giunti, Paola; Houlden, Henry] UCL, Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Bettencourt, Conceicao] UCL, Inst Neurol, Dept Clin & Expt Epilepsy, London WC1N 3BG, England. [Hensman-Moss, Davina; Flower, Michael; Tabrizi, Sarah J.] UCL, Inst Neurol, Dept Neurodegenerat Dis, London WC1N 3BG, England. [Wiethoff, Sarah] Univ Tubingen, Ctr Neurol, Tubingen, Germany. [Wiethoff, Sarah] Univ Tubingen, Hertie Inst Clin Brain Res, Tubingen, Germany. [Brice, Alexis; Stevanin, Giovanni; Durr, Alexandra] Univ Paris 06, Sorbonne Univ, UMR S 1127,CNRS,UMR 7225, Inst Cerveau & Moelle Epiniere ICM,Inserm,U1127, Paris, France. [Brice, Alexis; Durr, Alexandra] Univ Hosp Pitie Salpetriere, Dept Genet, APHP, F-75013 Paris, France. [Goizet, Cyril] Univ Bordeaux, Lab Malad Rares Genet & Metab, INSERM1211, Bordeaux, France. [Goizet, Cyril] CHU Pellegrin, Serv Genet Med, F-33000 Bordeaux, France. [Stevanin, Giovanni] Ecole Prat Hautes Etud, F-75014 Paris, France. [Koutsis, Georgios; Karadima, Georgia; Panas, Marios] Univ Athens, Eginit Hosp, Sch Med, Dept Neurol 1,Neurogenet Unit, GR-11528 Athens, Greece. [Yescas-Gomes, Petra; Esmeralda Garcia-Velazquez, Lizbeth; Elisa Alonso-Vilatela, Maria] Natl Inst Neurol & Neurosurg, Neurogenet Dept, Mexico City 10740, DF, Mexico. [Lima, Manuela; Raposo, Mafalda] Univ Azores, Dept Biol, P-9500321 Ponta Delgada, Portugal. [Lima, Manuela; Raposo, Mafalda] Univ Porto, Inst Invest & Inovacao Saude, P-4150180 Oporto, Portugal. [Lima, Manuela; Raposo, Mafalda] Univ Porto, Inst Mol & Cell Biol, P-4150180 Oporto, Portugal. [Traynor, Bryan] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Sweeney, Mary; Houlden, Henry] Univ Coll London Hosp, Natl Hosp Neurol & Neurosurg, Neurogenet Unit, London WC1N 3BG, England. [Giunti, Paola] UCL, Inst Neurol, Ataxia Ctr, London WC1N 3BG, England. [Holmans, Peter; Jones, Lesley] Cardiff Univ, Inst Psychol Med & Clin Neurosci, Ctr Neuropsychiat Genet & Gen, MRC, Cardiff CF24 4HQ, S Glam, Wales. RP Jones, L (reprint author), Cardiff Univ, Inst Psychol Med & Clin Neurosci, MRC Ctr Neuropsychiat Genet & Genom, Hadyn Ellis Bldg,Maindy Rd, Cardiff CF24 4HQ, S Glam, Wales. EM JonesL1@cardiff.ac.uk RI Giunti, Paola /E-5526-2012; Houlden, Henry/C-1532-2008; Wood, Nicholas/C-2505-2009; OI Giunti, Paola /0000-0003-3508-4788; Houlden, Henry/0000-0002-2866-7777; Wood, Nicholas/0000-0002-9500-3348; Holmans, Peter/0000-0003-0870-9412; Stevanin, Giovanni/0000-0001-9368-8657 FU UCLH/UCL; European Commission [2012305121]; Medical Research Council (MRC UK) [MR/L010305/1]; Wellcome Trust [WT093205MA, WT104033/Z/14/Z]; Brain Research Trust (BRT); MSA Trust; National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre FX This work was undertaken at UCLH/UCL who acknowledges support from the Department of Health's NIHR Biomedical Research Centre. This work was supported by the European Commission 7th Framework Program (FP7/2007-2013) under grant agreement no. 2012305121 "Integrated European -omics research project for diagnosis and therapy in rare neuromuscular and neuro-degenerative diseases (NeurOmics)", the Medical Research Council (MRC UK, MR/L010305/1), the Wellcome Trust in equipment and strategic award (Synaptopathies) funding (WT093205MA and WT104033/Z/14/Z), the Brain Research Trust (BRT), the MSA Trust, and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre. NR 40 TC 3 Z9 3 U1 4 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 JUN PY 2016 VL 79 IS 6 BP 983 EP 990 DI 10.1002/ana.24656 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DN0ST UT WOS:000376775400012 PM 27044000 ER PT J AU Fiorentino, DF Presby, M Baer, AN Petri, M Rieger, KE Soloski, M Rosen, A Mammen, AL Christopher-Stine, L Casciola-Rosen, L AF Fiorentino, David F. Presby, Matthew Baer, Alan N. Petri, Michelle Rieger, Kerri E. Soloski, Mark Rosen, Antony Mammen, Andrew L. Christopher-Stine, Lisa Casciola-Rosen, Livia TI PUF60: a prominent new target of the autoimmune response in dermatomyositis and Sjogren's syndrome SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID CANCER-ASSOCIATED DERMATOMYOSITIS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; INCLUSION-BODY MYOSITIS; INTERACTING REPRESSOR; REVISED CRITERIA; COPY NUMBER; AUTOANTIBODIES; PROTEIN; IDENTIFICATION; ANTIBODIES AB Objectives Autoantibodies are used clinically to phenotype and subset patients with autoimmune rheumatic diseases. We detected a novel 60 kDa autoantibody specificity by immunoblotting using a dermatomyositis (DM) patient's serum. Our objective was to identify the targeted autoantigen and to evaluate disease specificity and clinical significance of this new autoantibody. Methods A new 60 kDa specificity was detected by immunoblotting HeLa cell lysates. The targeted autoantigen was identified as poly(U)-binding-splicing factor 60 kDa (PUF60) using (i) a human protein array and (ii) two-dimensional gel electrophoresis and liquid chromatography tandem mass spectrometry peptide sequencing. Anti-PUF60 antibodies were assayed by ELISA using sera from patients with primary Sjogren's syndrome (SS; n=84), systemic lupus erythematosus (SLE; n=71), DM (n=267), polymyositis (n=45), inclusion body myositis (n=45) and healthy controls (n=38). Results PUF60 was identified as a new autoantigen. Anti-PUF60 antibodies were present in 25/84 (30%) patients with SS, 6/71 (8.5%) patients with SLE and 2/38 (5.0%) control subjects (SS vs controls, p=0.002; SLE vs controls, p=0.711). Anti-PUF60 antibodies were present in 48/267 (18.0%) patients with DM versus 4/45 (8.9%) and 5/45 (11.1%) patients with inclusion body myositis and polymyositis, respectively. The antibody was significantly associated with anti-Ro52 antibodies, rheumatoid factor and hyperglobulinemia in the patients with primary SS. In patients with DM, the antibody was associated with anti-transcription intermediary factor 1 gamma seropositivity and Caucasian race. Conclusions PUF60 represents a novel autoantigen in patients with SS and DM. PUF60 antibodies are associated with distinct clinical features and different immune responses in different diseases. C1 [Fiorentino, David F.] Stanford Univ, Sch Med, Dept Dermatol, Redwood City, CA USA. [Presby, Matthew; Baer, Alan N.; Petri, Michelle; Soloski, Mark; Rosen, Antony; Christopher-Stine, Lisa; Casciola-Rosen, Livia] Johns Hopkins Univ, Sch Med, Dept Med, Div Rheumatol, Baltimore, MD 21205 USA. [Rieger, Kerri E.] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA. [Mammen, Andrew L.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Mammen, Andrew L.] NIAMSD, Muscle Dis Unit, NIH, Bethesda, MD 20892 USA. RP Casciola-Rosen, L (reprint author), Johns Hopkins Bayview, Div Rheumatol, Dept Med, Mason F Lord Bldg,Ctr Tower,Suite 5300, Baltimore, MD 21224 USA. EM lcr@jhmi.edu FU NIH [R56A062615, R01-AR-44684, R01 DE12354-15A1, RO1-AR 43727, P30-AR-053503]; Jerome L. Greene Foundation; Dorothy and Donald Stabler Foundation; National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health; Huayi and Siuling Zhang Discovery Fund FX These studies were supported by NIH grants R56A062615 (LCR, DF), R01-AR-44684 (LC-R), R01 DE12354-15A1 (AR) and RO1-AR 43727 (MP). ANB and LC-R's work was additionally supported by the Jerome L. Greene Foundation and the Dorothy and Donald Stabler Foundation. ALM's work was supported (in part) by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. LC-S's work and The Johns Hopkins Myositis Cohort is supported by the Huayi and Siuling Zhang Discovery Fund. The Johns Hopkins Rheumatic Disease Research Core Center, where the assays were performed, is supported by the NIH (grant P30-AR-053503). NR 43 TC 8 Z9 8 U1 1 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2016 VL 75 IS 6 BP 1145 EP 1151 DI 10.1136/annrheumdis-2015-207509 PG 7 WC Rheumatology SC Rheumatology GA DM6DP UT WOS:000376440900033 PM 26253095 ER PT J AU Wang, RS Dasgupta, A Ward, MM AF Wang, Runsheng Dasgupta, Abhijit Ward, Michael M. TI Comparative efficacy of non-steroidal anti-inflammatory drugs in ankylosing spondylitis: a Bayesian network meta-analysis of clinical trials SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID DOUBLE-BLIND CROSSOVER; INDOMETHACIN; DICLOFENAC; CELECOXIB; TENOXICAM; PIROXICAM; PHENYLBUTAZONE; KETOPROFEN; ARTHRITIS; SULINDAC AB Objective To compare the efficacy of 20 non-steroidal anti-inflammatory drugs (NSAIDs) in the short-term treatment of ankylosing spondylitis (AS). Methods We performed a systematic literature review of randomised controlled trials of NSAIDs in patients with active AS. We included trials that reported efficacy at 2-12 weeks. Efficacy outcomes were the change in pain score and change in the duration of morning stiffness. We also examined the number of adverse events. We used Bayesian network meta-analysis to compare effects directly and indirectly between drugs. Results We included 26 trials (66 treatment arms) of 20 NSAIDs with 3410 participants in the network meta-analysis. Fifty-eight per cent of trials had fewer than 50 participants. All 20 NSAIDs reduced pain more than placebo (standardised mean difference ranging from -0.65 to -2.2), with 15 NSAIDs significantly better than placebo. Etoricoxib was superior to celecoxib, ketoprofen and tenoxicam in pain reduction, but no other interdrug comparisons were significant. There were no significant differences among NSAIDs in decreases in the duration of morning stiffness or the likelihood of adverse events. Adverse events were uncommon in these short-term studies. In 16 trials that used NSAIDs at full doses, etoricoxib was superior to all but two other NSAIDs in pain reduction. Conclusions Etoricoxib was more effective in reducing pain in AS than some other NSAIDs, but there was otherwise insufficient evidence to conclude that any particular NSAID was more effective in the treatment of AS. Comparisons were limited by small studies. C1 [Wang, Runsheng; Dasgupta, Abhijit; Ward, Michael M.] NIAMSD, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMS, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health FX This study was supported by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. NR 48 TC 3 Z9 4 U1 2 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2016 VL 75 IS 6 BP 1152 EP 1160 DI 10.1136/annrheumdis-2015-207677 PG 9 WC Rheumatology SC Rheumatology GA DM6DP UT WOS:000376440900034 PM 26248636 ER PT J AU Unizony, S Villarreal, M Miloslavsky, EM Lu, N Merkel, PA Spiera, R Seo, P Langford, CA Hoffman, GS Kallenberg, CGM St Clair, EW Ikle, D Tchao, NK Ding, LN Brunetta, P Choi, HK Monach, PA Fervenza, F Stone, JH Specks, U AF Unizony, Sebastian Villarreal, Miguel Miloslavsky, Eli M. Lu, Na Merkel, Peter A. Spiera, Robert Seo, Philip Langford, Carol A. Hoffman, Gary S. Kallenberg, C. G. M. St Clair, E. William Ikle, David Tchao, Nadia K. Ding, Linna Brunetta, Paul Choi, Hyon K. Monach, Paul A. Fervenza, Fernando Stone, John H. Specks, Ulrich CA RAVE-ITN Res Grp TI Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID WEGENERS-GRANULOMATOSIS; SYSTEMIC VASCULITIDES; RANDOMIZED-TRIAL; RENAL VASCULITIS; RITUXIMAB; CYCLOPHOSPHAMIDE; MAINTENANCE; RELAPSE; DAMAGE; INDEX AB Objective To evaluate whether the classification of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) according to ANCA type (anti-proteinase 3 (PR3) or anti-myeloperoxidase (MPO) antibodies) predicts treatment response. Methods Treatment responses were assessed among patients enrolled in the Rituximab in ANCA-associated Vasculitis trial according to both AAV diagnosis (granulomatosis with polyangiitis (GPA)/microscopic polyangiitis (MPA)) and ANCA type (PR3-AAV/MPO-AAV). Complete remission (CR) was defined as disease activity score of 0 and successful completion of the prednisone taper. Results PR3-AAV patients treated with rituximab (RTX) achieved CR at 6 months more frequently than did those randomised to cyclophosphamide (CYC)/azathioprine (AZA) (65% vs 48%; p=0.04). The OR for CR at 6 months among PR3-AAV patients treated with RTX as opposed to CYC/AZA was 2.11 (95% CI 1.04 to 4.30) in analyses adjusted for age, sex and new-onset versus relapsing disease at baseline. PR3-AAV patients with relapsing disease achieved CR more often following RTX treatment at 6 months (OR 3.57; 95% CI 1.43 to 8.93), 12 months (OR 4.32; 95% CI 1.53 to 12.15) and 18 months (OR 3.06; 95% CI 1.05 to 8.97). No association between treatment and CR was observed in the MPO-AAV patient subset or in groups divided according to AAV diagnosis. Conclusions Patients with PR3-AAV respond better to RTX than to CYC/AZA. An ANCA type-based classification may guide immunosuppression in AAV. C1 [Unizony, Sebastian; Miloslavsky, Eli M.; Lu, Na; Choi, Hyon K.; Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Villarreal, Miguel; Ikle, David] Rho, Chapel Hill, NC USA. [Merkel, Peter A.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Spiera, Robert] Hosp Special Surg, 535 E 70th St, New York, NY 10021 USA. [Seo, Philip] Johns Hopkins Univ, Baltimore, MD USA. [Langford, Carol A.; Hoffman, Gary S.] Cleveland Clin, Cleveland, OH 44106 USA. [Kallenberg, C. G. M.] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [St Clair, E. William] Duke Univ, Med Ctr, Durham, NC USA. [Tchao, Nadia K.] Immune Tolerance Network, San Francisco, CA USA. [Ding, Linna] NIAID, DAIT, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Brunetta, Paul] Genentech Inc, San Francisco, CA USA. [Monach, Paul A.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Fervenza, Fernando; Specks, Ulrich] Mayo Clin, Rochester, MN USA. RP Stone, JH (reprint author), Massachusetts Gen Hosp, Rheumatol Unit, Yawkey 2C,55 Fruit St, Boston, MA 02114 USA. EM jhstone@mgh.harvard.edu FU Immune Tolerance Network (NIH) [N01-AI-15416, ITN021AI]; National Institute of Allergy and Infectious Diseases; Juvenile Diabetes Research Foundation; Genentech; Biogen-Idec; Clinical and Translational Science Award (CTSA) [1 UL1 RR024150-01]; NCRR [UL1 RR 025005]; CTSA [UL1RR 025771]; NIH [M01 RR00533, K24 AR02224]; Arthritis Foundation Investigator Award; National Center for Advancing Translational Sciences (NCATS), NIH [UL1TR000439]; [K24 AR049185]; [K23 AR052820] FX This research was performed as a project of the Immune Tolerance Network (NIH Contract N01-AI-15416; Protocol number ITN021AI), an international clinical research consortium headquartered at the University of California San Francisco and supported by the National Institute of Allergy and Infectious Diseases and the Juvenile Diabetes Research Foundation; Genentech and Biogen-Idec. At the Mayo Clinic, the trial was supported by Clinical and Translational Science Award (CTSA) Grant Number 1 UL1 RR024150-01 (National Center for Research Resources; NCRR). At Johns Hopkins, the trial was supported by UL1 RR 025005 (NCRR) and by grants K24 AR049185 (JHS) and K23 AR052820 (PS). At Boston University, the trial was supported by CTSA grant number UL1RR 025771, NIH M01 RR00533, K24 AR02224 (PAM), and an Arthritis Foundation Investigator Award (PAM). At Cleveland Clinic, the trial was supported by UL1TR000439, National Center for Advancing Translational Sciences (NCATS), NIH. ANCA ELISA kits were provided by EUROIMMUN AG (Lubeck, Germany). NR 20 TC 9 Z9 9 U1 3 U2 8 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2016 VL 75 IS 6 BP 1166 EP 1169 DI 10.1136/annrheumdis-2015-208073 PG 4 WC Rheumatology SC Rheumatology GA DM6DP UT WOS:000376440900036 PM 26621483 ER PT J AU Howe, MK Speer, BL Hughes, PE Loiselle, DR Vasudevan, S Haystead, TAJ AF Howe, Matthew K. Speer, Brittany L. Hughes, Philip E. Loiselle, David R. Vasudevan, Subhash Haystead, Timothy A. J. TI An inducible heat shock protein 70 small molecule inhibitor demonstrates anti-dengue virus activity, validating Hsp70 as a host antiviral target SO ANTIVIRAL RESEARCH LA English DT Article DE Heat shock protein 70; Dengue virus; Small molecule inhibitor; Antiviral target; Antiviral therapy ID HEAT-SHOCK-PROTEIN; VIRAL REPLICATION; CELLS; HSP90; INFECTION; DISCOVERY; CHAPERONE; CANCER; FEVER; DRUG AB An estimated three billion people are at risk of Dengue virus (DENV) infection worldwide and there are currently no approved therapeutic interventions for DENV infection. Due to the relatively small size of the DENV genome, DENV is reliant on host factors throughout the viral life cycle. The inducible form of Heat Shock Protein 70 (Hsp70i) has been implicated as a host factor in DENV pathogenesis, however the complete role remains to be elucidated. Here we further illustrate the importance of Hsp70i in dengue virus pathogenesis and describe the antiviral activity of the allosteric small molecule inhibitor that is selective for Hsp70i, called HS-72. In monocytes, Hsp70i is expressed at low levels preceding DENV infection, but Hsp70i expression is induced upon DENV infection. Targeting Hsp70i with HS-72, results in a dose dependent reduction in DENV infected monocytes, while cell viability was maintained. HS-72 works to reduce DENV infection by inhibiting the entry stage of the viral life cycle, through disrupting the association of Hsp70i with the DENV receptor complex. This work highlights Hsp70i as an antiviral target and HS-72 as a potential anti-DENV therapeutic agent. (C) 2016 Elsevier B.V. All rights reserved. C1 [Howe, Matthew K.; Speer, Brittany L.; Hughes, Philip E.; Loiselle, David R.; Haystead, Timothy A. J.] Duke Univ, Sch Med, Dept Pharmacol & Canc Biol, Durham, NC USA. [Vasudevan, Subhash] Duke NUS Grad & Med Sch, Emerging Infect Dis Program, Singapore, Singapore. [Howe, Matthew K.] NIAID, Med Virol Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Haystead, TAJ (reprint author), Duke Univ, Sch Med, Dept Pharmacol & Canc Biol, Durham, NC USA. EM timothy.haystead@dm.duke.edu FU NIH [R01-AI089526-04]; Duke/Duke-NUS Collaborative grant FX Special thanks to Dr. Mariano Garcia-Blanco for providing DENV antibodies and DENV stocks as well as helpful discussions. The structure and use of the HS-72 scaffold and its resynthesis have been disclosed to Duke University in accordance with Duke University guidelines concerning potential intellectual property. This work was funded by NIH grant R01-AI089526-04 to TAJH and a Duke/Duke-NUS Collaborative grant to TAJH and SV. NR 51 TC 3 Z9 3 U1 3 U2 8 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 JUN PY 2016 VL 130 BP 81 EP 92 DI 10.1016/j.antiviral.2016.03.017 PG 12 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA DM2ZW UT WOS:000376217600010 PM 27058774 ER PT J AU Wendell, CR Waldstein, SR Evans, MK Zonderman, AB AF Wendell, Carrington R. Waldstein, Shari R. Evans, Michele K. Zonderman, Alan B. TI Subclinical carotid atherosclerosis and neurocognitive function in an urban population SO ATHEROSCLEROSIS LA English DT Article DE Carotid intimal medial thickness; Subclinical cardiovascular disease; Cognitive function ID INTIMA-MEDIA THICKNESS; ALZHEIMERS-DISEASE; ARTERY INTIMA; CARDIOVASCULAR-DISEASE; COGNITIVE IMPAIRMENT; SOCIOECONOMIC-STATUS; HEART-DISEASE; RISK-FACTORS; OLDER-ADULTS; DEMENTIA AB Background and aims: Examine age, sex, race, and socioeconomic status as modifiers of the association between carotid intimal medial thickness (IMT) and neurocognitive performance in a socioeconomically diverse, biracial, urban, adult population. Methods: Participants were 1712 community-dwelling adults (45% men, 56% African-American, 38% below poverty threshold, aged 30-64 years) enrolled in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. Participants underwent initial carotid ultrasonography followed by cognitive testing on up to two occasions over 4 years. Mixed-effects regression analyses were adjusted for demographic, behavioral, and biomedical covariates. Results: Significant cross-sectional IMT x race x poverty interactions were identified for measures of delayed recall memory, auditory-verbal attention, and working memory. An IMT x race interaction also appeared for auditory-verbal learning. Higher IMT was generally associated with worse cognitive performance, but the disadvantage was most pronounced among those with higher socioeconomic status and white participants. No longitudinal associations were identified. Conclusions: Carotid IMT-cognition associations differed as a function of race and socioeconomic status and were most compelling for measures of attention, executive function, and memory. These findings highlight the possibility that subclinical atherosclerosis may be differentially informative as a predictor of cognitive performance among varied demographic subgroups. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Wendell, Carrington R.; Waldstein, Shari R.] Univ Maryland Baltimore Cty, Dept Psychol, 1000 Hilltop Circle, Baltimore, MD 21250 USA. [Wendell, Carrington R.; Evans, Michele K.; Zonderman, Alan B.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Waldstein, Shari R.] Univ Maryland, Sch Med, Dept Med, Div Gerontol & Geriatr Med, College Pk, MD 20742 USA. [Waldstein, Shari R.] Baltimore VA Med Ctr, Geriatr Res Educ & Clin Ctr, Baltimore, MD USA. RP Wendell, CR (reprint author), Univ Maryland Baltimore Cty, Dept Psychol, 1000 Hilltop Circle, Baltimore, MD 21250 USA. EM crwendell@umbc.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institute on Aging Intramural Research Program of the National Institutes of Health [ZIA-AG000195]; National Institutes of Health [RO1 AG034161] FX This work was supported by the National Institute on Aging Intramural Research Program of the National Institutes of Health (ZIA-AG000195) and a National Institutes of Health grant (RO1 AG034161). We thank the HANDLS Mobile Medical Research Vehicle Staff with special recognition to the psychometrists and the ultrasonographer, Mary Lassiter, for their careful evaluation of HANDLS participants. NR 46 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD JUN PY 2016 VL 249 BP 125 EP 131 DI 10.1016/j.atherosclerosis.2016.04.009 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DM7BA UT WOS:000376505800019 PM 27092741 ER PT J AU Merritt, MA Strickler, HD Einstein, MH Yang, HP Sherman, ME Wentzensen, N Brouwer-Visser, J Cossio, MJ Whitney, KD Yu, H Gunter, MJ Huang, GS AF Merritt, Melissa A. Strickler, Howard D. Einstein, Mark H. Yang, Hannah P. Sherman, Mark E. Wentzensen, Nicolas Brouwer-Visser, Jurriaan Cossio, Maria Jose Whitney, Kathleen D. Yu, Herbert Gunter, Marc J. Huang, Gloria S. TI Insulin/IGF and sex hormone axes in human endometrium and associations with endometrial cancer risk factors SO CANCER CAUSES & CONTROL LA English DT Article DE Insulin-like growth factor; Insulin; Estrogen receptor; Endometrium; Endometrial cancer ID GROWTH-FACTOR-I; BODY-MASS INDEX; ESTROGEN-RECEPTORS; MENSTRUAL-CYCLE; IMMUNOCYTOCHEMICAL ANALYSIS; POSTMENOPAUSAL ENDOMETRIUM; PROGESTERONE-RECEPTORS; PTEN EXPRESSION; GENE-EXPRESSION; ADIPOSE-TISSUE AB Experimental and observational data link insulin, insulin-like growth factor (IGF), and estrogens to endometrial tumorigenesis. However, there are limited data regarding insulin/IGF and sex hormone axes protein and gene expression in normal endometrial tissues, and very few studies have examined the impact of endometrial cancer risk factors on endometrial tissue biology. We evaluated endometrial tissues from 77 premenopausal and 30 postmenopausal women who underwent hysterectomy for benign indications and had provided epidemiological data. Endometrial tissue mRNA and protein levels were measured using quantitative real-time PCR and immunohistochemistry, respectively. In postmenopausal women, we observed higher levels of phosphorylated IGF-I/insulin receptor (pIGF1R/pIR) in diabetic versus non-diabetic women (p value =0.02), while women who reported regular nonsteroidal anti-inflammatory drug use versus no use had higher levels of insulin and progesterone receptors (both p values a parts per thousand currency sign0.03). We also noted differences in pIGF1R/pIR staining with OC use (postmenopausal women only), and the proportion of estrogen receptor-positive tissues varied by the number of live births and PTEN status (premenopausal only) (p values a parts per thousand currency sign0.04). Compared to premenopausal proliferative phase women, postmenopausal women exhibited lower mRNA levels of IGF1, but higher IGFBP1 and IGFBP3 expression (all p values a parts per thousand currency sign0.004), and higher protein levels of the receptors for estrogen, insulin, and IGF-I (all p values a parts per thousand currency sign0.02). Conversely, pIGF1R/pIR levels were higher in premenopausal proliferative phase versus postmenopausal endometrium (p value =0.01). These results highlight links between endometrial cancer risk factors and mechanistic factors that may contribute to early events in the multistage process of endometrial carcinogenesis. C1 [Merritt, Melissa A.; Gunter, Marc J.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, Sch Publ Hlth, St Marys Campus,Norfolk Pl, London W2 1PG, England. [Strickler, Howard D.; Einstein, Mark H.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Jack & Pearl Resnick Campus,1300 Morris Pk Ave, Bronx, NY 10461 USA. [Einstein, Mark H.; Brouwer-Visser, Jurriaan; Cossio, Maria Jose; Huang, Gloria S.] Albert Einstein Coll Med, Div Gynecol Oncol, Dept Obstet & Gynecol, 1300 Morris Pk Ave, Bronx, NY 10461 USA. [Einstein, Mark H.; Brouwer-Visser, Jurriaan; Cossio, Maria Jose; Huang, Gloria S.] Albert Einstein Coll Med, Womens Hlth, 1300 Morris Pk Ave, Bronx, NY 10461 USA. [Einstein, Mark H.; Brouwer-Visser, Jurriaan; Cossio, Maria Jose; Huang, Gloria S.] Montefiore Med Ctr, 1300 Morris Pk Ave, Bronx, NY 10461 USA. [Yang, Hannah P.; Sherman, Mark E.; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Sherman, Mark E.] NCI, Canc Prevent Div, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Whitney, Kathleen D.] Yeshiva Univ Albert Einstein Coll Med, Jack D Weiler Hosp, Dept Pathol, Univ Hosp,Montefiore Med Ctr, 1825 Eastchester Rd,Room 338, Bronx, NY 10461 USA. [Yu, Herbert] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, 701 Ilalo St, Honolulu, HI 96813 USA. RP Merritt, MA (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, Sch Publ Hlth, St Marys Campus,Norfolk Pl, London W2 1PG, England. EM m.merritt@imperial.ac.uk FU National Institutes of Health National Cancer Institute [1R01CA133010]; Reproductive Scientist Development Program through the American Congress of Obstetricians and Gynecologists FX This study was funded by the National Institutes of Health National Cancer Institute (Grant Number 1R01CA133010 to M.J.G.), and G.S.H. was supported by the Reproductive Scientist Development Program through the American Congress of Obstetricians and Gynecologists. NR 50 TC 2 Z9 2 U1 2 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUN PY 2016 VL 27 IS 6 BP 737 EP 748 DI 10.1007/s10552-016-0751-4 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DM8MZ UT WOS:000376619500003 PM 27125830 ER PT J AU Samala, N Wright, EC Buckler, AG Vargas, V Shetty, K Reddy, KR Lucey, MR Alter, HJ Hoofnagle, JH Ghany, MG AF Samala, Niharika Wright, Elizabeth C. Buckler, A. Gretchen Vargas, Vanessa Shetty, Kirti Reddy, K. Rajender Lucey, Michael R. Alter, Harvey J. Hoofnagle, Jay H. Ghany, Marc G. TI Hepatitis E Virus Does Not Contribute to Hepatic Decompensation Among Patients With Advanced Chronic Hepatitis C SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE HALT-C; Complication; HCV Infection; CHC ID CHRONIC LIVER-DISEASE; UNITED-STATES; NATIONAL-HEALTH; ANTIBODY; ASSAYS; SUPERINFECTION; EPIDEMIOLOGY; INFECTION; SERUM; HEV AB BACKGROUND & AIMS: Hepatitis E (HEV) can cause acute-on-chronic liver failure in persons with pre-existing liver disease. We investigated whether HEV infection contributes to hepatic decompensation in patients with previously stable, advanced chronic hepatitis C. METHODS: We performed a case-control study using stored serum samples from subjects enrolled in the randomized phase of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial (n=1050; mean age, 51 y; 70% male; 40% with cirrhosis at baseline). Cases were subjects who developed hepatic decompensation within a 24-week period. Controls (3 per case) were subjects without hepatic decompensation matched for fibrosis stage and followed up for a similar period. A serum sample obtained within 6 months after the decompensation event in cases and the same follow-up period in controls were tested for anti-HEV IgG. Subjects with a positive result had a baseline sample similarly tested for anti-HEV IgG. We measured levels of anti-HEV IgM and HEV RNA in blood samples from incident cases. RESULTS: Of the 1050 subjects analyzed, 314 (30%) experienced a clinical event. Of the 314 subjects who experienced decompensation as defined, 89 (28%) were tested for anti-HEV, along with 267 controls (without decompensation). Similar proportions of cases and controls tested positive for anti-HEV (22.5% and 20.6%, respectively; P=.70). Ten incident HEV infections were identified-4 in cases (4.5%) and 6 in controls (2.2%) (P=.28). HEV RNA was not detected in blood samples from the 10 incident infections. Only 2 of the 4 incident infections among cases were related temporally to the decompensation event. CONCLUSIONS: HEV does not appear to be a significant cause of hepatic decompensation among persons with previously stable, advanced chronic hepatitis C in the United States. C1 [Samala, Niharika; Ghany, Marc G.] NIDDK, Liver Dis Branch, Bethesda, MD 20892 USA. [Wright, Elizabeth C.] NIDDK, Off Director, Bethesda, MD 20892 USA. [Buckler, A. Gretchen; Vargas, Vanessa; Alter, Harvey J.] NIDDK, Liver Dis Res Branch, Bethesda, MD 20892 USA. [Shetty, Kirti] NIH, Infect Dis Sect, Dept Transfus Med, Bldg 10, Bethesda, MD 20892 USA. [Reddy, K. Rajender] Johns Hopkins Univ, Dept Med, Div Gastroenterol, Sibley Mem Hosp, Washington, DC USA. [Lucey, Michael R.] Univ Penn, Dept Med, Div Gastroenterol & Hepatol, Philadelphia, PA 19104 USA. [Hoofnagle, Jay H.] Univ Wisconsin, Dept Med, Div Gastroenterol & Hepatol, Madison, WI USA. RP Ghany, MG (reprint author), NIDDK, Liver Dis Branch, NIH, Bldg 10,Room 9B16,10 Ctr Dr,MSC 1800, Bethesda, MD 20892 USA. EM MarcG@intra.niddk.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX Supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. This manuscript was not prepared in collaboration with Investigators of the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis Trial and does not necessarily reflect the opinions or views of the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis Trial, the National Institute of Diabetes and Digestive and Kidney Diseases Central Repositories, or the National Institute of Diabetes and Digestive and Kidney Diseases. NR 25 TC 4 Z9 4 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD JUN PY 2016 VL 14 IS 6 BP 896 EP 902 DI 10.1016/j.cgh.2015.12.048 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DM6IY UT WOS:000376456400024 PM 26820399 ER PT J AU Frank, JA Burks, S AF Frank, J. A. Burks, S. TI MESENCHYMAL STROMAL CELL DELIVERY ENHANCED BY FOCUSED ULTRASOUND LATE IN CRITICAL HINDLIMB ISCHEMIA MODEL RESTORES PERFUSION SO CYTOTHERAPY LA English DT Meeting Abstract C1 [Frank, J. A.; Burks, S.] NIH, Frank Lab, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD JUN PY 2016 VL 18 IS 6 SU S MA 124 BP S45 EP S46 PG 2 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA DM3BW UT WOS:000376222800117 ER PT J AU Stroncek, D Ren, J Sabatino, M Khuu, H Lee, DW Mackall, C AF Stroncek, D. Ren, J. Sabatino, M. Khuu, H. Lee, D. W. Mackall, C. TI USE OF ELTJTRIATED LYMPHOCYTES FOR MANUFACTURING CD19-CHIMERIC ANTIGEN RECEPTOR T CELLS IMPROVES THE QUANTITY OF TRANSDUCED T CELLS IN THE FINAL PRODUCT SO CYTOTHERAPY LA English DT Meeting Abstract C1 [Stroncek, D.; Ren, J.; Sabatino, M.; Khuu, H.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Lee, D. W.; Mackall, C.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD JUN PY 2016 VL 18 IS 6 SU S MA 187 BP S65 EP S65 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA DM3BW UT WOS:000376222800175 ER PT J AU Polidori, DC Bergman, RN Chung, ST Sumner, AE AF Polidori, David C. Bergman, Richard N. Chung, Stephanie T. Sumner, Anne E. TI Hepatic and Extrahepatic Insulin Clearance Are Differentially Regulated: Results From a Novel Model-Based Analysis of Intravenous Glucose Tolerance Data SO DIABETES LA English DT Article ID BETA-CELL FUNCTION; AFRICAN-AMERICAN; KINETIC-PARAMETERS; MINIMAL MODEL; SENSITIVITY; EXTRACTION; SECRETION; RESISTANCE; WOMEN AB Insulin clearance is a highly variable and important factor that affects circulating insulin concentrations. We developed a novel model-based method to estimate both hepatic and extrahepatic insulin clearance using plasma insulin and C-peptide profiles obtained from the insulin-modified frequently sampled intravenous glucose tolerance test. Data from 100 African immigrants without diabetes (mean age 38 years, body weight 81.7 kg, fasting plasma glucose concentration 83 mg/dL, and fasting insulin concentration 37 pmol/L) were used. Endogenous insulin secretion (calculated by C-peptide deconvolution) and insulin infusion rates were used as inputs to a new two-compartment model of insulin kinetics and hepatic and extrahepatic clearance parameters were estimated. Good agreement between modeled and measured plasma insulin profiles was observed (mean normalized root mean square error 6.8%), and considerable intersubject variability in parameters of insulin clearance among individuals was identified (the mean [interquartile range] for hepatic extraction was 25.8% [32.7%], and for extrahepatic insulin clearance was 20.7 mL/kg/min [11.7 mL/kg/min]). Parameters of insulin clearance were correlated with measures of insulin sensitivity and acute insulin response to glucose. The method described appears promising for future research aimed at characterizing variability in insulin clearance and the mechanisms involved in the regulation of insulin clearance. C1 [Polidori, David C.] Janssen Res & Dev, San Diego, CA USA. [Bergman, Richard N.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Chung, Stephanie T.; Sumner, Anne E.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Polidori, DC (reprint author), Janssen Res & Dev, San Diego, CA USA. EM dpolido1@its.jnj.com FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK-27619, DK-29867]; NIDDK, National Institutes of Health FX This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants DK-27619 and DK-29867 to R.N.B. S.T.C. and A.E.S. were supported by the Intramural Program of NIDDK, National Institutes of Health. NR 22 TC 0 Z9 0 U1 0 U2 1 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 JUN PY 2016 VL 65 IS 6 BP 1556 EP 1564 DI 10.2337/db15-1373 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DM7OA UT WOS:000376548700014 PM 26993071 ER PT J AU Kang, L Mokshagundam, S Reuter, B Lark, DS Sneddon, CC Hennayake, C Williams, AS Bracy, DP James, FD Pozzi, A Zent, R Wasserman, DH AF Kang, Li Mokshagundam, Shilpa Reuter, Bradley Lark, Daniel S. Sneddon, Claire C. Hennayake, Chandani Williams, Ashley S. Bracy, Deanna P. James, Freyja D. Pozzi, Ambra Zent, Roy Wasserman, David H. TI Integrin-Linked Kinase in Muscle Is Necessary for the Development of Insulin Resistance in Diet-Induced Obese Mice SO DIABETES LA English DT Article; Proceedings Paper CT 74th Annual Scientific Sessions of the American-Diabetes-Association CY JUN 13-17, 2014 CL San Francisco, CA SP Amer Diabet Assoc ID HIGH-FAT DIET; CELL-SURVIVAL; ILK; PROLIFERATION; ARCHITECTURE; PARVIN; MOUSE; PINCH AB Diet-induced muscle insulin resistance is associated with expansion of extracellular matrix (ECM) components, such as collagens, and the expression of collagen binding integrin, alpha 2 beta 1. Integrins transduce signals from ECM via their cytoplasmic domains, which bind to intracellular integrin-binding proteins. The integrin-linked kinase (ILK)-PINCH-parvin (IPP) complex interacts with the cytoplasmic domain of beta-integrin subunits and is critical for integrin signaling. In this study we defined the role of ILK, a key component of the IPP complex, in diet-induced muscle insulin resistance. Wild-type (ILKlox/lox) and muscle-specific ILK-deficient (ILK(lox/lox)HSAcre) mice were fed chow or a high-fat (HF) diet for 16 weeks. Body weight was not different between ILKlox/lox and ILK(lox/lox)HSAcre mice. However, HF-fed ILK(lox/lox)HSAcre mice had improved muscle insulin sensitivity relative to HF-fed ILKlox/lox mice, as shown by increased rates of glucose infusion, glucose disappearance, and muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. Improved muscle insulin action in the HF-fed ILK(lox/lox)HSAcre mice was associated with increased insulin-stimulated phosphorylation of Akt and increased muscle capillarization. These results suggest that ILK expression in muscle is a critical component of diet-induced insulin resistance, which possibly acts by impairing insulin signaling and insulin perfusion through capillaries. C1 [Kang, Li; Mokshagundam, Shilpa; Reuter, Bradley; Lark, Daniel S.; Williams, Ashley S.; Bracy, Deanna P.; James, Freyja D.; Pozzi, Ambra; Wasserman, David H.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37235 USA. [Kang, Li; Bracy, Deanna P.; James, Freyja D.; Wasserman, David H.] Vanderbilt Univ, Mouse Metab Phenotyping Ctr, 221 Kirkland Hall, Nashville, TN 37235 USA. [Kang, Li; Sneddon, Claire C.; Hennayake, Chandani] Univ Dundee, Sch Med, Div Mol & Clin Med, Dundee, Scotland. [Pozzi, Ambra; Zent, Roy] Vanderbilt Univ, Dept Med, Div Nephrol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Pozzi, Ambra; Zent, Roy] Vet Affairs Hosp, Dept Med, Nashville, TN USA. RP Kang, L (reprint author), Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37235 USA.; Kang, L (reprint author), Vanderbilt Univ, Mouse Metab Phenotyping Ctr, 221 Kirkland Hall, Nashville, TN 37235 USA.; Kang, L (reprint author), Univ Dundee, Sch Med, Div Mol & Clin Med, Dundee, Scotland. EM Lkang@dundee.ac.uk FU BLRD VA [I01 BX002025, I01 BX002196]; NCI NIH HHS [R01 CA162433]; NIDDK NIH HHS [R01 DK054902, R01 DK075594, R01 DK095761, R56 DK054902, U24 DK059637, R01 DK083187] NR 33 TC 0 Z9 0 U1 2 U2 5 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 JUN PY 2016 VL 65 IS 6 BP 1590 EP 1600 DI 10.2337/db15-1434 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DM7OA UT WOS:000376548700017 PM 27207548 ER PT J AU Naples, JG Marcum, ZA Perera, S Newman, AB Greenspan, SL Gray, SL Bauer, DC Simonsick, EM Shorr, RI Hanlon, JT AF Naples, Jennifer G. Marcum, Zachary A. Perera, Subashan Newman, Anne B. Greenspan, Susan L. Gray, Shelly L. Bauer, Douglas C. Simonsick, Eleanor M. Shorr, Ronald I. Hanlon, Joseph T. TI Impact of Drug-Drug and Drug-Disease Interactions on Gait Speed in Community-Dwelling Older Adults SO DRUGS & AGING LA English DT Article ID PHYSICAL PERFORMANCE-MEASURES; BODY-COMPOSITION; FUNCTIONAL STATUS; MEDICATION USE; HEALTH ABC; DECLINE; ASSOCIATION; PEOPLE; ELDERS; FALLS AB Background Gait speed decline, an early marker of functional impairment, is a sensitive predictor of adverse health outcomes in older adults. The effect of potentially inappropriate medications, including drug-disease and drug-drug interactions, on gait speed decline is not well known. Objective The aim of this study was to determine if drug interactions impair functional status as measured by gait speed. Methods The sample included 2402 older adults with medication and gait speed data from the Health, Aging and Body Composition study. The independent variable was the frequency of drug-disease and/or drug-drug interactions at baseline and 3 additional years. The main outcome was a clinically meaningful gait speed decline of >= 0.1 m/s the year following drug interaction assessment. Adjusted odds ratios and 95 % confidence intervals (CIs) were calculated using multivariate generalized estimating equations for both the overall sample and a sample stratified by gait speed at time of drug interaction assessment. Results The prevalence of drug-disease and drug-drug interactions ranged from 7.6 to 9.3 and 10.5 to 12.3 %, respectively, with few participants (3.8-5.7 %) having multiple drug interactions. At least 22 % of participants had a gait speed decline of >= 0.1 m/s annually. Drug interactions were not significantly associated with gait speed decline overall or in the stratified sample of fast walkers. There was some evidence, however, that drug interactions increased the risk of gait speed decline among those participants with slower gait speeds, though p values did not reach statistical significance (adjusted odds ratio 1.22; 95 % CIs 0.96-1.56; p = 0.11). Moreover, a marginally significant dose-response relationship was seen with multiple drug interactions and gait speed decline (adjusted odds ratio 1.40; 95 % CIs 0.95-2.04; p = 0.08). Conclusions Drug interactions may increase the likelihood of gait speed decline among older adults with evidence of preexisting debility. Future studies should focus on frail elders with less physiological reserve who may be more susceptible to the harms associated with potentially inappropriate medications. C1 [Naples, Jennifer G.; Perera, Subashan; Newman, Anne B.; Greenspan, Susan L.; Hanlon, Joseph T.] Univ Pittsburgh, Sch Med, Div Geriatr, Dept Med, Kaufmann Med Bldg,Suite 500,3471 Fifth Ave, Pittsburgh, PA 15213 USA. [Naples, Jennifer G.; Hanlon, Joseph T.] Univ Pittsburgh, Sch Pharm, Dept Pharm & Therapeut, Pittsburgh, PA 15213 USA. [Naples, Jennifer G.; Hanlon, Joseph T.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Marcum, Zachary A.; Gray, Shelly L.] Univ Washington, Sch Pharm, Seattle, WA 98195 USA. [Perera, Subashan] Univ Pittsburgh, Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15213 USA. [Newman, Anne B.; Hanlon, Joseph T.] Univ Pittsburgh, Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Simonsick, Eleanor M.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Shorr, Ronald I.] Malcolm Randall Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Gainesville, FL USA. RP Naples, JG (reprint author), Univ Pittsburgh, Sch Med, Div Geriatr, Dept Med, Kaufmann Med Bldg,Suite 500,3471 Fifth Ave, Pittsburgh, PA 15213 USA.; Naples, JG (reprint author), Univ Pittsburgh, Sch Pharm, Dept Pharm & Therapeut, Pittsburgh, PA 15213 USA.; Naples, JG (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. EM jgn13@pitt.edu RI Newman, Anne B./C-6408-2013 OI Newman, Anne B./0000-0002-0106-1150 FU NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, P30-AG024827, T32-AG021885, K07-AG033174, R01-AG028050, R01-AG037451]; NINR Grant [R01-NR012459]; Intramural Research Program of the NIH, National Institute on Aging FX This research was supported by NIA contracts (N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106), Grants (P30-AG024827, T32-AG021885, K07-AG033174, R01-AG028050, R01-AG037451), NINR Grant (R01-NR012459), and in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 28 TC 0 Z9 0 U1 5 U2 5 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 1170-229X EI 1179-1969 J9 DRUG AGING JI Drugs Aging PD JUN PY 2016 VL 33 IS 6 BP 411 EP 418 DI 10.1007/s40266-016-0373-2 PG 8 WC Geriatrics & Gerontology; Pharmacology & Pharmacy SC Geriatrics & Gerontology; Pharmacology & Pharmacy GA DM5UT UT WOS:000376416400004 PM 27138955 ER PT J AU Hentschel, M Lange-Kuttner, C Averbeck, BB AF Hentschel, Maren Lange-Kuttner, Christiane Averbeck, Bruno B. TI Sequence Learning with Stochastic Feedback in a Cross-Cultural Sample of Boys in the Autistic Spectrum SO EDUCATION AND TRAINING IN AUTISM AND DEVELOPMENTAL DISABILITIES LA English DT Article ID CHILDHOOD AUTISM; EXECUTIVE FUNCTION; IMPLICIT; CHILDREN; ERROR; DISORDER; ADULTS; IQ; ADOLESCENTS; PERSPECTIVE AB The study investigated sequence learning from stochastic feedback in boys with Autistic Spectrum Disorder (ASD) and typically developed (TD) boys. We asked boys with ASD from Nigeria and the UK as well as age- and gender-matched controls (also males only) to deduce a sequence of four left and right button presses, LLRR, RRLL, LRLR, RLRL, LRRL and RLLR from a feedback signal. Results revealed no significant differences between the boys with ASD from Nigeria and the UK as both groups of boys improved during the task. Most interestingly, the ASD and TD group of boys learning differed for certainty, but not uncertainty of feedback. We concluded that further research is needed why boys with ASD did not benefit from true, logical and reliable feedback. C1 [Hentschel, Maren; Lange-Kuttner, Christiane] London Metropolitan Univ, London, England. [Averbeck, Bruno B.] NIH, New York, NY USA. [Averbeck, Bruno B.] NIMH, Bethesda, MD USA. RP Hentschel, M (reprint author), London Metropolitan Univ, Dept Psychol, Tower Bldg T6-20,166-220 Holloway Rd, London N7 8DB, England. EM mah1197@my.londonmet.ac.uk NR 69 TC 0 Z9 0 U1 11 U2 12 PU COUNCIL EXCEPTIONAL CHILDREN PI ARLINGTON PA 1110 N GLEBE RD, ARLINGTON, VA 22201-5704 USA SN 2154-1647 J9 EDUC TRAIN AUTISM DE JI Educ. Train. Autism Dev. Disabil. PD JUN PY 2016 VL 51 IS 2 BP 179 EP 194 PG 16 WC Education, Special; Rehabilitation SC Education & Educational Research; Rehabilitation GA DM5VX UT WOS:000376419500006 ER PT J AU Zeng, CJ Matsuda, K Jia, WH Chang, J Kweon, SS Xiang, YB Shin, AS Jee, SH Kim, DH Zhang, B Cai, QY Guo, XY Long, JR Wang, N Courtney, R Pan, ZZ Wu, C Takahashi, A Shin, MH Matsuo, K Matsuda, F Gao, YT Oh, JH Kim, S Jung, KJ Ahn, YO Ren, ZF Li, HL Wu, J Shi, JJ Wen, WQ Yang, G Li, BS Ji, BT Brenner, H Schoen, RE Kury, S Gruber, SB Schumacher, FR Stenzel, SL Casey, G Hopper, JL Jenkins, MA Kim, HR Jeong, JY Park, JW Tajima, K Cho, SH Kubo, M Shu, XO Lin, DX Zeng, YX Zheng, W AF Zeng, Chenjie Matsuda, Koichi Jia, Wei-Hua Chang, Jiang Kweon, Sun-Seog Xiang, Yong-Bing Shin, Aesun Jee, Sun Ha Kim, Dong-Hyun Zhang, Ben Cai, Qiuyin Guo, Xingyi Long, Jirong Wang, Nan Courtney, Regina Pan, Zhi-Zhong Wu, Chen Takahashi, Atsushi Shin, Min-Ho Matsuo, Keitaro Matsuda, Fumihiko Gao, Yu-Tang Oh, Jae Hwan Kim, Soriul Jung, Keum Ji Ahn, Yoon-Ok Ren, Zefang Li, Hong-Lan Wu, Jie Shi, Jiajun Wen, Wanqing Yang, Gong Li, Bingshan Ji, Bu-Tian Brenner, Hermann Schoen, Robert E. Kuery, Sebastien Gruber, Stephen B. Schumacher, Fredrick R. Stenzel, Stephanie L. Casey, Graham Hopper, John L. Jenkins, Mark A. Kim, Hyeong-Rok Jeong, Jin-Young Park, Ji Won Tajima, Kazuo Cho, Sang-Hee Kubo, Michiaki Shu, Xiao-Ou Lin, Dongxin Zeng, Yi-Xin Zheng, Wei CA GECCO Colorectal Transdisciplinary CCFR TI Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk SO GASTROENTEROLOGY LA English DT Article DE Epidemiology; Single Nucleotide Polymorphisms; Colon Cancer; eQTL ID GENOME-WIDE ASSOCIATION; SOCS BOX; METAANALYSIS; SCAN; AUTOPHAGY; VARIANTS; TFEB; TRANSFORMATION; DYSREGULATION; DEGRADATION AB BACKGROUND & AIMS: Known genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC. METHODS: This discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases. RESULTS: We identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 x 10(-8) to 1.24 x 10(-12): 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P < .05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2. CONCLUSIONS: We identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis. C1 [Zeng, Chenjie; Zhang, Ben; Cai, Qiuyin; Guo, Xingyi; Long, Jirong; Wang, Nan; Courtney, Regina; Wu, Jie; Shi, Jiajun; Wen, Wanqing; Yang, Gong; Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA. [Matsuda, Koichi] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab Genome Technol, Tokyo, Japan. [Jia, Wei-Hua; Pan, Zhi-Zhong; Zeng, Yi-Xin] Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol South China, Guangzhou 510275, Guangdong, Peoples R China. [Chang, Jiang; Wu, Chen; Lin, Dongxin] Chinese Acad Med Sci, Canc Inst & Hosp, State Key Lab Mol Oncol, Beijing 100730, Peoples R China. [Chang, Jiang; Wu, Chen; Lin, Dongxin] Peking Union Med Coll, Beijing 100021, Peoples R China. [Kweon, Sun-Seog; Shin, Min-Ho] Chonnam Natl Univ, Dept Prevent Med, Sch Med, Gwangju, South Korea. [Kweon, Sun-Seog] Chonnam Natl Univ, Jeonnam Reg Canc Ctr, Hwasun Hosp, Hwasun, South Korea. [Xiang, Yong-Bing; Gao, Yu-Tang; Li, Hong-Lan] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Shin, Aesun] Natl Canc Ctr, Mol Epidemiol Branch, Goyang Si, South Korea. [Shin, Aesun; Ahn, Yoon-Ok] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Jee, Sun Ha; Kim, Soriul; Jung, Keum Ji] Yonsei Univ, Grad Sch Publ Hlth, Dept Epidemiol & Hlth Promot, Inst Hlth Promot, Seoul 120749, South Korea. [Kim, Dong-Hyun; Jeong, Jin-Young] Hallym Univ, Coll Med, Dept Social & Prevent Med, Okcheon Dong, South Korea. [Wang, Nan] Fourth Mil Med Univ, Tangdu Hosp, Gen Dept, Xian, Shaanxi, Peoples R China. [Takahashi, Atsushi; Kubo, Michiaki] RIKEN Ctr Integrat Med Sci, Yokohama, Kanagawa, Japan. [Matsuo, Keitaro] Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan. [Matsuda, Fumihiko] Kyoto Univ, Grad Sch Med, Ctr Genom Med, Kyoto, Japan. [Oh, Jae Hwan; Park, Ji Won] Natl Canc Ctr, Ctr Colorectal Canc, Goyang Si, South Korea. [Ren, Zefang] Sun Yat Sen Univ, Sch Publ Hlth, Guangzhou, Guangdong, Peoples R China. [Li, Bingshan] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37203 USA. [Ji, Bu-Tian] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] Natl Ctr Tumor Dis NCT, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Dept Med & Epidemiol, Pittsburgh, PA USA. [Kuery, Sebastien] CHU Nantes, Gen Med Serv, F-44035 Nantes 01, France. [Gruber, Stephen B.; Schumacher, Fredrick R.; Stenzel, Stephanie L.; Casey, Graham] Univ So Calif, USC Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Hopper, John L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Jenkins, Mark A.] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia. [Kim, Hyeong-Rok] Chonnam Natl Univ, Sch Med, Dept Surg, Gwangju, South Korea. [Park, Ji Won] Seoul Natl Univ Hosp, Dept Surg, Seoul 110744, South Korea. [Tajima, Kazuo] Mie Univ, Grad Sch Med, Dept Publ Hlth & Occupat Med, Tsu, Mie, Japan. [Cho, Sang-Hee] Chonnam Natl Univ, Sch Med, Dept Hematooncol, Gwangju, South Korea. RP Zheng, W (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA. EM wei.zheng@vanderbilt.edu RI Jenkins, Mark/P-7803-2015; Gallinger, Steven/E-4575-2013; Zheng, Wei/O-3351-2013; Brenner, Hermann/B-4627-2017; OI Jenkins, Mark/0000-0002-8964-6160; Zheng, Wei/0000-0003-1226-070X; Brenner, Hermann/0000-0002-6129-1572; Matsuda, Koichi/0000-0001-7292-2686; Matsuo, Keitaro/0000-0003-1761-6314; Hoffmeister, Michael/0000-0002-8307-3197 FU US National Institutes of Health [R01CA188214, R37CA070867, R01CA124558, P50CA095103, R01CA148667]; Vanderbilt University School of Medicine; Vanderbilt-Ingram Cancer Center [P30CA068485]; Shanghai Women's Health Study (US NIH) [R37CA070867, UM1CA182910]; Shanghai Men's Health Study (US NIH) [R01CA082729, UM1CA173640]; Shanghai Breast and Endometrial Cancer Studies (US NIH) [R01CA064277, R01CA092585]; Shanghai Colorectal Cancer Study 3 (US NIH) [R01CA188214, R37CA070867]; Guangzhou Colorectal Cancer Study (National Key Scientific and Technological Project) [2011ZX09307-001-04;]; Guangzhou Colorectal Cancer Study (National Basic Research Program) [2011CB504303]; Guangzhou Colorectal Cancer Study (Natural Science Foundation of China) [81072383]; Japan BioBank Colorectal Cancer Study (Ministry of Education, Culture, Sports, Science and Technology of the Japanese government); Hwasun Cancer Epidemiology Study-Colon and Rectum Cancer (HCES-CRC) [HCRI15011-1]; Japanese Ministry of Education, Culture, Sports, Science and Technology [17015018, 221S0001]; Korea-NCC (National Cancer Center) Colorectal Cancer Study (Basic Science Research Program through the National Research Foundation of Korea [2010-0010276, 2013R1A1A2A10008260]; National Cancer Center Korea [0910220]; KCPS-II Colorectal Cancer Study (National R&D Program for Cancer Control [1220180]; KCPS-II Colorectal Cancer Study (Seoul RD Program) [10526]; GECCO; CORECT; GECCO (US NIH) [U01CA137088, R01CA059045]; DALS (US NIH) [R01CA048998]; DACHS (German Federal Ministry of Education and Research) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, 01KH0404, 01ER0814]; HPFS [P01 CA 055075, UM1 CA167552, R01 CA137178, R01 CA151993, P50 CA127003]; NHS [R01 CA137178, R01 CA151993, P50 CA127003, UM1 CA186107, P01 CA87969]; OFCCR (US NIH) [U01CA074783]; PMH (US NIH) [R01CA076366]; PHS (US NIH) [R01CA042182]; VITAL (US NIH) [K05CA154337]; WHI (US NIH) [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; PLCO (US NIH) [Z01CP 010200, U01HG004446, U01HG 004438]; National Cancer Institute as part of the GAME-ON consortium (US NIH) [U19CA148107]; National Cancer Institute [R01CA81488, P30CA014089]; National Human Genome Research Institute at the US NIH [T32HG000040]; National Institute of Environmental Health Sciences at the US NIH [T32ES013678]; National Cancer Institute; US NIH under RFA [CA-95-011]; National Cancer Institute grant (US NIH) [U01CA122839]; Ontario Research Fund; Canadian Institutes of Health Research; Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute; Ontario Institute for Cancer Research through Ontario Ministry of Economic Development and Innovation; Regional Hospital Clinical Research Program (PHRC); Regional Council of Pays de la Loire; Groupement des Entreprises Francaises dans la Lutte Contre le Cancer (GEFLUC); Association Anne de Bretagne Genetique; Ligue Regionale Contre le Cancer (LRCC); US NIH [Z01CP 010200, U01HG004446, U01HG 004438] FX The work at the Vanderbilt University School of Medicine was supported by US National Institutes of Health grants R01CA188214, R37CA070867, R01CA124558, P50CA095103, and R01CA148667, as well as Ingram Professorship and Anne Potter Wilson Chair funds from the Vanderbilt University School of Medicine. The Survey and Biospecimen Shared Resources and Vanderbilt Microarray Shared Resource are supported in part by the Vanderbilt-Ingram Cancer Center (P30CA068485). Studies (grant support) participating in the Asia Colorectal Cancer Consortium include the Shanghai Women's Health Study (US NIH, R37CA070867, UM1CA182910), Shanghai Men's Health Study (US NIH, R01CA082729, UM1CA173640), Shanghai Breast and Endometrial Cancer Studies (US NIH, R01CA064277 and R01CA092585; contributing only controls), Shanghai Colorectal Cancer Study 3 (US NIH, R37CA070867, R01CA188214 and Ingram Professorship funds), Guangzhou Colorectal Cancer Study (National Key Scientific and Technological Project, 2011ZX09307-001-04; National Basic Research Program, 2011CB504303, contributing only controls; Natural Science Foundation of China, 81072383, contributing only controls), Japan BioBank Colorectal Cancer Study (grant from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government), Hwasun Cancer Epidemiology Study-Colon and Rectum Cancer (HCES-CRC; grants from Chonnam National University Hwasun Hospital, HCRI15011-1). The Aichi Colorectal Cancer Study (Grant-in-Aid for Cancer Research, grant for the Third Term Comprehensive Control Research for Cancer and Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology, 17015018 and 221S0001), Korea-NCC (National Cancer Center) Colorectal Cancer Study (Basic Science Research Program through the National Research Foundation of Korea, 2010-0010276 and 2013R1A1A2A10008260; National Cancer Center Korea, 0910220), and the KCPS-II Colorectal Cancer Study (National R&D Program for Cancer Control, 1220180; Seoul R&D Program, 10526).; Participating studies (grant support) in the GECCO, CORECT, and CCFR GWAS meta-analysis are GECCO (US NIH, U01CA137088 and R01CA059045), DALS (US NIH, R01CA048998), DACHS (German Federal Ministry of Education and Research, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, 01KH0404 and 01ER0814), HPFS (P01 CA 055075, UM1 CA167552, R01 CA137178, R01 CA151993 and P50 CA127003), NHS (UM1 CA186107, R01 CA137178, P01 CA87969, R01 CA151993 and P50 CA127003), OFCCR (US NIH, U01CA074783), PMH (US NIH, R01CA076366), PHS (US NIH, R01CA042182), VITAL (US NIH, K05CA154337), WHI (US NIH, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C), and PLCO (US NIH, Z01CP 010200, U01HG004446 and U01HG 004438). CORECT is supported by the National Cancer Institute as part of the GAME-ON consortium (US NIH, U19CA148107) with additional support from National Cancer Institute grants (R01CA81488 and P30CA014089), the National Human Genome Research Institute at the US NIH (T32HG000040) and the National Institute of Environmental Health Sciences at the US NIH (T32ES013678). CCFR is supported by the National Cancer Institute, US NIH under RFA CA-95-011 and through cooperative agreements with members of the Colon Cancer Family Registry and principal investigators of the Australasian Colorectal Cancer Family Registry (US NIH, U01CA097735), Familial Colorectal Neoplasia Collaborative Group (US NIH, U01CA074799) (University of Southern California), the Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (US NIH, U01CA074800), Ontario Registry for Studies of Familial Colorectal Cancer (US NIH, U01CA074783), Seattle Colorectal Cancer Family Registry (US NIH, U01CA074794). and the University of Hawaii Colorectal Cancer Family Registry (US NIH, U01CA074806). The GWAS work was supported by a National Cancer Institute grant (US NIH, U01CA122839). OFCCR was supported by a GL2 grant from the Ontario Research Fund, Canadian Institutes of Health Research and a Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. T.J. Hudson and B.W. Zanke are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through support from the Ontario Ministry of Economic Development and Innovation. ASTERISK was funded by a Regional Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Francaises dans la Lutte Contre le Cancer (GEFLUC), the Association Anne de Bretagne Genetique and the Ligue Regionale Contre le Cancer (LRCC). PLCO data sets were accessed with approval through dbGaP (CGEMS prostate cancer scan, phs000207.v1.p1 (Yeager, M et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 2007;39:645-649); CGEMS pancreatic cancer scan, phs000206.v4.p3 (Amundadottir, L et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet 2009;41:986-990, and Petersen, GM et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet 2010; 42: 224-228); and GWAS of Lung Cancer and Smoking, phs000093.v2.p2 (Landi MT, et al. A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am J Hum Genet 2009;85:679-691), which was funded by Z01CP 010200, U01HG004446 and U01HG 004438 from the US NIH). NR 59 TC 4 Z9 4 U1 6 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2016 VL 150 IS 7 BP 1633 EP 1645 DI 10.1053/j.gastro.2016.02.076 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DN0TW UT WOS:000376778800035 PM 26965516 ER PT J AU Gao, B Tsukamoto, H AF Gao, Bin Tsukamoto, Hidekazu TI Inflammation in Alcoholic and Nonalcoholic Fatty Liver Disease: Friend or Foe? SO GASTROENTEROLOGY LA English DT Editorial Material DE Neutrophils; Macrophages; Alcoholic Hepatitis; NASH ID HEPATITIS; INJURY; MICE; PREVENTS; DIET C1 [Gao, Bin] NIAAA, Lab Liver Dis, NIH, 5625 Fishers Lane, Bethesda, MD USA. [Tsukamoto, Hidekazu] Univ So Calif, Keck Sch Med, Dept Pathol, Southern Calif Res Ctr Alcohol Liver & Pancreat D, Los Angeles, CA 90033 USA. [Tsukamoto, Hidekazu] Dept Vet Affairs Greater Los Angeles Healthcare S, Los Angeles, CA USA. RP Gao, B (reprint author), NIAAA, Lab Liver Dis, NIH, 5625 Fishers Lane, Bethesda, MD USA.; Tsukamoto, H (reprint author), Univ So Calif, Keck Sch Med, Dept Pathol, Southern Calif Res Ctr Alcohol Liver & Pancreat D, Los Angeles, CA 90033 USA. EM bgao@mail.nih.gov; htsukamo@med.usc.edu FU Intramural NIH HHS [Z01 AA000368-06, Z01 AA000369-06] NR 20 TC 6 Z9 6 U1 2 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2016 VL 150 IS 8 BP 1704 EP 1709 DI 10.1053/j.gastro.2016.01.025 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DN0TZ UT WOS:000376779300003 PM 26826669 ER PT J AU Matter, MS Marquardt, JU Andersen, JB Quintavalle, C Korokhov, N Stauffer, JK Kaji, K Decaens, T Quagliata, L Elloumi, F Hoang, T Molinolo, A Conner, EA Weber, A Heikenwalder, M Factor, VM Thorgeirsson, SS AF Matter, Matthias S. Marquardt, Jens U. Andersen, Jesper B. Quintavalle, Cristina Korokhov, Nikolay Stauffer, Jim K. Kaji, Kosuke Decaens, Thomas Quagliata, Luca Elloumi, Fathi Hoang, Tanya Molinolo, Alfredo Conner, Elizabeth A. Weber, Achim Heikenwalder, Mathias Factor, Valentina M. Thorgeirsson, Snorri S. TI Oncogenic Driver Genes and the Inflammatory Microenvironment Dictate Liver Tumor Phenotype SO HEPATOLOGY LA English DT Article ID HEPATOCELLULAR-CARCINOMA; EXPRESSION; CANCER; PROGNOSIS; MICE; CARCINOGENESIS; METASTASIS; RECURRENCE; ACTIVATION; MECHANISMS AB The majority of hepatocellular carcinoma develops in the background of chronic liver inflammation caused by viral hepatitis and alcoholic or nonalcoholic steatohepatitis. However, the impact of different types of chronic inflammatory microenvironments on the phenotypes of tumors generated by distinct oncogenes is largely unresolved. To address this issue, we generated murine liver tumors by constitutively active AKT-1 (AKT) and beta-catenin (CAT), followed by induction of chronic liver inflammation by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and carbon tetrachloride. Also, the impact of DDC-induced chronic liver inflammation was compared between two liver tumor models using a combination of AKT-CAT or AKT-NRAS(G12V). Treatment with DDC and carbon tetrachloride significantly facilitated the adenoma-to-carcinoma conversion and accelerated the growth of AKT-CAT tumors. Furthermore, DDC treatment altered the morphology of AKT-CAT tumors and caused loss of lipid droplets. Transcriptome analysis of AKT-CAT tumors revealed that cellular growth and proliferation were mainly affected by chronic inflammation and caused up-regulation of Cxcl16, Galectin-3, and Nedd9, among others. Integration with transcriptome profiles from human hepatocellular carcinomas further demonstrated that AKT-CAT tumors generated in the context of chronic liver inflammation showed enrichment of poor prognosis gene sets or decrease of good prognosis gene sets. In contrast, DDC had a more subtle effect on AKT-NRAS(G12V) tumors and primarily enhanced already existent tumor characteristics as supported by transcriptome analysis. However, it also reduced lipid droplets in AKT-NRAS(G12V) tumors. Conclusion: Our study suggests that liver tumor phenotype is defined by a combination of driving oncogenes but also the nature of chronic liver inflammation. C1 [Matter, Matthias S.; Marquardt, Jens U.; Andersen, Jesper B.; Korokhov, Nikolay; Kaji, Kosuke; Decaens, Thomas; Conner, Elizabeth A.; Factor, Valentina M.; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Matter, Matthias S.; Quintavalle, Cristina; Quagliata, Luca; Hoang, Tanya] Univ Basel Hosp, Inst Pathol, CH-4003 Basel, Switzerland. [Marquardt, Jens U.] Johannes Gutenberg Univ Mainz, Dept Med 1, Mainz, Germany. [Andersen, Jesper B.] Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark. [Stauffer, Jim K.] NCI, Canc & Inflammat Program, Frederick, MD 21701 USA. [Elloumi, Fathi] NCI, CCR, Leidos Inc, NIH, Bethesda, MD 20892 USA. [Molinolo, Alfredo] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Weber, Achim] Univ Zurich Hosp, Inst Surg Pathol, CH-8091 Zurich, Switzerland. [Heikenwalder, Mathias] Tech Univ Munich, Helmholtz Zentrum Munchen, Inst Virol, D-80290 Munich, Germany. [Heikenwalder, Mathias] German Canc Res Ctr, Div Chron Inflammat & Canc, Heidelberg, Germany. RP Matter, MS (reprint author), NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.; Matter, MS (reprint author), Univ Basel Hosp, Inst Pathol, CH-4003 Basel, Switzerland. EM matthias.matter@usb.ch RI Quagliata, Luca/B-8321-2015; OI Quagliata, Luca/0000-0001-8249-9914; Andersen , Jesper B/0000-0003-1760-5244 FU Intramural Research Program of the National Institutes of Health/National Cancer Institute/Center for Cancer Research; Schweizerische Stiftung fur Medizinisch-Biologische Stipendien [PASMP-3_14007]; Forschungsfond of the University of Basel/Lichtenstein Stiftung [DMS2287]; Oncosuisse [KFS_3302_08_13, KFS 2773_02_2011]; German Cancer Aid [DKH110989]; Volkswagen Foundation (Lichtenberg Program) FX Supported by the Intramural Research Program of the National Institutes of Health/National Cancer Institute/Center for Cancer Research; the Schweizerische Stiftung fur Medizinisch-Biologische Stipendien (PASMP-3_14007, to M.S.M.); the Forschungsfond of the University of Basel/Lichtenstein Stiftung (DMS2287, to M.S.M.); Oncosuisse (to C.Q., A.W.). (KFS_3302_08_13 to M.S.M. and C.Q.; KFS 2773_02_2011 to A.W.); German Cancer Aid (DKH110989) and Volkswagen Foundation (Lichtenberg Program) to J.V.M. NR 30 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD JUN PY 2016 VL 63 IS 6 BP 1888 EP 1899 DI 10.1002/hep.28487 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DM5BN UT WOS:000376361800017 PM 26844528 ER PT J AU Li, SS Zhu, YY Chavarro, JE Bao, W Tobias, DK Ley, SH Forman, JP Liu, AY Mills, J Bowers, K Strom, M Hansen, S Hu, FB Zhang, CL AF Li, Shanshan Zhu, Yeyi Chavarro, Jorge E. Bao, Wei Tobias, Deirdre K. Ley, Sylvia H. Forman, John P. Liu, Aiyi Mills, James Bowers, Katherine Strom, Marin Hansen, Susanne Hu, Frank B. Zhang, Cuilin TI Healthful Dietary Patterns and the Risk of Hypertension Among Women With a History of Gestational Diabetes Mellitus A Prospective Cohort Study SO HYPERTENSION LA English DT Article DE dietary pattern; gestational diabetes mellitus; hypertension; nutrition; women ID FOOD FREQUENCY QUESTIONNAIRE; RANDOMIZED CONTROLLED-TRIALS; BLOOD-PRESSURE; MEDITERRANEAN DIET; CLINICAL-TRIAL; DASH DIET; SEGUIMIENTO-UNIVERSIDAD; INCIDENT HYPERTENSION; YOUNGER WOMEN; FATTY-ACIDS AB Women who developed gestational diabetes mellitus represent a high-risk population for hypertension later in life. The role of diet in the progression of hypertension among this susceptible population is unknown. We conducted a prospective cohort study of 3818 women with a history of gestational diabetes mellitus in the Nurses' Health Study II as part of the ongoing Diabetes & Women's Health Study. These women were followed-up from 1989 to 2011. Incident hypertension was identified through self-administered questionnaires that were validated previously by medical record review. Adherence scores for the alternative Healthy Eating Index 2010, the alternative Mediterranean diet, and the Dietary Approaches to Stop Hypertension were computed for each participant. Cox proportional hazard models were used to evaluate the associations between dietary scores and hypertension while adjusting for major risk factors for hypertension. We documented 1069 incident hypertension cases during a median of 18.5 years of follow-up. After adjustment for major risk factors for hypertension, including body mass index, alternative Healthy Eating Index 2010, alternative Mediterranean diet, and Dietary Approaches to Stop Hypertension scores were significantly inversely associated with the risk of hypertension; hazard ratio and 95% confidence interval comparing the extreme quartiles (highest versus lowest) were 0.76 (0.61-0.94; P for linear trend = 0.03) for AHEI score, 0.72 (0.58-0.90; P for trend = 0.01) for Dietary Approach to Stop Hypertension score, and 0.70 (0.56-0.88; P for trend = 0.002) for alternative Mediterranean diet score. Adherence to a healthful dietary pattern was related to a lower subsequent risk of developing hypertension among women with a history of gestational diabetes mellitus. C1 [Li, Shanshan; Zhu, Yeyi; Bao, Wei; Mills, James; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. [Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD USA. [Chavarro, Jorge E.; Hu, Frank B.] Harvard Univ, Dept Epidemiol, Dept Nutr, TH Chan Sch Publ Hlth, Boston, MA USA. [Chavarro, Jorge E.; Hu, Frank B.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Chavarro, Jorge E.; Tobias, Deirdre K.; Forman, John P.; Hu, Frank B.] Harvard Univ, Sch Med, Boston, MA USA. [Tobias, Deirdre K.; Ley, Sylvia H.] Harvard Univ, Dept Nutr, TH Chan Sch Publ Hlth, Boston, MA USA. [Tobias, Deirdre K.] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Forman, John P.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Bowers, Katherine] Cincinnati Childrens Hosp, Dept Pediat, Cincinnati, OH USA. [Strom, Marin; Hansen, Susanne] Statens Serum Inst, Ctr Fetal Programming, Dept Epidemiol Res, Natl Hlth Surveillance & Res, DK-2300 Copenhagen, Denmark. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. EM zhangcu@mail.nih.gov OI Liu, Aiyi/0000-0002-6618-5082 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN275201000020C]; National Institutes of Health [DK58845, CA50385, P30 DK46200, UM1 CA176726] FX The 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), and grants DK58845, CA50385, P30 DK46200, and UM1 CA176726 from the National Institutes of Health. The funding agency played no role in the design and conduct of this study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the article. NR 54 TC 2 Z9 2 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD JUN PY 2016 VL 67 IS 6 BP 1157 EP + DI 10.1161/HYPERTENSIONAHA.115.06747 PG 21 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DM6NK UT WOS:000376469500020 PM 27091899 ER PT J AU Matsuda, K Chen, CY Whitted, S Chertova, E Roser, DJ Wu, F Plishka, RJ Ourmanov, I Buckler-White, A Lifson, JD Strebel, K Hirsch, VM AF Matsuda, Kenta Chen, Chia-Yen Whitted, Sonya Chertova, Elena Roser, David J. Wu, Fan Plishka, Ronald J. Ourmanov, Ilnour Buckler-White, Alicia Lifson, Jeffrey D. Strebel, Klaus Hirsch, Vanessa M. TI Enhanced antagonism of BST-2 by a neurovirulent SIV envelope SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; CENTRAL-NERVOUS-SYSTEM; POTENT ANTIRETROVIRAL THERAPY; INFECTIOUS MOLECULAR CLONES; GP41 CYTOPLASMIC TAIL; NEUTRALIZATION SENSITIVITY; IMMUNE ACTIVATION; PARTICLE RELEASE; HIV-1 INFECTION; RHESUS MACAQUES AB Current antiretroviral therapy (ART) is not sufficient to completely suppress disease progression in the CNS, as indicated by the rising incidence of HIV-1-associated neurocognitive disorders (HAND) among infected individuals on ART. It is not clear why some HIV-1-infected patients develop HAND, despite effective repression of viral replication in the circulation. SIV-infected nonhuman primate models are widely used to dissect the mechanisms of viral pathogenesis in the CNS. Here, we identified 4 amino acid substitutions in the cytoplasmic tail of viral envelope glycoprotein gp41 of the neurovirulent virus SIVsm804E that enhance replication in macrophages and associate with enhanced antagonism of the host restriction factor BM stromal cell antigen 2 (BST-2). Rhesus macaques were inoculated with a variant of the parental virus SIVsmE543-3 that had been engineered to contain the 4 amino acid substitutions present in gp41 of SIVsm804E. Compared with WT virus-infected controls, animals infected with mutant virus exhibited higher viral load in cerebrospinal fluid. Together, these results are consistent with a potential role for BST-2 in the CNS microenvironment and suggest that BST-2 antagonists may serve as a possible target for countermeasures against HAND. C1 [Matsuda, Kenta; Chen, Chia-Yen; Whitted, Sonya; Wu, Fan; Plishka, Ronald J.; Ourmanov, Ilnour; Buckler-White, Alicia; Strebel, Klaus; Hirsch, Vanessa M.] NIAID, Lab Mol Microbiol, NIH, Bldg 4,Room B1-41,4 Ctr Dr, Bethesda, MD 20892 USA. [Chertova, Elena; Roser, David J.; Lifson, Jeffrey D.] AIDS & Canc Virus Program Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Hirsch, VM (reprint author), NIAID, LMM, NIH, Bldg 4,Room B1-41,4 Ctr Dr, Bethesda, MD 20892 USA. EM vhirsch@niaid.nih.gov FU NIAID; NIH; National Cancer Institute, NIH [HHSN261200800001E] FX We thank Heather Cronise, Joanne Swerzyck, and Richard Herbert at the NIH Animal Center for excellent care of study animals. This work was supported with federal funds from the intramural program of the NIAID, NIH, and with federal funds from the National Cancer Institute, NIH (contract HHSN261200800001E). NR 49 TC 2 Z9 2 U1 0 U2 1 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 JUN PY 2016 VL 126 IS 6 BP 2295 EP 2307 DI 10.1172/JCI83725 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DN4IF UT WOS:000377027500025 PM 27159392 ER PT J AU Feng, DC Dai, S Liu, FM Ohtake, Y Zhou, Z Wang, H Zhang, YG Kearns, A Peng, X Zhu, FL Hayat, U Li, M He, Y Xu, MJ Zhao, CL Cheng, M Zhang, LN Wang, H Yang, XF Ju, C Bryda, EC Gordon, J Khalili, K Hu, WH Li, SX Qin, XB Gao, B AF Feng, Dechun Dai, Shen Liu, Fengming Ohtake, Yosuke Zhou, Zhou Wang, Hua Zhang, Yonggang Kearns, Alison Peng, Xiao Zhu, Faliang Hayat, Umar Li, Man He, Yong Xu, Mingjiang Zhao, Chunling Cheng, Min Zhang, Lining Wang, Hong Yang, Xiaofeng Ju, Cynthia Bryda, Elizabeth C. Gordon, Jennifer Khalili, Kamel Hu, Wenhui Li, Shuxin Qin, Xuebin Gao, Bin TI Cre-inducible human CD59 mediates rapid cell ablation after intermedilysin administration SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; DIPHTHERIA-TOXIN; TRANSGENIC MICE; LIVER-INJURY; RECEPTOR; DISEASE; ROLES; INFLAMMATION; RECOMBINASE; PROGRESSION AB Cell ablation is a powerful tool for studying cell lineage and/or function; however, current cell-ablation models have limitations. Intermedilysin (ILY), a cytolytic pore-forming toxin that is secreted by Streptococcus intermedius, lyses human cells exclusively by binding to the human complement regulator CD59 (hCD59), but does not react with CD59 from nonprimates. Here, we took advantage of this feature of ILY and developed a model of conditional and targeted cell ablation by generating floxed STOP-CD59 knockin mice (ihCD59), in which expression of human CD59 only occurs after Cre-mediated recombination. The administration of ILY to ihCD59(+) mice crossed with various Cre-driver lines resulted in the rapid and specific ablation of immune, epithelial, or neural cells without off-target effects. ILY had a large pharmacological window, which allowed us to perform dose-dependent studies. Finally, the ILY/ihCD59-mediated cell-ablation method was tested in several disease models to study immune cell functionalities, hepatocyte and/or biliary epithelial damage and regeneration, and neural cell damage. Together, the results of this study demonstrate the utility of the ihCD59 mouse model for studying the effects of cell ablation in specific organ systems in a variety of developmental and disease states. C1 [Feng, Dechun; Zhou, Zhou; Wang, Hua; Li, Man; He, Yong; Xu, Mingjiang; Gao, Bin] NIAAA, Lab Liver Dis, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. [Dai, Shen; Zhu, Faliang; Zhang, Lining] Shandong Univ, Dept Immunol, Sch Med, Jinan 250100, Peoples R China. [Dai, Shen; Zhang, Yonggang; Kearns, Alison; Peng, Xiao; Zhu, Faliang; Zhao, Chunling; Cheng, Min; Gordon, Jennifer; Khalili, Kamel; Hu, Wenhui; Qin, Xuebin] Temple Univ, Sch Med, Dept Neurosci, Room 749,3500 N Broad St, Philadelphia, PA 19140 USA. [Ohtake, Yosuke; Hayat, Umar; Li, Shuxin] Temple Univ, Sch Med, Dept Anat & Cell Biol, Shriners Hosp Pediat Res Ctr, Room 749,3500 N Broad St, Philadelphia, PA 19140 USA. [Zhao, Chunling; Cheng, Min] Weifang Med Univ, Key Lab Immunol Univ Shandong Prov, Weifang, Peoples R China. [Wang, Hong; Yang, Xiaofeng] Temple Univ, Sch Med, Ctr Metab Dis Res, Room 749,3500 N Broad St, Philadelphia, PA 19140 USA. [Wang, Hong; Yang, Xiaofeng] Temple Univ, Sch Med, Cardiovasc Res Ctr, Room 749,3500 N Broad St, Philadelphia, PA 19140 USA. [Ju, Cynthia] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci & Integrated Im, Anschutz Med Campus, Aurora, CO USA. [Bryda, Elizabeth C.] Univ Missouri, Rat Resource & Res Ctr, Columbia, MO USA. [Bryda, Elizabeth C.] Univ Missouri, Dept Vet Pathobiol, Columbia, MO USA. RP Gao, B (reprint author), NIAAA, Lab Liver Dis, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA.; Qin, XB (reprint author), Temple Univ, Sch Med, Dept Neurosci, Room 749,3500 N Broad St, Philadelphia, PA 19140 USA. EM xuebin.qin@temple.edu; bgao@mail.nih.gov RI Feng, Dechun/Q-5962-2016; Zhou, Zhou/R-7788-2016 FU NIAAA; NIH [1R01CA166144, RO1 AI061174, 1R01 NS079432, 1R01 EY024575]; China Scholarship [201306220151]; Major Research Plan of the National Natural Science Foundation of China [91439124]; Shangdong Province Taishan Scholar Project of China; Comprehensive NeuroAIDS Center (CNAC NIMH) [P30 MH092177]; Shriners Research Foundation [SHC-86300]; NIH under a Ruth L. Kirschstein National Research Service Award [5T32MH079785] FX This work was supported by the intramural program of NIAAA (to B. Gao), NIH 1R01CA166144 and RO1 AI061174 (to X. Qin), China Scholarship 201306220151 (to S. Dai), Major Research Plan of the National Natural Science Foundation of China 91439124 (to L. Zhang), Shangdong Province Taishan Scholar Project of China, core facilities grant for the Comprehensive NeuroAIDS Center (CNAC NIMH P30 MH092177) (to K. Khalili), and NIH 1R01 NS079432 and 1R01 EY024575, and Shriners Research Foundation (SHC-86300) grants (to S. Li). A. Kearns was supported by NIH under a Ruth L. Kirschstein National Research Service Award (5T32MH079785). We thank David Lovinger and Li Zhang (NIAAA, NIH) for advice on the neural cell-ablation study and Chuxia Deng (NIDDK, NIH) for advice on the generation of the ihCD59 construct. We also thank Liangyou Rui (University of Michigan, Ann Arbor, Michigan, USA) for providing the Alb-Cre adenovirus, NR 31 TC 1 Z9 1 U1 0 U2 2 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 JUN PY 2016 VL 126 IS 6 BP 2321 EP 2333 DI 10.1172/JCI84921 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DN4IF UT WOS:000377027500027 PM 27159394 ER PT J AU Boum, Y Kim, S Orikiriza, P Acuna-Villaorduna, C Vinhas, S Bonnet, M Nyehangane, D Mwanga-Amumpaire, J Fennelly, KP Jones-Lopez, EC AF Boum, Yap, II Kim, Soyeon Orikiriza, Patrick Acuna-Villaorduna, Carlos Vinhas, Solange Bonnet, Maryline Nyehangane, Dan Mwanga-Amumpaire, Juliet Fennelly, Kevin P. Jones-Lopez, Edward C. TI Diagnostic Accuracy of the Small Membrane Filtration Method for Diagnosis of Pulmonary Tuberculosis in a High-HIV-Prevalence Setting SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID XPERT(R) MTB/RIF ASSAYS; SMEAR MICROSCOPY; BLEACH-SEDIMENTATION; SPUTUM MICROSCOPY; FILTER METHOD; SENSITIVITY; RESISTANCE; TB AB Sputum acid-fast bacilli (AFB) smear microscopy has suboptimal sensitivity but remains the most commonly used laboratory test to diagnose pulmonary tuberculosis (TB). We prospectively evaluated the small membrane filtration (SMF) method that concentrates AFB in a smaller area to facilitate detection to improve the diagnostic performance of microscopy. We enrolled adults with suspicion of pulmonary TB from health facilities in southwestern Uganda. Clinical history, physical examination, and 3 sputum samples were obtained for direct fluorescent AFB smear, SMF, Xpert MTB/RIF, and MGIT culture media. Sensitivity and specificity were estimated for SMF, AFB smear, and Xpert MTB/RIF, using MGIT as the reference standard. The analysis was stratified according to HIV status. From September 2012 to April 2014, 737 participants were included in the HIV-infected stratum (146 [20.5%] were culture positive) and 313 were in the HIV-uninfected stratum (85 [28%] were culture positive). In HIV-infected patients, the sensitivity of a single SMF was 67.4% (95% confidence interval [CI], 59.9% to 74.1%); for AFB, 68.0% (95% CI, 60.6% to 74.6%); and for Xpert MTB/RIF, 91.0% (95% CI, 85.0% to 94.8%). In HIV-uninfected patients, the corresponding sensitivities were 72.5% (95% CI, 62.1% to 80.9%), 80.3% (95% CI, 70.8% to 87.2%), and 93.5% (95% CI, 85.7% to 97.2%). The specificity for all 3 tests in both HIV groups was >= 96%. In this setting, the SMF method did not improve the diagnostic accuracy of sputum AFB. The Xpert MTB/RIF assay performed well in both HIV-infected and -uninfected groups. C1 [Boum, Yap, II; Orikiriza, Patrick; Bonnet, Maryline; Nyehangane, Dan; Mwanga-Amumpaire, Juliet] Med Sans Frontieres, Epictr, Mbarara, Uganda. [Boum, Yap, II; Orikiriza, Patrick; Mwanga-Amumpaire, Juliet] Mbarara Univ Sci & Technol, Fac Med, Mbarara, Uganda. [Kim, Soyeon] Rutgers State Univ, Rutgers Sch Publ Hlth, Dept Biostat, Newark, NJ 07102 USA. [Acuna-Villaorduna, Carlos; Jones-Lopez, Edward C.] Boston Med Ctr, Dept Med, Infect Dis Sect, Boston, MA USA. [Acuna-Villaorduna, Carlos; Jones-Lopez, Edward C.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Vinhas, Solange] Univ Fed Espirito Santo, NDI, Vitoria, Brazil. [Bonnet, Maryline] UM, IRD, INSERM, U1175,UMI 233,TransVIHMI, Montpellier, France. [Fennelly, Kevin P.] Univ Florida, Dept Med, Div Global Med, Gainesville, FL USA. [Fennelly, Kevin P.] NHLBI, Pulm Clin Med Sect, Cardiovasc & Pulm Branch, Div Intramural Res,NIH, Bldg 10, Bethesda, MD 20892 USA. RP Jones-Lopez, EC (reprint author), Boston Med Ctr, Dept Med, Infect Dis Sect, Boston, MA USA.; Jones-Lopez, EC (reprint author), Boston Univ, Sch Med, Boston, MA 02118 USA. EM edward.jones@bmc.org FU Medecins sans Frontieres FX This work, including the efforts of Yap Boum II, Kevin P. Fennelly, and Edward C. Jones-Lopez, was funded by Medecins sans Frontieres. NR 33 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD JUN PY 2016 VL 54 IS 6 BP 1520 EP 1527 DI 10.1128/JCM.00017-16 PG 8 WC Microbiology SC Microbiology GA DM7HM UT WOS:000376529200018 PM 27030493 ER PT J AU Shou, HC Shinohara, RT Liu, H Reich, DS Crainiceanu, CM AF Shou, Haochang Shinohara, Russell T. Liu, Han Reich, Daniel S. Crainiceanu, Ciprian M. TI Soft Null Hypotheses: A Case Study of Image Enhancement Detection in Brain Lesions SO JOURNAL OF COMPUTATIONAL AND GRAPHICAL STATISTICS LA English DT Article DE Contrast enhancement; DCE-MRI; Hypothesis testing; Multiple sclerosis; Principal components analysis; Soft null ID MULTIPLE-SCLEROSIS; BARRIER; MRI AB This work is motivated by a study of a population of multiple sclerosis (MS) patients using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to identify active brain lesions. At each visit, a contrast agent is administered intravenously to a subject and a series of images are acquired to reveal the location and activity of MS lesions within the brain. Our goal is to identify the enhancing lesion locations at the subject level and lesion enhancement patterns at the population level. We analyze a total of 20 subjects scanned at 63 visits (similar to 30Gb), the largest population of such clinical brain images. After addressing the computational challenges, we propose possible solutions to the difficult problem of transforming a qualitative scientific null hypothesis, such as "this voxel does not enhance," to a well-defined and numerically testable null hypothesis based on the existing data. We call such procedure "soft null" hypothesis testing as opposed to the standard "hard null" hypothesis testing. This problem is fundamentally different from: (1) finding testing statistics when a quantitative null hypothesis is given; (2) clustering using a mixture distribution; or (3) setting a reasonable threshold with a parametric null assumption. Supplementary materials are available online. C1 [Shou, Haochang; Shinohara, Russell T.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Liu, Han] Princeton Univ, Dept Operat Res & Financial Engn, Princeton, NJ 08544 USA. [Reich, Daniel S.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Crainiceanu, Ciprian M.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. RP Shou, HC; Shinohara, RT (reprint author), Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA.; Liu, H (reprint author), Princeton Univ, Dept Operat Res & Financial Engn, Princeton, NJ 08544 USA.; Reich, DS (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA.; Crainiceanu, CM (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. EM hshou@upenn.edu; rshi@upenn.edu; hanliu@princeton.edu; daniel.reich@nih.gov; ccrainic@jhsph.edu RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 FU NIH from the National Institute of Biomedical Imaging and Bioengineering [R01 EB012547]; NIH [R01 NS060910, R01 NS085211]; NINDS; NIH from the National Institute of Mental Health [R01 MH095836] FX The authors are very grateful to the reviewers and editors from JCGS for their insightful comments and suggestions through the revision process. We also thank Colin Shea and the National Institute of Neurological Disorders and Stroke (NINDS) Neuroimmunology Clinic for collecting and processing the data for this study. The project was supported by the NIH grant R01 EB012547 from the National Institute of Biomedical Imaging and Bioengineering, NIH grants R01 NS060910, R01 NS085211 and the Intramural Research Program of NINDS, the NIH grants R01 MH095836 from the National Institute of Mental Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. NR 15 TC 0 Z9 0 U1 0 U2 0 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1061-8600 EI 1537-2715 J9 J COMPUT GRAPH STAT JI J. Comput. Graph. Stat. PD JUN PY 2016 VL 25 IS 2 BP 570 EP 588 DI 10.1080/10618600.2015.1023396 PG 19 WC Statistics & Probability SC Mathematics GA DM7PF UT WOS:000376551800013 ER PT J AU Michalska, KJ Shechner, T Hong, M Britton, JC Leibenluft, E Pine, DS Fox, NA AF Michalska, Kalina J. Shechner, Tomer Hong, Melanie Britton, Jennifer C. Leibenluft, Ellen Pine, Daniel S. Fox, Nathan A. TI A developmental analysis of threat/safety learning and extinction recall during middle childhood SO JOURNAL OF EXPERIMENTAL CHILD PSYCHOLOGY LA English DT Article DE Fear learning; Fear generalization; Extinction recall; Aversive conditioning; Skin conductance; Development ID CONDITIONED FEAR; ANXIETY; MEMORY; DISORDERS; BRAIN; OVERGENERALIZATION; ADOLESCENTS; THREAT; ADULTS AB The current study examined developmental changes in fear learning and generalization in 54 healthy 5-10-year old children using a novel fear conditioning paradigm. In this task, the conditioned stimuli (CS+/CS-) were two blue and yellow colored cartoon bells, and the unconditioned stimulus was an unpleasant loud alarm sound presented with a red cartoon bell. Physiological and subjective data were acquired. Three weeks after conditioning, 48 of these participants viewed the CS-, CS+, and morphed images resembling the CS+. Participants made threat-safety discriminations while appraising threat and remembering the CS+. Although no age-related differences in fear learning emerged, patterns of generalization were qualified by child age. Older children demonstrated better discrimination between the CS+ and CS morphs than younger age groups and also reported more fear to stimuli resembling the CS+ than younger children. Clinical implications and future directions are discussed. (C) 2016 Published by Elsevier Inc. C1 [Michalska, Kalina J.; Leibenluft, Ellen; Pine, Daniel S.] NIMH, NIH, Bethesda, MD 20892 USA. [Shechner, Tomer] Univ Haifa, Dept Psychol, IL-31999 Haifa, Israel. [Hong, Melanie; Fox, Nathan A.] Univ Maryland, Dept Human Dev & Quantitat Methodol, College Pk, MD 20742 USA. [Britton, Jennifer C.] Univ Miami, Dept Psychol, POB 248185, Coral Gables, FL 33124 USA. RP Michalska, KJ (reprint author), NIMH, NIH, Bethesda, MD 20892 USA. EM kalina.michalska@nih.gov FU Intramural NIH HHS [ZIA MH002781-15]; NIMH NIH HHS [R00 MH091183] NR 25 TC 1 Z9 1 U1 9 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-0965 EI 1096-0457 J9 J EXP CHILD PSYCHOL JI J. Exp. Child Psychol. PD JUN PY 2016 VL 146 BP 95 EP 105 DI 10.1016/j.jecp.2016.01.008 PG 11 WC Psychology, Developmental; Psychology, Experimental SC Psychology GA DK0LA UT WOS:000374603100007 PM 26922673 ER PT J AU Peshkin, BN Kelly, S Nusbaum, RH Similuk, M DeMarco, TA Hooker, GW Valdimarsdottir, HB Forman, AD Joines, JR Davis, C McCormick, SR McKinnon, W Graves, KD Isaacs, C Garber, J Wood, M Jandorf, L Schwartz, MD AF Peshkin, Beth N. Kelly, Scott Nusbaum, Rachel H. Similuk, Morgan DeMarco, Tiffani A. Hooker, Gillian W. Valdimarsdottir, Heiddis B. Forman, Andrea D. Joines, Jessica Rispoli Davis, Claire McCormick, Shelley R. McKinnon, Wendy Graves, Kristi D. Isaacs, Claudine Garber, Judy Wood, Marie Jandorf, Lina Schwartz, Marc D. TI Patient Perceptions of Telephone vs. In-Person BRCA1/BRCA2 Genetic Counseling SO JOURNAL OF GENETIC COUNSELING LA English DT Article DE BRCA1/BRCA2; Genetic counseling; Patient satisfaction; Telephone counseling ID NEW-YORK-CITY; RANDOMIZED CONTROLLED-TRIAL; AT-RISK LATINAS; BREAST-CANCER; HEREDITARY BREAST; OVARIAN-CANCER; RACIAL DISPARITIES; AFRICAN DESCENT; COMMUNICATION; HEALTH AB Telephone genetic counseling (TC) for hereditary breast/ovarian cancer risk has been associated with positive outcomes in high risk women. However, little is known about how patients perceive TC. As part of a randomized trial of TC versus usual care (UC; in-person genetic counseling), we compared high risk women's perceptions of: (1) overall satisfaction with genetic counseling; (2) convenience; (3) attentiveness during the session; (4) counselor effectiveness in providing support; and (5) counselor ability to recognize emotional responses during the session. Among the 554 participants (TC, N = 272; UC, N = 282), delivery mode was not associated with self-reported satisfaction. However, TC participants found counseling significantly more convenient than UC participants (OR = 4.78, 95 % CI = 3.32, 6.89) while also perceiving lower levels of support (OR = 0.56, 95 % CI = 0.40-0.80) and emotional recognition (OR = 0.53, 95 % CI = 0.37-0.76). In exploratory analyses, we found that non-Hispanic white participants reported higher counselor support in UC than in TC (69.4 % vs. 52.8 %; OR = 3.06, 95 % CI = 1.39-6.74), while minority women perceived less support in UC vs. TC (58.3 % vs. 38.7 %; OR = 0.80, 95 % CI = 0.39-1.65). We discuss potential research and practice implications of these findings which may further improve the effectiveness and utilization of TC. C1 [Peshkin, Beth N.; Graves, Kristi D.; Isaacs, Claudine; Schwartz, Marc D.] Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Peshkin, Beth N.; Graves, Kristi D.; Isaacs, Claudine; Schwartz, Marc D.] Georgetown Univ, Jess & Mildred Fisher Ctr Hereditary Canc & Clin, 3300 Whitehaven St NW,Suite 4100, Washington, DC 20007 USA. [Kelly, Scott] George Washington Univ, Dept Epidemiol & Biostat, Washington, DC USA. [Nusbaum, Rachel H.] GeneDx, Gaithersburg, MD USA. [Similuk, Morgan] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [DeMarco, Tiffani A.] Inova Hlth Syst, Inova Translat Med Inst, Canc Genet Counseling Program, Falls Church, VA USA. [Hooker, Gillian W.] NextGxDx Inc, Franklin, TN USA. [Valdimarsdottir, Heiddis B.; Jandorf, Lina] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA. [Valdimarsdottir, Heiddis B.] Reyjavik Univ, Dept Psychol, Reyjavik, Iceland. [Forman, Andrea D.] Fox Chase Canc Ctr, Risk Assessment Program, Dept Clin Genet, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Joines, Jessica Rispoli] Univ Maryland, Med Ctr, Dept Med, Marlene & Stewart Greenebaum Canc Ctr,Div Hematol, Baltimore, MD 21201 USA. [Davis, Claire] Sarah Lawrence Coll, Joan H Marks Grad Program Human Genet, Yonkers, NY USA. [McCormick, Shelley R.; Garber, Judy] Harvard Univ, Sch Med, Ctr Canc Genet & Prevent, Dana Farber Canc Inst, Boston, MA 02115 USA. [McKinnon, Wendy; Wood, Marie] Univ Vermont, Ctr Canc, Familial Canc Program, Burlington, VT USA. RP Peshkin, BN (reprint author), Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC USA.; Peshkin, BN (reprint author), Georgetown Univ, Jess & Mildred Fisher Ctr Hereditary Canc & Clin, 3300 Whitehaven St NW,Suite 4100, Washington, DC 20007 USA. EM peshkinb@georgetown.edu RI Kelly, Scott/D-3195-2013 OI Kelly, Scott/0000-0002-0375-1040 FU National Cancer Institute [R01 CA108933, P30 CA051008]; Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research FX The study was supported by Grants R01 CA108933 and P30 CA051008 from the National Cancer Institute and by the Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 55 TC 3 Z9 3 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1059-7700 EI 1573-3599 J9 J GENET COUNS JI J. Genet. Couns. PD JUN PY 2016 VL 25 IS 3 BP 472 EP 482 DI 10.1007/s10897-015-9897-6 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA DM4AL UT WOS:000376287800007 PM 26455498 ER PT J AU Peters, JA Kenen, R Bremer, R Givens, S Savage, SA Mai, PL AF Peters, June A. Kenen, Regina Bremer, Renee Givens, Shannon Savage, Sharon A. Mai, Phuong L. TI Easing the Burden: Describing the Role of Social, Emotional and Spiritual Support in Research Families with Li-Fraumeni Syndrome SO JOURNAL OF GENETIC COUNSELING LA English DT Article DE Li-fraumeni syndrome (LFS); TP53 germline mutation; Hereditary cancer susceptibility; Genetic counseling; Genetic testing; Social support; Psychosocial; Psychosocial adaptation; Resilience; Qualitative research; Cegrm; Religious; Spiritual ID GERMLINE TP53 MUTATIONS; CHILDHOOD-CANCER SURVIVORS; QUALITY-OF-LIFE; BREAST-CANCER; ETHICAL ISSUES; P53 MUTATIONS; HEALTH; RISK; STRESS; DISEASE AB This study presents findings of a mixed-method descriptive exploration of the role of friends and spirituality/religiosity in easing the burden of families with the rare inherited disorder, Li-Fraumeni Syndrome (LFS). LFS is caused by germline mutations in the TP53 gene and is associated with very high lifetime risk of developing one or more malignancies. During the first clinical visit we assessed several types of social support among a subset of study participants (N = 66) using an established interactive research tool called the Colored Eco-Genetic Relationship Map (CEGRM). We performed both quantitative and qualitative analyses of social relationships with LFS family members and close non-kin. Distress scores (N = 59) were mostly low normal, with some outliers. We found that reported friendships varied widely, that the friendships were often deep and enduring, and were important sources of informational, tangible, emotional and spiritual support. Confidantes tended to be best friends and/or spouses. Organized religion was important in selected families, typically from mainstream traditions. However, a number of people identified themselves as "spiritual" and reported spiritual and humanist explorations. Our results shed preliminary light on how some people in families with LFS cope in the face of tremendous medical, social and emotional challenges. C1 [Peters, June A.; Bremer, Renee; Givens, Shannon; Savage, Sharon A.; Mai, Phuong L.] NCI, CGB, DCEG, NIH,DHHS, Rockville, MD USA. [Kenen, Regina] Coll New Jersey, Dept Sociol & Anthropol, Ewing, NJ USA. RP Peters, JA (reprint author), NCI, CGB, DCEG, NIH,DHHS, Rockville, MD USA. EM petersju@mail.nih.gov FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics (DCEG) of the National Cancer Institute (NCI); Westat; [HHSN261201300003C] FX This research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics (DCEG) of the National Cancer Institute (NCI) and by contract # HHSN261201300003C with Westat. NR 79 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1059-7700 EI 1573-3599 J9 J GENET COUNS JI J. Genet. Couns. PD JUN PY 2016 VL 25 IS 3 BP 529 EP 542 DI 10.1007/s10897-015-9905-x PG 14 WC Genetics & Heredity SC Genetics & Heredity GA DM4AL UT WOS:000376287800013 PM 26621765 ER PT J AU Yao, X Lu, YC Parker, LL Li, YF El-Gamil, M Black, MA Xu, H Feldman, SA van der Bruggen, P Rosenberg, SA Robbins, PF AF Yao, Xin Lu, Yong-Chen Parker, Linda L. Li, Yong F. El-Gamil, Mona Black, Mary A. Xu, Hui Feldman, Steven A. van der Bruggen, Pierre Rosenberg, Steven A. Robbins, Paul F. TI Isolation and Characterization of an HLA-DPB1*04:01-restricted MAGE-A3 T-Cell Receptor for Cancer Immunotherapy SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE cancer-germline antigens; cancer immunotherapy; tumor immunology ID CHIMERIC-ANTIGEN-RECEPTOR; LARGE ESTABLISHED MELANOMA; TUMOR-ANTIGEN; GENE-THERAPY; ENGINEERED LYMPHOCYTES; CANCER/TESTIS ANTIGENS; LUNG-CANCER; CD4+T CELLS; EXPRESSION; REGRESSION AB Long-term tumor regressions have been observed in patients following the adoptive transfer of autologous tumor infiltrating lymphocytes or genetically modified T cells expressing MHC class I-restricted T-cell receptors (TCRs), but clinical trials have not evaluated responses to genetically modified T cells expressing antitumor MHC class II-restricted TCRs. As studies carried out in a murine tumor model system have demonstrated that the adoptive transfer of CD4(+) T cells could lead to the regression of established tumors, we plan to test the hypothesis that CD4(+) T cells can also induce tumor regressions in cancer patients. In this study, 2 MAGE-A3-specific TCRs were isolated from a regulatory T-cell clone (6F9) and an effector clone (R12C9), generated from the peripheral blood of 2 melanoma patients after MAGE-A3 vaccination. The results indicated that T cells transduced with 6F9 TCR mediated stronger effector functions than R12C9 TCR. The 6F9 TCR specifically recognized MAGE-A3 and the closely related MAGE-A6 gene product, but not other members of the MAGE-A family in the context of HLA-DPB1*04:01. To test the feasibility of a potential clinical trial using this TCR, a clinical-scale procedure was developed to obtain a large number of purified CD4(+) T cells transduced with 6F9 TCR. Because HLA-DPB1*04:0 1 is present in similar to 60% of the Caucasian population and MAGE-A3 is frequently expressed in a variety of cancer types, this TCR immunotherapy could potentially be applicable for a significant portion of cancer patients. C1 [Yao, Xin; Lu, Yong-Chen; Parker, Linda L.; Li, Yong F.; El-Gamil, Mona; Black, Mary A.; Xu, Hui; Feldman, Steven A.; Rosenberg, Steven A.; Robbins, Paul F.] NCI, Surg Branch, NIH, Bldg 10 CRC,Rm 3W-5744,10 Ctr Dr, Bethesda, MD 20892 USA. [Yao, Xin] Cellular Biomed Grp Inc, Cupertino, CA USA. [van der Bruggen, Pierre] Ludwig Inst Canc Res, Zurich, Switzerland. [van der Bruggen, Pierre] WELBIO, Wallonia, Belgium. [van der Bruggen, Pierre] Catholic Univ Louvain, De Duve Inst, B-1200 Brussels, Belgium. RP Robbins, PF (reprint author), NCI, Surg Branch, NIH, Bldg 10 CRC,Rm 3W-5744,10 Ctr Dr, Bethesda, MD 20892 USA. EM Paul_Robbins@nih.gov FU Intramural Research Program of the National Cancer Institute, National Institutes of Health FX None reported. All authors have declared there are no financial conflicts of interest with regard to this work. This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 59 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1524-9557 EI 1537-4513 J9 J IMMUNOTHER JI J. Immunother. PD JUN PY 2016 VL 39 IS 5 BP 191 EP 201 PG 11 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA DM6NX UT WOS:000376470800001 PM 27163739 ER PT J AU Caucheteux, SM Mitchell, JP Ivory, MO Hirosue, S Hakobyan, S Dolton, G Ladell, K Miners, K Price, DA Kan-Mitchell, J Sewell, AK Nestle, F Moris, A Karoo, RO Birchall, JC Swartz, MA Hubbel, JA Blanchet, FP Piguet, V AF Caucheteux, Stephan M. Mitchell, John P. Ivory, Matthew O. Hirosue, Sachiko Hakobyan, Svetlana Dolton, Garry Ladell, Kristin Miners, Kelly Price, David A. Kan-Mitchell, June Sewell, Andrew K. Nestle, Frank Moris, Arnaud Karoo, Richard O. Birchall, James C. Swartz, Melody A. Hubbel, Jeffrey A. Blanchet, Fabien P. Piguet, Vincent TI Polypropylene Sulfide Nanoparticle p24 Vaccine Promotes Dendritic Cell-Mediated Specific Immune Responses against HIV-1 SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID ANTIGEN-PRESENTING CELLS; HUMAN LANGERHANS CELLS; VIRUS-LIKE PARTICLES; REGULATORY T-CELLS; HUMAN SKIN; MICRONEEDLE DELIVERY; LYMPH-NODES; ACTIVATION; TRANSPORT; INJECTION AB Delivery of vaccine formulations into the dermis using antigen-coated microneedle patches is a promising and safe approach because of efficient antigen delivery and safety. We evaluated an intradermal vaccine using HIV-1 p24 Gag peptide-conjugated polypropylene sulfide nanoparticles to induce immunity against HIV-1. This peptide-conjugated polypropylene sulfide nanoparticle formulation did not accelerate the maturation of blood-or skin-derived subsets of dendritic cells, either generated in vitro or purified ex vivo, despite efficient uptake in the absence of adjuvant. Moreover, dendritic cell-mediated capture of particulate antigen in this form induced potent HIV-1-specific CD4(+) T-cell responses, as well as B-cell-mediated antibody production. Nanoparticle-based intradermal antigen delivery may therefore provide a new option in the global effort to develop an effective vaccine against HIV-1. C1 [Caucheteux, Stephan M.; Mitchell, John P.; Ivory, Matthew O.; Hakobyan, Svetlana; Dolton, Garry; Ladell, Kristin; Miners, Kelly; Price, David A.; Sewell, Andrew K.; Blanchet, Fabien P.; Piguet, Vincent] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. [Ivory, Matthew O.; Birchall, James C.] Cardiff Univ, Sch Pharm & Pharmaceut Sci, Cardiff CF14 4XN, S Glam, Wales. [Hirosue, Sachiko; Swartz, Melody A.; Hubbel, Jeffrey A.] Sch Life Sci, Inst Bioengn, Lausanne, Switzerland. [Hirosue, Sachiko; Swartz, Melody A.; Hubbel, Jeffrey A.] Sch Engn, Lausanne, Switzerland. [Price, David A.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kan-Mitchell, June] Univ Texas El Paso, Dept Biol Sci, El Paso, TX 79968 USA. [Nestle, Frank] Kings Coll London, St Johns Inst Dermatol, London, England. [Moris, Arnaud] Univ Paris 06, Sorbonne Univ, INSERM U1135, CNRS ERL 8255,Ctr Immunol & Microbial Infect, F-75013 Paris, France. [Karoo, Richard O.] Spire Cardiff Hosp, Cardiff, S Glam, Wales. [Swartz, Melody A.; Hubbel, Jeffrey A.] Univ Chicago, Inst Mol Engn, Chicago, IL 60637 USA. [Blanchet, Fabien P.] Univ Montpellier, CNRS, FRE 3689, F-34059 Montpellier, France. RP Piguet, V (reprint author), Cardiff Univ, Sch Med, Inst Infect & Immun, Dept Dermatol, 3rd Floor,Glamorgan House,Heath Pk, Cardiff CF14 4XN, S Glam, Wales.; Piguet, V (reprint author), Cardiff Univ, Sch Med, Inst Infect & Immun, Acad Wound Healing, 3rd Floor,Glamorgan House,Heath Pk, Cardiff CF14 4XN, S Glam, Wales.; Piguet, V (reprint author), Univ Wales Hosp, 3rd Floor,Glamorgan House,Heath Pk, Cardiff CF14 4XN, S Glam, Wales. EM piguetv@cardiff.ac.uk RI Price, David/C-7876-2013; OI Price, David/0000-0001-9416-2737; Ivory, Matthew Owen/0000-0002-8736-395X; Moris, Arnaud/0000-0002-5052-1678 FU Bill AMP; Melinda Gates Foundation; Wellcome Trust FX This research was supported by the Bill & Melinda Gates Foundation and by the Wellcome Trust Institutional Strategic Support Fund to Cardiff University to VP. NR 38 TC 2 Z9 2 U1 9 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUN PY 2016 VL 136 IS 6 BP 1172 EP 1181 DI 10.1016/j.jid.2016.01.033 PG 10 WC Dermatology SC Dermatology GA DN0VI UT WOS:000376784200018 PM 26896775 ER PT J AU Singh, R Savitz, J Teague, TK Polanski, DW Mayer, AR Bellgowan, PSF Meier, TB AF Singh, Rashmi Savitz, Jonathan Teague, T. Kent Polanski, David W. Mayer, Andrew R. Bellgowan, Patrick S. F. Meier, Timothy B. TI Mood symptoms correlate with kynurenine pathway metabolites following sports-related concussion SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID TRAUMATIC BRAIN-INJURY; MAJOR DEPRESSIVE DISORDER; PROFESSIONAL FOOTBALL PLAYERS; LIFE COGNITIVE IMPAIRMENT; QUINOLINIC ACID; RECURRENT CONCUSSION; HIGH-SCHOOL; HIPPOCAMPAL; RAT; ANTAGONISTS AB Objective An imbalance of neuroactive kynurenine pathway metabolites has been proposed as one mechanism behind the neuropsychiatric sequelae of certain neurological disorders. We hypothesized that concussed football players would have elevated plasma levels of neurotoxic kynurenine metabolites and reduced levels of neuroprotective metabolites relative to healthy football players and that altered kynurenine levels would correlate with post-concussion mood symptoms. Methods Mood scales and plasma concentrations of kynurenine metabolites were assessed in concussed (N=18; 1.61 days post-injury) and healthy football players (N=18). A subset of football players returned at 1-week (N=14; 9.29 days) and 1-month post-concussion (N=14, 30.93 days). Results Concussed athletes had significantly elevated levels of quinolinic acid (QUIN) and significantly lower ratios of kynurenic acid (KYNA) to QUIN at all time points compared with healthy athletes (p's<0.05), with no longitudinal evidence of normalization of KYNA or KYNA/QUIN. At 1-day post-injury, concussed athletes with lower levels of the putatively neuroprotective KYNA/QUIN ratio reported significantly worse depressive symptoms (p=0.04), and a trend toward worse anxiety symptoms (p=0.06), while at 1-month higher QUIN levels were associated with worse mood symptoms (p's<0.01). Finally, concussed athletes with worse concussion outcome, defined as number of days until return-to-play, had higher QUIN and lower KYNA/QUIN at 1-month post-injury (p's<0.05). Conclusions These results converge with existing kynurenine literature on psychiatric patients and provide the first evidence of altered peripheral levels of kynurenine metabolites following sports-related concussion. C1 [Singh, Rashmi; Savitz, Jonathan; Meier, Timothy B.] Laureate Inst Brain Res, Tulsa, OK USA. [Savitz, Jonathan] Univ Tulsa, Fac Community Med, Tulsa, OK 74104 USA. [Teague, T. Kent] Univ Oklahoma, Coll Med, Dept Surg, Tulsa, OK USA. [Teague, T. Kent] Univ Oklahoma, Coll Med, Dept Psychiat, Tulsa, OK USA. [Teague, T. Kent] Univ Oklahoma, Coll Pharm, Dept Pharmaceut Sci, Tulsa, OK USA. [Teague, T. Kent] Oklahoma State Univ, Ctr Hlth Sci, Dept Biochem & Microbiol, Tulsa, OK USA. [Polanski, David W.] Univ Tulsa, Dept Athlet, Tulsa, OK 74104 USA. [Mayer, Andrew R.; Meier, Timothy B.] Lovelace Biomed & Environm Res Inst, Mind Res Network, Pete & Nancy Domenici Hall,1101 Yale Blvd NE, Albuquerque, NM 87106 USA. [Mayer, Andrew R.] Univ New Mexico, Sch Med, Dept Neurol, Albuquerque, NM 87131 USA. [Mayer, Andrew R.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. [Bellgowan, Patrick S. F.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Meier, TB (reprint author), Lovelace Biomed & Environm Res Inst, Mind Res Network, Pete & Nancy Domenici Hall,1101 Yale Blvd NE, Albuquerque, NM 87106 USA. EM timothybmeier@gmail.com RI Savitz, Jonathan/C-3088-2009; Teague, Kent/A-2527-2008 OI Savitz, Jonathan/0000-0001-8143-182X; Teague, Kent/0000-0002-4680-5440 FU Laureate Institute for Brain Research; William K Warren Foundation FX This research was conducted using internal funds from the Laureate Institute for Brain Research, which is supported by The William K Warren Foundation. NR 32 TC 1 Z9 1 U1 1 U2 8 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 EI 1468-330X J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD JUN PY 2016 VL 87 IS 6 BP 670 EP 675 DI 10.1136/jnnp-2015-311369 PG 6 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA DM9KX UT WOS:000376686100015 PM 26269650 ER PT J AU Hao, SY Hong, CS Feng, J Yang, CZ Chittiboina, P Zhang, JT Zhuang, ZP AF Hao, Shuyu Hong, Christopher S. Feng, Jie Yang, Chunzhang Chittiboina, Prashant Zhang, Junting Zhuang, Zhengping TI Somatic IDH1 mutation in a pituitary adenoma of a patient with Maffucci syndrome SO JOURNAL OF NEUROSURGERY LA English DT Article DE pituitary adenoma; isocitrate dehydrogenase; somatic mosaicism; Maffucci syndrome; oncology ID ISOCITRATE DEHYDROGENASE 1; OLLIER DISEASE; CHONDROSARCOMA; TUMORS AB Maffucci syndrome is a rare disease characterized by multiple enchondromas and soft-tissue hemangiomas. Additionally, neuroendocrine tumors including pituitary adenomas have been described in these patients. The underlying genetic etiology lies in somatic mosaicism of mutations in isocitrate dehydrogenase 1 (IDH1) or isocitrate dehydrogenase 2 (IDH2). This report describes a patient with Maffucci syndrome who presented with intracranial tumors of the skull base and suprasellar region. The patient underwent resection of both intracranial tumors, revealing histopathological diagnoses of chondrosarcoma and pituitary adenoma. DNA sequencing of the tumors was performed to identify common IDH1/2 mutations. Clinical, radiological, and biochemical assessments were performed. Genotypic studies used standard Sanger sequencing in conjunction with a target-specific peptide nucleic acid to detect IDH1 mutations in tumor tissues. DNA sequencing demonstrated identical IDH1 mutations (c.394C > T) in both tumors. To the authors' knowledge, this report provides the first genetic evidence for the inclusion of pituitary adenomas among tumors characterizing Maffucci syndrome. In patients who are newly diagnosed with Maffucci syndrome, it is appropriate to monitor for development of pituitary pathology and neuroendocrine dysfunction. C1 [Hao, Shuyu; Zhang, Junting] Beijing Tiantan Hosp, Dept Neurol Surg, Beijing, Peoples R China. [Hong, Christopher S.; Yang, Chunzhang; Chittiboina, Prashant; Zhuang, Zhengping] Capital Med Univ, Beijing Neurosurg Inst, Beijing, Peoples R China. [Feng, Jie] NINDS, Surg Neurol Branch, NIH, 10 Ctr Dr,Rm 3D05, Bethesda, MD 20892 USA. RP Zhuang, ZP (reprint author), NINDS, Surg Neurol Branch, NIH, 10 Ctr Dr,Rm 3D05, Bethesda, MD 20892 USA. EM zhuangp@ninds.nih.gov FU Intramural NIH HHS [Z99 NS999999] NR 30 TC 1 Z9 1 U1 3 U2 3 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD JUN PY 2016 VL 124 IS 6 BP 1562 EP 1567 DI 10.3171/2015.4.JNS15191 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA DM6PZ UT WOS:000376476200004 PM 26473790 ER PT J AU Bronstad, A Newcomer, CE Decelle, T Everitt, JI Guillen, J Laber, K AF Bronstad, Aurora Newcomer, Christian E. Decelle, Thierry Everitt, Jeffrey I. Guillen, Javier Laber, Kathy TI Current concepts of Harm-Benefit Analysis of Animal Experiments - Report from the AALAS-FELASA Working Group on Harm-Benefit Analysis - Part 1 SO LABORATORY ANIMALS LA English DT Article DE harm-benefit; ethical review; animal experiment ID ETHICAL ACCEPTABILITY; BIOTECHNOLOGY; WELFARE; HUMANS; SYSTEM; COSTS; RISK AB International regulations and guidelines strongly suggest that the use of animal models in scientific research should be initiated only after the authority responsible for the review of animal studies has concluded a well-thought-out harm-benefit analysis (HBA) and deemed the project to be appropriate. Although the process for conducting HBAs may not be new, the relevant factors and algorithms used in conducting them during the review process are deemed to be poorly defined or lacking by committees in many institutions. This paper presents the current concept of HBAs based on a literature review. References on cost or risk benefit from clinical trials and other industries are also included. Several approaches to HBA have been discovered including algorithms, graphic presentations and generic processes. The aim of this study is to better aid and harmonize understanding of the concepts of harm', benefit' and harm-benefit analysis'. C1 [Bronstad, Aurora] Univ Bergen, Dept Clin Med, Bergen, Norway. [Newcomer, Christian E.] AAALAC Int, Frederick, MD USA. [Decelle, Thierry] Sanofi, Marcy Letoile, France. [Everitt, Jeffrey I.] GlaxoSmithKline, Dept Lab Anim Sci, Res Triangle Pk, NC USA. [Guillen, Javier] AAALAC Int, Pamplona, Spain. [Laber, Kathy] NIEHS, Comparat Med Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Bronstad, A (reprint author), Univ Bergen, Vivarium Haukeland Hosp, N-5021 Bergen, Norway. EM aurora.bronstad@uib.no OI Everitt, Jeffrey/0000-0003-0273-6284 NR 73 TC 0 Z9 0 U1 4 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0023-6772 EI 1758-1117 J9 LAB ANIM-UK JI Lab. Anim. PD JUN PY 2016 VL 50 SU 1 BP 1 EP 20 DI 10.1177/0023677216642398 PG 20 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA DM9JL UT WOS:000376682000001 PM 27188275 ER PT J AU Laber, K Newcomer, CE Decelle, T Everitt, JI Guillen, J Bronstad, A AF Laber, Kathy Newcomer, Christian E. Decelle, Thierry Everitt, Jeffrey I. Guillen, Javier Bronstad, Aurora TI Recommendations for Addressing Harm-Benefit Analysis and Implementation in Ethical Evaluation - Report from the AALAS-FELASA Working Group on Harm-Benefit Analysis - Part 2 SO LABORATORY ANIMALS LA English DT Article DE harm-benefit; ethical review ID SYSTEMATIC REVIEWS; ANIMAL RESEARCH; HUMANS; RISK AB International regulations and guidelines strongly suggest that the use of animal models in scientific research should be initiated only after the authority responsible for the review of animal studies has concluded a well-thought-out harm-benefit analysis (HBA) and deemed the project to be appropriate. The AALAS-FELASA working group on HBA has performed a literature review and based on this review, proposed a method for HBA. Examples of the working group's approach are included in this report. C1 [Laber, Kathy] NIEHS, Comparat Med Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Newcomer, Christian E.] AAALAC Int, Frederick, MD USA. [Decelle, Thierry] Sanofi, Marcy Letoile, France. [Everitt, Jeffrey I.] GlaxoSmithKline, Dept Lab Anim Sci, Res Triangle Pk, NC USA. [Guillen, Javier] AAALAC Int, Pamplona, Spain. [Bronstad, Aurora] Univ Bergen, Dept Clin Med, Bergen, Norway. RP Laber, K (reprint author), NIEHS, 111 TW Alexander Dr,D108,Bldg 101, Res Triangle Pk, NC 27709 USA. EM kathy.laber@nih.gov OI Everitt, Jeffrey/0000-0003-0273-6284 NR 32 TC 0 Z9 0 U1 3 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0023-6772 EI 1758-1117 J9 LAB ANIM-UK JI Lab. Anim. PD JUN PY 2016 VL 50 SU 1 BP 21 EP 42 DI 10.1177/0023677216642397 PG 22 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA DM9JL UT WOS:000376682000002 PM 27188276 ER PT J AU Habgood, AN Tatler, AL Porte, J Wahl, SM Laurent, GJ John, AE Johnson, SR Jenkins, G AF Habgood, Anthony N. Tatler, Amanda L. Porte, Joanne Wahl, Sharon M. Laurent, Geoffrey J. John, Alison E. Johnson, Simon R. Jenkins, Gisli TI Secretory leukocyte protease inhibitor gene deletion alters bleomycin-induced lung injury, but not development of pulmonary fibrosis SO LABORATORY INVESTIGATION LA English DT Article ID NEUTROPHIL ELASTASE INHIBITOR; TGF-BETA ACTIVATION; CATHEPSIN-K; EPITHELIAL-CELLS; VI COLLAGEN; EXPRESSION; MICE; PATHOGENESIS; MATRIX; GROWTH AB Idiopathic pulmonary fibrosis is a progressive, fatal disease with limited treatment options. Protease-mediated transforming growth factor-beta (TGF-beta) activation has been proposed as a pathogenic mechanism of lung fibrosis. Protease activity in the lung is tightly regulated by protease inhibitors, particularly secretory leukocyte protease inhibitor (SLPI). The bleomycin model of lung fibrosis was used to determine the effect of increased protease activity in the lungs of Slpi(-/-) mice following injury. Slpi(-/-), and wild-type, mice received oropharyngeal administration of bleomycin (30 IU) and the development of pulmonary fibrosis was assessed. Pro and active forms of matrix metalloproteinase (MMP)-2 and MMP-9 were measured. Lung fibrosis was determined by collagen subtype-specific gene expression, hydroxyproline concentration, and histological assessment. Alveolar TGF-beta activation was measured using bronchoalveolar lavage cell pSmad2 levels and global TGF-beta activity was assessed by pSmad2 immunohistochemistry. The active-MMP-9 to pro-MMP-9 ratio was significantly increased in Slpi(-/-) animals compared with wild-type animals, demonstrating enhanced metalloproteinase activity. Wild-type animals showed an increase in TGF-beta activation following bleomycin, with a progressive and sustained increase in collagen type I, alpha 1 (Col1 alpha 1), III, alpha 1(Col3 alpha 1), IV, alpha 1(Col4 alpha 1) mRNA expression, and a significant increase in total lung collagen 28 days post bleomycin. In contrast Slpi(-/-) mice showed no significant increase of alveolar TGF-beta activity following bleomycin, above their already elevated levels, although global TGF-beta activity did increase. Slpi(-/-) mice had impaired collagen gene expression but animals demonstrated minimal reduction in lung fibrosis compared with wild-type animals. These data suggest that enhanced proteolysis does not further enhance TGF-beta activation, and inhibits sustained Col1 alpha 1, Col3 alpha 1, and Col4 alpha 1 gene expression following lung injury. However, these changes do not prevent the development of lung fibrosis. Overall, these data suggest that the absence of Slpi does not markedly modify the development of lung fibrosis following bleomycin-induced lung injury. C1 [Habgood, Anthony N.; Tatler, Amanda L.; Porte, Joanne; John, Alison E.; Johnson, Simon R.; Jenkins, Gisli] Univ Nottingham, Nottingham Resp Res Unit, Nottingham NG7 2RD, England. [Wahl, Sharon M.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Laurent, Geoffrey J.] Univ Western Australia, Lung Inst Western Australia, Perth, WA 6009, Australia. RP Habgood, AN (reprint author), Univ Nottingham, Nottingham Resp Res Unit, Univ Nottingham Hosp, Clin Sci Bldg,City Hosp Campus, Nottingham NG5 1PB, England. EM anthony.habgood@nottingham.ac.uk OI Tatler, Amanda/0000-0002-4644-4614; Johnson, Simon/0000-0002-9837-2763 FU Wellcome Trust Research Grant [WT085350MA]; Wellcome Trust [085350]; Intramural Research Program of the NIH, National Institute of Dental and Craniofacial Research FX This work was funded by a Wellcome Trust Research Grant Number WT085350MA. Slpi-/- mice on a B6D2F1 background were kindly donated by Sharon Wahl. This research was funded by the Wellcome Trust (project grant number 085350), and in part supported by the Intramural Research Program of the NIH, National Institute of Dental and Craniofacial Research. NR 39 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 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD JUN PY 2016 VL 96 IS 6 BP 623 EP 631 DI 10.1038/labinvest.2016.40 PG 9 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA DM6ZO UT WOS:000376501800003 PM 26974397 ER PT J AU Iwanishi, H Fujita, N Tomoyose, K Okada, Y Yamanaka, O Flanders, KC Saika, S AF Iwanishi, Hiroki Fujita, Norihito Tomoyose, Katsuo Okada, Yuka Yamanaka, Osamu Flanders, Kathleen C. Saika, Shizuya TI Inhibition of development of laser-induced choroidal neovascularization with suppression of infiltration of macrophages in Smad3-null mice SO LABORATORY INVESTIGATION LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; FACTOR-H POLYMORPHISM; GROWTH-FACTOR-BETA; MACULAR DEGENERATION; ENDOTHELIAL-CELLS; EXTRACELLULAR-MATRIX; SUBRETINAL FIBROSIS; BRUCHS MEMBRANE; LENS EPITHELIUM; I RECEPTORS AB We evaluated the effects of the loss of Smad3 on the development of experimental argon laser-induced choroidal neovascularization (CNV) in mice. An in vitro angiogenesis model was also used to examine the role of transforming growth factor-beta 1 (TGF beta 1)/Smad3 signaling in vessel-like tube formation by human umbilical vein endothelial cells (HUVECs). CNV was induced in eyes of 8-12-week-old B6.129-background Smad3-deficient (KO) mice (n = 47) and wild-type (WT) mice (n= 47) by argon laser irradiation. Results showed that the size of the CNV induced was significantly smaller in KO mice as compared with WT mice at day 14 as revealed by high-resolution angiography with fluorescein isothiocyanate-dextran. Immunohistochemistry and real-time reverse transcription-polymerase chain reaction of RNA extracted from laser-irradiated choroidal tissues were conducted on specimens at specific timepoints. Invasion of macrophages (F4/80+), but not neutrophils (myeloperoxidase+), and appearance of myofibroblasts (alpha-smooth muscle actin+) were suppressed in laser-irradiated KO tissues. mRNA expression of inflammation-related factors, that is, vascular endothelial growth factor (VEGF), macrophage-chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and TGF beta 1 in choroidal tissues was suppressed by the loss of Smad3. We then examined the effects of adding a Smad3 inhibitor, SIS3, or an ALK5 inhibitor, SB431542, on tube formation promoted by TGF beta 1 or VEGF in HUVECs cocultured with fibroblast feeder. Further addition of SIS3 or SB431542 augmented vessel-like tube formation by HUVECs in the presence of TGF beta 1 or VEGF. In conclusion, lack of Smad3 attenuated the growth of laser-induced CNV with suppression of inflammation by macrophages in mice. Because blocking TGF beta 1/Smad3 signal stimulated the activity of angiogenesis of HUVECs in vitro, the reduction of CNV in vivo in KO mice is attributed to a decrease in growth factor levels in the tissue by the loss of Smad3. C1 [Iwanishi, Hiroki; Fujita, Norihito; Tomoyose, Katsuo; Okada, Yuka; Yamanaka, Osamu; Saika, Shizuya] Wakayama Med Univ, Dept Ophthalmol, Sch Med, 811-1 Kimiidera, Wakayama 6410012, Japan. [Flanders, Kathleen C.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP Iwanishi, H; Saika, S (reprint author), Wakayama Med Univ, Dept Ophthalmol, Sch Med, 811-1 Kimiidera, Wakayama 6410012, Japan. EM hiwanish@heart.ocn.ne.jp; shizuya@wakayama-med.ac.jp FU Ministry of Education, Science, Sports, and Culture of Japan [C25462730, C24592638, C25462759, C19592036] FX This study was supported by the Grants from the Ministry of Education, Science, Sports, and Culture of Japan (C25462730 (to KT), C24592638 (to YO), C25462759 (to OY), and C19592036 (to SS)). NR 56 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD JUN PY 2016 VL 96 IS 6 BP 641 EP 651 DI 10.1038/labinvest.2016.30 PG 11 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA DM6ZO UT WOS:000376501800005 PM 26950486 ER PT J AU Lauer, MS AF Lauer, Michael S. TI Testosterone replacement therapy: intent matters SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Editorial Material ID CARDIOVASCULAR-DISEASE; POSTMENOPAUSAL; PROGESTIN; ESTROGEN C1 [Lauer, Michael S.] NIH, Off Extramural Res, Bldg 10, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NIH, Off Extramural Res, Bldg 10, Bethesda, MD 20892 USA. EM Michael.Lauer@nih.gov NR 8 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2213-8587 J9 LANCET DIABETES ENDO JI Lancet Diabetes Endocrinol. PD JUN PY 2016 VL 4 IS 6 BP 471 EP 473 DI 10.1016/S2213-8587(16)30008-0 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DM6LD UT WOS:000376462800004 PM 27165608 ER PT J AU Paireau, J Chen, A Broutin, H Grenfell, B Basta, NE AF Paireau, Juliette Chen, Angelica Broutin, Helene Grenfell, Bryan Basta, Nicole E. TI Seasonal dynamics of bacterial meningitis: a time-series analysis SO LANCET GLOBAL HEALTH LA English DT Article ID MENINGOCOCCAL DISEASE; STREPTOCOCCUS-PNEUMONIAE; CHILDREN YOUNGER; EPIDEMIOLOGY; AFRICA; BURDEN; PRIORITIES; BELT AB Background Bacterial meningitis, which is caused mainly by Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae, inflicts a substantial burden of disease worldwide. Yet, the temporal dynamics of this disease are poorly characterised and many questions remain about the ecology of the disease. We aimed to comprehensively assess seasonal trends in bacterial meningitis on a global scale. Methods We developed the first bacterial meningitis global database by compiling monthly incidence data as reported by country-level surveillance systems. Using country-level wavelet analysis, we identified whether a 12 month periodic component (annual seasonality) was detected in time-series that had at least 5 years of data with at least 40 cases reported per year. We estimated the mean timing of disease activity by computing the centre of gravity of the distribution of cases and investigated whether synchrony exists between the three pathogens responsible for most cases of bacterial meningitis. Findings We used country-level data from 66 countries, including from 47 countries outside the meningitis belt in sub-Saharan Africa. A persistent seasonality was detected in 49 (96%) of the 51 time-series from 38 countries eligible for inclusion in the wavelet analyses. The mean timing of disease activity had a latitudinal trend, with bacterial meningitis seasons peaking during the winter months in countries in both the northern and southern hemispheres. The three pathogens shared similar seasonality, but time-shifts differed slightly by country. Interpretation Our findings provide key insight into the seasonal dynamics of bacterial meningitis and add to knowledge about the global epidemiology of meningitis and the host, environment, and pathogen characteristics driving these patterns. Comprehensive understanding of global seasonal trends in meningitis could be used to design more effective prevention and control strategies. Copyright (C) Paireau et al. Open Access article distributed under the terms of CC BY NC-ND. C1 [Paireau, Juliette] Princeton Univ, Princeton Environm Inst, Princeton, NJ 08544 USA. [Paireau, Juliette] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Chen, Angelica] Princeton Univ, Dept Comp Sci, Princeton, NJ 08544 USA. [Broutin, Helene] Univ Montpellier, MIVEGEC Mixed Res Grp, CNRS 5290, IRD 224, Montpellier, France. [Broutin, Helene] Univ Cheikh Anta Diop, Fac Med Pharm & Odontol, Serv Parasitol Mycol, Dakar, Senegal. [Grenfell, Bryan; Basta, Nicole E.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Basta, Nicole E.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. RP Paireau, J (reprint author), Princeton Univ, Princeton Environm Inst, Princeton, NJ 08544 USA. EM juliette.paireau@gmail.com FU Princeton University Health Grand Challenge; US National Institutes of Health (NIH); NIH Fogarty International Center Research and Policy for Infectious Disease Dynamics programme (RAPIDD); Bill & Melinda Gates Foundation FX Princeton University Health Grand Challenge, US National Institutes of Health (NIH), NIH Fogarty International Center Research and Policy for Infectious Disease Dynamics programme (RAPIDD), Bill & Melinda Gates Foundation. NR 28 TC 1 Z9 1 U1 2 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2214-109X J9 LANCET GLOB HEALTH JI Lancet Glob. Health PD JUN PY 2016 VL 4 IS 6 BP E370 EP E377 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DM6LH UT WOS:000376463200017 PM 27198841 ER PT J AU Stanaway, JD Shepard, DS Undurraga, EA Halasa, YA Coffeng, LE Brady, OJ Hay, SI Bedi, N Bensenor, IM Castaneda-Orjuela, CA Chuang, TW Gibney, KB Memish, ZA Rafay, A Ukwaja, KN Yonemoto, N Murray, CJL AF Stanaway, Jeffrey D. Shepard, Donald S. Undurraga, Eduardo A. Halasa, Yara A. Coffeng, Luc E. Brady, Oliver J. Hay, Simon I. Bedi, Neeraj Bensenor, Isabela M. Castaneda-Orjuela, Carlos A. Chuang, Ting-Wu Gibney, Katherine B. Memish, Ziad A. Rafay, Anwar Ukwaja, Kingsley N. Yonemoto, Naohiro Murray, Christopher J. L. TI The global burden of dengue: an analysis from the Global Burden of Disease Study 2013 SO LANCET INFECTIOUS DISEASES LA English DT Article ID SYSTEMATIC ANALYSIS; DISABILITY WEIGHTS; 188 COUNTRIES; INJURIES; FEVER; CHILDREN; AMERICA; VACCINE; DEATH AB Background Dengue is the most common arbovirus infection globally, but its burden is poorly quantified. We estimated dengue mortality, incidence, and burden for the Global Burden of Disease Study 2013. Methods We modelled mortality from vital registration, verbal autopsy, and surveillance data using the Cause of Death Ensemble Modelling tool. We modelled incidence from officially reported cases, and adjusted our raw estimates for under-reporting based on published estimates of expansion factors. In total, we had 1780 country-years of mortality data from 130 countries, 1636 country-years of dengue case reports from 76 countries, and expansion factor estimates for 14 countries. Findings We estimated an average of 9221 dengue deaths per year between 1990 and 2013, increasing from a low of 8277 (95% uncertainty estimate 5353-10 649) in 1992, to a peak of 11 302 (6790-13 722) in 2010. This yielded a total of 576 900 (330 000-701200) years of life lost to premature mortality attributable to dengue in 2013. The incidence of dengue increased greatly between 1990 and 2013, with the number of cases more than doubling every decade, from 8.3 million (3.3 million-17.2 million) apparent cases in 1990, to 58.4 million (23.6 million-121.9 million) apparent cases in 2013. When accounting for disability from moderate and severe acute dengue, and post-dengue chronic fatigue, 566 000 (186 000-1 415 000) years lived with disability were attributable to dengue in 2013. Considering fatal and non-fatal outcomes together, dengue was responsible for 1.14 million (0.73 million-1.98 million) disability-adjusted life-years in 2013. Interpretation Although lower than other estimates, our results offer more evidence that the true symptomatic incidence of dengue probably falls within the commonly cited range of 50 million to 100 million cases per year. Our mortality estimates are lower than those presented elsewhere and should be considered in light of the totality of evidence suggesting that dengue mortality might, in fact, be substantially higher. C1 [Stanaway, Jeffrey D.; Hay, Simon I.; Murray, Christopher J. L.] Univ Washington, Inst Hlth Metr & Evaluat, 2301 5th Ave,Suite 600, Seattle, WA USA. [Shepard, Donald S.; Undurraga, Eduardo A.; Halasa, Yara A.] Brandeis Univ, Schneider Inst Hlth Policy, Heller Sch Social Policy & Management, Waltham, MA USA. [Coffeng, Luc E.] Erasmus MC Univ, Med Ctr, Dept Publ Hlth, Rotterdam, Netherlands. [Brady, Oliver J.; Hay, Simon I.] Univ Oxford, WellcomeTrust Ctr Human Genet, Oxford, England. [Hay, Simon I.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Bedi, Neeraj] Jazan Univ, Coll Publ Hlth & Trop Med, Jazan, Saudi Arabia. [Bensenor, Isabela M.] Univ Sao Paulo, Univ Hosp, Sao Paulo, Brazil. [Castaneda-Orjuela, Carlos A.] Colombian Natl Hlth Observ, Bogota, DC, Colombia. [Castaneda-Orjuela, Carlos A.] Univ Nacl Colombia, Epidemiol & Publ Hlth Evaluat Grp, Fac Med, Dept Publ Hlth, Ciudad Univ, Bogota, Colombia. [Chuang, Ting-Wu] Taipei Med Univ, Taipei, Taiwan. [Gibney, Katherine B.] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. [Gibney, Katherine B.] Royal Melbourne Hosp, Victorian Infect Dis Serv, Melbourne Hlth, Parkville, Vic 3050, Australia. [Memish, Ziad A.] Alfaisal Univ, Coll Med, Riyadh, Saudi Arabia. [Memish, Ziad A.] Saudi Minist Hlth, Prince Riyadh, Saudi Arabia. [Rafay, Anwar] Int Hlth Consultants, Lahore, Pakistan. [Rafay, Anwar] Contech Sch Publ Hlth, Lahore, Pakistan. [Ukwaja, Kingsley N.] Fed Teaching Hosp, Dept Internal Med, Abakaliki, Ebonyi State, Nigeria. [Yonemoto, Naohiro] Natl Ctr Neurol & Psychiat, Tokyo, Japan. RP Stanaway, JD (reprint author), Univ Washington, Inst Hlth Metr & Evaluat, 2301 5th Ave,Suite 600, Seattle, WA USA. EM stanaway@uw.edu RI Undurraga, Eduardo/I-3739-2014; OI Undurraga, Eduardo/0000-0002-4425-1253; Hay, Simon/0000-0002-0611-7272; Brady, Oliver/0000-0002-3235-2129; Castaneda-Orjuela, Carlos/0000-0002-8735-6223 FU Bill & Melinda Gates Foundation FX Bill & Melinda Gates Foundation. NR 31 TC 30 Z9 31 U1 8 U2 18 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JUN PY 2016 VL 16 IS 6 BP 712 EP 723 DI 10.1016/S1473-3099(16)00026-8 PG 12 WC Infectious Diseases SC Infectious Diseases GA DM6QC UT WOS:000376476500050 PM 26874619 ER PT J AU Masuda, H Toda, T AF Masuda, Hirohisa Toda, Takashi TI Synergistic role of fission yeast Alp16(GCP6) and Mzt1(MOZART1) in gamma-tubulin complex recruitment to mitotic spindle pole bodies and spindle assembly SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID MICROTUBULE-ORGANIZING CENTER; SCHIZOSACCHAROMYCES-POMBE; RING COMPLEX; PROTEIN COMPLEXES; NUCLEATION; CENTROSOME; COMPONENT; TURC; BODY; PHOSPHORYLATION AB In fission yeast, gamma-tubulin ring complex (gamma TuRC)-specific components Gfh1(GCP4), Mod21(GCP5), and Alp16(GCP6) are nonessential for cell growth. Of these 0deletion mutants, only alp16 Delta shows synthetic lethality with temperature-sensitive mutants of Mzt1(MOZART1), a component of the gamma TuRC required for recruitment of the complex to microtubule-organizing centers. gamma-Tubulin small complex levels at mitotic spindle pole bodies (SPBs, the centrosome equivalent in fungi) and microtubule levels for preanaphase spindles are significantly reduced in alp16 Delta cells but not in gfh1 Delta or mod21 Delta cells. Furthermore, alp16 Delta cells often form monopolar spindles and frequently lose a minichromosome when the spindle assembly checkpoint is inactivated. Alp16(GCP6) promotes Mzt1-dependent gamma TuRC recruitment to mitotic SPBs and enhances spindle microtubule assembly in a manner dependent on its expression levels. Gfh1(GCP4) and Mod21(GCP5) are not required for Alp16(GCP6)-dependent gamma TuRC recruitment. Mzt1 has an additional role in the activation of the gamma TuRC for spindle microtubule assembly. The ratio of Mzt1 to gamma TuRC levels for preanaphase spindles is higher than at other stages of the cell cycle. Mzt1 overproduction enhances spindle microtubule assembly without affecting gamma TuRC levels at mitotic SPBs. We propose that Alp16(GCP6) and Mzt1 act synergistically for efficient bipolar spindle assembly to ensure faithful chromosome segregation. C1 [Masuda, Hirohisa; Toda, Takashi] Francis Crick Inst, Lincolns Inn Fields Lab, London WC2A 3LY, England. [Toda, Takashi] Hiroshima Univ, Hiroshima Res Ctr Hlth Aging, Dept Mol Biotechnol, Grad Sch Adv Sci Matter, Higashihiroshima 7398530, Japan. [Masuda, Hirohisa] NCI, Telomere Biol Sect, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Masuda, H (reprint author), Francis Crick Inst, Lincolns Inn Fields Lab, London WC2A 3LY, England.; Masuda, H (reprint author), NCI, Telomere Biol Sect, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM hirohisa.masuda@nih.gov FU Cancer Research UK; Francis Crick Institute, Hiroshima University; Japan Society for the Promotion of Science KAKENHI Scientific Research [16H02503]; Japan Society for the Promotion of Science Challenging Exploratory Research [16K14672] FX We thank Frank Uhlmann and Julie Cooper for allowing work for revision of the manuscript to be carried out in their laboratories. We thank Ken Sawin, Yuji Chikashige, and Yasushi Hiraoka for reagents and Risa Mori for critical reading of the manuscript. This work was supported by Cancer Research UK, the Francis Crick Institute, Hiroshima University, and the Japan Society for the Promotion of Science KAKENHI Scientific Research (A) (16H02503) and Challenging Exploratory Research (16K14672) (T.T.). NR 52 TC 3 Z9 3 U1 2 U2 2 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 JUN 1 PY 2016 VL 27 IS 11 BP 1753 EP 1763 DI 10.1091/mbc.E15-08-0577 PG 11 WC Cell Biology SC Cell Biology GA DN0TN UT WOS:000376777600006 PM 27053664 ER PT J AU Pham, TT Yin, J Eid, JS Adams, E Lam, R Turner, SW Loomis, EW Wang, JY Hagerman, PJ Hanes, JW AF Pham, Thang T. Yin, Jun Eid, John S. Adams, Evan Lam, Regina Turner, Stephen W. Loomis, Erick W. Wang, Jun Yi Hagerman, Paul J. Hanes, Jeremiah W. TI Single-locus enrichment without amplification for sequencing and direct detection of epigenetic modifications SO MOLECULAR GENETICS AND GENOMICS LA English DT Article DE Targeted enrichment; Single molecule sequencing; FMR1; Fragile X syndrome; Epigenetic modification; Tandem repeats ID FMR1 MESSENGER-RNA; FRAGILE-X-SYNDROME; TREMOR/ATAXIA SYNDROME; DNA; DISEASE; PREMUTATION; GENERATION; REVEALS; ALLELES; ROLES AB A gene-level targeted enrichment method for direct detection of epigenetic modifications is described. The approach is demonstrated on the CGG-repeat region of the FMR1 gene, for which large repeat expansions, hitherto refractory to sequencing, are known to cause fragile X syndrome. In addition to achieving a single-locus enrichment of nearly 700,000-fold, the elimination of all amplification steps removes PCR-induced bias in the repeat count and preserves the native epigenetic modifications of the DNA. In conjunction with the single-molecule real-time sequencing approach, this enrichment method enables direct readout of the methylation status and the CGG repeat number of the FMR1 allele(s) for a clonally derived cell line. The current method avoids potential biases introduced through chemical modification and/or amplification methods for indirect detection of CpG methylation events. C1 [Pham, Thang T.; Eid, John S.; Lam, Regina; Turner, Stephen W.; Hanes, Jeremiah W.] Pacific Biosci, Menlo Pk, CA 94025 USA. [Yin, Jun; Adams, Evan; Loomis, Erick W.; Wang, Jun Yi; Hagerman, Paul J.] Univ Calif Davis, Sch Med, Dept Biochem & Mol Med, Davis, CA 95616 USA. [Yin, Jun] NINDS, Dendrite Morphogenesis & Plast Unit, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Eid, John S.] Whole Biome Inc, San Francisco, CA 94107 USA. [Loomis, Erick W.] Univ London Imperial Coll Sci Technol & Med, Inst Reprod & Dev Biol, Dept Surg & Canc, Fac Med, Hammersmith Campus, London, England. RP Hanes, JW (reprint author), Pacific Biosci, Menlo Pk, CA 94025 USA. EM jhanes@pacb.com OI Hanes, Jeremiah/0000-0002-2818-6885 FU National Institutes of Health [R01HD040661] FX This work was supported by the National Institutes of Health (R01HD040661 to P.J.H.). NR 36 TC 2 Z9 2 U1 0 U2 2 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1617-4615 EI 1617-4623 J9 MOL GENET GENOMICS JI Mol. Genet. Genomics PD JUN PY 2016 VL 291 IS 3 BP 1491 EP 1504 DI 10.1007/s00438-016-1167-2 PG 14 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DM7BY UT WOS:000376509100038 PM 26825750 ER PT J AU Borgnia, MJ Banerjee, S Merk, A Matthies, D Bartesaghi, A Rao, P Pierson, J Earl, LA Falconieri, V Subramaniam, S Milne, JLS AF Borgnia, Mario J. Banerjee, Soojay Merk, Alan Matthies, Doreen Bartesaghi, Alberto Rao, Prashant Pierson, Jason Earl, Lesley A. Falconieri, Veronica Subramaniam, Sriram Milne, Jacqueline L. S. TI Using Cryo-EM to Map Small Ligands on Dynamic Metabolic Enzymes: Studies with Glutamate Dehydrogenase SO MOLECULAR PHARMACOLOGY LA English DT Article ID ADP ACTIVATION; MECHANISM; BINDING; MICROSCOPY; NUCLEOTIDE; COMPLEXES; EVOLUTION; COENZYME; SYSTEM; GTP AB Cryo-electron microscopy (cryo-EM) methods are now being used to determine structures at near-atomic resolution and have great promise in molecular pharmacology, especially in the context of mapping the binding of small-molecule ligands to protein complexes that display conformational flexibility. We illustrate this here using glutamate dehydrogenase (GDH), a 336-kDa metabolic enzyme that catalyzes the oxidative deamination of glutamate. Dysregulation of GDH leads to a variety of metabolic and neurologic disorders. Here, we report near-atomic resolution cryo-EM structures, at resolutions ranging from 3.2 t 3.6 for GDH complexes, including complexes for which crystal structures are not available. We show that the binding of the coenzyme NADH alone or in concert with GTP results in a binary mixture in which the enzyme is in either an "open" or "closed" state. Whereas the structure of NADH in the active site is similar between the open and closed states, it is unexpectedly different at the regulatory site. Our studies thus demonstrate that even in instances when there is considerable structural information available from X-ray crystallography, cryo-EM methods can provide useful complementary insights into regulatory mechanisms for dynamic protein complexes. C1 [Borgnia, Mario J.; Banerjee, Soojay; Merk, Alan; Matthies, Doreen; Bartesaghi, Alberto; Rao, Prashant; Earl, Lesley A.; Falconieri, Veronica; Subramaniam, Sriram; Milne, Jacqueline L. S.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Pierson, Jason] FEI Co, Hillsboro, OR USA. RP Subramaniam, S; Milne, JLS (reprint author), 50 South Dr,Rm 4306,MSC 8008, Bethesda, MD 20892 USA. EM ss1@nih.gov; jmilne@mail.nih.gov FU National Institutes of Health National Cancer Institute Center for Cancer Research; IATAP program at NIH; NIH-FEI Living Laboratory for Structural Biology; Intramural Research Program of the National Institutes of Health National Cancer Institute FX This research was supported by funds from the National Institutes of Health National Cancer Institute Center for Cancer Research, the IATAP program at NIH, and the NIH-FEI Living Laboratory for Structural Biology (S.S., J.L.S.M.). This work was supported by the Intramural Research Program of the National Institutes of Health National Cancer Institute. NR 25 TC 3 Z9 3 U1 3 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUN PY 2016 VL 89 IS 6 BP 645 EP 651 DI 10.1124/mol.116.103382 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DM9NL UT WOS:000376692900003 PM 27036132 ER PT J AU Okbay, A Baselmans, BML De Neve, JE Turley, P Nivard, MG Fontana, MA Meddens, SFW Linner, RK Rietveld, CA Derringer, J Gratten, J Lee, JJ Liu, JZ de Vlaming, R Ahluwalia, TS Buchwald, J Cavadino, A Frazier-Wood, AC Furlotte, NA Garfield, V Geisel, MH Gonzalez, JR Haitjema, S Karlsson, R van der Laan, SW Ladwig, KH Lahti, J van der Lee, SJ Lind, PA Liu, T Matteson, L Mihailov, E Miller, MB Minica, CC Nolte, IM Mook-Kanamori, D van der Most, PJ Oldmeadow, C Qian, Y Raitakari, O Rawal, R Realo, A Rueedi, R Schmidt, B Smith, AV Stergiakouli, E Tanaka, T Taylor, K Wedenoja, J Wellmann, J Westra, HJ Willems, SM Zhao, W Amin, N Bakshi, A Boyle, PA Cherney, S Cox, SR Davies, G Davis, OSP Ding, J Direk, N Eibich, P Emeny, RT Fatemifar, G Faul, JD Ferrucci, L Forstner, A Gieger, C Gupta, R Harris, TB Harris, JM Holliday, EG Hottenga, JJ De Jager, PL Kaakinen, MA Kajantie, E Karhunen, V Kolcic, I Kumari, M Launer, LJ Franke, L Li-Gao, R Koini, M Loukola, A Marques-Vidal, P Montgomery, GW Mosing, MA Paternoster, L Pattie, A Petrovic, KE Pulkki-Raback, L Quaye, L Raikkonen, K Rudan, I Scott, RJ Smith, JA Sutin, AR Trzaskowski, M Vinkhuyzen, AE Yu, L Zabaneh, D Attia, JR Bennett, DA Berger, K Bertram, L Boomsma, DI Snieder, H Chang, SC Cucca, F Deary, IJ van Duijn, CM Eriksson, JG Bultmann, U de Geus, EJC Groenen, PJF Gudnason, V Hansen, T Hartman, CA Haworth, CMA Hayward, C Heath, AC Hinds, DA Hypponen, E Iacono, WG Jarvelin, MR Jockel, KH Kaprio, J Kardia, SLR Keltikangas-Jarvinen, L Kraft, P Kubzansky, LD Lehtimaki, T Magnusson, PKE Martin, NG Mcgue, M Metspalu, A Mills, M de Mutsert, R Oldehinkel, AJ Pasterkamp, G Pedersen, NL Plomin, R Polasek, O Power, C Rich, SS Rosendaal, FR den Ruijter, HM Schlessinger, D Schmidt, H Svento, R Schmidt, R Alizadeh, BZ Sorensen, TIA Spector, TD Steptoe, A Terracciano, A Thurik, AR Timpson, NJ Tiemeier, H Uitterlinden, AG Vollenweider, P Wagner, GG Weir, DR Yang, J Conley, DC Smith, GD Hofman, A Johannesson, M Laibson, DI Medland, SE Meyer, MN Pickrell, JK Esko, T Krueger, RF Beauchamp, JP Koellinger, PD Benjamin, DJ Bartels, M Cesarini, D AF Okbay, Aysu Baselmans, Bart M. L. De Neve, Jan-Emmanuel Turley, Patrick Nivard, Michel G. Fontana, Mark Alan Meddens, S. Fleur W. Linner, Richard Karlsson Rietveld, Cornelius A. Derringer, Jaime Gratten, Jacob Lee, James J. Liu, Jimmy Z. de Vlaming, Ronald Ahluwalia, Tarunveer S. Buchwald, Jadwiga Cavadino, Alana Frazier-Wood, Alexis C. Furlotte, Nicholas A. Garfield, Victoria Geisel, Marie Henrike Gonzalez, Juan R. Haitjema, Saskia Karlsson, Robert van der Laan, Sander W. Ladwig, Karl-Heinz Lahti, Jari van der Lee, Sven J. Lind, Penelope A. Liu, Tian Matteson, Lindsay Mihailov, Evelin Miller, Michael B. Minica, Camelia C. Nolte, Ilja M. Mook-Kanamori, Dennis van der Most, Peter J. Oldmeadow, Christopher Qian, Yong Raitakari, Olli Rawal, Rajesh Realo, Anu Rueedi, Rico Schmidt, Borge Smith, Albert V. Stergiakouli, Evie Tanaka, Toshiko Taylor, Kent Wedenoja, Juho Wellmann, Juergen Westra, Harm-Jan Willems, Sara M. Zhao, Wei Amin, Najaf Bakshi, Andrew Boyle, Patricia A. Cherney, Samantha Cox, Simon R. Davies, Gail Davis, Oliver S. P. Ding, Jun Direk, Nese Eibich, Peter Emeny, Rebecca T. Fatemifar, Ghazaleh Faul, Jessica D. Ferrucci, Luigi Forstner, Andreas Gieger, Christian Gupta, Richa Harris, Tamara B. Harris, Juliette M. Holliday, Elizabeth G. Hottenga, Jouke-Jan De Jager, Philip L. Kaakinen, Marika A. Kajantie, Eero Karhunen, Ville Kolcic, Ivana Kumari, Meena Launer, Lenore J. Franke, Lude Li-Gao, Ruifang Koini, Marisa Loukola, Anu Marques-Vidal, Pedro Montgomery, Grant W. Mosing, Miriam A. Paternoster, Lavinia Pattie, Alison Petrovic, Katja E. Pulkki-Raback, Laura Quaye, Lydia Raikkonen, Katri Rudan, Igor Scott, Rodney J. Smith, Jennifer A. Sutin, Angelina R. Trzaskowski, Maciej Vinkhuyzen, Anna E. Yu, Lei Zabaneh, Delilah Attia, John R. Bennett, David A. Berger, Klaus Bertram, Lars Boomsma, Dorret I. Snieder, Harold Chang, Shun-Chiao Cucca, Francesco Deary, Ian J. van Duijn, Cornelia M. Eriksson, Johan G. Bultmann, Ute de Geus, Eco J. C. Groenen, Patrick J. F. Gudnason, Vilmundur Hansen, Torben Hartman, Catharine A. Haworth, Claire M. A. Hayward, Caroline Heath, Andrew C. Hinds, David A. Hypponen, Elina Iacono, William G. Jarvelin, Marjo-Riitta Jockel, Karl-Heinz Kaprio, Jaakko Kardia, Sharon L. R. Keltikangas-Jarvinen, Liisa Kraft, Peter Kubzansky, Laura D. Lehtimaki, Terho Magnusson, Patrik K. E. Martin, Nicholas G. Mcgue, Matt Metspalu, Andres Mills, Melinda de Mutsert, Renee Oldehinkel, Albertine J. Pasterkamp, Gerard Pedersen, Nancy L. Plomin, Robert Polasek, Ozren Power, Christine Rich, Stephen S. Rosendaal, Frits R. den Ruijter, Hester M. Schlessinger, David Schmidt, Helena Svento, Rauli Schmidt, Reinhold Alizadeh, Behrooz Z. Sorensen, Thorkild I. A. Spector, Tim D. Steptoe, Andrew Terracciano, Antonio Thurik, A. Roy Timpson, Nicholas J. Tiemeier, Henning Uitterlinden, Andre G. Vollenweider, Peter Wagner, Gert G. Weir, David R. Yang, Jian Conley, Dalton C. Smith, George Davey Hofman, Albert Johannesson, Magnus Laibson, David I. Medland, Sarah E. Meyer, Michelle N. Pickrell, Joseph K. Esko, Tonu Krueger, Robert F. Beauchamp, Jonathan P. Koellinger, Philipp D. Benjamin, Daniel J. Bartels, Meike Cesarini, David CA LifeLines Cohort Study TI Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses SO NATURE GENETICS LA English DT Article ID MAJOR DEPRESSION; COMMON VARIANTS; HUMAN HEIGHT; RISK; HERITABILITY; METAANALYSIS; PERSONALITY; HAPPINESS; RESOURCE; DISEASE AB Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association. C1 [Okbay, Aysu; Rietveld, Cornelius A.; de Vlaming, Ronald; Thurik, A. Roy] Erasmus Univ, Erasmus Sch Econ, Dept Appl Econ, Rotterdam, Netherlands. [Okbay, Aysu; Rietveld, Cornelius A.; de Vlaming, Ronald; van der Lee, Sven J.; Willems, Sara M.; Amin, Najaf; van Duijn, Cornelia M.; Tiemeier, Henning; Uitterlinden, Andre G.; Hofman, Albert] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Okbay, Aysu; Meddens, S. Fleur W.; Linner, Richard Karlsson; Rietveld, Cornelius A.; de Vlaming, Ronald; Groenen, Patrick J. F.; Thurik, A. Roy; Uitterlinden, Andre G.; Koellinger, Philipp D.] Erasmus Univ, Inst Behav & Biol, Rotterdam, Netherlands. [Baselmans, Bart M. L.; Nivard, Michel G.; Minica, Camelia C.; Hottenga, Jouke-Jan; Boomsma, Dorret I.; de Geus, Eco J. C.; Bartels, Meike] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Baselmans, Bart M. L.; Hottenga, Jouke-Jan; Boomsma, Dorret I.; de Geus, Eco J. C.; Bartels, Meike] EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [De Neve, Jan-Emmanuel] Univ Oxford, Said Business Sch, Oxford, England. [Turley, Patrick; Laibson, David I.; Beauchamp, Jonathan P.] Harvard Univ, Dept Econ, Cambridge, MA 02138 USA. [Fontana, Mark Alan; Benjamin, Daniel J.] Univ So Calif, Ctr Econ & Social Res, Los Angeles, CA USA. [Meddens, S. Fleur W.; Linner, Richard Karlsson; Koellinger, Philipp D.] Vrije Univ, Ctr Neurogenom & Cognit Res, Dept Complex Trait Genet, Amsterdam, Netherlands. [Meddens, S. Fleur W.; Linner, Richard Karlsson; Koellinger, Philipp D.] Univ Amsterdam, Amsterdam Business Sch, Amsterdam, Netherlands. [Derringer, Jaime] Univ Illinois, Dept Psychol, Champaign, IL USA. [Gratten, Jacob; Bakshi, Andrew; Trzaskowski, Maciej; Vinkhuyzen, Anna E.; Yang, Jian] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Lee, James J.; Matteson, Lindsay; Miller, Michael B.; Iacono, William G.; Mcgue, Matt; Krueger, Robert F.] Univ Minnesota Twin Cities, Dept Psychol, Minneapolis, MN USA. [Liu, Jimmy Z.; Pickrell, Joseph K.] New York Genome Ctr, New York, NY USA. 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[Plomin, Robert] Kings Coll London, Social Genet & Dev Psychiat Ctr, De Crespigny Pk, London, England. [Rich, Stephen S.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Schmidt, Helena] Gen Hosp, Ctr Mol Med, Res Unit Genet Epidemiol, Inst Mol Biol & Biochem, Graz, Austria. [Schmidt, Helena] Med Univ Graz, Graz, Austria. [Svento, Rauli] Oulu Business Sch, Dept Econ, Oulu, Finland. [Alizadeh, Behrooz Z.] Univ Groningen, Univ Med Ctr Groningen, Dept Gastroenterol & Hepatol, Groningen, Netherlands. [Sorensen, Thorkild I. A.] Bispebjerg & Frederiksberg Hosp, Inst Prevent Med, Frederiksberg, Denmark. [Thurik, A. Roy] Montpellier Business Sch, Montpellier, France. [Thurik, A. Roy] Panteia, Zoetermeer, Netherlands. [Tiemeier, Henning] Erasmus MC, Dept Psychiat, Rotterdam, Netherlands. [Tiemeier, Henning] Erasmus MC, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Wagner, Gert G.] Berlin Univ Technol, Sch Econ & Management, Berlin, Germany. [Yang, Jian] Univ Queensland Diamantina Inst, Translat Res Inst, Brisbane, Qld, Australia. [Conley, Dalton C.] Princeton Univ, Dept Sociol, Princeton, NJ 08544 USA. [Hofman, Albert] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Johannesson, Magnus] Stockholm Sch Econ, Dept Econ, S-11383 Stockholm, Sweden. [Meyer, Michelle N.] Clarkson Univ, Dept Bioeth, Schenectady, NY USA. [Meyer, Michelle N.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Pickrell, Joseph K.] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Cesarini, David] NYU, Dept Econ, New York, NY 10003 USA. [Cesarini, David] Res Inst Ind Econ, Stockholm, Sweden. RP Koellinger, PD (reprint author), Erasmus Univ, Inst Behav & Biol, Rotterdam, Netherlands.; Bartels, M (reprint author), Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands.; Bartels, M (reprint author), EMGO Inst Hlth & Care Res, Amsterdam, Netherlands.; Benjamin, DJ (reprint author), Univ So Calif, Ctr Econ & Social Res, Los Angeles, CA USA.; Koellinger, PD (reprint author), Vrije Univ, Ctr Neurogenom & Cognit Res, Dept Complex Trait Genet, Amsterdam, Netherlands.; Koellinger, PD (reprint author), Univ Amsterdam, Amsterdam Business Sch, Amsterdam, Netherlands.; Bartels, M (reprint author), Neurosci Campus Amsterdam, Amsterdam, Netherlands. EM p.d.koellinger@vu.nl; djbenjam@usc.edu; m.bartels@vu.nl RI Bertram, Lars/K-3889-2015; Ladwig, Karl-Heinz/B-5351-2014; Thurik, Roy/A-9386-2012; Davey Smith, George/A-7407-2013; Magnusson, Patrik/C-4458-2017; Gratten, Jake (Jacob)/G-1485-2011; Yang, Jian/A-5852-2010; Johannesson, Magnus/E-9680-2011; Haworth, Claire/C-7073-2009; Realo, Anu/M-9524-2016; Bartels, Meike/D-4492-2014; Franke, Lude/P-7036-2016; Colaus, PsyColaus/K-6607-2013; Polasek, Ozren/B-6002-2011; Kolcic, Ivana/E-2713-2017; OI Trzaskowski, Maciej/0000-0001-8559-6525; Nivard, Michel/0000-0003-2015-1888; Stergiakouli, Evangelia/0000-0003-3586-0927; Kaprio, Jaakko/0000-0002-3716-2455; Smith, Jennifer/0000-0002-3575-5468; Medland, Sarah/0000-0003-1382-380X; Timpson, Nicholas/0000-0002-7141-9189; Lahti, Jari/0000-0002-4310-5297; de Geus, Eco/0000-0001-6022-2666; Hypponen, Elina/0000-0003-3670-9399; Bertram, Lars/0000-0002-0108-124X; Ladwig, Karl-Heinz/0000-0003-0710-1720; Thurik, Roy/0000-0002-0242-6908; Davey Smith, George/0000-0002-1407-8314; Gratten, Jake (Jacob)/0000-0003-1293-409X; Yang, Jian/0000-0003-2001-2474; Johannesson, Magnus/0000-0001-8759-6393; Haworth, Claire/0000-0002-8608-289X; Bartels, Meike/0000-0002-9667-7555; Franke, Lude/0000-0002-5159-8802; Polasek, Ozren/0000-0002-5765-1862; Kolcic, Ivana/0000-0001-7918-6052; Gupta, Richa/0000-0001-7700-5828; Cesarini, David/0000-0002-0043-009X; Gieger, Christian/0000-0001-6986-9554; Buchwald, Jadwiga/0000-0001-6688-8346; Loukola, Anu-Maria/0000-0003-0542-5967; Kumari, Meena/0000-0001-9716-1035; Wedenoja, Juho/0000-0002-6155-0378; Bakshi, Andrew/0000-0001-5650-7036 FU Social Science Genetic Association Consortium (SSGAC); US National Science Foundation (EAGER: 'Workshop for the Formation of a Social Science Genetic Association Consortium'); National Institute of Health Office of Behavioral and Social Science Research; Ragnar Soderberg Foundation [E9/11]; Swedish Research Council [421-2013-1061]; Jan Wallander and Tom Hedelius Foundation; ERC Consolidator Grant [647648 EdGe]; Pershing Square Fund of the Foundations of Human Behavior; NIA/NIH [P01-AG005842, P01-AG005842-20S2, P30-AG012810, T32-AG000186-23, R01-AG042568-02] FX We are grateful to P.M. Visscher for advice, support, and feedback. We thank S. Cunningham and N. Galla for research assistance. This research was carried out under the auspices of the Social Science Genetic Association Consortium (SSGAC). The SSGAC seeks to facilitate studies that investigate the influence of genes on human behavior, well-being, and social-scientific outcomes using large GWAS meta-analyses. The SSGAC also provides opportunities for replication and promotes the collection of accurately measured, harmonized phenotypes across cohorts. The SSGAC operates as a working group within the CHARGE Consortium. This research has also been conducted using the UK Biobank Resource. The study was supported by funding from the US National Science Foundation (EAGER: 'Workshop for the Formation of a Social Science Genetic Association Consortium'), a supplementary grant from the National Institute of Health Office of Behavioral and Social Science Research, the Ragnar Soderberg Foundation (E9/11), the Swedish Research Council (421-2013-1061), the Jan Wallander and Tom Hedelius Foundation, an ERC Consolidator Grant (647648 EdGe), the Pershing Square Fund of the Foundations of Human Behavior, and the NIA/NIH through grants P01-AG005842, P01-AG005842-20S2, P30-AG012810, and T32-AG000186-23 to NBER and R01-AG042568-02 to the University of Southern California. A full list of acknowledgments is provided in the Supplementary Note. NR 47 TC 27 Z9 27 U1 18 U2 40 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 JUN PY 2016 VL 48 IS 6 BP 624 EP + DI 10.1038/ng.3552 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA DN0HE UT WOS:000376744200009 PM 27089181 ER PT J AU Hebart, MN Baker, CI AF Hebart, Martin N. Baker, Chris I. TI Facing up to stereotypes SO NATURE NEUROSCIENCE LA English DT Editorial Material ID CORTEX C1 [Hebart, Martin N.; Baker, Chris I.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Hebart, MN; Baker, CI (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM martin.hebart@nih.gov; bakerchris@mail.nih.gov OI Baker, Chris/0000-0001-6861-8964 NR 8 TC 0 Z9 0 U1 0 U2 4 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 JUN PY 2016 VL 19 IS 6 BP 763 EP 764 DI 10.1038/nn.4309 PG 2 WC Neurosciences SC Neurosciences & Neurology GA DN0HI UT WOS:000376744600001 PM 27227362 ER PT J AU Belkaid, Y Tamoutounour, S AF Belkaid, Yasmine Tamoutounour, Samira TI The influence of skin microorganisms on cutaneous immunity SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID REGULATORY T-CELLS; LEISHMANIA-MAJOR INFECTION; CD103(+) DENDRITIC CELLS; STAPHYLOCOCCUS-AUREUS; ATOPIC-DERMATITIS; LANGERHANS CELLS; PROPIONIBACTERIUM-ACNES; ANTIGEN PRESENTATION; ADAPTIVE IMMUNITY; SENSORY NEURONS AB The skin is a complex and dynamic ecosystem that is inhabited by many microorganisms. Recent evidence highlights the profound reliance of the skin immune system on its resident microbiota for both host defence and tissue repair. This tissue is also a primary target for infections, which are in some cases caused by normal constituents of the microbiota. In the context of infections and genetic predispositions that are associated with barrier or regulatory network defects, microorganism-induced inflammatory cycles can contribute to the initiation and/or amplification of skin disorders. This Review will discuss some of our current understanding of skin-microbiota and skin-pathogen interactions in the context of homeostasis and diseases and highlight current gaps in our understanding of the skin immune ecosystem. C1 [Belkaid, Yasmine] NIAID, Microbiome Program, US Natl Inst Hlth NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Belkaid, Yasmine; Tamoutounour, Samira] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, US NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Belkaid, Y (reprint author), NIAID, Microbiome Program, US Natl Inst Hlth NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Belkaid, Y (reprint author), NIAID, Mucosal Immunol Sect, Parasit Dis Lab, US NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ybelkaid@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases; EMBO FX The authors apologize to their colleagues for not having cited all papers relevant to this expanding field of research (and in particular older literature) because of space constraints and strict editorial limitation for reference number. This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases. S. T. was supported by an EMBO fellowship. The authors thank all members of the Belkaid laboratory for discussion and more particularly N. Bouladoux and J. Kehr for their editorial help with the manuscript. NR 142 TC 2 Z9 3 U1 14 U2 27 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 EI 1474-1741 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD JUN PY 2016 VL 16 IS 6 BP 353 EP 366 DI 10.1038/nri.2016.48 PG 14 WC Immunology SC Immunology GA DN0GP UT WOS:000376742700009 PM 27231051 ER PT J AU Fisher, DE Klein, BEK Wong, TY Rotter, JI Li, XH Shrager, S Burke, GL Klein, R Cotch, MF AF Fisher, Diana E. Klein, Barbara E. K. Wong, Tien Y. Rotter, Jerome I. Li, Xiaohui Shrager, Sandi Burke, Gregory L. Klein, Ronald Cotch, Mary Frances TI Incidence of Age-Related Macular Degeneration in a Multi-Ethnic United States Population The Multi-Ethnic Study of Atherosclerosis SO OPHTHALMOLOGY LA English DT Article ID COMPLEMENT FACTOR-H; BEAVER DAM EYE; NUTRITION EXAMINATION SURVEY; EVALUATION SEE PROJECT; BLUE MOUNTAINS EYE; RISK-FACTORS; 5-YEAR INCIDENCE; CARDIOVASCULAR-DISEASE; RACIAL/ETHNIC GROUPS; RACIAL-DIFFERENCES AB Purpose: To describe the incidence of age-related macular degeneration (AMD) and associated risk factors in 4 racial/ethnic groups (white, black, Hispanic, and Chinese) residing in the United States. Design: Prospective cohort study. Participants: A total of 3811 participants, aged 46 to 86 years, from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, with retinal data collected twice, on average, 8 years apart. Methods: Fundus images, taken using a digital camera through dark-adapted pupils using a standard protocol and the same equipment at both study visits, were graded centrally for early and late AMD on the basis of drusen size, type and area, increased retinal pigment, retinal pigment epithelial depigmentation, neovascular lesions, and geographic atrophy using the modified Wisconsin Age-Related Maculopathy Grading System. Demographic, clinical, and laboratory measures were included in multivariable regression models to determine their impact on the variation in AMD incidence among racial/ethnic groups. Main Outcome Measures: Incident early and late AMD. Results: The overall 8-year age- and sex-standardized incidence of early and late AMD were 4.1% and 2.3%, respectively, with incidence of early and late AMD highest in whites (5.3% and 4.1%, respectively), intermediate in Chinese (4.5% and 2.2%, respectively) and Hispanics (3.3% and 0.8%, respectively), and lowest in blacks (1.6% and 0.4%, respectively). By adjusting for age and sex, blacks had a 70% lower risk of developing early AMD than whites, and this decreased only slightly to a 67% lower risk after multivariable adjustment. By adjusting for age, sex, and race/ethnicity, hyperopia was associated with early AMD (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.04-2.20), as was astigmatism (OR, 1.47; 95% CI, 1.00-2.16), but not myopia (P = 0.29). Age, race/ethnicity, current smoking, hyperopia, and AMD-susceptibility genotypes Complement Factor H (CFH) RS1061170 and Age Related Maculopathy Susceptibility 2 (ARMS2) RS3793917 were independently associated with incident early AMD in multivariable models for the combined sample. However, the only statistically significant factor consistently associated with incident early AMD across the 4 racial/ethnic groups was increasing age. Risk factors for late AMD were not assessed because of its low incidence, particularly across racial/ethnic groups. Conclusions: Variation in the incidence of early AMD exists among racial/ethnic groups in the United States and is not explained by the clinical, genetic, and environmental factors included in this study. (C) 2016 Published by Elsevier on behalf of the American Academy of Ophthalmology. C1 [Fisher, Diana E.; Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, Intramural Res Program, NIH, Bldg 10 CRC,Room 3-2521, Bethesda, MD 20892 USA. [Klein, Barbara E. K.; Klein, Ronald] Univ Wisconsin, Ophthalmol & Visual Sci, Madison, WI USA. [Wong, Tien Y.] Natl Univ Singapore, Ophthalmol & Visual Sci Acad Clin Program, Duke NUS Med Sch, Singapore 117548, Singapore. [Wong, Tien Y.] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. [Rotter, Jerome I.; Li, Xiaohui] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles BioMed Res Inst, Torrance, CA 90509 USA. [Rotter, Jerome I.; Li, Xiaohui] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Shrager, Sandi] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Burke, Gregory L.] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. RP Fisher, DE (reprint author), NEI, Div Epidemiol & Clin Applicat, Intramural Res Program, NIH, Bldg 10 CRC,Room 3-2521, Bethesda, MD 20892 USA. EM diana.fisher@nih.gov FU National Heart, Lung, and Blood Institute; National Institutes of Health Intramural Research Program [HL069979, ZIAEY000403]; [N01-HC-95159]; [N01-HC-95160]; [N01-HC-95161]; [N01-HC-95162]; [N01-HC-95163]; [N01-HC-95164]; [N01-HC-95165]; [N01-HC-95166]; [N01-HC-95167]; [N01-HC-95168]; [N01-HC-95169]; [UL1-TR-001079]; [UL1-TR-000040]; [DK063491]; [R01HL98077]; [N02-HL-64278]; [HL071205]; [UL1TR000124]; [RD831697]; [P50 ES015915] FX The Multi-Ethnic Study of Atherosclerosis (MESA) and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with MESA investigators. Support for MESA is provided by Contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, UL1-TR-000040, and DK063491. Funding support for the eye datasets was provided by Grant HL069979 and an award from the National Institutes of Health Intramural Research Program ZIAEY000403. Cardiometabochip genotyping data were supported in part by Grants and Contracts R01HL98077, N02-HL-64278, HL071205, UL1TR000124, DK063491, RD831697, and P50 ES015915. The funders had no role in data collection, management, analysis and interpretation of the data, preparation, writing and approval of the manuscript, or decision to submit the manuscript for publication. NR 51 TC 2 Z9 2 U1 4 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD JUN PY 2016 VL 123 IS 6 BP 1297 EP 1308 DI 10.1016/j.ophtha.2015.12.026 PG 12 WC Ophthalmology SC Ophthalmology GA DM7BD UT WOS:000376506400027 PM 26896123 ER PT J AU Wells, JA Glassman, AR Ayala, AR Jampol, LM Bressler, NM Bressler, SB Brucker, AJ Ferris, FL Hampton, GR Jhaveri, C Melia, M Beck, RW AF Wells, John A. Glassman, Adam R. Ayala, Allison R. Jampol, Lee M. Bressler, Neil M. Bressler, Susan B. Brucker, Alexander J. Ferris, Frederick L. Hampton, G. Robert Jhaveri, Chirag Melia, Michele Beck, Roy W. CA Diabetic Retinopathy Clinical Res TI Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial SO OPHTHALMOLOGY LA English DT Article ID INTRAVITREAL AFLIBERCEPT; TRIAL; RISK AB Purpose: To provide 2-year results comparing anti vascular endothelial growth factor (VEGF) agents for center-involved diabetic macular edema (DME) using a standardized follow-up and retreatment regimen. Design: Randomized clinical trial. Participants: Six hundred sixty participants with visual acuity (VA) impairment from DME. Methods: Randomization to 2.0-mg aflibercept, 1.25-mg repackaged (compounded) bevacizumab, or 0.3-mg ranibizumab intravitreous injections performed up to monthly using a protocol-specific follow-up and retreatment regimen. Focal/grid laser photocoagulation was added after 6 months if DME persisted. Visits occurred every 4 weeks during year 1 and were extended up to every 4 months thereafter when VA and macular thickness were stable. Main Outcome Measures: Change in VA, adverse events, and retreatment frequency. Results: Median numbers of injections were 5, 6, and 6 in year 2 and 15, 16, and 15 over 2 years in the aflibercept, bevacizumab, and ranibizumab groups, respectively (global P = 0.08). Focal/grid laser photocoagulation was administered in 41%, 64%, and 52%, respectively (aflibercept vs. bevacizumab, P < 0.001; aflibercept vs. ranibizumab, P = 0.04; bevacizumab vs. ranibizumab, P = 0.01). At 2 years, mean VA improved by 12.8, 10.0, and 12.3 letters, respectively. Treatment group differences varied by baseline VA (P = 0.02 for interaction). With worse baseline VA (20/50 to 20/320), mean improvement was 18.1, 13.3, and 16.1 letters, respectively (aflibercept vs. bevacizumab, P = 0.02; aflibercept vs. ranibizumab, P = 0.18; ranibizumab vs. bevacizumab, P = 0.18). With better baseline VA (20/32 to 20/40), mean improvement was 7.8, 6.8, and 8.6 letters, respectively (P > 0.10, for pairwise comparisons). Anti-Platelet Trialists' Collaboration (APTC) events occurred in 5% with aflibercept, 8% with bevacizumab, and 12% with ranibizumab (global P = 0.047; aflibercept vs. bevacizumab, P = 0.34; aflibercept vs. ranibizumab, P = 0.047; ranibizumab vs. bevacizumab, P = 0.20; global P = 0.09 adjusted for potential confounders). Conclusions: All 3 anti-VEGF groups showed VA improvement from baseline to 2 years with a decreased number of injections in year 2. Visual acuity outcomes were similar for eyes with better baseline VA. Among eyes with worse baseline VA, aflibercept had superior 2-year VA outcomes compared with bevacizumab, but superiority of aflibercept over ranibizumab, noted at 1 year, was no longer identified. Higher APTC event rates with ranibizumab over 2 years warrants continued evaluation in future trials. (C) 2016 by the American Academy of Ophthalmology. C1 [Wells, John A.] Palmetto Retina Ctr, Columbia, SC USA. [Glassman, Adam R.; Ayala, Allison R.; Melia, Michele; Beck, Roy W.] Jaeb Ctr Hlth Res, 15310 Amberly Dr,Suite 350, Tampa, FL 33647 USA. [Jampol, Lee M.] Northwestern Univ, Dept Ophthalmol, Feinberg Sch Med, Chicago, IL 60611 USA. [Bressler, Neil M.; Bressler, Susan B.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Brucker, Alexander J.] Univ Penn, Scheie Eye Inst, Philadelphia, PA 19104 USA. [Ferris, Frederick L.] NEI, NIH, Bethesda, MD 20892 USA. [Hampton, G. Robert] Retina Vitreous Surg Cent New York, PC, Syracuse, NY USA. [Jhaveri, Chirag] Retina Res Ctr, Austin, TX USA. RP Ayala, AR (reprint author), Jaeb Ctr Hlth Res, 15310 Amberly Dr,Suite 350, Tampa, FL 33647 USA. EM drcrstat1@jaeb.org FU Allergan; Ampio; Kalvista; Emmes; Neurotech; LPath; NIH; Ophthotech; Genentech; Regeneron; Bayer; Genentech, Inc (South San Francisco, CA); Novartis (Basel, Switzerland); Regeneron, Inc (Tarrytown, NY); Allergan, Inc (Irvine, CA); Bausch & Lomb (Rochester, NY); Bayer HealthCare Pharmaceuticals Inc; Boehringer Ingelheim Pharma GmbH & Co. KG (Ingelheim am Rhein, Germany); Emmes Corporation (Rockville, MD) Genentech, Inc; Lumenis Ltd (Yokneam, Israel); Notal Vision Ltd; Novartis Pharma AG; Regeneron Pharmaceuticals Inc; ThromboGenics NV (Leuven, Belgium); Jaeb Center for Health Research Inc.; National Eye Institute, Bethesda, Maryland; National Institute on Deafness and Communication Disorders FX The author(s) have made the following disclosure(s): J.A.W.: Grants - Allergan, Ampio, Kalvista, Emmes, Neurotech, LPath, NIH, Ophthotech; Grants and non-financial support - Genentech, Regeneron, during the conduct of the study; Grants, personal fees and non-financial support - Iconic; Grants and personal fees - Panoptica, outside the submitted work. N.M.B.: Financial support (to the Johns Hopkins University School of Medicine) - Bayer; Genentech, Inc (South San Francisco, CA); Novartis (Basel, Switzerland); Regeneron, Inc (Tarrytown, NY).; S.B.B.: Consultant - GlaxoSmithKline (Brentford, UK) Financial support (to Johns Hopkins University School of Medicine) - Allergan, Inc (Irvine, CA); Bausch & Lomb (Rochester, NY); Bayer HealthCare Pharmaceuticals Inc; Boehringer Ingelheim Pharma GmbH & Co. KG (Ingelheim am Rhein, Germany); Emmes Corporation (Rockville, MD) Genentech, Inc; Lumenis Ltd (Yokneam, Israel); Notal Vision Ltd (Headquarters: TelAviv, Israel; US office & distribution center; St. Louis, MO); Novartis Pharma AG; Regeneron Pharmaceuticals Inc; ThromboGenics NV (Leuven, Belgium); Jaeb Center for Health Research Inc.; M.M.: Financial support (for grants review) - National Eye Institute, Bethesda, Maryland; National Institute on Deafness and Communication Disorders. NR 14 TC 32 Z9 32 U1 6 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD JUN PY 2016 VL 123 IS 6 BP 1351 EP 1359 DI 10.1016/j.ophtha.2016.02.022 PG 9 WC Ophthalmology SC Ophthalmology GA DM7BD UT WOS:000376506400033 PM 26935357 ER PT J AU Magpantay, FMG de Celles, MD Rohani, P King, AA AF Magpantay, F. M. G. de Celles, M. Domenech Rohani, P. King, A. A. TI Pertussis immunity and epidemiology: mode and duration of vaccine-induced immunity SO PARASITOLOGY LA English DT Article DE pertussis; imperfect vaccine; leaky vaccine; waning immunity; disease dynamics; iterated filtering; likelihood-based inference ID ACELLULAR VACCINES; IMPERFECT VACCINES; HERD-IMMUNITY; WHOLE-CELL; RESURGENCE; DYNAMICS; TRANSMISSION; PROTECTION; THAILAND; EFFICACY AB The resurgence of pertussis in some countries that maintain high vaccination coverage has drawn attention to gaps in our understanding of the epidemiological effects of pertussis vaccines. In particular, major questions surround the nature, degree and durability of vaccine protection. To address these questions, we used mechanistic transmission models to examine regional time series incidence data from Italy in the period immediately following the introduction of acellular pertussis (aP) vaccine. Our results concur with recent animal-challenge experiments wherein infections in aP-vaccinated individuals proved as transmissible as those in naive individuals but much less symptomatic. On the other hand, the data provide evidence for vaccine-driven reduction in susceptibility, which we quantify via a synthetic measure of vaccine impact. As to the precise nature of vaccine failure, the data do not allow us to distinguish between leakiness and waning of vaccine immunity, or some combination of these. Across the range of well-supported models, the nature and duration of vaccine protection, the age profile of incidence and the range of projected epidemiological futures differ substantially, underscoring the importance of the remaining unknowns. We identify key data gaps: sources of data that can supply the information needed to eliminate these remaining uncertainties. C1 [Magpantay, F. M. G.; de Celles, M. Domenech; Rohani, P.; King, A. A.] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Rohani, P.; King, A. A.] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Rohani, P.; King, A. A.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [King, A. A.] Univ Michigan, Dept Math, Ann Arbor, MI 48109 USA. RP King, AA (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. EM kingaa@umich.edu OI King, Aaron/0000-0001-6159-3207 FU Research and Policy in Infectious Disease Dynamics programme (Science and Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health); National Institutes of Health [1R01AI101155]; MIDAS, National Institute of General Medical Sciences [U54-GM111274] FX This work is supported by the Research and Policy in Infectious Disease Dynamics programme (Science and Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health) and by a research grant from the National Institutes of Health (grant number 1R01AI101155) and by MIDAS, National Institute of General Medical Sciences (grant number U54-GM111274). NR 52 TC 2 Z9 2 U1 3 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0031-1820 EI 1469-8161 J9 PARASITOLOGY JI Parasitology PD JUN PY 2016 VL 143 IS 7 SI SI BP 835 EP 849 DI 10.1017/S0031182015000979 PG 15 WC Parasitology SC Parasitology GA DN0UM UT WOS:000376781100004 PM 26337864 ER PT J AU Garnier, R Grenfell, BT Nisbet, AJ Matthews, JB Graham, AL AF Garnier, Romain Grenfell, Bryan T. Nisbet, Alasdair J. Matthews, Jacqueline B. Graham, Andrea L. TI Integrating immune mechanisms to model nematode worm burden: an example in sheep SO PARASITOLOGY LA English DT Article DE Teladorsagia circumcincta; Ovis aries; moment closure; immuno-epidemiology ID TELADORSAGIA-CIRCUMCINCTA INFECTION; OSTERTAGIA-CIRCUMCINCTA; GASTROINTESTINAL NEMATODES; SMALL RUMINANTS; GASTRIC LYMPH; EPIDEMIOLOGIC DYNAMICS; LOCAL IMMUNITY; COMPUTER-MODEL; NEONATAL LAMB; RESISTANCE AB Gastrointestinal nematodes represent important sources of economic losses in farmed ruminants, and the increasing frequency of anthelmintic resistance requires an increased ability to explore alternative strategies. Theoretical approaches at the crossroads of immunology and epidemiology are valuable tools in that context. In the case of Teladorsagia circumcincta in sheep, the immunological mechanisms important for resistance are increasingly well-characterized. However, despite the existence of a wide range of theoretical models, there is no framework integrating the characteristic features of this immune response into a tractable phenomenological model. Here, we propose to bridge that gap by developing a flexible modelling framework that allows for variability in nematode larval intake which can be used to track the variations in worm burdens. We parameterize this model using data from trickle infection of sheep and show that using simple immunological assumptions, our model can capture the dynamics of both adult worm burdens and nematode fecal egg counts. In addition, our analysis reveals interesting dose-dependent effects on the immune response. Finally, we discuss potential developments of this model and highlight how an improved cross-talk between empiricists and theoreticians would facilitate important advances in the study of infectious diseases. C1 [Garnier, Romain; Grenfell, Bryan T.; Graham, Andrea L.] Princeton Univ, Dept Ecol & Evolutionary Biol, 106A Guyot Hall, Princeton, NJ 08544 USA. [Grenfell, Bryan T.; Graham, Andrea L.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Nisbet, Alasdair J.; Matthews, Jacqueline B.] Moredun Res Inst, Pentlands Sci Pk, Edinburgh, Midlothian, Scotland. RP Garnier, R (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, 106A Guyot Hall, Princeton, NJ 08544 USA. EM romaing@princeton.edu RI Graham, Andrea/A-8808-2010; OI Graham, Andrea/0000-0002-6580-2755; Nisbet, Alasdair/0000-0002-4965-5396 FU Princeton University; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, US Department of Homeland Security; Fogarty International Center of the National Institutes of Health; Scottish Government RESAS FX RG was supported by a Princeton University Health Grand Challenges grant to ALG. ALG and BTG also acknowledge support from the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, US Department of Homeland Security and the Fogarty International Center of the National Institutes of Health. AJN and JBM acknowledge support from the Scottish Government RESAS. NR 65 TC 1 Z9 1 U1 3 U2 8 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0031-1820 EI 1469-8161 J9 PARASITOLOGY JI Parasitology PD JUN PY 2016 VL 143 IS 7 SI SI BP 894 EP 904 DI 10.1017/S0031182015000992 PG 11 WC Parasitology SC Parasitology GA DN0UM UT WOS:000376781100009 PM 26283186 ER PT J AU Cressler, CE McLeod, DV Rozins, C van den Hoogen, J Day, T AF Cressler, Clayton E. McLeod, David V. Rozins, Carly van den Hoogen, Josee Day, Troy TI The adaptive evolution of virulence: a review of theoretical predictions and empirical tests SO PARASITOLOGY LA English DT Review DE Tradeoff hypothesis; evolutionary medicine; infectious disease ID DIVERSE MALARIA INFECTIONS; VERTICALLY TRANSMITTED PARASITES; HOST POPULATION-STRUCTURE; MAREKS-DISEASE VIRUS; WITHIN-HOST; PATHOGEN VIRULENCE; TRADE-OFF; LIFE-HISTORY; BORDETELLA-PERTUSSIS; KIN SELECTION AB Why is it that some parasites cause high levels of host damage (i.e. virulence) whereas others are relatively benign? There are now numerous reviews of virulence evolution in the literature but it is nevertheless still difficult to find a comprehensive treatment of the theory and data on the subject that is easily accessible to non-specialists. Here we attempt to do so by distilling the vast theoretical literature on the topic into a set of relatively few robust predictions. We then provide a comprehensive assessment of the available empirical literature that tests these predictions. Our results show that there have been some notable successes in integrating theory and data but also that theory and empiricism in this field do not speak' to each other very well. We offer a few suggestions for how the connection between the two might be improved. C1 [Cressler, Clayton E.; McLeod, David V.; Rozins, Carly; van den Hoogen, Josee; Day, Troy] Queens Univ, Dept Math & Stat, Kingston, ON K7L 3N6, Canada. [Cressler, Clayton E.; Day, Troy] Queens Univ, Dept Biol, Kingston, ON K7L 3N6, Canada. [Day, Troy] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Day, T (reprint author), Queens Univ, Dept Math Stat & Biol, Kingston, ON K7L 3N6, Canada. EM tday@mast.queensu.ca FU Natural Sciences and Engineering Research Council of Canada FX We thank S. Alizon, S. Gandon, N. Mideo, and A. Read for comments and suggestions. The RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, provided support, as did the Natural Sciences and Engineering Research Council of Canada. NR 186 TC 9 Z9 9 U1 30 U2 55 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0031-1820 EI 1469-8161 J9 PARASITOLOGY JI Parasitology PD JUN PY 2016 VL 143 IS 7 SI SI BP 915 EP 930 DI 10.1017/S003118201500092X PG 16 WC Parasitology SC Parasitology GA DN0UM UT WOS:000376781100011 PM 26302775 ER PT J AU Karlsson, C Rehman, F Damdazic, R Atkins, AL Schank, JR Gehlert, DR Steensland, P Thorsell, A Heilig, M AF Karlsson, Camilla Rehman, Faazal Damdazic, Ruslan Atkins, Alison L. Schank, Jesse R. Gehlert, Donald R. Steensland, Pia Thorsell, Annika Heilig, Markus TI The melanin-concentrating hormone-1 receptor modulates alcohol-induced reward and DARPP-32 phosphorylation SO PSYCHOPHARMACOLOGY LA English DT Article DE Alcohol; Conditioned place preference (CPP); Knock-out mice; MCH1-R; p-DARPP-32; Reward ID CONDITIONED PLACE PREFERENCE; NUCLEUS-ACCUMBENS SHELL; FEEDING-BEHAVIOR; DEFICIENT MICE; DOPAMINE; ETHANOL; MCH; SYSTEM; BRAIN; RAT AB Melanin-concentrating hormone (MCH) is involved in the regulation of food intake and has recently been associated with alcohol-related behaviors. Blockade of MCH-1 receptors (MCH1-Rs) attenuates operant alcohol self-administration and decreases cue-induced reinstatement, but the mechanism through which the MCH1-R influences these behaviors remains unknown. MCH1-Rs are highly expressed in the nucleus accumbens shell (NAcSh) where they are co-expressed with dopamine (DA) receptors. MCH has been shown to potentiate responses to dopamine and to increase phosphorylation of DARPP-32, an intracellular marker of DA receptor activation, in the NAcSh. In the present study, we investigated the role of the MCH1-R in alcohol reward using the conditioned place preference (CPP) paradigm. We then used immunohistochemistry (IHC) to assess activation of downstream signaling after administration of a rewarding dose of alcohol. We found that alcohol-induced CPP was markedly decreased in mice with a genetic deletion of the MCH1-R as well as after pharmacological treatment with an MCH1-R antagonist, GW803430. In contrast, an isocaloric dose of dextrose did not produce CPP. The increase in DARPP-32 phosphorylation seen in wildtype (WT) mice after acute alcohol administration in the NAcSh was markedly reduced in MCH1-R knock-out (KO) mice. Our results suggest that MCH1-Rs regulate the rewarding properties of alcohol through interactions with signaling cascades downstream of DA receptors in the NAcSh. C1 [Karlsson, Camilla; Atkins, Alison L.; Thorsell, Annika; Heilig, Markus] Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden. [Rehman, Faazal; Damdazic, Ruslan] NIH, NIAAA, Lab Clin & Translat Studies, Bldg 10, Bethesda, MD 20892 USA. [Schank, Jesse R.] Univ Georgia, Dept Physiol & Pharmacol, Athens, GA 30602 USA. [Gehlert, Donald R.] Eli Lilly & Co, Lilly Res Labs, Neurosci & Endocrine Discovery Res, Indianapolis, IN 46285 USA. [Steensland, Pia] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. RP Heilig, M (reprint author), Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden. EM markus.heilig@liu.se NR 38 TC 2 Z9 2 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUN PY 2016 VL 233 IS 12 BP 2355 EP 2363 DI 10.1007/s00213-016-4285-y PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DM5SQ UT WOS:000376410800013 PM 27044354 ER PT J AU Bolnick, AD Fritz, R Jain, C Kadam, L Bolnick, JM Kilburn, BA Singh, M Diamond, MP Drewlo, S Armant, DR AF Bolnick, Alan D. Fritz, Rani Jain, Chandni Kadam, Leena Bolnick, Jay M. Kilburn, Brian A. Singh, Manvinder Diamond, Michael P. Drewlo, Sascha Armant, D. Randall TI Trophoblast Retrieval and Isolation From the Cervix for Noninvasive, First Trimester, Fetal Gender Determination in a Carrier of Congenital Adrenal Hyperplasia SO REPRODUCTIVE SCIENCES LA English DT Article DE congenital adrenal hyperplasia; prenatal genetic diagnosis; placenta; trophoblast; fluorescence in situ hybridization; steroids; 21-hydroxylase ID CELL-FREE DNA; 21-HYDROXYLASE DEFICIENCY; PRENATAL TREATMENT; PREGNANT-WOMEN; MATERNAL PLASMA; GESTATIONAL-AGE; DIAGNOSIS; CYTOBRUSH; DISORDERS; STANDARD AB Congenital adrenal hyperplasia (CAH) is an autosomal recessive defect in cortisol biosynthesis that elevates fetal androgen levels to cause genital ambiguity and external genital masculinization in newborn females. Introducing dexamethasone in utero by 7 weeks gestation precludes virilization of affected females. However, identification of a male fetus prior to week 7 could avert the necessity of steroid treatment in half of pregnancies at risk of CAH. We recently introduced trophoblast retrieval and isolation from the cervix (TRIC), an approach that noninvasively isolate homogeneous trophoblast cells from pregnant women as early as 5 weeks gestation, using a Papanicolaou test. Here, we have used TRIC to correctly identify male fetal DNA when both parents were carriers of the mutation that produces CAH and previously produced an affected child. Trophoblast cells (1400) obtained by TRIC were assessed using immunocytochemistry with an antibody against the trophoblast-specific subunit of human chorionic gonadotropin, which labeled 100% (17 of 17) of isolated cells, while none of the excluded maternal cervical cells were labeled. The isolated cells were examined by fluorescent in situ hybridization for chromosomes 18, X, and Y at a clinical cytogenetics laboratory, demonstrating 100% (18 of 18) of cells to be diploid 18/XY. Aliquots of DNA obtained from the isolated cells assayed for SRY and RNASEH genes by TaqMan assays confirmed a male fetus. This case study demonstrates the utility of TRIC to accurately identify fetal gender as a means of reducing the need for prophylactic administration of exogenous steroids in pregnancies at risk of CAH. C1 [Bolnick, Alan D.; Fritz, Rani; Jain, Chandni; Kadam, Leena; Bolnick, Jay M.; Kilburn, Brian A.; Singh, Manvinder; Drewlo, Sascha; Armant, D. Randall] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Fritz, Rani; Jain, Chandni; Kadam, Leena] Wayne State Univ, Dept Physiol, Detroit, MI 48201 USA. [Diamond, Michael P.] Georgia Regents Univ, Dept Obstet & Gynecol, Augusta, GA USA. [Armant, D. Randall] Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. [Armant, D. Randall] NICHHD, Program Reprod & Adult Endocrinol, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Armant, DR (reprint author), Wayne State Univ, Dept Obstet & Gynecol, Mott Ctr Human Growth & Dev, 275 East Hancock St, Detroit, MI 48201 USA. EM d.armant@wayne.edu OI Diamond, Michael/0000-0001-6353-4489; Armant, D. Randall/0000-0001-5904-9325 NR 35 TC 1 Z9 1 U1 2 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD JUN PY 2016 VL 23 IS 6 BP 717 EP 722 DI 10.1177/1933719116632922 PG 6 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA DM3YB UT WOS:000376281500005 PM 26919977 ER PT J AU Arimbasseri, AG Maraia, RJ AF Arimbasseri, Aneeshkumar G. Maraia, Richard J. TI RNA Polymerase III Advances: Structural and tRNA Functional Views SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID COMPOUND HETEROZYGOUS MUTATIONS; COPY NUMBER VARIATION; EMBRYONIC STEM-CELLS; POL-III; SACCHAROMYCES-CEREVISIAE; HYPOMYELINATING LEUKODYSTROPHY; TRANSCRIPTION TERMINATION; DIFFERENTIAL EXPRESSION; GENOME ORGANIZATION; RECESSIVE MUTATIONS AB RNA synthesis in eukaryotes is divided among three RNA polymerases (RNAPs). RNAP III transcribes hundreds of tRNA genes and fewer additional short RNA genes. We survey recent work on transcription by RNAP III including an atomic structure, mechanisms of action, interactions with chromatin and retroposons, and a conserved link between its activity and a tRNA modification that enhances mRNA decoding. Other new work suggests important mechanistic connections to oxidative stress, autoimmunity and cancer, embryonic stem cell pluripotency, and tissue-specific developmental effects. We consider that, for some of its complex functions, variation in RNAP III activity levels lead to nonuniform changes in tRNAs that can shift the translation profiles of key codon-biased mRNAs with resultant phenotypes or disease states. C1 [Arimbasseri, Aneeshkumar G.; Maraia, Richard J.] Kennedy Shriver Natl Inst Child Hlth & Human Dev, Intramural Res Program, NIH, Bethesda, MD USA. [Maraia, Richard J.] US PHS, Commissioned Corps, Rockville, MD USA. [Arimbasseri, Aneeshkumar G.] N Carolina State Univ, Dept Chem & Biomol Engn, Partners 2,3700, Raleigh, NC 27695 USA. RP Maraia, RJ (reprint author), Kennedy Shriver Natl Inst Child Hlth & Human Dev, Intramural Res Program, NIH, Bethesda, MD USA.; Maraia, RJ (reprint author), US PHS, Commissioned Corps, Rockville, MD USA. EM maraiar@mail.nih.gov OI Arimbasseri, Gopalakrishnan Aneeshkumar/0000-0001-5266-2688 FU Intramural NIH HHS [Z01 HD000412-21, ZIA HD000412-28] NR 107 TC 2 Z9 2 U1 5 U2 9 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 JUN PY 2016 VL 41 IS 6 BP 546 EP 559 DI 10.1016/j.tibs.2016.03.003 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DN1DL UT WOS:000376806400008 PM 27068803 ER PT J AU Luking, KR Pagliaccio, D Luby, JL Barch, DM AF Luking, Katherine R. Pagliaccio, David Luby, Joan L. Barch, Deanna M. TI Reward Processing and Risk for Depression Across Development SO TRENDS IN COGNITIVE SCIENCES LA English DT Review ID VENTRAL STRIATUM REACTIVITY; BLUNTED NEURAL RESPONSE; MAJOR DEPRESSION; PUBERTAL STATUS; POSITIVE AFFECT; MOOD DISORDERS; RETEST RELIABILITY; TAKING BEHAVIOR; BOLD SIGNALS; LIFE STRESS AB Striatal response to reward has been of great interest in the typical development and psychopathology literatures. These parallel lines of inquiry demonstrate that although typically developing adolescents show robust striatal response to reward, adolescents with major depressive disorder (MDD) and those at high risk for MDD show a blunted response to reward. Understanding how these findings intersect is crucial for the development and application of early preventative interventions in at-risk children, ideally before the sharp increase in the rate of MDD onset that occurs in adolescence. Robust findings relating blunted striatal response to reward and MDD risk are reviewed and situated within a normative developmental context. We highlight the need for future studies investigating longitudinal development, specificity to MDD, and roles of potential moderators and mediators. C1 [Luking, Katherine R.] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. [Pagliaccio, David] NIMH, Emot & Dev Branch, Bethesda, MD 20892 USA. [Luby, Joan L.; Barch, Deanna M.] Washington Univ, Dept Psychiat, St Louis, MO 63130 USA. [Barch, Deanna M.] Washington Univ, Dept Psychol, St Louis, MO 63130 USA. [Barch, Deanna M.] Washington Univ, Dept Radiol, St Louis, MO 63130 USA. [Barch, Deanna M.] Washington Univ, Neurosci Program, St Louis, MO 63130 USA. RP Luking, KR (reprint author), SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. EM katherine.luking@gmail.com FU Intramural Research Program of the NIMH; NIMH [MH098454, MH090786, MH097767, MH002782] FX This research was supported in part by the Intramural Research Program of the NIMH (D.P.) as well by NIMH grants MH098454 (J.L.L. and D.M.B.), MH090786 (J.L.L. and D.M.B.), MH097767 (K.R.L.), and MH002782 (D.P.) NR 93 TC 3 Z9 3 U1 9 U2 11 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1364-6613 J9 TRENDS COGN SCI JI TRENDS COGN. SCI. PD JUN PY 2016 VL 20 IS 6 BP 456 EP 468 DI 10.1016/j.tics.2016.04.002 PG 13 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA DM9TD UT WOS:000376707700009 PM 27131776 ER PT J AU Bergstrom, JCR Olmsted-Hawala, EL Bergstrom, HC AF Bergstrom, Jennifer C. Romano Olmsted-Hawala, Erica L. Bergstrom, Hadley C. TI Older adults fail to see the periphery in a Web site task SO UNIVERSAL ACCESS IN THE INFORMATION SOCIETY LA English DT Article DE Internet; UFoV; Aging; Eye tracking; Principal component analysis ID FIELD-OF-VIEW; AGE-DIFFERENCES; VISUAL-SEARCH; COGNITIVE FUNCTION; ATTENTION; TARGETS AB Eye movement deficiencies are inherent with age and tend to increase in distracting visual fields, in the useful field of view (UFoV), and when information is located in the periphery. Despite well-known age-related differences in eye movement, there has been limited empirical study into how older adults look at Web sites. The study of eye movement during Web site interaction is advantageous to the study of UFoV theory because Web sites are typically complex, with important navigational elements located in the periphery. Using non-invasive eye tracking, eye movement patterns were investigated in young, middle, and older adults while they initially interacted with a typical Web site (i.e., standard top and left navigation). Older adults looked less frequently at peripheral parts of the screen compared to young adults, with the left and top navigation accounting for the greatest age-related differences. Age-related differences in eye movement emerged during the initial 10 s and were independent from Internet experience, suggesting differences in eye movement while interacting with Web sites are inherent with aging. Results show age-related differences in eye movement during a Web site task. These applied, experimental results directly support UFoV cognitive theory in a real-world setting. C1 [Bergstrom, Jennifer C. Romano] Fors Marsh Grp, 1010 N Glebe Rd,Suite 510, Arlington, VA 22203 USA. [Bergstrom, Jennifer C. Romano; Olmsted-Hawala, Erica L.] US Bur Census, Ctr Survey Measurement, Human Factors & Usabil Res Grp, 4600 Silver Hill Rd, Washington, DC 20233 USA. [Bergstrom, Hadley C.] NIAAA, Lab Behav & Genom Neurosci, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA. RP Bergstrom, JCR (reprint author), Fors Marsh Grp, 1010 N Glebe Rd,Suite 510, Arlington, VA 22203 USA. EM jbergstrom@forsmarshgroup.com NR 54 TC 3 Z9 3 U1 3 U2 6 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1615-5289 EI 1615-5297 J9 UNIVERSAL ACCESS INF JI Univers. Access Inf. Soc. PD JUN PY 2016 VL 15 IS 2 BP 261 EP 270 DI 10.1007/s10209-014-0382-z PG 10 WC Computer Science, Cybernetics; Ergonomics SC Computer Science; Engineering GA DM8OC UT WOS:000376622800008 ER PT J AU Kongnyuy, M Sidana, A George, AK Muthigi, A Iyer, A Fascelli, M Kadakia, M Frye, TP Ho, R Mertan, F Siddiqui, MM Su, D Merino, MJ Turkbey, B Choyke, PL Wood, BJ Pinto, PA AF Kongnyuy, Michael Sidana, Abhinav George, Arvin K. Muthigi, Akhil Iyer, Amogh Fascelli, Michele Kadakia, Meet Frye, Thomas P. Ho, Richard Mertan, Francesca Siddiqui, M. Minhaj Su, Daniel Merino, Maria J. Turkbey, Baris Choyke, Peter L. Wood, Bradford J. Pinto, Peter A. TI The significance of anterior prostate lesions on multiparametric magnetic resonance imaging in African-American men SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE Anterior prostate lesion; African-American; Multiparametric MRI ID FUSION-GUIDED BIOPSY; RADICAL PROSTATECTOMY; WHITE MEN; LOW-RISK; PATHOLOGICAL FEATURES; ACTIVE SURVEILLANCE; RACIAL-DIFFERENCES; CLINICAL-TRIALS; ONCOLOGY-GROUP; CANCER AB Introduction: African-American (AA) men tend to harbor high-risk prostate cancer (PCa) and exhibit worse outcomes when compared to other groups. It has been postulated that AA men may harbor more anterior prostate lesions (APLs) that are undersampled by the standard transrectal ultrasound guided-biopsy (SBx), potentially resulting in greater degree of Gleason score (GS) upgrading at radical prostatectomy. We aimed to evaluate the detection rate of anterior PCa significance of APLs in AA men on multiparametric magnetic resonance imaging (mpMRI) and compare it to a matched cohort of White/Other (W/O) men. Materials and methods: A review of 1,267 men who had an mpMRI with suspicious prostate lesions and who underwent magnetic resonance transrectal ultrasound fusion-guided biopsy (FBx) with concurrent SBx in the same biopsy session was performed. All AA men were matched to a control group of W/O using a 1:1 propensity score-matching algorithm with age, prostate-specific antigen, and prostate volume as matching variables. Logistic regression analysis was used to determine predictors of APLs in AA men. Results: Of the 195 AA men who underwent mpMRI, 93 (47.7%) men had a total of 109 APLs. Prior negative SBx was associated with the presence of APLs in AA men (Odds ratio = 1.81; 95% CI: 1.03-3.20; P = 0.04). On multivariate logistic regression analysis, smaller prostate (P = 0.001) and rising prostate-specific antigen (P = 0.007) were independent predictors of cancer-positive APLs in AA men. Comparative analysis of AA (93/195, 47.7%) vs. W/O (100/194, 52%) showed no difference in the rates of APLs (P = 0.44) or in cancer detection rate within those lesions or the distribution of GS within those cancers (P = 0.63) despite an overall higher cancer detection rate in AA men (AA: 124/195 [63.6%] vs. W/O: 97/194 [50.0%], P = 0.007). In cases where APLs were positive for PCa on FBx, the GS of APL was equal to the highest GS of the entire gland in 82.9% (29/35) and 90.9% (30/33) of the time in AA and W/O men, respectively. Conclusion: Cancer-positive APLs represented the highest risk GS in most cases. AA men with prior negative SBx are twice as likely to harbor a concerning APL. In our cohort, AA and W/O men had comparable rates of APLs on mpMRI. Thus, differences in APLs do not explain the higher risk of AA men for deahth due to PCa. However, targeting of APLs via FBx can clinically improve PCa risk stratification and guide appropriate treatment options. (c) 2016 Published by Elsevier Inc. C1 [Kongnyuy, Michael; Sidana, Abhinav; George, Arvin K.; Muthigi, Akhil; Iyer, Amogh; Fascelli, Michele; Kadakia, Meet; Frye, Thomas P.; Ho, Richard; Su, Daniel; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Mertan, Francesca; Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Siddiqui, M. Minhaj] Univ Maryland, Sch Med, Dept Urol, Baltimore, MD 21201 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Wood, Bradford J.] NCI, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Wood, Bradford J.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. EM pintop@mail.nih.gov OI Ho, Richard/0000-0002-6792-3411 NR 50 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD JUN PY 2016 VL 34 IS 6 DI 10.1016/j.urolonc.2015.12.018 PG 7 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA DM7EV UT WOS:000376520300004 ER PT J AU Kang, JH Mollenhauer, B Coffey, CS Toledo, JB Weintraub, D Galasko, DR Irwin, DJ Van Deerlin, V Chen-Plotkin, AS Caspell-Garcia, C Waligorska, T Taylor, P Shah, N Pan, S Zero, P Frasier, M Marek, K Kieburtz, K Jennings, D Tanner, CM Simuni, T Singleton, A Toga, AW Chowdhury, S Trojanowski, JQ Shaw, LM AF Kang, Ju-Hee Mollenhauer, Brit Coffey, Christopher S. Toledo, Jon B. Weintraub, Daniel Galasko, Douglas R. Irwin, David J. Van Deerlin, Vivianna Chen-Plotkin, Alice S. Caspell-Garcia, Chelsea Waligorska, Teresa Taylor, Peggy Shah, Nirali Pan, Sarah Zero, Pawel Frasier, Mark Marek, Kenneth Kieburtz, Karl Jennings, Danna Tanner, Caroline M. Simuni, Tanya Singleton, Andrew Toga, Arthur W. Chowdhury, Sohini Trojanowski, John Q. Shaw, Leslie M. TI CSF biomarkers associated with disease heterogeneity in early Parkinson's disease: the Parkinson's Progression Markers Initiative study SO ACTA NEUROPATHOLOGICA LA English DT Article DE Parkinson's disease; Cerebrospinal fluid biomarker; Parkinson's Progression Markers Initiative; A beta(1-42); Tau; Alpha-synuclein ID HEALTH-EXPLORATORY-TRIALS; NET-PD EXPERIENCE; ALPHA-SYNUCLEIN; AMYLOID-BETA; COGNITIVE PERFORMANCE; INCIDENT DEMENTIA; TAU; RISK; SUBTYPES; COHORT AB The development of biomarkers to predict the progression of Parkinson's disease (PD) from its earliest stage through its heterogeneous course is critical for research and therapeutic development. The Parkinson's Progression Markers Initiative (PPMI) study is an ongoing international multicenter, prospective study to validate biomarkers in drug-na < ve PD patients and matched healthy controls (HC). We quantified cerebrospinal fluid (CSF) alpha-synuclein (alpha-syn), amyloid-beta1-42 (A beta(1-42)), total tau (t-tau), and tau phosphorylated at Thr181 (p-tau) in 660 PPMI subjects at baseline, and correlated these data with measures of the clinical features of these subjects. We found that CSF alpha-syn, t-tau and p-tau levels, but not A beta(1-42), were significantly lower in PD compared with HC, while the diagnostic value of the individual CSF biomarkers for PD diagnosis was limited due to large overlap. The level of alpha-syn, but not other biomarkers, was significantly lower in PD patients with non-tremor-dominant phenotype compared with tremor-dominant phenotype. In addition, in PD patients the lowest A beta(1-42), or highest t-tau/A beta(1-42) and t-tau/alpha-syn quintile in PD patients were associated with more severe non-motor dysfunction compared with the highest or lowest quintiles, respectively. In a multivariate regression model, lower alpha-syn was significantly associated with worse cognitive test performance. APOE epsilon 4 genotype was associated with lower levels of A beta(1-42), but neither with PD diagnosis nor cognition. Our data suggest that the measurement of CSF biomarkers in early-stage PD patients may relate to disease heterogeneity seen in PD. Longitudinal observations in PPMI subjects are needed to define their prognostic performance. C1 [Kang, Ju-Hee; Toledo, Jon B.; Irwin, David J.; Van Deerlin, Vivianna; Waligorska, Teresa; Shah, Nirali; Pan, Sarah; Zero, Pawel; Trojanowski, John Q.; Shaw, Leslie M.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, 7-103 Founders Pavil 3400 Spruce St, Philadelphia, PA 19104 USA. [Kang, Ju-Hee] Inha Univ, Hypoxiarelated Dis Res Ctr, Sch Med, Dept Pharmacol, Inchon, South Korea. [Mollenhauer, Brit] Paracelsus Elena Klin, Kassel, Germany. [Mollenhauer, Brit] Univ Med Ctr Goettingen, Dept Neuropathol & Neurosurg, Gottingen, Germany. [Coffey, Christopher S.; Caspell-Garcia, Chelsea] Univ Iowa, Coll Publ Hlth, Dept Biostat, Iowa City, IA USA. [Toledo, Jon B.; Irwin, David J.; Van Deerlin, Vivianna; Chen-Plotkin, Alice S.; Trojanowski, John Q.; Shaw, Leslie M.] Univ Penn, Ctr Neurodegenerat Dis Res, Perelman Sch Med, Inst Aging, Philadelphia, PA 19104 USA. [Weintraub, Daniel; Irwin, David J.; Chen-Plotkin, Alice S.; Trojanowski, John Q.] Univ Penn, Morris K Udall Ctr Excellence Parkinsons Dis Res, Perelman Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Dept Vet Affairs, Philadelphia, PA USA. [Galasko, Douglas R.] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Taylor, Peggy] BioLegend Inc, Dedham, MA USA. [Frasier, Mark; Chowdhury, Sohini] Michael J Fox Fdn Parkinsons Res, New York, NY USA. [Marek, Kenneth; Jennings, Danna] Inst Neurodegenerat Disorders, New Haven, CT USA. [Kieburtz, Karl] Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY USA. [Tanner, Caroline M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Tanner, Caroline M.] San Francisco VA Med Ctr, San Francisco, CA USA. [Simuni, Tanya] Northwestern Univ, Feinberg Sch Med, Dept Neurol, Chicago, IL 60611 USA. [Singleton, Andrew] NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Toga, Arthur W.] Univ So Calif, Keck Sch Med, Inst Neuroimaging & Informat, Lab Neuro Imaging, Los Angeles, CA 90033 USA. RP Shaw, LM (reprint author), Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, 7-103 Founders Pavil 3400 Spruce St, Philadelphia, PA 19104 USA.; Shaw, LM (reprint author), Univ Penn, Ctr Neurodegenerat Dis Res, Perelman Sch Med, Inst Aging, Philadelphia, PA 19104 USA. EM Les.Shaw@uphs.upenn.edu RI Singleton, Andrew/C-3010-2009; OI Toledo, Jon/0000-0003-4366-9268 FU Michael J. Fox Foundation for Parkinson's Research; Abbott; Avid Radiopharmaceuticals; BiogenIdec; Covance; Elan; Eli Lilly and Co; F. Hoffman-LaRoche Ltd; GE Healthcare; Genentech; Glaxo Smith Kline; Merck and Co; Pfizer Inc; UCB Pharma SA; Morris K. Udall Center of Excellence for Parkinson's Disease Research [P50NS053488-05]; Training in Age-Related Neurodegenerative Diseases from the National Institute on Aging, National Institutes of Health [T32-AG000255]; Intramural Research Program, National Institute on Aging, National Institutes of Health [Z01AG000949-06]; MRC FX This work was supported by The Michael J. Fox Foundation for Parkinson's Research, Abbott, Avid Radiopharmaceuticals, BiogenIdec, Covance, Elan, Eli Lilly and Co, F. Hoffman-LaRoche Ltd, GE Healthcare, Genentech, Glaxo Smith Kline, Merck and Co, Pfizer Inc, and UCB Pharma SA. Trojanowski and Chen-Plotkin were supported by core grant P50NS053488-05 from the Morris K. Udall Center of Excellence for Parkinson's Disease Research. Irwin was supported by Training in Age-Related Neurodegenerative Diseases grant T32-AG000255 from the National Institute on Aging, National Institutes of Health. Singleton was supported by Grant Z01AG000949-06 from the Intramural Research Program, National Institute on Aging, National Institutes of Health. Ju-Hee was supported by Grant MRC NR 43 TC 15 Z9 15 U1 4 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 EI 1432-0533 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD JUN PY 2016 VL 131 IS 6 BP 935 EP 949 DI 10.1007/s00401-016-1552-2 PG 15 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA DM3WM UT WOS:000376277400011 PM 27021906 ER PT J AU Hingson, R Zha, W White, A AF Hingson, R. Zha, W. White, A. TI THE USEFULNESS OF 'AGE AT FIRST DRINK' AS A CONCEPT IN ALCOHOL RESEARCH AND PREVENTION SO ADDICTION LA English DT Editorial Material DE Dependence; drinking initiation; related harms ID NATIONALLY REPRESENTATIVE SAMPLE; POLYSUBSTANCE USE; ADULT ALCOHOL; UNITED-STATES; USE DISORDERS; ONSET; DEPENDENCE; PATTERNS; ABUSE AB Kuntsche et al. raise concerns about age of first drinking research. Although numerous studies have linked age of first drinking with alcohol dependence and other problems, first drinking age measurement warrants improvement. None the less, given the rapid transition from first drink to drunkenness episodes, delaying drinking onset remains a reasonable prevention goal. C1 [Hingson, R.; Zha, W.] NIAAA, Div Epidemiol & Prevent Res, Bethesda, MD USA. [White, A.] NIAAA, Off Director, Bethesda, MD USA. RP Hingson, R (reprint author), NIAAA, Div Epidemiol & Prevent Res, Bethesda, MD USA. EM rhingson@mail.nih.gov NR 19 TC 3 Z9 3 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD JUN PY 2016 VL 111 IS 6 BP 968 EP 970 DI 10.1111/add.13218 PG 4 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DL9CJ UT WOS:000375938700005 PM 26899549 ER PT J AU Calvo-Rubio, M Buron, MI Lopez-Lluch, G Navas, P de Cabo, R Ramsey, JJ Villalba, JM Gonzalez-Reyes, JA AF Calvo-Rubio, Miguel Isabel Buron, Ma Lopez-Lluch, Guillermo Navas, Placido de Cabo, Rafael Ramsey, Jon J. Villalba, Jose M. Gonzalez-Reyes, Jose A. TI Dietary fat composition influences glomerular and proximal convoluted tubule cell structure and autophagic processes in kidneys from calorie-restricted mice SO AGING CELL LA English DT Article DE aging; calorie restriction; dietary fat; kidney; mice ID LIFE-SPAN; SKELETAL-MUSCLE; LIPID COMPOSITION; RHESUS-MONKEYS; AGING RAT; MITOCHONDRIAL; SENESCENCE; LIVER; ADAPTATION; ACCUMULATION AB Calorie restriction (CR) has been repeatedly shown to prevent cancer, diabetes, hypertension, and other age-related diseases in a wide range of animals, including non-human primates and humans. In rodents, CR also increases lifespan and is a powerful tool for studying the aging process. Recently, it has been reported in mice that dietary fat plays an important role in determining lifespan extension with 40% CR. In these conditions, animals fed lard as dietary fat showed an increased longevity compared with mice fed soybean or fish oils. In this paper, we study the effect of these dietary fats on structural and physiological parameters of kidney from mice maintained on 40% CR for 6 and 18months. Analyses were performed using quantitative electron microcopy techniques and protein expression in Western blots. CR mitigated most of the analyzed age-related parameters in kidney, such as glomerular basement membrane thickness, mitochondrial mass in convoluted proximal tubules and autophagic markers in renal homogenates. The lard group showed improved preservation of several renal structures with aging when compared to the other CR diet groups. These results indicate that dietary fat modulates renal structure and function in CR mice and plays an essential role in the determination of health span in rodents. C1 [Calvo-Rubio, Miguel; Isabel Buron, Ma; Villalba, Jose M.; Gonzalez-Reyes, Jose A.] Univ Cordoba, Dept Biol Celular Fisiol & Inmunol, CeiA3, Campus Excelencia Int Agroalimentario, Cordoba 14014, Spain. [Lopez-Lluch, Guillermo; Navas, Placido] Univ Pablo de Olavide, CSIC, Ctr Andaluz Biol Desarrollo, CIBERER,Inst Salud Carlos III, Seville, Spain. [de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Ramsey, Jon J.] Univ Calif Davis, VM Mol Biosci, Davis, CA 95616 USA. RP Gonzalez-Reyes, JA (reprint author), Univ Cordoba, Dept Biol Celular Fisiol & Inmunol, CeiA3, Campus Excelencia Int Agroalimentario, Cordoba 14014, Spain. EM bc1gorej@uco.es RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; Gonzalez-Reyes, Jose A./0000-0003-1918-5490; , rafael/0000-0003-2830-5693 FU NIH [1R01AG028125]; Ministerio de Economia y Competitividad [BFU2011-23578, DEP2012-39985]; Junta de Andalucia Proyectos de Excelencia [P09-CVI-4887]; Junta de Andalucia Proyectos Internacionales; Fondo de Investigaciones Sanitarias [FIS PI14-01962]; Intramural Research Program of the National Institute on Aging of the National Institutes of Health; Spanish Ministerio de Educacion [BIO-276]; Junta de Andalucia [BIO-276]; University of Cordoba [BIO-276] FX Supported by NIH grant 1R01AG028125 (to JJR, PN, and JMV), Ministerio de Economia y Competitividad BFU2011-23578 (to JMV) and DEP2012-39985 (to GL-L), Junta de Andalucia Proyectos de Excelencia grant P09-CVI-4887 (to JMV), Junta de Andalucia Proyectos Internacionales (to JMV), BIO-276 (Junta de Andalucia and the University of Cordoba, to JMV) and Fondo de Investigaciones Sanitarias FIS PI14-01962 (to PN). RdC is supported by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health. MC-R is funded by predoctoral fellowship of the Spanish Ministerio de Educacion and by BIO-276. NR 45 TC 0 Z9 0 U1 3 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD JUN PY 2016 VL 15 IS 3 BP 477 EP 487 DI 10.1111/acel.12451 PG 11 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA DL8AA UT WOS:000375860500010 PM 26853994 ER PT J AU Hooten, NN Martin-Montalvo, A Dluzen, DF Zhang, YQ Bernier, M Zonderman, AB Becker, KG Gorospe, M de Cabo, R Evans, MK AF Noren Hooten, Nicole Martin-Montalvo, Alejandro Dluzen, Douglas F. Zhang, Yongqing Bernier, Michel Zonderman, Alan B. Becker, Kevin G. Gorospe, Myriam de Cabo, Rafael Evans, Michele K. TI Metformin-mediated increase in DICER1 regulates microRNA expression and cellular senescence SO AGING CELL LA English DT Article DE aging; AUF1; caloric restriction; diabetes mellitus; microRNA; RNA-binding proteins ID MESSENGER-RNA DECAY; LIFE-SPAN; CANCER-CELLS; FACTOR AUF1; C. ELEGANS; MECHANISMS; PATHWAY; STRESS; AMPK; PHOSPHORYLATION AB Metformin, an oral hypoglycemic agent, has been used for decades to treat type 2 diabetes mellitus. Recent studies indicate that mice treated with metformin live longer and have fewer manifestations of age-related chronic disease. However, the molecular mechanisms underlying this phenotype are unknown. Here, we show that metformin treatment increases the levels of the microRNA-processing protein DICER1 in mice and in humans with diabetes mellitus. Our results indicate that metformin upregulates DICER1 through a post-transcriptional mechanism involving the RNA-binding protein AUF1. Treatment with metformin altered the subcellular localization of AUF1, disrupting its interaction with DICER1 mRNA and rendering DICER1 mRNA stable, allowing DICER1 to accumulate. Consistent with the role of DICER1 in the biogenesis of microRNAs, we found differential patterns of microRNA expression in mice treated with metformin or caloric restriction, two proven life-extending interventions. Interestingly, several microRNAs previously associated with senescence and aging, including miR-20a, miR-34a, miR-130a, miR-106b, miR-125, and let-7c, were found elevated. In agreement with these findings, treatment with metformin decreased cellular senescence in several senescence models in a DICER1-dependent manner. Metformin lowered p16 and p21 protein levels and the abundance of inflammatory cytokines and oncogenes that are hallmarks of the senescence-associated secretory phenotype (SASP). These data lead us to hypothesize that changes in DICER1 levels may be important for organismal aging and to propose that interventions that upregulate DICER1 expression (e.g., metformin) may offer new pharmacotherapeutic approaches for age-related disease. C1 [Noren Hooten, Nicole; Dluzen, Douglas F.; Zonderman, Alan B.; Evans, Michele K.] CABIMER Andalusian Ctr Mol Biol & Regenerat Med, Dept Stem Cells, Lab Epidemiol & Populat Sci, Ave Amer Vespucio, Seville 41092, Spain. [Martin-Montalvo, Alejandro; Bernier, Michel; de Cabo, Rafael] CABIMER Andalusian Ctr Mol Biol & Regenerat Med, Dept Stem Cells, Translat Gerontol Branch, Ave Amer Vespucio, Seville 41092, Spain. [Martin-Montalvo, Alejandro] CABIMER Andalusian Ctr Mol Biol & Regenerat Med, Dept Stem Cells, Pancreat Islet Dev & Regenerat Unit, Ave Amer Vespucio, Seville 41092, Spain. [Zhang, Yongqing; Becker, Kevin G.; Gorospe, Myriam] NIA, Genet Lab, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Evans, MK (reprint author), NIA, NIH, Baltimore, MD 21224 USA. EM me42v@nih.gov RI de Cabo, Rafael/J-5230-2016; Martin-Montalvo, Alejandro/C-2031-2017; OI de Cabo, Rafael/0000-0002-3354-2442; Martin-Montalvo, Alejandro/0000-0002-3886-5355; Dluzen, Douglas/0000-0002-9426-5071; , rafael/0000-0003-2830-5693; Zonderman, Alan B/0000-0002-6523-4778 FU Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. The authors wish to thank Kotb Abdelmohsen for valuable discussions and critical reading of the manuscript, the HANDLS staff for care of participants and sample acquisition, and William H. Wood III, Yoonseo Kim, and Althaf Lohani for technical assistance. NR 45 TC 7 Z9 7 U1 3 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD JUN PY 2016 VL 15 IS 3 BP 572 EP 581 DI 10.1111/acel.12469 PG 10 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA DL8AA UT WOS:000375860500019 ER PT J AU El-Bassel, N Jemmott, JB Bellamy, SL Pequegnat, W Wingood, GM Wyatt, GE Landis, JR Remien, RH AF El-Bassel, Nabila Jemmott, John B., III Bellamy, Scarlett L. Pequegnat, Willo Wingood, Gina M. Wyatt, Gail E. Landis, J. Richard Remien, Robert H. CA NIMH Multisite HIV STD Prevention TI Mediation Analysis of the Efficacy of the Eban HIV/STD Risk-Reduction Intervention for African American HIV Serodiscordant Couples SO AIDS AND BEHAVIOR LA English DT Article DE HIV serodiscordant couples; Intervention; Social Cognitive Theory; Mediation analysis; Condom use ID RANDOMIZED-CONTROLLED-TRIAL; CONDOM-USE; SEXUAL RISK; SELF-EFFICACY; PREVENTION INTERVENTION; BEHAVIOR-CHANGE; HETEROSEXUAL COUPLES; NATIONAL-INSTITUTE; ADOLESCENT GIRLS; HEALTH AB Targeting couples is a promising behavioral HIV risk-reduction strategy, but the mechanisms underlying the effects of such interventions are unknown. We report secondary analyses testing whether Social-Cognitive-Theory variables mediated the Eban HIV-risk-reduction intervention's effects on condom-use outcomes. In a multisite randomized controlled trial conducted in four US cities, 535 African American HIV-serodiscordant couples were randomized to the Eban HIV risk-reduction intervention or attention-matched control intervention. Outcomes were proportion condom-protected sex, consistent condom use, and frequency of unprotected sex measured pre-, immediately post-, and 6 and 12 months post-intervention. Potential mediators included Social-Cognitive-Theory variables: outcome expectancies and self-efficacy. Mediation analyses using the product-of-coefficients approach in a generalized-estimating-equations framework revealed that condom-use outcome expectancy, partner-reaction outcome expectancy, intention, self-efficacy, and safer-sex communication improved post-intervention and mediated intervention-induced improvements in condom-use outcomes. These findings underscore the importance of targeting outcome expectancies, self-efficacy, and safer-sex communication in couples-level HIV risk-reduction interventions. C1 [El-Bassel, Nabila] Columbia Univ, Sch Social Work, Social Intervent Grp, New York, NY USA. [Jemmott, John B., III] Univ Penn, Annenberg Sch Commun, 3535 Market St,Suite 520, Philadelphia, PA 19104 USA. [Jemmott, John B., III] Univ Penn, Perelman Sch Med, Ctr Hlth Behav & Commun Res, Dept Psychiat, 3535 Market St,Suite 520, Philadelphia, PA 19104 USA. [Bellamy, Scarlett L.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, 3535 Market St,Suite 520, Philadelphia, PA 19104 USA. [Pequegnat, Willo] NIMH, NIH, Bethesda, MD 20892 USA. [Wingood, Gina M.] Emory Univ, Rollins Sch Publ Hlth, Dept Behav Sci & Hlth Educ, Atlanta, GA 30322 USA. [Wyatt, Gail E.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA USA. [Landis, J. Richard] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, 3535 Market St,Suite 520, Philadelphia, PA 19104 USA. [Remien, Robert H.] Columbia Univ, Ctr Clin & Behav Studies, Dept Psychiat, New York, NY USA. RP Jemmott, JB (reprint author), Univ Penn, Annenberg Sch Commun, 3535 Market St,Suite 520, Philadelphia, PA 19104 USA.; Jemmott, JB (reprint author), Univ Penn, Perelman Sch Med, Ctr Hlth Behav & Commun Res, Dept Psychiat, 3535 Market St,Suite 520, Philadelphia, PA 19104 USA. EM jjemmott@asc.upenn.edu FU National Institute of Mental Health (NIMH) of the US National Institutes of Health [U10 MH064395, U10 MH064394, U10 MH078819, U10 MH064393, U10 MH064404]; NIMH [P30-MH45320] FX This trial was funded by the National Institute of Mental Health (NIMH) of the US National Institutes of Health through research grants to Dr. El-Bassel (U10 MH064395), Dr. Jemmott (U10 MH064394), Dr. Landis (U10 MH078819), Dr. Wingood (U10 MH064393), and Dr. Wyatt (U10 MH064404). Dr. Remien was supported by a grant from NIMH to the HIV Center for Clinical and Behavioral Studies (P30-MH45320). Dr. Pequegnat was the federal principal investigator (the NIMH staff collaborator). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the National Institutes of Health. NR 63 TC 0 Z9 0 U1 4 U2 4 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 JUN PY 2016 VL 20 IS 6 BP 1197 EP 1207 DI 10.1007/s10461-015-1249-x PG 11 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DM4FB UT WOS:000376300700005 PM 26577402 ER PT J AU Isler, MR Golin, C Wang, J Hughes, J Justman, J Haley, D Kuo, I Adimora, A Chege, W Hodder, S AF Isler, M. Roman Golin, C. Wang, J. Hughes, J. Justman, J. Haley, D. Kuo, I. Adimora, A. Chege, W. Hodder, S. CA HIV Prevention Trials Network HPTN TI Venues for Meeting Sex Partners and Partner HIV Risk Characteristics: HIV Prevention Trials Network (HPTN064) Women's HIV Seroincidence Study (ISIS) SO AIDS AND BEHAVIOR LA English DT Article DE HIV; Women; Venue; Sexual risk behavior; Sexual partners ID YOUNG MEN; BEHAVIOR; FEMALE; PREVALENCE; INTERNET; WORKERS; CHINA; INFECTION; MSM; TRANSMISSION AB Identifying venues where women meet sexual partners, particular partners who increase women's risk of acquiring HIV, could inform prevention efforts. We categorized venues where women enrolled in HPTN 064 reported meeting their last three sex partners as: (1) Formal, (2) Public, (3) Private, and (4) Virtual spaces. We used multinomial logistic regression to assess the association between these venues and women's individual characteristics and reports of their partners' HIV risk characteristics. The 2099 women reported meeting 3991 partners, 51 % at Public, 30 % Private, 17 % Formal and 3 % at Virtual venues. Women meeting partners at Formal venues reported more education and condom use than women meeting partners at other venues. Fewer partners met through Formal venues had "high" risk characteristics for HIV than through other venues and hence may pose less risk of HIV transmission. HIV prevention interventions can help women choose partners with fewer risk characteristics across all venue types. C1 [Isler, M. Roman] Univ N Carolina, Sch Med, Dept Social Med, CB 7240, Chapel Hill, NC 27599 USA. [Golin, C.] Univ N Carolina, Dept Hlth Behav, Chapel Hill, NC USA. [Wang, J.] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent SCHARP, 1124 Columbia St, Seattle, WA 98104 USA. [Hughes, J.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Justman, J.] Columbia Univ, Dept Epidemiol & Med, New York, NY USA. [Haley, D.] FHI360, Durham, NC USA. [Haley, D.] Emory Univ, Rollins Sch Publ Hlth, Dept Behav Sci & Hlth Educ, Atlanta, GA USA. [Kuo, I.] George Washington Univ, Milken Inst, Sch Publ Hlth, Dept Epidemiol & Biostat, Washington, DC USA. [Adimora, A.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Chege, W.] NIAID, Prevent Sci Program, DAIDS, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hodder, S.] Rutgers State Univ, New Jersey Med Sch, Newark, NJ 07102 USA. RP Isler, MR (reprint author), Univ N Carolina, Sch Med, Dept Social Med, CB 7240, Chapel Hill, NC 27599 USA. EM mromanisler@med.unc.edu FU National Institute of Allergy and Infectious Diseases; National Institute on Drug Abuse; National Institute of Mental Health [UM1 AI068619, UM1 AI068617, UM1-AI068613]; Centers for Innovative Research to Control AIDS, Mailman School of Public Health, Columbia University [5U1Al069466]; University of North Carolina Clinical Trials Unit [AI069423]; University of North Carolina Clinical Trials Research Center of the Clinical and Translational Science Award [RR 025747]; University of North Carolina Center for AIDS Research [AI050410]; Emory University HIV/AIDS Clinical Trials Unit [5UO1AI069418]; Center for AIDS Research [P30 AI050409]; Clinical and Translational Science Award [UL1 RR025008]; Terry Beirn Community Programs for Clinical Research on AIDS Clinical Trials Unit [5 UM1 AI069503-07]; Johns Hopkins Adult AIDS Clinical Trial Unit [AI069465]; Johns Hopkins Clinical and Translational Science Award [UL1 RR 25005]; HPTN Scholars Program - National Institute of Allergy and Infectious Disease; National Institute of Mental Health; National Institute of Mental Health of the National Institutes of Health [F31MH105238]; George W. Woodruff Fellowship of the Laney Graduate School, Emory University FX The authors thank the study participants, community stakeholders, and staff from each study site. In particular, they acknowledge Lynda Emel, Jonathan Lucas, Nirupama Sista, Kathy Hinson, Elizabeth DiNenno, Ann O'Leary, Lisa Diane White, Waheedah Shabaaz-El, Quarraisha Abdool-Karim, Sten Vermund, LeTanya Johnson-Lewis, Manya Magnus, Christopher Chauncey Watson, Ann Dey, Aaron Frasier, Makisha Ruffin, Genda Dockery, Lorenna Rodriguez, Noranik Zadeyan, Cheryl Guity, Stephanie Lykes, Ilene Wiggins, Tracey Chambers Thomas, Paula Frew, and Carlos del Rio. Support for this study was provided by the National Institute of Allergy and Infectious Diseases, National Institute on Drug Abuse, and National Institute of Mental Health (cooperative agreement Nos. UM1 AI068619, UM1 AI068617, and UM1-AI068613); Centers for Innovative Research to Control AIDS, Mailman School of Public Health, Columbia University (5U1Al069466); University of North Carolina Clinical Trials Unit (AI069423); University of North Carolina Clinical Trials Research Center of the Clinical and Translational Science Award (RR 025747); University of North Carolina Center for AIDS Research (AI050410); Emory University HIV/AIDS Clinical Trials Unit (5UO1AI069418), Center for AIDS Research (P30 AI050409), and Clinical and Translational Science Award (UL1 RR025008); The Terry Beirn Community Programs for Clinical Research on AIDS Clinical Trials Unit (5 UM1 AI069503-07) and; The Johns Hopkins Adult AIDS Clinical Trial Unit (AI069465) and The Johns Hopkins Clinical and Translational Science Award (UL1 RR 25005). The primary author's work on this manuscript was supported through the HPTN Scholars Program funded by the National Institute of Allergy and Infectious Disease and the National Institute of Mental Health. Ms. Haley's time was supported by the National Institute of Mental Health of the National Institutes of Health under Award Number F31MH105238, the George W. Woodruff Fellowship of the Laney Graduate School, Emory University Ms. Haley's time was supported by the National Institute of Mental Health of the National Institutes of Health under Award Number F31MH105238, the George W. Woodruff Fellowship of the Laney Graduate School, Emory University. NR 42 TC 0 Z9 0 U1 2 U2 4 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 JUN PY 2016 VL 20 IS 6 BP 1208 EP 1218 DI 10.1007/s10461-015-1057-3 PG 11 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DM4FB UT WOS:000376300700006 ER PT J AU Khoury, P Desmond, R Pabon, A Holland-Thomas, N Ware, JM Arthur, DC Kurlan-der, R Fay, MP Maric, I Klion, AD AF Khoury, P. Desmond, R. Pabon, A. Holland-Thomas, N. Ware, J. M. Arthur, D. C. Kurlan-der, R. Fay, M. P. Maric, I. Klion, A. D. TI Clinical features predict responsiveness to imatinib in platelet-derived growth factor receptor-alpha-negative hypereosinophilic syndrome SO ALLERGY LA English DT Article DE eosinophilia; hypereosinophilic syndrome; imatinib; myeloid neoplasm; PDGFRA-negative ID CHRONIC EOSINOPHILIC LEUKEMIA; MYELOPROLIFERATIVE VARIANT; MOLECULAR REMISSION; MESYLATE; FUSION; EFFICACY; DISCONTINUATION; FIP1L1-PDGFRA; CESSATION; PDGFRA AB Background: With the exception of the presence of the FIP1L1-PDGFRA fusion gene, little is known about predictors of imatinib response in clinically-defined hypereosinophilic syndrome (HES). Methods: Subjects with FIP1L1-PDGFRA-myeloid neoplasm (FP; n = 12), PDGFRA-negative HES with >= 4 criteria suggestive of a myeloid neoplasm (MHES; n = 10), or steroid-refractory PDGFRA-negative HES with < 4 myeloid criteria (SR; n = 5) were enrolled in a prospective study of imatinib therapy (NCT00044304: registered at clinicaltrials.gov). The primary outcome was an eosinophil count < 1.5 x 109/L at one month and improvement of clinical symptoms. Clinical, molecular, and bone marrow responses to imatinib were assessed. A retrospective cohort of 18 subjects with clinically-defined HES who received imatinib (300-400 mg daily >= 1 month) were classified according to the criteria used in the prospective study. Results: Overall, imatinib response rates were 100% in the FP group (n = 16), 54% in the MHES group (n = 13) and 0% in the SR group (n = 16). The presence of >= 4 myeloid features was the sole predictor of response. After >= 18 months in complete remission, imatinib was tapered and discontinued in 8 FP and 1 MHES subjects. Seven subjects (6 FP, 1 MHES) remain in remission off therapy for a median of 29 months (range 14-36). Conclusions: Clinical features of MHES predict imatinib response in PDGFRA-negative HES. C1 [Khoury, P.; Pabon, A.; Ware, J. M.; Klion, A. D.] NIAID, Parasit Dis Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Desmond, R.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Desmond, R.] Tallaght Hosp, Dept Hematol, Dublin, Ireland. [Holland-Thomas, N.] Leidos Biomed Res Inc, Clin Res Directorate, Clin Monitoring Res Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Arthur, D. C.] NCI, Pathol Lab, Bldg 10, Bethesda, MD 20892 USA. [Kurlan-der, R.; Maric, I.] NIAID, Dept Lab Med, Ctr Clin, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Fay, M. P.] NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Khoury, P (reprint author), NIAID, Parasit Dis Lab, NIH, 10 Ctr Dr,Rm 9N224B, Bethesda, MD 20892 USA. EM khouryp@niaid.nih.gov FU Division of Intramural Research, NIAID, National Institutes of Health; Division of Intramural Research, NHLBI, National Institutes of Health; Division of Intramural Research, NCI, National Institutes of Health; National Cancer Institute, National Institute of Health [HHSN2612 00800001E]; National Institute of Allergy and Infectious Diseases FX This research was supported by the Division of Intramural Research, NIAID, National Institutes of Health, Division of Intramural Research, NHLBI, National Institutes of Health; Division of Intramural Research, NCI, National Institutes of Health. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institute of Health, under contract No. HHSN2612 00800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported in part by the National Institute of Allergy and Infectious Diseases. Clinicaltrials.gov identifiers: NCT00001406 and NCT00044304. NR 25 TC 4 Z9 5 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-4538 EI 1398-9995 J9 ALLERGY JI Allergy PD JUN PY 2016 VL 71 IS 6 BP 803 EP 810 DI 10.1111/all.12843 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA DM2AM UT WOS:000376148100006 PM 26797802 ER PT J AU Siebenhaar, F von Tschirnhaus, E Hartmann, K Rabenhorst, A Staubach, P Peveling-Oberhag, A Wagner, N Martus, P Carter, MC Metcalfe, DD Church, MK Maurer, M Weller, K AF Siebenhaar, F. von Tschirnhaus, E. Hartmann, K. Rabenhorst, A. Staubach, P. Peveling-Oberhag, A. Wagner, N. Martus, P. Carter, M. C. Metcalfe, D. D. Church, M. K. Maurer, M. Weller, K. TI Development and validation of the mastocytosis quality of life questionnaire: MC-QoL SO ALLERGY LA English DT Article DE health; instrument; mastocytosis; quality-of-life; questionnaire ID MAST-CELL DISORDERS; PATIENT-REPORTED OUTCOMES; SYSTEMIC MASTOCYTOSIS; CONSENSUS PROPOSAL; RISK-FACTORS; ANAPHYLAXIS; CLASSIFICATION; ACTIVATION; VALIDITY; CRITERIA AB Background: Mastocytosis is a heterogeneous disease characterized by a clonal expansion of mast cells in various organs. The vast majority of patients affected suffer from signs and symptoms caused by mediator release from mast cells. Although the disease burden is high, there is currently no specific instrument to measure health-related quality of life (HRQoL) impairment in patients with mastocytosis. Objective: The aim of this study was to develop and validate a disease-specific tool to assess HRQoL impairment in patients with cutaneous and indolent systemic mastocytosis, the Mastocytosis Quality of Life Questionnaire (MC-QoL). Methods: Sixty-two potential MC-QoL items were developed in a combined approach consisting of semi-structured patient interviews, expert input and literature research. Item selection was performed by impact analysis with 76 patients and a final review for face validity. The resulting MC-QoL was tested for validity, reliability and influence factors. In parallel, an US American-English version of the MC-QoL was developed. Results: A total of 158 patients (41 CM, 41 MIS and 76 ISM) took part in the MC-QoL validation study. The final 27-item questionnaire was found to have a four-domain structure ('symptoms', 'emotions', 'social life/functioning' and 'skin'), a valid total score and an excellent test-retest reliability. Multiple regression analysis revealed disease duration, but not age, gender or skin involvement to be a significant determinant of HRQoL impairment in mastocytosis. Conclusions: The MC-QoL is the first disease-specific HRQoL questionnaire for adult patients with cutaneous and indolent systemic mastocytosis. This short, validated and reliable instrument will serve as a valuable tool in future clinical studies and in routine patient care. C1 [Siebenhaar, F.; von Tschirnhaus, E.; Church, M. K.; Maurer, M.; Weller, K.] Charite, Dept Dermatol & Allergy, Interdisciplinary Mastocytosis Ctr Charite, D-13353 Berlin, Germany. [Hartmann, K.] Univ Lubeck, Dept Dermatol, Lubeck, Germany. [Rabenhorst, A.] Univ Cologne, Dept Dermatol, D-50931 Cologne, Germany. [Staubach, P.; Peveling-Oberhag, A.] Univ Med Ctr Mainz, Dept Dermatol, Mainz, Germany. [Wagner, N.] Clin Ctr Darmstadt, Dept Dermatol, Darmstadt, Germany. [Martus, P.] Univ Klinikum Tubingen, Dept Med Biostat, Tubingen, Germany. [Carter, M. C.; Metcalfe, D. D.] NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Siebenhaar, F (reprint author), Charite, Dept Dermatol & Allergy, Allergie Ctr Charite, Charite Pl 1, D-10117 Berlin, Germany. EM frank.siebenhaar@charite.de RI Hartmann, Karin/N-4865-2015; Rabenhorst, Anja/J-3217-2016 OI Hartmann, Karin/0000-0002-4595-8226; FU European Centre for Allergy Research Foundation; urticaria network e. V.; COST Action [BM1007]; European Mast Cell and Basophil Research Network; Division of Intramural Research/NIAID/NIH FX We wish to thank the European Centre for Allergy Research Foundation (www.ecarf.org), the urticaria network e. V. (www.urticaria.net), the COST Action BM1007 'Mast cells and basophils' and the European Mast Cell and Basophil Research Network (www.embrn.org) for their support. Participation of DDM and MC in this work was supported by the Division of Intramural Research/NIAID/NIH. In addition, we thank all patients who took part in the item generation, item selection and in the MC-QoL validation study. NR 32 TC 1 Z9 1 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-4538 EI 1398-9995 J9 ALLERGY JI Allergy PD JUN PY 2016 VL 71 IS 6 BP 869 EP 877 DI 10.1111/all.12842 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA DM2AM UT WOS:000376148100013 PM 26797792 ER PT J AU Persky, S Ferrer, RA Klein, WMP AF Persky, Susan Ferrer, Rebecca A. Klein, William M. P. TI Genomic Information may Inhibit Weight-Related Behavior Change Inclinations Among Individuals in a Fear State SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Health-care communication; Weight management; Obesity; Genomics ID LOSS MAINTENANCE; DECISION-MAKING; HEALTH BEHAVIOR; BODY-WEIGHT; OBESITY; EMOTION; RISK; APPRAISAL; COMMUNICATION; METAANALYSIS AB Background As evidence mounts regarding associations between genetics and body weight, it is essential to understand how to communicate this information, and factors like emotion that could moderate the effectiveness of messages. Purpose We assessed influences of emotion on reactions to weight-related genomic information in a virtual clinical setting. Methods An online representative US sample of overweight women was randomized to receive an emotion induction (anger, fear, or neutral) paired with information about genomic or behavioral influences on weight in an interaction with a virtual doctor. Results Receiving genomic information led to reduced attributions of lifestyle causes for weight and behavioral intentions, but only among individuals in a fear state. Conclusions The current study is among the first to reinforce the concern that discussing genomic underpinnings of overweight could undercut health behavior, and highlights the importance of identifying factors like emotion that influence interpretation of genomic information. C1 [Persky, Susan] NHGRI, Social & Behav Res Branch, NIH, 31 Ctr Dr,B1B36, Bethesda, MD 20892 USA. [Ferrer, Rebecca A.] NCI, Basic Biobehav & Psychol Sci Branch, Behav Res Program, Rockville, MD USA. [Klein, William M. P.] NCI, Behav Res Program, Rockville, MD USA. RP Persky, S (reprint author), NHGRI, Social & Behav Res Branch, NIH, 31 Ctr Dr,B1B36, Bethesda, MD 20892 USA. EM perskys@mail.nih.gov FU Intramural NIH HHS [ZIA HG200383-04] NR 39 TC 2 Z9 2 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD JUN PY 2016 VL 50 IS 3 BP 452 EP 459 DI 10.1007/s12160-016-9771-2 PG 8 WC Psychology, Multidisciplinary SC Psychology GA DM3YI UT WOS:000376282200012 PM 26850762 ER PT J AU Gavara, N Chadwick, R AF Gavara, Nuria Chadwick, Richard S. TI Relationship between cell stiffness and stress fiber amount, assessed by simultaneous atomic force microscopy and live-cell fluorescence imaging SO BIOMECHANICS AND MODELING IN MECHANOBIOLOGY LA English DT Article DE Cytoskeleton; Stress fibers; Actomyosin; Atomic force microscopy; Cell mechanics; Image processing and quantification ID MECHANICAL-PROPERTIES; LIVING CELLS; ACTOMYOSIN BUNDLES; POLYMER NETWORKS; CYTOCHALASIN-D; STEM-CELLS; ACTIN; ELASTICITY; CYTOSKELETON; FIBROBLASTS AB Actomyosin stress fibers, one of the main components of the cell's cytoskeleton, provide mechanical stability to adherent cells by applying and transmitting tensile forces onto the extracellular matrix (ECM) at the sites of cell-ECM adhesion. While it is widely accepted that changes in spatial and temporal distribution of stress fibers affect the cell's mechanical properties, there is no quantitative knowledge on how stress fiber amount and organization directly modulate cell stiffness. We address this key open question by combining atomic force microscopy with simultaneous fluorescence imaging of living cells, and combine for the first time reliable quantitative parameters obtained from both techniques. We show that the amount of myosin and (to a lesser extent) actin assembled in stress fibers directly modulates cell stiffness in adherent mouse fibroblasts (NIH3T3). In addition, the spatial distribution of stress fibers has a second-order modulatory effect. In particular, the presence of either fibers located in the cell periphery, aligned fibers or thicker fibers gives rise to reinforced cell stiffness. Our results provide basic and significant information that will help design optimal protocols to regulate the mechanical properties of adherent cells via pharmacological interventions that alter stress fiber assembly or via micropatterning techniques that restrict stress fiber spatial organization. C1 [Gavara, Nuria] Queen Mary Univ London, Sch Engn & Mat Sci, Mile End Rd, London E1 3NS, England. [Chadwick, Richard S.] NIDCD, Auditory Mech Sect, NIH, Bldg 10 Rm 5D49,10 Ctr Dr,MSC 1417, Bethesda, MD 20892 USA. RP Gavara, N (reprint author), Queen Mary Univ London, Sch Engn & Mat Sci, Mile End Rd, London E1 3NS, England. EM n.gavara@qmul.ac.uk FU US National Institute on Deafness and Other Communication Disorders [Z01-DC000033-10] FX The authors thank A. LaCroix and V. Luo for critical input. This work was supported by the Intramural Program of the US National Institute on Deafness and Other Communication Disorders (Project Z01-DC000033-10). NR 54 TC 3 Z9 3 U1 8 U2 22 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1617-7959 EI 1617-7940 J9 BIOMECH MODEL MECHAN JI Biomech. Model. Mechanobiol. PD JUN PY 2016 VL 15 IS 3 BP 511 EP 523 DI 10.1007/s10237-015-0706-9 PG 13 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA DM0EE UT WOS:000376014800003 PM 26206449 ER PT J AU Masci, M Wang, M Imbert, L Barnes, AM Spevak, L Lukashova, L Huang, YH Ma, Y Marini, JC Jacobsen, CM Warman, ML Boskey, AL AF Masci, Marco Wang, Min Imbert, Laurianne Barnes, Aileen M. Spevak, Lyudmila Lukashova, Lyudmila Huang, Yihe Ma, Yan Marini, Joan C. Jacobsen, Christina M. Warman, Matthew L. Boskey, Adele L. TI Bone mineral properties in growing Col1a2(+/G610C) mice, an animal model of osteogenesis imperfecta SO BONE LA English DT Article DE Osteogenesis imperfecta; FTIRI; Micro-computed tomography; Old order Amish mice; G610C mutation ID SCLEROSTIN ANTIBODY TREATMENT; COLLAGEN CROSS-LINKS; BRTL/+ MOUSE MODEL; MECHANICAL-PROPERTIES; TISSUE-LEVEL; MURINE MODEL; I COLLAGEN; STRENGTH; AGE; OSTEOPOROSIS AB The Col1a2(+/G610C) knock-in mouse, models osteogenesis imperfecta in a large old order Amish family (OOA) with type IV OI, caused by a G-to-T transversion at nucleotide 2098, which alters the gly-610 codon in the triple-helical domain of the alpha 2(I) chain of type I collagen. Mineral and matrix properties of the long bones and vertebrae of male Col1a2(+/G610C) and their wild-type controls (Col1a2(+/+)), were characterized to gain insight into the role of alpha 2-chain collagen mutations in mineralization. Additionally, we examined the rescuability of the composition by sclerostin inhibition initiated by crossing Col1a2(+/G610C) with an LRP+/A214V high bone mass allele. At age 10-days, vertebrae and tibia showed few alterations by micro-CT or Fourier transform infrared imaging (FTIRI). At 2-months-of-age, Col1a2(+/G610C) tibias had 13% fewer secondary trabeculae than Col1a2(+/+), these were thinner (11%) and more widely spaced (20%) than those of Col1a2(+/+) mice. Vertebrae of Col1a2(+/G610C) mice at 2-months also had lower bone volume fraction (38%), trabecular number (13%), thickness (13%) and connectivity density (32%) compared to Col1a2(+/+). The cortical bone of Col1a2(+/G610C) tibias at 2-months had 3% higher tissue mineral density compared to Col1a2(+/+); Col1a2(+/G610C) vertebrae had lower cortical thickness (29%), bone area (37%) and polar moment of inertia (38%) relative to Col1a2(+/+) FTIRI analysis, which provides information on bone chemical composition at similar to 7 mu m-spatial resolution, showed tibias at 10-days did not differ between genotypes. Comparing identical bone types in Col1a2(+/G610C) to Col1a2(+/+) at 2-months-of-age, tibias showed higher mineral-to-matrix ratio in trabeculae (17%) and cortices (31%). and in vertebral cortices (28%). Collagen maturity was 42% higher at 10-days-of-age in Col1a2(+/G610C) vertebral trabeculae and in 2-month tibial cortices (12%), vertebral trabeculae (42%) and vertebral cortices (12%). Higher acid-phosphate substitution was noted in 10-day old trabecular bone in vertebrae (31%) and in 2-month old trabecular bone in both tibia (31%) and vertebrae (4%). There was also a 16% lower carbonate-to-phosphate ratio in vertebral trabeculae and a correspondingly higher (22%) carbonate-to-phosphate ratio in 2 month-old vertebral cortices. At age 3-months-of-age, male femurs with both a Col1a2(+/G610C) allele and a Lrp5 high bone mass allele (Lrp5 +/A214V) showed an improvement in bone composition, presenting higher trabecular carbonate-to-phosphate ratio (18%) and lower trabecular and cortical acid-phosphate substitutions (8% and 18%, respectively). Together, these results indicate that mutant collagen alpha 2(I) chain affects both bone quantity and composition, and the usefulness of this model for studies of potential OI therapies such as anti-sclerostin treatments. (C) 2016 Elsevier Inc. All rights reserved. C1 [Masci, Marco; Boskey, Adele L.] Weill Cornell Med Coll, New York, NY USA. [Wang, Min; Imbert, Laurianne; Spevak, Lyudmila; Lukashova, Lyudmila; Boskey, Adele L.] Hosp Special Surg, Mineralized Tissues Lab, 535 E 70th St, New York, NY 10021 USA. [Barnes, Aileen M.; Marini, Joan C.] NICHHD, NIH, Bethesda, MD 20892 USA. [Huang, Yihe; Ma, Yan] George Washington Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Milken Inst, Washington, DC USA. [Jacobsen, Christina M.] Childrens Hosp, Div Endocrinol & Genet, 300 Longwood Ave, Boston, MA 02115 USA. [Jacobsen, Christina M.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Warman, Matthew L.] Boston Childrens Hosp, Dept Orthopaed Surg, Orthopaed Res Labs, Boston, MA USA. [Wang, Min] Cent S Univ, Xiang Ya Hosp, Dept Endocrinol, Changsha 410008, Hunan, Peoples R China. RP Boskey, AL (reprint author), Hosp Special Surg, 535 E 70th St, New York, NY 10021 USA. EM mam2147@med.cornell.edu; 19650877@qq.com; ImbertL@HSS.edu; Barnesai@mail.Nih.gov; SpevakM@HSS.edu; Lukashoval@HSS.edu; Yihehuang@email.gwu.edu; yanma@email.gwu.edu; oidoc@helix.nih.gov; Christina.Jacobsen@childrens.harvard.edu; Matthew.Warman@childrens.harvard.edu; Boskeya@HSS.edu FU NIH [AR041325, AR046121, AR062326, AR063813]; China Scholarship Council [81401835]; National Scientific Foundation of China; NICHD FX The authors appreciates the assistance of Shamriz Tamanna, a student with the Traveler's Fellow's Program of Weill Cornell University. The study was supported by NIH grants AR041325 and AR046121 (ALB), AR062326 (MLW), and AR063813 (CMJ), grant # 81401835 from the China Scholarship Council and National Scientific Foundation of China (M Wang) and NICHD intramural funding (JCM). NR 48 TC 4 Z9 4 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD JUN PY 2016 VL 87 BP 120 EP 129 DI 10.1016/j.bone.2016.04.011 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DM0SC UT WOS:000376055100014 PM 27083399 ER PT J AU Hsieh, MM Callacondo, D Rojas-Camayo, J Quesada-Olarte, J Wang, XD Uchida, N Maric, I Remaley, AT Leon-Velarde, F Villafuerte, FC Tisdale, JF AF Hsieh, Matthew M. Callacondo, David Rojas-Camayo, Jose Quesada-Olarte, Jose Wang, Xunde Uchida, Naoya Maric, Irina Remaley, Alan T. Leon-Velarde, Fabiola Villafuerte, Francisco C. Tisdale, John F. TI SENP1, but not fetal hemoglobin, differentiates Andean highlanders with chronic mountain sickness from healthy individuals among Andean highlanders SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID HIGH-ALTITUDE DISEASES; EXCESSIVE ERYTHROCYTOSIS; OXYGEN-TRANSPORT; NATRIURETIC-PEPTIDE; AUTONOMIC FUNCTION; NEWBORN-INFANTS; GENE-EXPRESSION; HEART-DISEASE; HYPOXIA; ADAPTATION AB Chronic mountain sickness (CMS) results from chronic hypoxia. It is unclear why certain highlanders develop CMS. We hypothesized that modest increases in fetal hemoglobin (HbF) are associated with lower CMS severity. In this cross-sectional study, we found that HbF levels were normal (median = 0.4%) in all 153 adult Andean natives in Cerro de Pasco, Peru. Compared with healthy adults, the borderline elevated hemoglobin group frequently had symptoms (headaches, tinnitus, cyanosis, dilatation of veins) of CMS. Although the mean hemoglobin level differed between the healthy (17.1 g/dL) and CMS (22.3 g/dL) groups, mean plasma erythropoietin (EPO) levels were similar (healthy, 17.7 mIU/mL; CMS, 12.02 mIU/mL). Sanger sequencing determined that single-nucleotide polymorphisms in endothelial PAS domain 1 (EPAS1) and egl nine homolog 1 (EGLN1), associated with lower hemoglobin in Tibetans, were not identified in Andeans. Sanger sequencing of sentrin-specific protease 1 (SENP1) and acidic nuclear phosphoprotein 32 family, member D (ANP32D), in healthy and CMS individuals revealed that non-G/G genotypes were associated with higher CMS scores. No JAK2 V617F mutation was detected in CMS individuals. Thus, HbF and other classic erythropoietic parameters did not differ between healthy and CMS individuals. However, the non-G/G genotypes of SENPI appeared to differentiate individuals with CMS from healthy Andean highlanders. Published by Elsevier Inc. on behalf of ISEH - International Society for Experimental Hematology. C1 [Hsieh, Matthew M.; Uchida, Naoya; Tisdale, John F.] NHLBI, Mol & Clin Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Callacondo, David] Univ Privada Tacna, Sch Med, Fac Hlth Sci, Tacna, Peru. [Callacondo, David; Rojas-Camayo, Jose; Quesada-Olarte, Jose; Leon-Velarde, Fabiola; Villafuerte, Francisco C.] Univ Peruana Cayetano Heredia UPCH, Fac Ciencias & Filosofia, Lima, Peru. [Callacondo, David] Clin Int, Lima, Peru. [Wang, Xunde] NHLBI, Sickle Cell Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Maric, Irina; Remaley, Alan T.] Ctr Clin, Dept Lab Med, Bethesda, MD USA. RP Hsieh, MM (reprint author), 9000 Rockville Pike,Bldg 10, Bethesda, MD 20892 USA. EM matthewhs@mail.nih.gov OI Villafuerte, Francisco/0000-0003-0731-8911 FU intramural research program at the Clinical Center; National Heart, Lung, and Blood Institute; National Institute of Diabetes, Digestive, and Kidney Diseases at the NIH FX We wish to thank Maxine Weissman (DLM/CC), Jodie Keary (DLM/CC), Cheryl Johnson (DLM/CC), Jordan Perlman (MCHB/NHLBI), and Oswald Phang (MCHB/NHLBI) for their technical assistance. This work is supported in part by the intramural research program at the Clinical Center, the National Heart, Lung, and Blood Institute, and the National Institute of Diabetes, Digestive, and Kidney Diseases at the NIH. NR 44 TC 1 Z9 1 U1 7 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2016 VL 44 IS 6 BP 483 EP 490 DI 10.1016/j.exphem.2016.02.010 PG 8 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA DM0SD UT WOS:000376055200008 PM 26952840 ER PT J AU van't Erve, TJ Lih, FB Jelsema, C Deterding, LJ Eling, TE Mason, RP Kadiiska, MB AF van't Erve, Thomas J. Lih, Fred B. Jelsema, Casey Deterding, Leesa J. Eling, Thomas E. Mason, Ronald P. Kadiiska, Maria B. TI Reinterpreting the best biomarker of oxidative stress: The 8-iso-prostaglandin F-2 alpha/prostaglandin F-2 alpha ratio shows complex origins of lipid peroxidation biomarkers in animal models SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE 8-iso-PGF(2 alpha)/PGF(2 alpha) ratio; F2-isoprostanes; Oxidative stress; Inflammation; Biomarkers; Lipid peroxidation ID 8-EPI-PROSTAGLANDIN F-2 ALPHA; FREE-RADICALS; ENDOTHELIAL EXPRESSION; ISCHEMIA-REPERFUSION; DEPENDENT FORMATION; IN-VIVO; INJURY; CYTOCHROME-P450; GENERATION; LIPOPOLYSACCHARIDE AB Oxidative stress is elevated in numerous environmental exposures and diseases. Millions of dollars have been spent to try to ameliorate this damaging process using anti-oxidant therapies. Currently, the best accepted biomarker of oxidative stress is the lipid oxidation product 8-iso-prostaglandin F-2 alpha (8-iso-PGF(2 alpha)), which has been measured in over a thousand human and animal studies. 8-iso-PGF(2 alpha) generation has been exclusively attributed to nonenzymatic chemical lipid peroxidation (CLP). However, 8-iso-PGF(2 alpha) can also be produced enzymatically by prostaglandin-endoperoxide synthases (PGHS) in vivo. When failing to account for PGHS-dependent generation, 8-iso-PGF(2 alpha) cannot be interpreted as a selective biomarker of oxidative stress. We investigated the formation of 8-iso-PGF(2 alpha) in rats exposed to carbon tetrachloride (CCl4) or lipopolysaccharide (LPS) using the 8-iso-PGF(2 alpha)/PGF(2 alpha) ratio to quantitatively determine the source(s) of 8-iso-PGF(2 alpha). Upon exposure to a 120 mg/kg dose of CCl4, the contribution of CLP accounted for only 55.6 +/- 19.4% of measured 8-iso-PGF(2 alpha), whereas in the 1200 mg/kg dose, CLP was the predominant source of 8-iso-PGF(2 alpha) (86.6 +/- 8.0% of total). In contrast to CCl4, exposure to 0.5 mg/kg LPS was characterized by a significant increase in both the contribution of PGHS (59.5 +/- 7.0) and CLP (40.5 +/- 14.0%). In conclusion, significant generation of 8-iso-PGF(2 alpha) occurs through enzymatic as well as chemical lipid peroxidation. The distribution of the contribution is dependent on the exposure agent as well as the dose. The 8-iso-PGF(2 alpha)/PGF(2 alpha) ratio accurately determines the source of 8-iso-PGF(2 alpha) and provides an absolute measure of oxidative stress in vivo. (C) 2016 Published by Elsevier Inc. C1 [van't Erve, Thomas J.; Mason, Ronald P.; Kadiiska, Maria B.] NIEHS, Immun Inflammat & Dis Lab, POB 12233, Res Triangle Pk, NC 27709 USA. [Lih, Fred B.; Deterding, Leesa J.] NIEHS, Epigenet & Stem Cell Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. [Jelsema, Casey] W Virginia Univ, Dept Stat, Morgantown, WV 26505 USA. [Eling, Thomas E.] NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. RP van't Erve, TJ (reprint author), NIEHS, Immun Inflammat & Dis Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM thomas.vanterve@nih.gov OI van 't Erve, Thomas/0000-0002-3260-6627 FU Intramural Research Program, National Institutes of Health, National Institute of Environmental Health Sciences FX The authors gratefully acknowledge Shyamal Peddada for his help with the statistics; Drs. Matt Edin and Stephanie London for their review of this manuscript; and Jean Corbett, Dr. Ann Motten, and Mary Mason for their editorial expertise. This work was supported by the Intramural Research Program, National Institutes of Health, National Institute of Environmental Health Sciences. NR 37 TC 0 Z9 0 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUN PY 2016 VL 95 BP 65 EP 73 DI 10.1016/j.freeradbiomed.2016.03.001 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DM2IH UT WOS:000376169800006 PM 26964509 ER PT J AU Ariza, J Gonzalez-Reyes, JA Jodar, L Diaz-Ruiz, A de Cabo, R Villalba, JM AF Ariza, Julia Gonzalez-Reyes, Jose A. Jodar, Laura Diaz-Ruiz, Alberto de Cabo, Rafael Manuel Villalba, Jose TI Mitochondrial permeabilization without caspase activation mediates the increase of basal apoptosis in cells lacking Nrf2 SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE NRF2; Apoptosis; Caspase ID TRANSCRIPTION FACTOR NRF2; COLORECTAL-CANCER; OXIDATIVE STRESS; SKELETAL-MUSCLE; FACTOR-2 NRF2; EXPRESSION; PATHWAY; PROTEIN; DEFICIENCY; RESISTANCE AB Nuclear factor E2-related factor-2 (Nrf2) is a cap'n'collar/basic leucine zipper (b-ZIP) transcription factor which acts as sensor of oxidative and electrophilic stress. Low levels of Nrf2 predispose cells to chemical carcinogenesis but a dark side of Nrf2 function also exists because its unrestrained activation may allow the survival of potentially dangerous damaged cells. Since Nrf2 inhibition may be of therapeutic interest in cancer, and a decrease of Nrf2 activity may be related with degenerative changes associated with aging, it is important to investigate how the lack of Nrf2 function activates molecular mechanisms mediating cell death. Murine Embryonic Fibroblasts (MEFs) bearing a Nrf2 deletion (Nrf2KO) displayed diminished cellular growth rate and shortened lifespan compared with wild-type MEFs. Basal rates of DNA fragmentation and histone H2A.X phosphorylation were higher in Nrf2KO MEFs, although steadystate levels of reactive oxygen species were not significantly increased. Enhanced rates of apoptotic DNA fragmentation were confirmed in liver and lung tissues from Nrf2KO mice. Apoptosis in Nrf2KO MEFs was associated with a decrease of Bcl-2 but not Bax levels, and with the release of the mitochondrial proapoptotic factors cytochrome c and AIF. Procaspase-9 and Apaf-1 were also increased in Nrf2KO MEFs but caspase-3 was not activated. Inhibition of XIAP increased death in Nrf2KO but not in wild-type MEFs. Mitochondrial ultrastructure was also altered in Nrf2KO MEFs. Our results support that Nrf2 deletion produces mitochondrial dysfunction associated with mitochondrial permeabilization, increasing basal apoptosis through a caspase-independent and AIF-dependent pathway. Published by Elsevier Inc. C1 [Ariza, Julia; Gonzalez-Reyes, Jose A.; Jodar, Laura; Manuel Villalba, Jose] Univ Cordoba, Dept Biol Celular Fisiol & Inmunol, Campus Excelencia Int Agroalimentario, ceiA3, E-14071 Cordoba, Spain. [Diaz-Ruiz, Alberto; de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP Villalba, JM (reprint author), Univ Cordoba, Dept Biol Celular Fisiol & Inmunol, Campus Excelencia Int Agroalimentario, ceiA3, E-14071 Cordoba, Spain.; de Cabo, R (reprint author), NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RI de Cabo, Rafael/J-5230-2016 OI de Cabo, Rafael/0000-0002-3354-2442 FU Junta de Andalucia Proyectos de Excelencia Grant [P09-CVI-4887]; NIH Grant [1R01AG028125]; Ministerio de Economia y Competitividad [BFU2011-23578]; Junta de Andalucia Proyectos Internacionales grant; Junta de Andalucia [BIO-276]; University of Cordoba [BIO-276]; predoctoral fellowship of the Spanish Ministerio de Educacion; Intramural Research Program of the NIH, National Institute on Aging FX Supported by Junta de Andalucia Proyectos de Excelencia Grant P09-CVI-4887, NIH Grant 1R01AG028125, Ministerio de Economia y Competitividad BFU2011-23578, Junta de Andalucia Proyectos Internacionales grant, and BIO-276 (Junta de Andalucia and the University of Cordoba). JA was funded by a predoctoral fellowship of the Spanish Ministerio de Educacion and BIO-276. LJ was supported by BIO-276. The authors thank the personnel from the Servicio Centralizado de Apoyo a la Investigacion (SCAI; University of Cordoba) for technical support.; The study was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 72 TC 1 Z9 1 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUN PY 2016 VL 95 BP 82 EP 95 DI 10.1016/j.freeadbiomed.2016.02.015 PG 14 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DM2IH UT WOS:000376169800008 PM 27016073 ER PT J AU Rouleau, L Antony, AN Bisetto, S Newberg, A Doria, C Levine, M Monti, DA Hoek, JB AF Rouleau, Lauren Antony, Anil Noronha Bisetto, Sara Newberg, Andrew Doria, Cataldo Levine, Mark Monti, Daniel A. Hoek, Jan B. TI Synergistic effects of ascorbate and sorafenib in hepatocellular carcinoma: New insights into ascorbate cytotoxicity SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Ascorbate; Calcium homeostasis; Glucose oxidase; Hepatocellular carcinoma; Hep G2; Hydrogen peroxide; Mitochondrial membrane potential; Sorafenib; Synergy; Vitamin C ID INTRACELLULAR HYDROGEN-PEROXIDE; VITAMIN-C PHARMACOKINETICS; TERMINAL HUMAN CANCER; RAF/MEK/ERK PATHWAY; REDOX REGULATION; CELL-DEATH; SUPPLEMENTAL ASCORBATE; GLUTATHIONE-PEROXIDASE; SUPPORTIVE TREATMENT; PANCREATIC-CANCER AB We investigated the mechanism of selective ascorbate-induced cytotoxicity in tumor cells, including Hep G2 cells, compared to primary hepatocytes. H2O2 formation was required for ascorbate cytotoxicity, as extracellular catalase treatment protected tumor cells. H2O2 generated by glucose oxidase treatment also caused cell killing, but treatment with a pharmacologic dose (5-20 mM) of ascorbate was significantly more cytotoxic at comparable rates of H2O2 production, suggesting that ascorbate enhanced H2O2 cytotoxicity. This was further supported by the finding that ascorbate at a non-cytotoxic dose (1 mM) enhanced cell killing caused by glucose oxidase. Consistent with this conclusion, ascorbate treatment caused deregulation of cellular calcium homeostasis, resulting in massive mitochondrial calcium accumulation. Ascorbate acted synergistically with the chemotherapeutic sorafenib in killing Hep G2 cells, but not primary hepatocytes, suggesting adjuvant ascorbate treatment can broaden sorafenib's therapeutic range. Sorafenib caused mitochondrial depolarization and prevented mitochondrial calcium sequestration. Subsequent ascorbate addition further deregulated cellular calcium homeostasis promoting cell death. Additionally, we present the case of a patient with hepatocellular carcinoma (HCC) who had prolonged regression of a rib metastasis upon combination treatment with ascorbate and sorafenib, indicating that these studies have direct clinical relevance. (C) 2016 Elsevier Inc. All rights reserved. C1 [Rouleau, Lauren; Antony, Anil Noronha; Bisetto, Sara; Hoek, Jan B.] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, MitoCare Ctr, Suite 527G JAH,1020 Locust St, Philadelphia, PA 19107 USA. [Levine, Mark] NIDDK, Mol & Clin Nutr Sect, Digest Dis Branch, Bethesda, MD 20892 USA. [Newberg, Andrew; Monti, Daniel A.] Thomas Jefferson Univ Hosp, Jefferson Myrna Brind Ctr Integrat Med, Philadelphia, PA 19107 USA. [Doria, Cataldo] Thomas Jefferson Univ Hosp, Div Transplantat, Liver Tumor Ctr, Philadelphia, PA 19107 USA. RP Hoek, JB (reprint author), Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, MitoCare Ctr, Suite 527G JAH,1020 Locust St, Philadelphia, PA 19107 USA.; Monti, DA (reprint author), Thomas Jefferson Univ Hosp, Jefferson Myrna Brind Ctr Integrat Med, Philadelphia, PA 19107 USA. EM jan.hoek@jefferson.edu OI Hoek, Jan/0000-0001-7127-4218 FU Marcus Foundation; Circle of Light Foundation; NIH [R01 AA018873]; NIH Institutional Training grants [T32 GM100836, T32 AA007463]; Intramural Research Program, NIDDK, NIH FX This project was supported by a generous grant from the Marcus Foundation to DAM and by a grant from the Circle of Light Foundation to DAM. Additional support came from NIH grant R01 AA018873 to JBH. LR received support from NIH Institutional Training grants T32 GM100836 and T32 AA007463. ML was supported by the Intramural Research Program, NIDDK, NIH. Additionally, we acknowledge John Eisenbrey, PhD, of Thomas Jefferson University for his generous gift of the HuH-7 cell line. NR 68 TC 1 Z9 1 U1 3 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUN PY 2016 VL 95 BP 308 EP 322 DI 10.1016/j.freeradbiomed.2016.03.031 PG 15 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DM2IH UT WOS:000376169800026 PM 27036367 ER PT J AU Guertin, KA Grant, RK Arnold, KB Burwell, L Hartline, J Goodman, PJ Minasian, LM Lippman, SM Klein, E Cassano, PA AF Guertin, Kristin A. Grant, Rachael K. Arnold, Kathryn B. Burwell, Lindsay Hartline, JoAnn Goodman, Phyllis J. Minasian, Lori M. Lippman, Scott M. Klein, Eric Cassano, Patricia A. TI Effect of long-term vitamin E and selenium supplementation on urine F-2-isoprostanes, a biomarker of oxidative stress SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Isoprostanes; Antioxidant nutrients; Alpha-tocopherol; Vitamin E; Selenium; Cigarette smoking; Lung function; Oxidative stress; Lipid peroxidation; Randomized controlled trial; Chronic obstructive pulmonary disease ID PREVENTION TRIAL SELECT; OBSTRUCTIVE PULMONARY-DISEASE; CIGARETTE SMOKERS; IN-VIVO; PLASMA F-2-ISOPROSTANES; LIPID-PEROXIDATION; PROSTATE-CANCER; OXIDANT STRESS; 8-ISOPROSTANE; COPD AB Background: Cigarette smoking generates reactive oxidant species and contributes to systemic oxidative stress, which plays a role in the pathophysiology of chronic diseases. Nutrients with antioxidant properties, including vitamin E and selenium, are proposed to reduce systemic oxidative burden and thus to mitigate the negative health effects of reactive oxidant species. Objective: Our objective was to determine whether long-term supplementation with vitamin E and/or selenium reduces oxidative stress in smokers, as measured by urine 8-iso-prostaglandin F2-alpha (8-iso-PGF(2 alpha)). Design: We measured urine 8-iso-PGF(2 alpha) with competitive enzyme linked immunoassay (ELISA) in 312 male current smokers after 36 months of intervention in a randomized placebo-controlled trial of vitamin E (400 IU/d all rac-alpha-tocopheryl acetate) and/or selenium (200 mu g/d L-selenomethionine). We used linear regression to estimate the effect of intervention on urine 8-iso-PGF(2 alpha) with adjustments for age and race. Results: Compared to placebo, vitamin E alone lowered urine 8-iso-PGF(2 alpha) by 21% (p = 0.02); there was no effect of combined vitamin E and selenium (intervention arm lower by 9%; p = 0.37) or selenium alone (intervention arm higher by 8%; p = 0.52). Conclusions: Long-term vitamin E supplementation decreases urine 8-iso-PGF(2 alpha) among male cigarette smokers, but we observed little to no evidence for an effect of selenium supplementation, alone or combined with vitamin E. (C) 2016 Elsevier Inc. All rights reserved. C1 [Guertin, Kristin A.; Grant, Rachael K.; Burwell, Lindsay; Cassano, Patricia A.] Cornell Univ, Div Nutr Sci, 209 Savage Hall, Ithaca, NY 14853 USA. [Arnold, Kathryn B.; Hartline, JoAnn; Goodman, Phyllis J.] SWOG Stat Ctr, Seattle, WA USA. [Minasian, Lori M.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Lippman, Scott M.] Univ Calif San Diego, Ctr Canc, San Diego, CA 92103 USA. [Klein, Eric] Cleveland Clin, Cleveland, OH 44106 USA. [Cassano, Patricia A.] Weill Cornell Med Coll, Div Biostatist & Epidemiol, Dept Healthcare Policy & Res, New York, NY USA. [Guertin, Kristin A.] Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Burwell, Lindsay] Wells Coll, Aurora, NY USA. RP Cassano, PA (reprint author), Cornell Univ, Div Nutr Sci, 209 Savage Hall, Ithaca, NY 14853 USA. EM pac6@cornell.edu FU NHLBI [R01HL071022]; Public Health Service Grants from the National Cancer Institute [CA37429, 5UM1CA182883] FX Supported by the NHLBI (R01HL071022). SELECT was funded by Public Health Service Grants CA37429 and 5UM1CA182883 from the National Cancer Institute. NR 47 TC 2 Z9 2 U1 4 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUN PY 2016 VL 95 BP 349 EP 356 DI 10.1016/j.freeradbiomed.2016.03.010 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DM2IH UT WOS:000376169800029 PM 27012420 ER PT J AU Kane, AE Huizer-Pajkos, A Mach, J McKenzie, C Mitchell, SJ de Cabo, R Jones, B Cogger, V Le Couteur, DG Hilmer, SN AF Kane, Alice Elizabeth Huizer-Pajkos, Aniko Mach, John McKenzie, Catriona Mitchell, Sarah Jayne de Cabo, Rafael Jones, Brett Cogger, Victoria Le Couteur, David G. Hilmer, Sarah Nicole TI N-Acetyl cysteine does not prevent liver toxicity from chronic low-dose plus subacute high-dose paracetamol exposure in young or old mice SO FUNDAMENTAL & CLINICAL PHARMACOLOGY LA English DT Article DE ageing; chronic; hepatotoxicity; N-acetyl cysteine; paracetamol; supratherapeutic ID ACETAMINOPHEN TOXICITY; CHRONIC HEPATOTOXICITY; HEPATIC-NECROSIS; COVALENT BINDING; FISCHER-344 RATS; ACETYLCYSTEINE; INJURY; MITOCHONDRIAL; EXPLANATION; MANAGEMENT AB Paracetamol is an analgesic commonly used by people of all ages, which is well documented to cause severe hepatotoxicity with acute overexposures. The risk of hepatotoxicity from nonacute paracetamol exposures is less extensively studied, and this is the exposure most common in older adults. Evidence on the effectiveness of N-acetyl cysteine (NAC) for nonacute paracetamol exposures, in any age group, is lacking. This study aimed to examine the effect of long-term exposure to therapeutic doses of paracetamol and subacute paracetamol overexposure, in young and old mice, and to investigate whether NAC was effective at preventing paracetamol hepatotoxicity induced by these exposures. Young and old male C57BL/6 mice were fed a paracetamol-containing (1.33 g/kg food) or control diet for 6 weeks. Mice were then dosed orally eight times over 3 days with additional paracetamol (250 mg/kg) or saline, followed by either one or two doses of oral NAC (1200 mg/kg) or saline. Chronic low-dose paracetamol exposure did not cause hepatotoxicity in young or old mice, measured by serum alanine aminotransferase (ALT) elevation, and confirmed by histology and a DNA fragmentation assay. Subacute paracetamol exposure caused significant hepatotoxicity in young and old mice, measured by biochemistry (ALT) and histology. Neither a single nor double dose of NAC protected against this toxicity from subacute paracetamol in young or old mice. This finding has important clinical implications for treating toxicity due to different paracetamol exposure types in patients of all ages, and implies a need to develop new treatments for subacute paracetamol toxicity. C1 [Kane, Alice Elizabeth; Huizer-Pajkos, Aniko; Mach, John; Jones, Brett; Hilmer, Sarah Nicole] Royal N Shore Hosp, Kolling Inst Med Res, Reserve Rd, St Leonards, NSW 2065, Australia. [Kane, Alice Elizabeth; Huizer-Pajkos, Aniko; Mach, John; Jones, Brett; Hilmer, Sarah Nicole] Royal N Shore Hosp, Reserve Rd, St Leonards, NSW 2065, Australia. [Kane, Alice Elizabeth; Mach, John; Jones, Brett; Cogger, Victoria; Le Couteur, David G.; Hilmer, Sarah Nicole] Univ Sydney, Sydney Med Sch, Camperdown, NSW, Australia. [McKenzie, Catriona] Royal Prince Alfred Hosp, Missenden Rd, Camperdown, NSW 2050, Australia. [Mitchell, Sarah Jayne; de Cabo, Rafael] NIA, NIH, Nathan Shock Dr, Baltimore, MD 21224 USA. [Cogger, Victoria; Le Couteur, David G.] Ctr Educ & Res Ageing, Hosp Rd, Concord, NSW, Australia. [Cogger, Victoria; Le Couteur, David G.] ANZAC Res Inst, Hosp Rd, Concord, NSW, Australia. RP Kane, AE (reprint author), Royal N Shore Hosp, Kolling Inst Med Res, Reserve Rd, St Leonards, NSW 2065, Australia.; Kane, AE (reprint author), Royal N Shore Hosp, Reserve Rd, St Leonards, NSW 2065, Australia.; Kane, AE (reprint author), Univ Sydney, Sydney Med Sch, Camperdown, NSW, Australia. EM alice.kane@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 NIH HHS [Z99 AG999999] NR 35 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0767-3981 EI 1472-8206 J9 FUND CLIN PHARMACOL JI Fundam. Clin. Pharmacol. PD JUN PY 2016 VL 30 IS 3 BP 263 EP 275 DI 10.1111/fcp.12184 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DM2BN UT WOS:000376151100007 PM 26821200 ER PT J AU Li, QDQT Hao, JJ Zhang, Z Hsu, I Liu, Y Tao, Z Lewi, K Metwalli, AR Agarwal, PK AF Li, Qingdi Quentin Hao, Jian-Jiang Zhang, Zheng Hsu, Iawen Liu, Yi Tao, Zhen Lewi, Keidren Metwalli, Adam R. Agarwal, Piyush K. TI Histone deacetylase inhibitor-induced cell death in bladder cancer is associated with chromatin modification and modifying protein expression: A proteomic approach SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE apoptosis; bladder cancer; HDAC inhibitor; proteomics; pathway analysis; cell cycle; DNA damage repair ID ENDOPLASMIC-RETICULUM STRESS; SPECTRAL ABUNDANCE FACTORS; DNA-DAMAGE; OXIDATIVE STRESS; TRICHOSTATIN-A; PHOSPHORYLATION; APOPTOSIS; BCL-2; CYCLE; IDENTIFICATION AB The Cancer Genome Atlas (TCGA) project recently identified the importance of mutations in chromatin remodeling genes in human carcinomas. These findings imply that epigenetic modulators might have a therapeutic role in urothelial cancers. To exploit histone deacetylases (HDACs) as targets for cancer therapy, we investigated the HDAC inhibitors (HDACIs) romidepsin, trichostatin A, and vorinostat as potential chemotherapeutic agents for bladder cancer. We demonstrate that the three HDACIs suppressed cell growth and induced cell death in the bladder cancer cell line 5637. To identify potential mechanisms associated with the anti proliferative and cytotoxic effects of the HDACIs, we used quantitative proteomics to determine the proteins potentially involved in these processes. Our proteome studies identified a total of 6003 unique proteins. Of these, 2472 proteins were upregulated and 2049 proteins were downregulated in response to HDACI exposure compared to the untreated controls (P<0.05). Bioinformatic analysis further revealed that those differentially expressed proteins were involved in multiple biological functions and enzyme-regulated pathways, including cell cycle progression, apoptosis, autophagy, free radical generation and DNA damage repair. HDACIs also altered the acetylation status of histones and non-histone proteins, as well as the levels of chromatin modification proteins, suggesting that HDACIs exert multiple cytotoxic actions in bladder cancer cells by inhibiting HDAC activity or altering the structure of chromatin. We conclude that HDACIs are effective in the inhibition of cell proliferation and the induction of apoptosis in the 5637 bladder cancer cells through multiple cell death-associated pathways. These observations support the notion that HDACIs provide new therapeutic options for bladder cancer treatment and thus warrant further preclinical exploration. C1 [Li, Qingdi Quentin; Hsu, Iawen; Lewi, Keidren; Metwalli, Adam R.; Agarwal, Piyush K.] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hao, Jian-Jiang; Zhang, Zheng; Liu, Yi; Tao, Zhen] Poochon Sci, Frederick, MD 21704 USA. RP Li, QDQT; Agarwal, PK (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM liquenti@mail.nih.gov; agarwalpk2@mail.nih.gov FU Intramural Research Program of the U.S. National Cancer Institute; National Institutes of Health FX The present study was supported by the Intramural Research Program of the U.S. National Cancer Institute, the National Institutes of Health. NR 56 TC 1 Z9 1 U1 1 U2 4 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 EI 1791-2423 J9 INT J ONCOL JI Int. J. Oncol. PD JUN PY 2016 VL 48 IS 6 BP 2591 EP 2607 DI 10.3892/ijo.2016.3478 PG 17 WC Oncology SC Oncology GA DL7GB UT WOS:000375807900037 PM 27082124 ER PT J AU Kummar, S Wade, JL Oza, AM Sullivan, D Chen, AP Gandara, DR Ji, JP Kinders, RJ Wang, LH Allen, D Coyne, GO Steinberg, SM Doroshow, JH AF Kummar, Shivaani Wade, James L. Oza, Amit M. Sullivan, Daniel Chen, Alice P. Gandara, David R. Ji, Jiuping Kinders, Robert J. Wang, Lihua Allen, Deborah Coyne, Geraldine O'Sullivan Steinberg, Seth M. Doroshow, James H. TI Randomized phase II trial of cyclophosphamide and the oral poly (ADP-ribose) polymerase inhibitor veliparib in patients with recurrent, advanced triple-negative breast cancer SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Metronomic cyclophosphamide; PARP inhibition; DNA damage repair; BRCA; HR defect ID TUMOR-INFILTRATING LYMPHOCYTES; SOLID TUMORS; PROGNOSTIC VALUE; PARP INHIBITORS; CLINICAL-TRIAL; POLY(ADP-RIBOSE); MULTICENTER; BIOMARKER; BRCA1; CELLS AB Background In tumors carrying BRCA mutations, DNA damage caused by standard cytotoxic chemotherapy can be potentiated by poly [ADP-ribose] polymerase (PARP) inhibitors, leading to increased cell death through synthetic lethality. Individuals carrying mutations in BRCA have an increased incidence of triple negative breast cancer (TNBC). In order to assess the role of PARP inhibition in the treatment of TNBC, we conducted a randomized phase II trial of the combination of veliparib, a small molecule PARP inhibitor, with the cytotoxic agent cyclophosphamide versus cyclophosphamide alone in patients with refractory TNBC. Methods Adult patients with TNBC were randomized to receive oral cyclophosphamide 50 mg once daily with or without oral veliparib at 60 mg daily in 21-day cycles. Patients on the cyclophosphamide arm could crossover to the combination arm at disease progression. Results Forty-five patients were enrolled; 18 received cyclophosphamide alone and 21 received the combination as their initial treatment regimen. Lymphopenia was the most common grade 3/4 toxicity noted in both arms. One patient in the cyclophosphamide alone arm, and 2 in the combination arm had objective responses. Response rates and median progression free survival did not significantly differ between both treatment arms. Conclusion The addition of veliparib to cyclophosphamide, at the dose and schedule evaluated, did not improve the response rate over cyclophosphamide treatment alone in patients with heavily pre-treated triple-negative breast cancer. C1 [Kummar, Shivaani; Chen, Alice P.; Allen, Deborah; Coyne, Geraldine O'Sullivan; Steinberg, Seth M.; Doroshow, James H.] NCI, NIH, 31 Ctr Dr,Room 3A44, Bethesda, MD 20814 USA. [Wade, James L.] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Oza, Amit M.] Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. [Sullivan, Daniel] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Gandara, David R.] Univ Calif Davis, Ctr Canc, Davis, CA 95616 USA. [Ji, Jiuping; Kinders, Robert J.; Wang, Lihua] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Doroshow, JH (reprint author), NCI, NIH, 31 Ctr Dr,Room 3A44, Bethesda, MD 20814 USA. EM doroshoj@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E, N01-CM-2011-00071, N01-CM-2011-00032, N01-CM-2011-00100, N01-CM-2011-00038] FX We thank Drs. Andrea Regier Voth, Leidos Biomedical Research, Inc., and Mariam Konate, Capital Consulting Corporation, for editorial assistance in the preparation of this manuscript. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contracts No. HHSN261200800001E, N01-CM-2011-00071, N01-CM-2011-00032, N01-CM-2011-00100, and N01-CM-2011-00038. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 29 TC 2 Z9 2 U1 2 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 EI 1573-0646 J9 INVEST NEW DRUG JI Invest. New Drugs PD JUN PY 2016 VL 34 IS 3 BP 355 EP 363 DI 10.1007/s10637-016-0335-x PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA DM1TJ UT WOS:000376129000010 PM 26996385 ER PT J AU Itsko, M Schaaper, RM AF Itsko, Mark Schaaper, Roel M. TI Transcriptome Analysis of Escherichia coli during dGTP Starvation SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ACID RESISTANCE; RIBONUCLEOTIDE REDUCTASE; DNA-REPLICATION; GENE-EXPRESSION; SALMONELLA-TYPHIMURIUM; THYMINE STARVATION; LAMBDOID PROPHAGE; DNTP POOLS; WILD-TYPE; K-12 AB Our laboratory recently discovered that Escherichia coli cells starved for the DNA precursor dGTP are killed efficiently (dGTP starvation) in a manner similar to that described for thymineless death (TLD). Conditions for specific dGTP starvation can be achieved by depriving an E. coli optA1 gpt strain of the purine nucleotide precursor hypoxanthine (Hx). To gain insight into the mechanisms underlying dGTP starvation, we conducted genome-wide gene expression analyses of actively growing optA1 gpt cells subjected to hypoxanthine deprivation for increasing periods. The data show that upon Hx withdrawal, the optA1 gpt strain displays a diminished ability to derepress the de novo purine biosynthesis genes, likely due to internal guanine accumulation. The impairment in fully inducing the purR regulon may be a contributing factor to the lethality of dGTP starvation. At later time points, and coinciding with cell lethality, strong induction of the SOS response was observed, supporting the concept of replication stress as a final cause of death. No evidence was observed in the starved cells for the participation of other stress responses, including the rpoS-mediated global stress response, reinforcing the lack of feedback of replication stress to the global metabolism of the cell. The genome-wide expression data also provide direct evidence for increased genome complexity during dGTP starvation, as a markedly increased gradient was observed for expression of genes located near the replication origin relative to those located toward the replication terminus. IMPORTANCE Control of the supply of the building blocks (deoxynucleoside triphosphates [dNTPs]) for DNA replication is important for ensuring genome integrity and cell viability. When cells are starved specifically for one of the four dNTPs, dGTP, the process of DNA replication is disturbed in a manner that can lead to eventual death. In the present study, we investigated the transcriptional changes in the bacterium E. coli during dGTP starvation. The results show increasing DNA replication stress with an increased time of starvation, as evidenced by induction of the bacterial SOS system, as well as a notable lack of induction of other stress responses that could have saved the cells from cell death by slowing down cell growth. C1 [Itsko, Mark; Schaaper, Roel M.] NIEHS, Genome Integr & Struct Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. RP Schaaper, RM (reprint author), NIEHS, Genome Integr & Struct Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM schaaper@niehs.nih.gov FU HHS \ NIH \ National Institute of Environmental Health Sciences (NIEHS) [ES101905]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES101905] FX This work, including the efforts of Roel M. Schaaper, was funded by HHS vertical bar NIH vertical bar National Institute of Environmental Health Sciences (NIEHS) (ES101905).; This research was supported by project number Z01 ES101905 of the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, to Roel M. Schaaper. NR 71 TC 0 Z9 0 U1 4 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD JUN PY 2016 VL 198 IS 11 BP 1631 EP 1644 DI 10.1128/JB.00218-16 PG 14 WC Microbiology SC Microbiology GA DM2VN UT WOS:000376206300011 PM 27002130 ER PT J AU Shaffer, BC Ahn, KW Hu, ZH Nishihori, T Malone, AK Valcarcel, D Grunwald, MR Bacher, U Hamilton, B Kharfan-Dabaja, MA Saad, A Cutler, C Warlick, E Reshef, R Wirk, BM Sabloff, M Fasan, O Gerds, A Marks, D Olsson, R Wood, WA Costa, LJ Miller, AM Cortes, J Daly, A Kindwall-Keller, TL Kamble, R Rizzieri, DA Cahn, JY Gale, RP William, B Litzow, M Wiernik, PH Liesveld, J Savani, BN Vij, R Ustun, C Copelan, E Popat, U Kalaycio, M Maziarz, R Alyea, E Sobecks, R Pavletic, S Tallman, M Saber, W AF Shaffer, Brian C. Ahn, Kwang Woo Hu, Zhen-Huan Nishihori, Taiga Malone, Adriana K. Valcarcel, David Grunwald, Michael R. Bacher, Ulrike Hamilton, Betty Kharfan-Dabaja, Mohamed A. Saad, Ayman Cutler, Corey Warlick, Erica Reshef, Ran Wirk, Baldeep Mona Sabloff, Mitchell Fasan, Omotayo Gerds, Aaron Marks, David Olsson, Richard Wood, William Allen Costa, Luciano J. Miller, Alan M. Cortes, Jorge Daly, Andrew Kindwall-Keller, Tamila L. Kamble, Rammurti Rizzieri, David A. Cahn, Jean-Yves Gale, Robert Peter William, Basem Litzow, Mark Wiernik, Peter H. Liesveld, Jane Savani, Bipin N. Vij, Ravi Ustun, Celalettin Copelan, Edward Popat, Uday Kalaycio, Matt Maziarz, Richard Alyea, Edwin Sobecks, Ron Pavletic, Steven Tallman, Martin Saber, Wad TI Scoring System Prognostic of Outcome in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACUTE MYELOID-LEUKEMIA; BONE-MARROW-TRANSPLANTATION; MONOSOMAL KARYOTYPE; DECISION-ANALYSIS; RISK; MDS; CLASSIFICATION; DISEASE; BLOOD; INDEX AB Purpose To develop a system prognostic of outcome in those undergoing allogeneic hematopoietic cell transplantation (allo HCT) for myelodysplastic syndrome (MDS). Patients and Methods We examined 2,133 patients with MDS undergoing HLA-matched (n = 1,728) or -mismatched (n = 405) allo HCT from 2000 to 2012. We used a Cox multivariable model to identify factors prognostic of mortality in a training subset (n = 1,151) of the HLA-matched cohort. A weighted score using these factors was assigned to the remaining patients undergoing HLA-matched allo HCT (validation cohort; n = 577) as well as to patients undergoing HLA-mismatched allo HCT. Results Blood blasts greater than 3% (hazard ratio [HR], 1.41; 95% CI, 1.08 to 1.85), platelets 50 3 10(9)/L or less at transplantation (HR, 1.37; 95% CI, 1.18 to 1.61), Karnofsky performance status less than 90% (HR, 1.25; 95% CI, 1.06 to 1.28), comprehensive cytogenetic risk score of poor or very poor (HR, 1.43; 95% CI, 1.14 to 1.80), and age 30 to 49 years (HR, 1.60; 95% CI, 1.09 to 2.35) were associated with increased hazard of death and assigned 1 point in the scoring system. Monosomal karyotype (HR, 2.01; 95% CI, 1.65 to 2.45) and age 50 years or older (HR, 1.93; 95% CI, 1.36 to 2.83) were assigned 2 points. The 3-year overall survival after transplantation in patients with low (0 to 1 points), intermediate (2 to 3), high (4 to 5) and very high (>= 6) scores was 71% (95% CI, 58% to 85%), 49% (95% CI, 42% to 56%), 41% (95% CI, 31% to 51%), and 25% (95% CI, 4% to 46%), respectively (P < .001). Increasing score was predictive of increased relapse (P < .001) and treatment-related mortality (P < .001) in the HLA-matched set and relapse (P < .001) in the HLA-mismatched cohort. Conclusion The proposed system is prognostic of outcome in patients undergoing HLA-matched and -mismatched allo HCT for MDS. (C) 2016 by American Society of Clinical Oncology C1 [Shaffer, Brian C.; Tallman, Martin] Mem Sloan Kettering Canc Ctr, 12-b York Ave, New York, NY 10065 USA. [Malone, Adriana K.] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Reshef, Ran] Columbia Univ, Med Ctr, New York, NY USA. [Litzow, Mark] Mayo Clin Rochester, Rochester, NY USA. [Liesveld, Jane] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Wiernik, Peter H.] Our Lady Mercy Med Ctr, Bronx, NY USA. [Ahn, Kwang Woo; Hu, Zhen-Huan; Saber, Wad] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Nishihori, Taiga; Kharfan-Dabaja, Mohamed A.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Valcarcel, David] Hosp Valle De Hebron, Barcelona, Spain. [Grunwald, Michael R.; Fasan, Omotayo; Copelan, Edward] Carolinas HealthCare Syst, Levine Canc Inst, Charlotte, NC USA. [Wood, William Allen] Univ N Carolina, Chapel Hill, NC USA. [Rizzieri, David A.] Duke Univ, Med Ctr, Durham, NC USA. [Bacher, Ulrike] Univ Med Gottingen, Gottingen, Germany. [Hamilton, Betty; Gerds, Aaron] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Kalaycio, Matt; Sobecks, Ron] Cleveland Clin Fdn, 9500 Euclid Ave, Cleveland, OH 44195 USA. [William, Basem] Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. [Saad, Ayman; Costa, Luciano J.] Univ Alabama Birmingham, Birmingham, AL USA. [Cutler, Corey; Alyea, Edwin] Dana Farber Canc Inst, Boston, MA 02115 USA. [Warlick, Erica; Ustun, Celalettin] Univ Minnesota, Med Ctr, Minneapolis, MN 55455 USA. [Wirk, Baldeep Mona] Seattle Canc Care Alliance, Seattle, WA USA. [Sabloff, Mitchell] Univ Ottawa, Ottawa, ON, Canada. [Sabloff, Mitchell] Ottawa Hosp, Res Inst, Ottawa, ON, Canada. [Daly, Andrew] Tom Baker Canc Clin, Calgary, AB, Canada. [Marks, David] Univ Hosp Bristol Natl Hlth Serv Trust, Bristol, Avon, England. [Gale, Robert Peter] Univ London Imperial Coll Sci Technol & Med, London, England. [Olsson, Richard] Karolinska Inst, Stockholm, Sweden. [Miller, Alan M.] Baylor Univ, Med Ctr, Dallas, TX USA. [Kamble, Rammurti] Baylor Coll Med, Dallas, TX USA. [Cortes, Jorge; Popat, Uday] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Kindwall-Keller, Tamila L.] Univ Virginia Hlth Syst, Charlottesville, VA USA. [Cahn, Jean-Yves] Univ Hosp Grenoble, La Tronche, France. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Vij, Ravi] Washington Univ, Sch Med, St Louis, MO USA. [Maziarz, Richard] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Pavletic, Steven] NCI, Bethesda, MD 20892 USA. RP Shaffer, BC (reprint author), Mem Sloan Kettering Canc Ctr, 12-b York Ave, New York, NY 10065 USA. EM shaffeb1@mskcc.org OI Saad, Ayman /0000-0003-0003-0130 FU Public Health Service Grant from the National Cancer Institute (NCI) [U24-CA76518]; National Heart, Lung and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases (NIAID); NHLBI [5U01HL069294]; NCI; Health Resources and Services Administration (HRSA/DHHS) [HHSH234200637015C]; Office of Naval Research [N00014-06-1-0704, N00014-08-1-0058]; Allos, Inc.; Amgen, Inc.; Angioblast; Be the Match Foundation; Blue Cross and Blue Shield Association; Buchanan Family Foundation; CaridianBCT; 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; Kiadis Pharma; Leukemia & Lymphoma Society; Medical College of Wisconsin; Millennium Pharmaceuticals, Inc.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; Swedish Orphan Biovitrum; THERAKOS, Inc.; Wellpoint, Inc. FX The CIBMTR 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 (NIAID); a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); two Grants, N00014-06-1-0704 and N00014-08-1-0058, from the Office of Naval Research; and grants from Allos, Inc.; Amgen, Inc.; Angioblast; an anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Buchanan Family Foundation; CaridianBCT; 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; Kiadis Pharma; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Millennium Pharmaceuticals, Inc.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; Swedish Orphan Biovitrum; THERAKOS, Inc.; and Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, or any other agency of the U.S. Government. NR 29 TC 6 Z9 6 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 1 PY 2016 VL 34 IS 16 BP 1864 EP + DI 10.1200/JCO.2015.65.0515 PG 11 WC Oncology SC Oncology GA DM6KU UT WOS:000376461900010 PM 27044940 ER PT J AU Desmedt, C Zoppoli, G Gundem, G Pruneri, G Larsimont, D Fornili, M Fumagalli, D Brown, D Rothe, F Vincent, D Kheddoumi, N Rouas, G Majjaj, S Brohee, S Van Loo, P Maisonneuve, P Salgado, R Van Brussel, T Lambrechts, D Bose, R Metzger, O Galant, C Bertucci, F Piccart-Gebhart, M Viale, G Biganzoli, E Campbell, PJ Sotiriou, C AF Desmedt, Christine Zoppoli, Gabriele Gundem, Gunes Pruneri, Giancarlo Larsimont, Denis Fornili, Marco Fumagalli, Debora Brown, David Rothe, Francoise Vincent, Delphine Kheddoumi, Naima Rouas, Ghizlane Majjaj, Samira Brohee, Sylvain Van Loo, Peter Maisonneuve, Patrick Salgado, Roberto Van Brussel, Thomas Lambrechts, Diether Bose, Ron Metzger, Otto Galant, Christine Bertucci, Francois Piccart-Gebhart, Martine Viale, Giuseppe Biganzoli, Elia Campbell, Peter J. Sotiriou, Christos TI Genomic Characterization of Primary Invasive Lobular Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID TRANSCRIPTION FACTOR; MUTATIONS; CARCINOMA; HER2; AMPLIFICATION; TAMOXIFEN; VARIANTS; COMPLEX; POINTS; PTEN AB Purpose Invasive lobular breast cancer (ILBC) is the second most common histologic subtype after invasive ductal breast cancer (IDBC). Despite clinical and pathologic differences, ILBC is still treated as IDBC. We aimed to identify genomic alterations in ILBC with potential clinical implications. Methods From an initial 630 ILBC primary tumors, we interrogated oncogenic substitutions and insertions and deletions of 360 cancer genes and genome-wide copy number aberrations in 413 and 170 ILBC samples, respectively, and correlated those findings with clinicopathologic and outcome features. Results Besides the high mutation frequency of CDH1 in 65% of tumors, alterations in one of the three key genes of the phosphatidylinositol 3-kinase pathway, PIK3CA, PTEN, and AKT1, were present in more than one-half of the cases. HER2 and HER3 were mutated in 5.1% and 3.6% of the tumors, with most of these mutations having a proven role in activating the human epidermal growth factor receptor/ERBB pathway. Mutations in FOXA1 and ESR1 copy number gains were detected in 9% and 25% of the samples. All these alterations were more frequent in ILBC than in IDBC. The histologic diversity of ILBC was associated with specific alterations, such as enrichment for HER2 mutations in the mixed, nonclassic, and ESR1 gains in the solid subtype. Survival analyses revealed that chromosome 1q and 11p gains showed independent prognostic value in ILBC and that HER2 and AKT1 mutations were associated with increased risk of early relapse. Conclusion This study demonstrates that we can now begin to individualize the treatment of ILBC, with HER2, HER3, and AKT1 mutations representing high-prevalence therapeutic targets and FOXA1 mutations and ESR1 gains deserving urgent dedicated clinical investigation, especially in the context of endocrine treatment. (C) 2016 by American Society of Clinical Oncology C1 [Desmedt, Christine; Zoppoli, Gabriele; Larsimont, Denis; Fumagalli, Debora; Brown, David; Rothe, Francoise; Vincent, Delphine; Kheddoumi, Naima; Rouas, Ghizlane; Majjaj, Samira; Brohee, Sylvain; Salgado, Roberto; Piccart-Gebhart, Martine; Sotiriou, Christos] Inst Jules Bordet, B-1000 Brussels, Belgium. [Galant, Christine] Clin Univ St Luc, B-1200 Brussels, Belgium. [Van Loo, Peter] Univ Leuven, Leuven, Belgium. [Van Brussel, Thomas; Lambrechts, Diether] VIB Vesalius Res Ctr, Leuven, Belgium. [Zoppoli, Gabriele] Univ Genoa, Genoa, Italy. [Zoppoli, Gabriele] Natl Canc Inst, Ist Ric Carattere Clin Sci San Martino, Genoa, Italy. [Pruneri, Giancarlo; Maisonneuve, Patrick; Viale, Giuseppe] European Inst Oncol, Milan, Italy. [Fornili, Marco; Biganzoli, Elia] Univ Milan, Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, Milan, Italy. [Gundem, Gunes; Campbell, Peter J.] Wellcome Trust Sanger Inst, Hinxton, Cambs, England. [Van Loo, Peter] Francis Crick Inst, London, England. [Bose, Ron] Washington Univ, Sch Med, St Louis, MO USA. [Metzger, Otto] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bertucci, Francois] Inst J Paoli I Calmettes, F-13009 Marseille, France. RP Desmedt, C (reprint author), Inst Jules Bordet, Breast Canc Translat Res Lab, 125 Blvd Waterloo, B-1000 Brussels, Belgium. EM christine.desmedt@bordet.be OI Desmedt, Christine/0000-0002-5223-5579 FU Susan G. Komen; Fondation MEDIC; Les Amis de Bordet; Fonds National de Recherche Scientifique; Breast Cancer Research Foundation; Wellcome Trust Clinical Research Training Fellowship Programs; Italian Association for Leukemia and Lymphoma; Italian Association for Cancer Research FX Supported by Susan G. Komen, Fondation MEDIC, Les Amis de Bordet, Fonds National de Recherche Scientifique, the Breast Cancer Research Foundation, the Wellcome Trust Clinical Research Training Fellowship Programs, the Italian Association for Leukemia and Lymphoma, and the Italian Association for Cancer Research. NR 33 TC 12 Z9 12 U1 4 U2 9 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 1 PY 2016 VL 34 IS 16 BP 1872 EP + DI 10.1200/JCO.2015.64.0334 PG 12 WC Oncology SC Oncology GA DM6KU UT WOS:000376461900011 PM 26926684 ER PT J AU Fletcher, P Bertram, R Tabak, J AF Fletcher, Patrick Bertram, Richard Tabak, Joel TI From global to local: exploring the relationship between parameters and behaviors in models of electrical excitability SO JOURNAL OF COMPUTATIONAL NEUROSCIENCE LA English DT Article DE Electrical activity; Pituitary lactotroph; Global parameter sampling; Bifurcation analysis; Graphics processing unit ID MULTICOMPARTMENT MODEL; BIFURCATION-ANALYSIS; PITUITARY-CELLS; CHANNEL DENSITY; MOTOR PATTERN; SPIKING; CONDUCTANCES; VARIABILITY; PHYSIOLOGY; DYNAMICS AB Models of electrical activity in excitable cells involve nonlinear interactions between many ionic currents. Changing parameters in these models can produce a variety of activity patterns with sometimes unexpected effects. Further more, introducing new currents will have different effects depending on the initial parameter set. In this study we combined global sampling of parameter space and local analysis of representative parameter sets in a pituitary cell model to understand the effects of adding K (+) conductances, which mediate some effects of hormone action on these cells. Global sampling ensured that the effects of introducing K (+) conductances were captured across a wide variety of contexts of model parameters. For each type of K (+) conductance we determined the types of behavioral transition that it evoked. Some transitions were counterintuitive, and may have been missed without the use of global sampling. In general, the wide range of transitions that occurred when the same current was applied to the model cell at different locations in parameter space highlight the challenge of making accurate model predictions in light of cell-to-cell heterogeneity. Finally, we used bifurcation analysis and fast/slow analysis to investigate why specific transitions occur in representative individual models. This approach relies on the use of a graphics processing unit (GPU) to quickly map parameter space to model behavior and identify parameter sets for further analysis. Acceleration with modern low-cost GPUs is particularly well suited to exploring the moderate-sized (5-20) parameter spaces of excitable cell and signaling models. C1 [Bertram, Richard] Florida State Univ, Dept Math, Tallahassee, FL 32306 USA. [Fletcher, Patrick] NIH, Lab Biol Modeling, Bldg 10, Bethesda, MD 20892 USA. [Tabak, Joel] Univ Exeter, Sch Med, Biomed Neurosci Res Grp, Exeter EX4 4PS, Devon, England. RP Bertram, R (reprint author), Florida State Univ, Dept Math, Tallahassee, FL 32306 USA. EM bertram@math.fsu.edu OI Fletcher, Patrick/0000-0003-0227-5895 FU National Science Foundation [DMS1220063] FX This work was supported by grant DMS1220063 from the National Science Foundation. NR 54 TC 0 Z9 0 U1 3 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5313 EI 1573-6873 J9 J COMPUT NEUROSCI JI J. Comput. Neurosci. PD JUN PY 2016 VL 40 IS 3 BP 331 EP 345 DI 10.1007/s10827-016-0600-1 PG 15 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA DM1LC UT WOS:000376105800006 PM 27033230 ER PT J AU Sanchez-Merino, V Fabra-Garcia, A Gonzalez, N Nicolas, D Merino-Mansilla, A Manzardo, C Ambrosioni, J Schultz, A Meyerhans, A Mascola, JR Gatell, JM Alcami, J Miro, JM Yuste, E AF Sanchez-Merino, V. Fabra-Garcia, A. Gonzalez, N. Nicolas, D. Merino-Mansilla, A. Manzardo, C. Ambrosioni, J. Schultz, A. Meyerhans, A. Mascola, J. R. Gatell, J. M. Alcami, J. Miro, J. M. Yuste, E. TI Detection of Broadly Neutralizing Activity within the First Months of HIV-1 Infection SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; SUBTYPE-C INFECTION; ANTIBODY-RESPONSES; PASSIVE TRANSFER; BINDING-SITE; VIREMIA; MACAQUES; PROTECTION; ENVELOPE; TRANSMISSION AB A fraction of HIV-1 patients are able to generate broadly neutralizing antibodies (bNAbs) after 2 to 4 years of infection. In rare occasions such antibodies are observed close to the first year of HIV-1 infection but never within the first 6 months. In this study, we analyzed the neutralization breadth of sera from 157 antiretroviral-naive individuals who were infected for less than 1 year. A range of neutralizing activities was observed with a previously described panel of six recombinant viruses from five different subtypes (M. Medina-Ramirez et al., J Virol 85:5804-5813, 2011, http://dx.doi.org/10.1128/JVI.02482-10). Some sera were broadly reactive, predominantly targeting envelope epitopes within the V2 glycan-dependent region. The neutralization breadth was positively associated with time postinfection (P = 0.0001), but contrary to what has been reported for chronic infections, no association with the viral load was observed. Notably, five individuals within the first 6 months of infection (two as early as 77 and 96 days postinfection) showed substantial cross-neutralization. This was confirmed with an extended panel of 20 Env pseudoviruses from four different subtypes (two in tier 3, 14 in tier 2, and four in tier 1). Sera from these individuals were capable of neutralizing viruses from four different subtypes with a geometric mean 50% infective dose (ID50) between 100 and 800. These results indicate that induction of cross-neutralizing responses, albeit rare, is achievable even within 6 months of HIV-1 infection. These observations encourage the search for immunogens able to elicit this kind of response in preventive HIV-1 vaccine approaches. IMPORTANCE There are very few individuals able to mount broadly neutralizing activity (bNA) close to the first year postinfection. It is not known how early in the infection cross-neutralizing responses can be induced. In the present study, we show that bNAbs, despite being rare, can be induced much earlier than previously thought. The identification of HIV-1-infected patients with these activities within the first months of infection and characterization of these responses will help in defining new immunogen designs and neutralization targets for vaccine-mediated induction of bNAbs. C1 [Sanchez-Merino, V.; Fabra-Garcia, A.; Merino-Mansilla, A.; Yuste, E.] Inst Invest Biomed August Pi & Sunyer IDIBAPS, AIDS Res Unit, Barcelona, Spain. [Sanchez-Merino, V.; Fabra-Garcia, A.; Merino-Mansilla, A.; Yuste, E.] HIVACAT, Barcelona, Spain. [Gonzalez, N.; Alcami, J.] Inst Salud Carlos III, Ctr Nacl Microbiol, AIDS Immunopathogenesis Unit, Madrid, Spain. [Nicolas, D.; Manzardo, C.; Ambrosioni, J.; Gatell, J. M.; Miro, J. M.] Univ Barcelona, Hosp Clin IDIBAPS, Infect Dis Sev, Barcelona, Spain. [Schultz, A.] Fraunhofer Inst Biomed Engn, Sulzbach, Germany. [Meyerhans, A.] Univ Pompeu Fabra, Infect Biol Lab, Barcelona, Spain. [Meyerhans, A.] ICREA, Barcelona, Spain. [Mascola, J. R.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Sanchez-Merino, V (reprint author), Inst Invest Biomed August Pi & Sunyer IDIBAPS, AIDS Res Unit, Barcelona, Spain.; Sanchez-Merino, V (reprint author), HIVACAT, Barcelona, Spain. EM vmsanchez@clinic.ub.es FU Ministerio de Ciencia y Tecnologia [RYC-2007-00788]; Instituto de Salud Carlos III (ISCIII) (ERDF, "A Way to Build Europe") [FIS PI13/01528]; Instituto de Salud Carlos III (ISCIII) [INT15/00168]; Ministerio de Economia y Competitividad (MINECO) (Juan de la Cierva Program) [FIS PI12/00506]; Spanish AIDS Research Network (Instituto de Salud Carlos III); Spanish AIDS Research Network (fondos FEDER); Spanish AIDS Research Network [RD12/0017/0015, RD12/0017/0001]; Josep Font Fellowship; European Union's Horizon [681137]; Ministerio de Economia y Competitividad (MINECO) [IPT2012-0325] FX This work, including the efforts of Eloisa Yuste, was funded by Ministerio de Ciencia y Tecnologia (RYC-2007-00788). This work, including the efforts of Eloisa Yuste, was funded by Instituto de Salud Carlos III (ISCIII) (ERDF, "A Way to Build Europe," and FIS PI13/01528). This work, including the efforts of Victor Sanchez-Merino, was funded by Ministerio de Economia y Competitividad (MINECO) (IPT2012-0325). This work, including the efforts of Juan Ambrosioni, was funded by Ministerio de Economia y Competitividad (MINECO) (Juan de la Cierva Program 2012 and FIS PI12/00506). This work, including the efforts of Nuria Gonzalez, was funded by Spanish AIDS Research Network (Instituto de Salud Carlos III, fondos FEDER, and RD12/0017/0015). This work, including the efforts of Alberto Merino-Mansilla, was funded by Spanish AIDS Research Network (Instituto de Salud Carlos III, fondos FEDER, and RD12/0017/0001). This work, including the efforts of David Nicolas, was funded by Josep Font Fellowship. This work, including the efforts of Jose Maria Miro, was funded by Instituto de Salud Carlos III (ISCIII) (INT15/00168). This work, including the efforts of Jose Maria Miro, was funded by European Union's Horizon 2020 (681137). NR 66 TC 1 Z9 1 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUN PY 2016 VL 90 IS 11 BP 5231 EP 5245 DI 10.1128/JVI.00049-16 PG 15 WC Virology SC Virology GA DM2ES UT WOS:000376160200004 PM 26984721 ER PT J AU van Doremalen, N Miazgowicz, KL Munster, VJ AF van Doremalen, Neeltje Miazgowicz, Kerri L. Munster, Vincent J. TI Mapping the Specific Amino Acid Residues That Make Hamster DPP4 Functional as a Receptor for Middle East Respiratory Syndrome Coronavirus SO JOURNAL OF VIROLOGY LA English DT Article ID DIPEPTIDYL PEPTIDASE 4; MERS-COV; MOUSE MODEL; RHESUS MACAQUES; INFECTION; GENERATION; BINDING; TRACT AB The novel emerging coronavirus Middle East respiratory syndrome coronavirus (MERS-CoV) binds to its receptor, dipeptidyl peptidase 4 (DPP4), via 14 interacting amino acids. We previously showed that if the five interacting amino acids which differ between hamster and human DPP4 are changed to the residues found in human DPP4, hamster DPP4 does act as a receptor. Here, we show that the functionality of hamster DPP4 as a receptor is severely decreased if less than 4 out of 5 amino acids are changed. IMPORTANCE The novel emerging coronavirus MERS-CoV has infected > 1,600 people worldwide, and the case fatality rate is similar to 36%. In this study, we show that by changing 4 amino acids in hamster DPP4, this protein functions as a receptor for MERS-CoV. This work is vital in the development of new small-animal models, which will broaden our understanding of MERS-CoV and be instrumental in the development of countermeasures. C1 [van Doremalen, Neeltje; Miazgowicz, Kerri L.; Munster, Vincent J.] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. [Miazgowicz, Kerri L.] Univ Georgia, Coll Vet Med, Dept Infect Dis, Athens, GA USA. RP Munster, VJ (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. EM vincent.munster@nih.gov OI Munster, Vincent/0000-0002-2288-3196 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID); Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) FX This work, including the efforts of Neeltje van Doremalen, Kerri Miazgowicz, and Vincent J. Munster, was funded by Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID).; This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). NR 17 TC 1 Z9 1 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 JUN PY 2016 VL 90 IS 11 BP 5499 EP 5502 DI 10.1128/JVI.03267-15 PG 4 WC Virology SC Virology GA DM2ES UT WOS:000376160200025 PM 27030263 ER PT J AU Sakamoto, K Wehde, BL Yoo, KH Kim, T Rajbhandari, N Shin, HY Triplett, AA Radler, PD Schuler, F Villunger, A Kang, K Hennighausen, L Wagner, KU AF Sakamoto, Kazuhito Wehde, Barbara L. Yoo, Kyung Hyun Kim, Taemook Rajbhandari, Nirakar Shin, Ha Youn Triplett, Aleata A. Radler, Patrick D. Schuler, Fabian Villunger, Andreas Kang, Keunsoo Hennighausen, Lothar Wagner, Kay-Uwe TI Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CONDITIONAL KNOCKOUT MICE; ESTROGEN-RECEPTOR-ALPHA; TRANSCRIPTION FACTOR; EPITHELIAL-CELLS; PROTEIN-KINASE; BREAST-CANCER; TUMOR BURDEN; IN-VIVO; GENE; STAT3 AB Despite a wealth of knowledge about the significance of individual signal transducers and activators of transcription (STATs), essential functions of their upstream Janus kinases (JAKs) during postnatal development are less well defined. Using a novel mammary gland-specific JAK1 knockout model, we demonstrate here that this tyrosine kinase is essential for the activation of STAT1, STAT3, and STAT6 in the mammary epithelium. The loss of JAK1 uncouples interleukin-6-class ligands from their downstream effector, STAT3, which leads to the decreased expression of STAT3 target genes that are associated with the acute-phase response, inflammation, and wound healing. Consequently, JAK1-deficient mice exhibit impaired apoptosis and a significant delay in mammary gland remodeling. Using RNA sequencing, we identified several new JAK1 target genes that are upregulated during involution. These include Bmf and Bim, which are known regulators of programmed cell death. Using a BMF/BIM-double-knockout epithelial transplant model, we further validated that the synergistic action of these proapoptotic JAK1 targets is obligatory for the remodeling of the mammary epithelium. The collective results of this study suggest that JAK1 has nonredundant roles in the activation of particular STAT proteins and this tyrosine kinase is essential for coupling inflammatory cytokine signals to the cell death machinery in the differentiated mammary epithelium. C1 [Sakamoto, Kazuhito; Wehde, Barbara L.; Rajbhandari, Nirakar; Triplett, Aleata A.; Radler, Patrick D.; Wagner, Kay-Uwe] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE USA. [Yoo, Kyung Hyun; Shin, Ha Youn; Hennighausen, Lothar] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. [Kim, Taemook] Dankook Univ, Dept Nanobiomed Sci, Cheonan, South Korea. [Kim, Taemook] Dankook Univ, PLUS NBM Global Res Ctr Regenerat Med BK21, Cheonan, South Korea. [Kang, Keunsoo] Dankook Univ, Dept Microbiol, Cheonan, South Korea. [Schuler, Fabian; Villunger, Andreas] Med Univ Innsbruck, Bioctr, Div Dev Immunol, A-6020 Innsbruck, Austria. [Schuler, Fabian; Villunger, Andreas] Tyrolean Canc Res Inst, Innsbruck, Austria. [Sakamoto, Kazuhito] Asahi Kasei Pharma Corp, Shizuoka, Japan. RP Wagner, KU (reprint author), Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE USA. EM kuwagner@unmc.edu FU HHS \ NIH \ National Cancer Institute (NCI) [CA117930, CA009476]; Austrian Science Fund (FWF) [W1101] FX This work, including the efforts of Kay-Uwe Wagner, was funded by HHS vertical bar NIH vertical bar National Cancer Institute (NCI) (CA117930). This work, including the efforts of Barbara L. Wehde, was funded by HHS vertical bar NIH vertical bar National Cancer Institute (NCI) (CA009476). This work, including the efforts of Andreas Villunger, was funded by Austrian Science Fund (FWF) (W1101). NR 59 TC 3 Z9 3 U1 2 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2016 VL 36 IS 11 BP 1673 EP 1690 DI 10.1128/MCB.00999-15 PG 18 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DM2ST UT WOS:000376198400006 PM 27044867 ER PT J AU Yang, YQ Park, JW Bebee, TW Warzecha, CC Guo, Y Shang, XQ Xing, Y Carstens, RP AF Yang, Yueqin Park, Juw Won Bebee, Thomas W. Warzecha, Claude C. Guo, Yang Shang, Xuequn Xing, Yi Carstens, Russ P. TI Determination of a Comprehensive Alternative Splicing Regulatory Network and Combinatorial Regulation by Key Factors during the Epithelial-to-Mesenchymal Transition SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RNA-BINDING PROTEIN; MESSENGER-RNAS; BREAST-CANCER; CELL-DIFFERENTIATION; MIR-200 FAMILY; STAR PROTEIN; STEM-CELLS; IN-VIVO; QUAKING; PHOSPHORYLATION AB The epithelial-to-mesenchymal transition (EMT) is an essential biological process during embryonic development that is also implicated in cancer metastasis. While the transcriptional regulation of EMT has been well studied, the role of alternative splicing (AS) regulation in EMT remains relatively uncharacterized. We previously showed that the epithelial cell-type-specific proteins epithelial splicing regulatory proteins 1 (ESRP1) and ESRP2 are important for the regulation of many AS events that are altered during EMT. However, the contributions of the ESRPs and other splicing regulators to the AS regulatory network in EMT require further investigation. Here, we used a robust in vitro EMT model to comprehensively characterize splicing switches during EMT in a temporal manner. These investigations revealed that the ESRPs are the major regulators of some but not all AS events during EMT. We determined that the splicing factor RBM47 is downregulated during EMT and also regulates numerous transcripts that switch splicing during EMT. We also determined that Quaking (QKI) broadly promotes mesenchymal splicing patterns. Our study highlights the broad role of posttranscriptional regulation during the EMT and the important role of combinatorial regulation by different splicing factors to fine tune gene expression programs during these physiological and developmental transitions. C1 [Yang, Yueqin; Bebee, Thomas W.; Warzecha, Claude C.; Carstens, Russ P.] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Yang, Yueqin; Bebee, Thomas W.; Warzecha, Claude C.; Carstens, Russ P.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Park, Juw Won; Guo, Yang; Xing, Yi] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA USA. [Park, Juw Won] Univ Louisville, Dept Comp Engn & Comp Sci, Louisville, KY 40292 USA. [Park, Juw Won] Univ Louisville, KBRIN Bioinformat Core, Louisville, KY 40292 USA. [Guo, Yang; Shang, Xuequn] Northwestern Polytech Univ, Sch Comp Sci, Xian 710072, Peoples R China. [Warzecha, Claude C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Carstens, RP (reprint author), Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA.; Carstens, RP (reprint author), Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA.; Xing, Y (reprint author), Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA USA. EM yxing@ucla.edu; russcars@upenn.edu FU Chinese National Natural Science Foundation [61332014]; HHS \ NIH \ National Institute of General Medical Sciences (NIGMS) [GM088809, GM088342]; HHS \ NIH \ National Institute of Dental and Craniofacial Research (NIDCR) [DE024949]; China Scholarship Council (CSC); Alfred P. Sloan Foundation; HHS \ NIH \ National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [AR066741] FX This work, including the efforts of Xuequn Shang, was funded by Chinese National Natural Science Foundation (61332014). This work, including the efforts of Russ P. Carstens, was funded by HHS vertical bar NIH vertical bar National Institute of General Medical Sciences (NIGMS) (GM088809). This work, including the efforts of Yi Xing, was funded by HHS vertical bar NIH vertical bar National Institute of General Medical Sciences (NIGMS) (GM088342). This work, including the efforts of Russ P. Carstens, was funded by HHS vertical bar NIH vertical bar National Institute of Dental and Craniofacial Research (NIDCR) (DE024949). This work, including the efforts of Yang Guo, was funded by China Scholarship Council (CSC). This work, including the efforts of Yi Xing, was funded by Alfred P. Sloan Foundation. This work, including the efforts of Russ P. Carstens, was funded by HHS vertical bar NIH vertical bar National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (AR066741). NR 72 TC 4 Z9 4 U1 4 U2 12 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2016 VL 36 IS 11 BP 1704 EP 1719 DI 10.1128/MCB.00019-16 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DM2ST UT WOS:000376198400008 PM 27044866 ER PT J AU Didion, JP Morgan, AP Yadgary, L Bell, TA McMullan, RC de Solorzano, LO Britton-Davidian, J Bult, CJ Campbell, KJ Castiglia, R Ching, YH Chunco, AJ Crowley, JJ Chesler, EJ Forster, DW French, JE Gabriel, SI Gatti, DM Garland, T Giagia-Athanasopoulou, EB Gimenez, MD Grize, SA Gunduz, I Holmes, A Hauffe, HC Herman, JS Holt, JM Hua, KJ Jolley, WJ Lindholm, AK Lopez-Fuster, MJ Mitsainas, G Mathias, MD McMillan, L Ramalhinho, MDM Rehermann, B Rosshart, SP Searle, JB Shiao, MS Solano, E Svenson, KL Thomas-Laemont, P Threadgill, DW Ventura, J Weinstock, GM Pomp, D Churchill, GA de Villena, FPM AF Didion, John P. Morgan, Andrew P. Yadgary, Liran Bell, Timothy A. McMullan, Rachel C. de Solorzano, Lydia Ortiz Britton-Davidian, Janice Bult, Carol J. Campbell, Karl J. Castiglia, Riccardo Ching, Yung-Hao Chunco, Amanda J. Crowley, James J. Chesler, Elissa J. Foerster, Daniel W. French, John E. Gabriel, Sofia I. Gatti, Daniel M. Garland, Theodore Giagia-Athanasopoulou, Eva B. Gimenez, Mabel D. Grize, Sofia A. Gunduz, Islam Holmes, Andrew Hauffe, Heidi C. Herman, Jeremy S. Holt, James M. Hua, Kunjie Jolley, Wesley J. Lindholm, Anna K. Lopez-Fuster, Maria J. Mitsainas, George Mathias, Maria da Luz McMillan, Leonard Morgado Ramalhinho, Maria da Graca Rehermann, Barbara Rosshart, Stephan P. Searle, Jeremy B. Shiao, Meng-Shin Solano, Emanuela Svenson, Karen L. Thomas-Laemont, Patricia Threadgill, David W. Ventura, Jacint Weinstock, George M. Pomp, Daniel Churchill, Gary A. de Villena, Fernando Pardo-Manuel TI R2d2 Drives Selfish Sweeps in the House Mouse SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE R2d2; Meiotic Drive; Selfish Genes; Selective Sweep; House Mouse ID TRANSMISSION-RATIO DISTORTION; RECENT POSITIVE SELECTION; MUS-MUSCULUS-DOMESTICUS; IDENTITY-BY-DESCENT; MEIOTIC DRIVE; DROSOPHILA-SIMULANS; HUMAN GENOME; INTERSPECIFIC BACKCROSS; COLLABORATIVE CROSS; NATURAL-POPULATIONS AB A selective sweep is the result of strong positive selection driving newly occurring or standing genetic variants to fixation, and can dramatically alter the pattern and distribution of allelic diversity in a population. Population-level sequencing data have enabled discoveries of selective sweeps associated with genes involved in recent adaptations in many species. In contrast, much debate but little evidence addresses whether "selfish" genes are capable of fixation-thereby leaving signatures identical to classical selective sweeps-despite being neutral or deleterious to organismal fitness. We previously described R2d2, a large copy-number variant that causes nonrandom segregation of mouse Chromosome 2 in females due to meiotic drive. Here we show population-genetic data consistent with a selfish sweep driven by alleles of R2d2 with high copy number (R2d2(HC)) in natural populations. We replicate this finding inmultiple closed breeding populations from six outbred backgrounds segregating for R2d2 alleles. We find that R2d2(HC) rapidly increases in frequency, and in most cases becomes fixed in significantly fewer generations than can be explained by genetic drift. R2d2(HC) is also associated with significantly reduced litter sizes in heterozygous mothers, making it a true selfish allele. Our data provide direct evidence of populations actively undergoing selfish sweeps, and demonstrate that meiotic drive can rapidly alter the genomic landscape in favor of mutations with neutral or even negative effects on overall Darwinian fitness. Further study will reveal the incidence of selfish sweeps, and will elucidate the relative contributions of selfish genes, adaptation and genetic drift to evolution. C1 [Didion, John P.; Morgan, Andrew P.; Yadgary, Liran; Bell, Timothy A.; McMullan, Rachel C.; de Solorzano, Lydia Ortiz; Crowley, James J.; Hua, Kunjie; Pomp, Daniel; de Villena, Fernando Pardo-Manuel] Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA. [Didion, John P.; Morgan, Andrew P.; Yadgary, Liran; Bell, Timothy A.; McMullan, Rachel C.; de Solorzano, Lydia Ortiz; de Villena, Fernando Pardo-Manuel] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Didion, John P.; Morgan, Andrew P.; Yadgary, Liran; Bell, Timothy A.; McMullan, Rachel C.; de Solorzano, Lydia Ortiz; Pomp, Daniel; de Villena, Fernando Pardo-Manuel] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Britton-Davidian, Janice] Univ Montpellier, CNRS, EPHE, Inst Sci Evolut,IRD, F-34059 Montpellier, France. [Bult, Carol J.; Chesler, Elissa J.; Gatti, Daniel M.; Svenson, Karen L.; Churchill, Gary A.] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. [Campbell, Karl J.] Isl Conservat, Puerto Ayora, Galapagos Islan, Ecuador. [Campbell, Karl J.] Univ Queensland, Sch Geog Planning & Environm Management, St Lucia, Qld, Australia. [Castiglia, Riccardo; Solano, Emanuela] Univ Roma La Sapienza, Dept Biol & Biotechnol Charles Darwin, Piazzale Aldo Moro 5, I-00185 Rome, Italy. [Ching, Yung-Hao] Tzu Chi Univ, Dept Mol Biol & Human Genet, Hualien, Taiwan. [Chunco, Amanda J.; Thomas-Laemont, Patricia] Elon Univ, Dept Environm Studies, Elon, NC 27244 USA. [Foerster, Daniel W.] Leibniz Inst Zoo & Wildlife Res, Dept Evolutionary Genet, Berlin, Germany. [French, John E.] Natl Inst Environm Sci, Natl Toxicol Program, NIH, Res Triangle Pk, NC USA. [Gabriel, Sofia I.; Mathias, Maria da Luz; Morgado Ramalhinho, Maria da Graca] Univ Lisbon, Dept Anim Biol, P-1699 Lisbon, Portugal. [Garland, Theodore] Univ Calif Riverside, Dept Biol, Riverside, CA 92521 USA. [Giagia-Athanasopoulou, Eva B.; Mitsainas, George] Univ Patras, Dept Biol, Sect Anim Biol, Patras, Greece. [Gimenez, Mabel D.] Univ Nacl Misiones, CONICET, Inst Biol Subtrop, Posadas, Misiones, Argentina. [Grize, Sofia A.; Lindholm, Anna K.] Univ Zurich, Inst Evolutionary Biol & Environm Studies, Zurich, Switzerland. [Gunduz, Islam] Ondokuz Mayis Univ, Fac Arts & Sci, Dept Biol, Samsun, Turkey. [Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD USA. [Hauffe, Heidi C.] Fdn Edmund Mach, Res & Innovat Ctr, Dept Biodivers & Mol Ecol, San Michele All Adige, TN, Italy. [Herman, Jeremy S.] Natl Museums Scotland, Dept Nat Sci, Edinburgh, Midlothian, Scotland. [Holt, James M.; McMillan, Leonard] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC USA. [Jolley, Wesley J.] Isl Conservat, Santa Cruz, CA USA. [Lopez-Fuster, Maria J.] Univ Barcelona, Fac Biol, Barcelona, Spain. [Rehermann, Barbara; Rosshart, Stephan P.] NIDDK, Immunol Sect, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Searle, Jeremy B.] Cornell Univ, Dept Ecol & Evolutionary Biol, Ithaca, NY USA. [Shiao, Meng-Shin] Mahidol Univ, Ramathibodi Hosp, Fac Med, Res Ctr, Bangkok 10400, Thailand. [Threadgill, David W.] Texas A&M Univ, Dept Vet Pathobiol, College Stn, TX USA. [Threadgill, David W.] Texas A&M Univ, Dept Mol & Cellular Med, College Stn, TX USA. [Ventura, Jacint] Univ Autonoma Barcelona, Fac Biociencias, Dept Biol Anim Biol Vegetal & Ecol, E-08193 Barcelona, Spain. [Weinstock, George M.] Jackson Lab Genom Med, Farmington, CT USA. RP de Villena, FPM (reprint author), Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA.; de Villena, FPM (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA.; de Villena, FPM (reprint author), Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. EM fernando@med.unc.edu RI Lindholm, Anna/E-5207-2012; Hauffe, Heidi Christine/B-9105-2011; Gabriel, Sofia/C-1770-2013; Mitsainas, George/C-4459-2008; OI Lindholm, Anna/0000-0001-8460-9769; Hauffe, Heidi Christine/0000-0003-3098-8964; Gabriel, Sofia/0000-0003-3702-4631; Mitsainas, George/0000-0003-4976-8275; Didion, John/0000-0002-8111-6261; McMullan, Rachel/0000-0003-0297-4549 FU National Institutes of Health [T32GM067553, F30MH103925, P50GM076468, K01MH094406, DK-076050, DK-056350, AG038070]; National Science Foundation [IOS-1121273]; Vaadia-BARD Postdoctoral Fellowship Award [FI-478-13]; U.S. Army Medical Research and Materiel Command [W81XWH-11-1-0762]; Jackson Laboratory new investigator funds; National Center for Scientific Research, France [ISEM 2016-002]; University of Rome "La Sapienza"; Claraz-Stiftung; Natural Environment Research Council (UK); EU Human Capital and Mobility Programme [CHRX-CT93-0192]; Foundation for Science and Technology, Portugal [PTDC/BIA-EVF/116884/2010, UID/AMB/50017/2013]; Spanish "Ministerio de Ciencia y Tecnologia" [CGL2007-62111]; "Ministerio de Economia y Competitividad" [CGL2010-15243]; School of Medicine at University of North Carolina FX We wish to thank all the scientists and research personnel who collected and processed the samples used in this study. In particular we acknowledge Luanne Peters and Alex Hong-Tsen Yu for providing critical samples; Ryan Buus and T. Justin Gooch for isolating DNA for high-density genotyping of wild-caught mice; and Vicki Cappa, A. Cerveira, Guila Ganem, Ron and Annabelle Lesher, K. Said, Toni Schelts, Dan Small, and J. Tapisso for aiding in mouse trapping. We thank Muriel Davisson at the Jackson Laboratory for maintaining, for several decades, tissue samples from breeding colonies used to generate wild-derived inbred strains. We also thank Francis Collins, Jim Evans, Matthew Hahn, and Corbin Jones for comments on an earlier version of this manuscript. This work was supported by the National Institutes of Health T32GM067553 to J.P.D. and A.P.M., F30MH103925 to A.P.M., P50GM076468 to E.J.C., G.A.C., and F.P.M.V., K01MH094406 to J.J.C., DK-076050 and DK-056350 to D.P., AG038070 to G.A.C, and the intramural research program to B.R. and S.P.R.; National Science Foundation IOS-1121273 to T.G.; Vaadia-BARD Postdoctoral Fellowship Award FI-478-13 to L.Y.; U.S. Army Medical Research and Materiel Command W81XWH-11-1-0762 to C.J.B.; The Jackson Laboratory new investigator funds to E.J.C.; The National Center for Scientific Research, France to J.B.D. (this is contribution no ISEM 2016-002); the University of Rome "La Sapienza" to R.C. and E.S.; Claraz-Stiftung to S.G. and A.L.; Natural Environment Research Council (UK) to M.D.G., H.C.H., and J.B.S.; EU Human Capital and Mobility Programme (CHRX-CT93-0192) to H.C.H. and J.B.S.; Foundation for Science and Technology, Portugal PTDC/BIA-EVF/116884/2010 and UID/AMB/50017/2013 to S.I.G., M.L.M., and J.B.S.; Spanish "Ministerio de Ciencia y Tecnologia" CGL2007-62111 and "Ministerio de Economia y Competitividad" CGL2010-15243 to J.V.;and the Oliver Smithies Investigator funds provided by the School of Medicine at University of North Carolina to F.P.M.V. All data are made available at http://csbio.unc.edu/r2d2/. The authors declare no competing financial interests. Correspondence and requests for materials should be addressed to F.P.M.V. (fernando@med.unc.edu). NR 66 TC 5 Z9 5 U1 13 U2 26 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 EI 1537-1719 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD JUN PY 2016 VL 33 IS 6 BP 1381 EP 1395 DI 10.1093/molbev/msw036 PG 15 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA DM2IM UT WOS:000376170300001 PM 26882987 ER PT J AU de Filippo, C Key, FM Ghirotto, S Benazzo, A Meneu, JR Weihmann, A Parra, G Green, ED Andres, AM AF de Filippo, Cesare Key, Felix M. Ghirotto, Silvia Benazzo, Andrea Meneu, Juan R. Weihmann, Antje Parra, Genis Green, Eric D. Andres, Aida M. CA NISC Comparative Sequence Program TI Recent Selection Changes in Human Genes under Long-Term Balancing Selection SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE natural selection; environmental changes; out-of-Africa ID POPULATION-GENETICS; TRANSSPECIES POLYMORPHISM; FUNCTIONAL VARIATION; POSITIVE SELECTION; NATURAL-SELECTION; HUMAN-EVOLUTION; DNA-SEQUENCE; HUMAN GENOME; SOFT SWEEPS; ADAPTATION AB Balancing selection is an important evolutionary force that maintains genetic and phenotypic diversity in populations. Most studies in humans have focused on long-standing balancing selection, which persists over long periods of time and is generally shared across populations. But balanced polymorphisms can also promote fast adaptation, especially when the environment changes. To better understand the role of previously balanced alleles in novel adaptations, we analyzed in detail four loci as case examples of this mechanism. These loci show hallmark signatures of long-term balancing selection in African populations, but not in Eurasian populations. The disparity between populations is due to changes in allele frequencies, with intermediate frequency alleles in Africans (likely due to balancing selection) segregating instead at lowor high-derived allele frequency in Eurasia. We explicitly tested the support for different evolutionary models with an approximate Bayesian computation approach and show that the patterns in PKDREJ, SDR39U1, and ZNF473 are best explained by recent changes in selective pressure in certain populations. Specifically, we infer that alleles previously under long-term balancing selection, or alleles linked to them, were recently targeted by positive selection in Eurasian populations. Balancing selection thus likely served as a source of functional alleles that mediated subsequent adaptations to novel environments. C1 [de Filippo, Cesare; Key, Felix M.; Meneu, Juan R.; Weihmann, Antje; Parra, Genis; Andres, Aida M.] Max Planck Inst Evolutionary Anthropol, Dept Evolutionary Genet, Leipzig, Germany. [Ghirotto, Silvia; Benazzo, Andrea] Univ Ferrara, Dept Life Sci & Biotechnol, I-44100 Ferrara, Italy. [Green, Eric D.; NISC Comparative Sequence Program] NHGRI, NIH, Bethesda, MD 20892 USA. RP de Filippo, C; Andres, AM (reprint author), Max Planck Inst Evolutionary Anthropol, Dept Evolutionary Genet, Leipzig, Germany. EM cesare_filippo@eva.mpg.de; aida.andres@eva.mpg.de RI Andres, Aida/B-4088-2014 OI Andres, Aida/0000-0002-8590-9672 FU Max-Planck-Gesenschaft; Intramural Research Program of the National Human Genome Research Institute of the U.S. National Institutes of Health FX We are thankful to Warren W. Kretzschmar for help with implementation of his code to run the neutrality tests; we also thank Carlos Bustamante, Andy Clark, Rasmus Nielsen, and Scott Williamson for insights during the design of the project, and Barbara Bitarello, Michael Dannemann, Romain Laurent, Fabrizio Mafessoni, Diogo Meyer, Kay Prufer, Fernando Racimo, Gabriel Renaud, Joshua Schmidt, Mark Stoneking, and Joao Teixeira for helpful discussions and statistical advices. We are thankful to the MPI-EVA's sequencing group and Martin Kircher for Illumina data production, and to Warren W. Kretzschmar and Valerie Maduro for visually checking some Sanger SNPs. We are also thankful to two anonymous reviewers who helped to improve the manuscript. This work was funded by the Max-Planck-Gesenschaft and was supported in part by the Intramural Research Program of the National Human Genome Research Institute of the U.S. National Institutes of Health. NR 68 TC 0 Z9 0 U1 10 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 EI 1537-1719 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD JUN PY 2016 VL 33 IS 6 BP 1435 EP 1447 DI 10.1093/molbev/msw023 PG 13 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA DM2IM UT WOS:000376170300004 PM 26831942 ER PT J AU Ko, D Rahman, F Schnabel, RB Yin, XY Benjamin, EJ Christophersen, IE AF Ko, Darae Rahman, Faisal Schnabel, Renate B. Yin, Xiaoyan Benjamin, Emelia J. Christophersen, Ingrid E. TI Atrial fibrillation in women: epidemiology, pathophysiology, presentation, and prognosis SO NATURE REVIEWS CARDIOLOGY LA English DT Review ID GENDER-RELATED DIFFERENCES; CONGESTIVE-HEART-FAILURE; PULMONARY VEIN CARDIOMYOCYTES; RISK STRATIFICATION SCHEMES; POPULATION-BASED COHORT; COMMUNITY-BASED COHORT; FOLLOW-UP; FAMILIAL AGGREGATION; MYOCARDIAL-INFARCTION; NATIONWIDE COHORT AB Atrial fibrillation (AF) is the most common sustained arrhythmia in women and men worldwide. During the past century, a range of risk factors has been associated with AF, severe complications from the arrhythmia have been identified, and its prevalence has been increasing steadily. Whereas evidence has accumulated regarding sex-specific differences in coronary heart disease and stroke, the differences between women and men with AF has received less attention. We review the current literature on sex-specific differences in the epidemiology of AF, including incidence, prevalence, risk factors, and genetics, and in the pathophysiology and the clinical presentation and prognosis of patients with this arrhythmia. We highlight current knowledge gaps and areas that warrant future research, which might advance understanding of variation in the risk factors and complications of AF, and ultimately aid more-tailored management of the arrhythmia. C1 [Christophersen, Ingrid E.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. [Ko, Darae] Boston Univ, Sch Med, Boston Med Ctr, Sect Gen Internal Med, Boston, MA 02215 USA. [Rahman, Faisal] Boston Univ, Sch Med, Boston Med Ctr, Dept Internal Med, Boston, MA 02215 USA. [Schnabel, Renate B.] Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, Martinistr 52, D-20246 Hamburg, Germany. [Schnabel, Renate B.] DZHK German Ctr Cardiovasc Res, Partner Site Hamburg Kiel Lubeck, D-13347 Berlin, Germany. [Yin, Xiaoyan; Benjamin, Emelia J.] Boston Univ, 73 Mt Wayte Ave, Framingham, MA 01702 USA. [Yin, Xiaoyan; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. [Yin, Xiaoyan] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Boston Med Ctr, Sect Cardiovasc Med, 72 East Concord St, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Boston Med Ctr, Sect Prevent Med, 72 East Concord St, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, 715 Albany St, Boston, MA 02118 USA. RP Christophersen, IE (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. EM ichristophersen@mgh.harvard.edu FU National Heart, Lung, and Blood Institute [5T32HL007224-38]; National Institutes of Health Clinical and Translational Science Award programme [UL1-TR000157]; European Research Council under the European Union's Horizon research and innovation programme [648131]; Junior Research Alliance symAtrial project - German Ministry of Research and Education [BMBF 01ZX1408A]; Deutsche Forschungsgemeinschaft (German Research Foundation) Emmy Noether Program [SCHN 1149/3-1]; NIH/NHLBI [HHSN268201500001I, N01-HC25195, 2R01HL092577, 1R01 HL102214, 1R01HL128914, 1RC1HL101056]; Research Council of Norway [240149/F20] FX D. K. is supported by the National Heart, Lung, and Blood Institute award 5T32HL007224-38 and the National Institutes of Health Clinical and Translational Science Award programme award UL1-TR000157. R. B. S. is supported by European Research Council under the European Union's Horizon 2020 research and innovation programme (agreement No 648131), and Junior Research Alliance symAtrial project funded by the German Ministry of Research and Education (BMBF 01ZX1408A) e: Med - Systems Medicine programme and by Deutsche Forschungsgemeinschaft (German Research Foundation) Emmy Noether Program SCHN 1149/3-1. E.J.B. is supported in part through NIH/NHLBI HHSN268201500001I; N01-HC25195, 2R01HL092577, 1R01 HL102214, 1R01HL128914, and 1RC1HL101056. I.E.C. is supported by a mobility grant from the Research Council of Norway (240149/F20). NR 174 TC 10 Z9 10 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5002 EI 1759-5010 J9 NAT REV CARDIOL JI Nat. Rev. Cardiol. PD JUN PY 2016 VL 13 IS 6 BP 321 EP 332 DI 10.1038/nrcardio.2016.45 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DM2SC UT WOS:000376196300004 PM 27053455 ER EF