FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Haddock, E Feldmann, F Feldmann, H AF Haddock, Elaine Feldmann, Friederike Feldmann, Heinz TI Effective Chemical Inactivation of Ebola Virus SO EMERGING INFECTIOUS DISEASES LA English DT Article ID IRRADIATION; MARBURG; LASSA AB Reliable inactivation of specimens before removal from high-level biocontainment is crucial for safe operation. To evaluate efficacy of methods of chemical inactivation, we compared in vitro and in vivo approaches using Ebola virus as a surrogate pathogen. Consequently, we have established parameters and protocols leading to reliable and effective inactivation. C1 [Haddock, Elaine] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. [Feldmann, Friederike; Feldmann, Heinz] NIAID, NIH, Hamilton, MT USA. RP Feldmann, H (reprint author), NIAID, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM feldmannh@niaid.nih.gov FU NIAID at NIH FX The study was supported by the Intramural Research Program of NIAID at NIH. NR 11 TC 5 Z9 5 U1 6 U2 13 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD JUL PY 2016 VL 22 IS 7 BP 1292 EP 1294 DI 10.3201/eid2207.160233 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DP5UR UT WOS:000378563900029 PM 27070504 ER PT J AU Gee, JR Saltzstein, DR Messing, E Kim, K Kolesar, J Huang, W Havighurst, TC Harris, L Wollmer, BW Jarrard, D House, M Parnes, H Bailey, HH AF Gee, Jason R. Saltzstein, Daniel R. Messing, Edward Kim, KyungMann Kolesar, Jill Huang, Wei Havighurst, Thomas C. Harris, Linda Wollmer, Barbara W. Jarrard, David House, Margaret Parnes, Howard Bailey, Howard H. TI Phase Ib placebo-controlled, tissue biomarker trial of diindolylmethane (BR-DIMNG) in patients with prostate cancer who are undergoing prostatectomy SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE chemoprevention; diindolymethane; prostate cancer ID AUTOMATED QUANTITATIVE-ANALYSIS; 3,3'-DIINDOLYLMETHANE; RISK; EXPRESSION; INDOLE-3-CARBINOL; CHEMOPREVENTION; TOLERABILITY AB Epidemiologic, preclinical, and early phase I studies of the cruciferous vegetable bioactive metabolite, 3,3-diindolylmethane (DIM), support its potential prostate cancer chemopreventive ability. We performed a multicenter, double-blind, placebo-controlled trial of DIM in patients diagnosed with prostate cancer and scheduled for radical prostatectomy. A total of 45 patients with organ-confined prostate cancer were randomized to 21-28 days of an absorption-enhanced formulation of DIM (BR-DIMNG) at doses of 100 or 200mg per os twice daily or to placebo twice daily. Prostate tissue levels of DIM were the primary endpoint, with selected secondary biomarker endpoints including blood levels of DIM, total prostate-specific antigen, testosterone, and the insulin-like growth factor-1:insulin-like growth factor binding protein-3 ratio and the urinary 2-hydroxyestrone/16-hydroxyestrone ratio, obtained at baseline, at day 15, and before surgery, as well as tissue expression of androgen receptor, prostate-specific antigen, Ki67, caspase 3 with cytochrome p450 mRNA expression and genotyping (polymorphisms). DIM was well tolerated with excellent study compliance and relatively rapid accrual of all 45 patients within 1 year. DIM levels were detected in only seven of 28 prostate tissue specimens. There was a statistically significant difference in the change in the urinary 2-hydroxyestrone/16-hydroxyestrone ratio from baseline until before surgery between the placebo and 400mg DIM groups, with otherwise statistically nonsignificant changes in plasma biomarker expression. The administration of BR-DIMNG to prostate cancer patients before prostatectomy yields detectable plasma levels but without consistent or significant tissue accumulation or biomarker modulation. This study demonstrates the feasibility of biologic evaluation of relatively nontoxic preventive agents in the preprostatectomy setting with the potential for rapid accrual. C1 [Gee, Jason R.; Kim, KyungMann; Kolesar, Jill; Huang, Wei; Havighurst, Thomas C.; Harris, Linda; Wollmer, Barbara W.; Jarrard, David; Bailey, Howard H.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [Saltzstein, Daniel R.] Urol San Antonio Res, San Antonio, TX USA. [Messing, Edward] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [House, Margaret; Parnes, Howard] NCI, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. RP Gee, JR (reprint author), Lahey Clin Med Ctr, Inst Urol, 41 Mall Rd, Burlington, MA 01805 USA. EM jason.r.gee@lahey.org FU NCI [N01 CN35153, P30 CA014520]; NCATS [UL1TR000427] FX This work is supported by NCI awards N01 CN35153 and P30 CA014520; and NCATS award UL1TR000427. NR 23 TC 1 Z9 1 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0959-8278 EI 1473-5709 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD JUL PY 2016 VL 25 IS 4 BP 312 EP 320 DI 10.1097/CEJ.0000000000000189 PG 9 WC Oncology SC Oncology GA DP6RK UT WOS:000378625900009 PM 26313229 ER PT J AU Boffetta, P Hayes, RB Sartori, S Lee, YCA Muscat, J Olshan, A Winn, DM Castellsague, X Zhang, ZF Morgenstern, H Chen, C Schwartz, SM Vaughan, TL Wunsch, V Purdue, M Koifman, S Curado, MP Vilensky, M Gillison, M Fernandez, L Menezes, A Daudt, AW Schantz, S Yu, GP D'Souza, G Haddad, RI La Vecchia, C Hashibe, M AF Boffetta, Paolo Hayes, Richard B. Sartori, Samantha Lee, Yuan-Chin A. Muscat, Joshua Olshan, Andrew Winn, Deborah M. Castellsague, Xavier Zhang, Zuo-Feng Morgenstern, Hal Chen, Chu Schwartz, Stephen M. Vaughan, Thomas L. Wunsch-Filho, Victor Purdue, Mark Koifman, Sergio Curado, Maria P. Vilensky, Marta Gillison, Maura Fernandez, Leticia Menezes, Ana Daudt, Alexander W. Schantz, Stimson Yu, Guopei D'Souza, Gypsyamber Haddad, Robert I. La Vecchia, Carlo Hashibe, Mia TI Mouthwash use and cancer of the head and neck: a pooled analysis from the International Head and Neck Cancer Epidemiology Consortium SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE alcohol; head and neck cancer; laryngeal cancer; mouthwash; oral cancer; pharyngeal cancer ID UPPER AERODIGESTIVE TRACT; SQUAMOUS-CELL CARCINOMA; ORAL-CANCER; HUMAN-PAPILLOMAVIRUS; RISK-FACTORS; OROPHARYNX; ESOPHAGUS; HEALTH AB Most mouthwashes contain alcohol, a known cause of head and neck cancer (oral cavity, pharynx, larynx), likely through the carcinogenic activity of acetaldehyde, formed in the oral cavity from alcohol. We carried out a pooled analysis of 8981 cases of head and neck cancer and 10090 controls from 12 case-control studies with comparable information on mouthwash use in the International Head and Neck Cancer Epidemiology Consortium. Logistic regression was used to assess the association of mouthwash use with cancers of the oral cavity, oropharynx, hypopharynx, and larynx, adjusting for study, age, sex, pack-years of tobacco smoking, number of alcoholic drinks/day, and education. Compared with never users of mouthwash, the odds ratio (OR) of all head and neck cancers was 1.01 [95% confidence interval (CI): 0.94-1.08] for ever users, based on 12 studies. The corresponding ORs of cancer of the oral cavity and oropharynx were 1.11 (95% CI: 1.00-1.23) and 1.28 (95% CI: 1.06-1.56), respectively. OR for all head and neck cancer was 1.15 (95% CI: 1.01-1.30) for use for more than 35 years, based on seven studies (P for linear trend=0.01), and OR 1.31 (95% CI: 1.09-1.58) for use more than one per day, based on five studies (P for linear trend <0.001). Although limited by the retrospective nature of the study and the limited ability to assess risks of mouthwash use in nonusers of tobacco and alcohol, this large investigation shows potential risks for head and neck cancer subsites and in long-term and frequent users of mouthwash. This pooled analysis provides the most precise estimate of the association between mouthwash use and head and neck cancer. C1 [Boffetta, Paolo; Sartori, Samantha] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Boffetta, Paolo; Sartori, Samantha] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA. [Hayes, Richard B.] NYU, Sch Med, Div Epidemiol, Dept Populat Hlth, New York, NY USA. [Schantz, Stimson] New York Eye & Ear Infirm, New York, NY USA. [Lee, Yuan-Chin A.; Hashibe, Mia] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Family & Prevent Med,Div Publ Hlth, Salt Lake City, UT USA. [Muscat, Joshua] Penn State Coll Med, Hershey, PA USA. [Olshan, Andrew] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. [Winn, Deborah M.; Purdue, Mark] NCI, Bethesda, MD 20892 USA. [Gillison, Maura] Johns Hopkins Med Inst, Baltimore, MD USA. [D'Souza, Gypsyamber] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Zhang, Zuo-Feng] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Epidemiol & Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Chen, Chu; Schwartz, Stephen M.; Vaughan, Thomas L.] Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Haddad, Robert I.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Castellsague, Xavier] Hosp Llobregat, Catalan Inst Oncol ICO IDIBELL, Barcelona, Spain. [Castellsague, Xavier] Consortium Biomed Res Epidemiol & Publ Hlth CIBER, Barcelona, Spain. [Wunsch-Filho, Victor] Univ Sao Paulo, Sao Paulo, Brazil. [Koifman, Sergio] Fundacao Oswaldo Cruz, Natl Sch Publ Hlth, Rio De Janeiro, Brazil. [Menezes, Ana] Univ Fed Pelotas, Pelotas, Brazil. [Daudt, Alexander W.] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Curado, Maria P.] Int Prevent Res Inst, Lyon, France. [Vilensky, Marta] Univ Buenos Aires, Inst Oncol Angel H Roffo, Buenos Aires, DF, Argentina. [Fernandez, Leticia] Inst Oncol & Radiobiol, Havana, Cuba. [Yu, Guopei] Peking Univ, Med Informat Ctr, Beijing 100871, Peoples R China. [La Vecchia, Carlo] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. RP Boffetta, P (reprint author), Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. EM paolo.boffetta@mssm.edu RI Castellsague Pique, Xavier/N-5795-2014; Kowalski, Luiz/D-1701-2012; Menezes, Ana/G-7266-2012; Curado, Maria Paula/M-6200-2013; OI Castellsague Pique, Xavier/0000-0002-0802-3595; Kowalski, Luiz/0000-0001-5865-9308; Curado, Maria Paula/0000-0001-8172-2483; La Vecchia, Carlo/0000-0003-1441-897X; Hayes, Richard/0000-0002-0918-661X FU NIH [NCI R03CA113157, NIDCR R03DE016611, P01CA068384 K07CA104231, R01CA048996, R01DE012609, R01CA061188, P50CA090388, R01DA011386, R03CA077954, T32CA 009142, U01CA096134, R21ES011667, R01CA051845, DE016631]; National Institute of Environmental Health Sciences [P30ES010126]; Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center; National Institutes of Health (NCI) US; NIDCR; Fondo para la Investigacion Cientifica y Tecnologica (FONCYT) Argentina; IMIM (Barcelona); Fundaco de Amparo a' Pesquisa no Estado de Sao Paulo (FAPESP) [01/01768-2]; European Commission [IC18-CT97-0222]; Fondo de Investigaciones Sanitarias (FIS) of the Spanish Government [FIS 97/0024, FIS 97/0662, BAE 01/5013]; International Union Against Cancer (UICC); Yamagiwa-Yoshida Memorial International Cancer Study Grant; NCI, NIH, United States; Johns Hopkins Richard Gelb Cancer Prevention Award FX The INHANCE Consortium was supported by NIH grants NCI R03CA113157 and NIDCR R03DE016611. Studies participating in the pooled analysis were supported by grants: New York multicenter: NIH [P01CA068384 K07CA104231]; Seattle (1985-1995): NIH [R01CA048996, R01DE012609]; North Carolina (1994-1997): NIH [R01CA061188], and in part by a grant from the National Institute of Environmental Health Sciences [P30ES010126]; Los Angeles: NIH [P50CA090388, R01DA011386, R03CA077954, T32CA 009142, U01CA096134, R21ES011667] and the Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center; Puerto Rico: jointly funded by National Institutes of Health (NCI) US and NIDCR intramural programs; Latin America: Fondo para la Investigacion Cientifica y Tecnologica (FONCYT) Argentina, IMIM (Barcelona), Fundaco de Amparo a' Pesquisa no Estado de Sao Paulo (FAPESP) [No 01/01768-2], and European Commission [IC18-CT97-0222]; IARC Multicenter: Fondo de Investigaciones Sanitarias (FIS) of the Spanish Government [FIS 97/0024, FIS 97/0662, BAE 01/5013], International Union Against Cancer (UICC), and Yamagiwa-Yoshida Memorial International Cancer Study Grant; US multicenter: The Intramural Program of the NCI, NIH, United States; MSKCC: NIH [R01CA051845]; Baltimore: NIH [DE016631]; Hotspot: Johns Hopkins Richard Gelb Cancer Prevention Award. NR 21 TC 0 Z9 1 U1 6 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0959-8278 EI 1473-5709 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD JUL PY 2016 VL 25 IS 4 BP 344 EP 348 DI 10.1097/CEJ.0000000000000179 PG 5 WC Oncology SC Oncology GA DP6RK UT WOS:000378625900013 PM 26275006 ER PT J AU Nager, CW Zyczynski, H Rogers, RG Barber, MD Richter, HE Visco, AG Rardin, CR Harvie, H Wallace, D Meikle, SF AF Nager, Charles W. Zyczynski, Halina Rogers, Rebecca G. Barber, Matthew D. Richter, Holly E. Visco, Anthony G. Rardin, Charles R. Harvie, Heidi Wallace, Dennis Meikle, Susan F. CA Pelvic Floor Disorders Network TI The Design of a Randomized Trial of Vaginal Surgery for Uterovaginal Prolapse: Vaginal Hysterectomy With Native Tissue Vault Suspension Versus Mesh Hysteropexy Suspension (The Study of Uterine Prolapse Procedures Randomized Trial) SO FEMALE PELVIC MEDICINE AND RECONSTRUCTIVE SURGERY LA English DT Article DE vaginal surgery; hysterectomy; vaginal hysterectomy; hysteropexy; mesh; mesh hysteropexy; randomized controlled trial; prolapse; uterovaginal prolapse; prolapse surgery ID PELVIC ORGAN PROLAPSE; QUALITY-OF-LIFE; UNITED-STATES; SACROSPINOUS HYSTEROPEXY; RECONSTRUCTIVE SURGERY; URINARY-INCONTINENCE; SYNTHETIC MESH; WOMEN; OUTCOMES; REPAIR AB Objectives: We present the rationale for and design of a randomized controlled superiority trial comparing 2 vaginal surgical approaches for the treatment of uterovaginal prolapse. The Study of Uterine Prolapse Procedures Randomized Trial (SUPeR) trial compares the efficacy and safety of native tissue repair with vaginal hysterectomy and suture apical suspension versus uterine conservation with mesh hysteropexy through 36 to 60 months postoperatively for primary repair of uterovaginal prolapse. Methods: The selection of the primary outcome measure, timing of randomization, patient and evaluator masking to surgical intervention, collection and adjudication of adverse events, cost effectiveness evaluations, partnering with industry, and surgeon certification of competency to perform the 2 procedures is described. A composite primary outcome of success defined as no prolapse symptoms, no objective prolapse beyond the hymen, and no retreatment of prolapse, with a minimum of 36 months postsurgery follow-up using survival analyses is planned. Secondary outcomes measured at baseline and every 6 months postsurgery include validated condition-specific and general quality of life assessments, global impression of improvement, body image, and sexual function measures. Unique challenges during the trial design include maintenance of patient masking to the intervention with routine gynecologic health maintenance and maintenance of evaluator masking. Results: Recruitment and randomization of 180 participants is complete, and participants are currently in the follow-up phase. Conclusions: This trial will provide information to help surgeons counsel patients and contribute evidence-based information regarding risks and benefits of 2 approaches for the treatment of uterovaginal prolapse. C1 [Nager, Charles W.] UC San Diego Hlth Care Syst, Dept Reprod Med, San Diego, CA USA. [Zyczynski, Halina] Univ Pittsburgh, Magee Womens Res Inst, Dept Obstet & Gynecol & Reprod Sci, Pittsburgh, PA USA. [Rogers, Rebecca G.] Univ New Mexico, Med Ctr, Dept Obstet & Gynecol, Albuquerque, NM 87131 USA. [Rogers, Rebecca G.] Univ New Mexico, Med Ctr, Dept Surg, Albuquerque, NM 87131 USA. [Barber, Matthew D.] Cleveland Clin, Obstet Gynecol & Womens Hlth Inst, Cleveland, OH 44106 USA. [Richter, Holly E.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Visco, Anthony G.] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Rardin, Charles R.] Brown Univ, Womens & Infants Hosp, Warren Alpert Med Sch, Dept Obstet & Gynecol, Providence, RI 02912 USA. [Harvie, Heidi] Hosp Univ Penn, Dept Obstet & Gynecol, 3400 Spruce St, Philadelphia, PA 19104 USA. [Wallace, Dennis] RTI Int, Res Triangle Pk, NC USA. [Meikle, Susan F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Gynecol Hlth & Dis Branch, NIH, Bethesda, MD USA. RP Nager, CW (reprint author), UC San Diego Hlth Syst, 200 W Arbor Dr 8433, San Diego, CA 92103 USA. EM cnager@ucsd.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD054214, HD069031, HD054215, HD069025, HD041261, HD041267, HD069006, HD069013, HD069010]; National Institutes of Health Office of Research on Women's Health; Boston Scientific Corporation through the Pelvic Floor Disorders Network Data Coordinating Center FX Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development grants HD054214, HD069031, HD054215, HD069025, HD041261, HD041267, HD069006, HD069013, HD069010, and the National Institutes of Health Office of Research on Women's Health. Partial support for the PFDN SUPeR trial is being supplied by Boston Scientific Corporation through an investigator initiated grant to Dr. Wallace through the Pelvic Floor Disorders Network Data Coordinating Center. NR 39 TC 3 Z9 3 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 2151-8378 EI 2154-4212 J9 FEMALE PELVIC MED RE JI Female Pelvic Med. Reconstr. Surg. PD JUL-AUG PY 2016 VL 22 IS 4 BP 182 EP 189 DI 10.1097/SPV.0000000000000270 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DP7XT UT WOS:000378713200002 PM 27054798 ER PT J AU Van Dyke, ME Drozdovitch, V Doody, MM Lim, H Bolus, NE Simon, SL Alexander, BH Kitahara, CM AF Van Dyke, Miriam E. Drozdovitch, Vladimir Doody, Michele M. Lim, Hyeyeun Bolus, Norman E. Simon, Steven L. Alexander, Bruce H. Kitahara, Cari M. TI Historical Patterns in the Types of Procedures Performed and Radiation Safety Practices Used in Nuclear Medicine From 1945-2009 SO HEALTH PHYSICS LA English DT Article DE exposure; occupational; nuclear medicine; radiation protection; radionuclide ID RADIOLOGIC TECHNOLOGISTS; IONIZING-RADIATION; UNITED-STATES; CIRCULATORY DISEASE; MORTALITY; CANCER; RISKS; EXPOSURE; WORKERS; COHORT AB The authors evaluated historical patterns in the types of procedures performed in diagnostic and therapeutic nuclear medicine and the associated radiation safety practices used from 1945-2009 in a sample of U.S. radiologic technologists. In 2013-2014, 4,406 participants from the U.S. Radiologic Technologists (USRT) Study who previously reported working with medical radionuclides completed a detailed survey inquiring about the performance of 23 diagnostic and therapeutic radionuclide procedures and the use of radiation safety practices when performing radionuclide procedure-related tasks during five time periods: 1945-1964, 1965-1979, 1980-1989, 1990-1999, and 2000-2009. An overall increase in the proportion of technologists who performed specific diagnostic or therapeutic procedures was observed across the five time periods. Between 1945-1964 and 2000-2009, the median frequency of diagnostic procedures performed substantially increased (from 5 wk(-1) to 30 wk(-1)), attributable mainly to an increasing frequency of cardiac and non-brain PET scans, while the median frequency of therapeutic procedures performed modestly decreased (from 4 mo(-1) to 3 mo(-1)). Also a notable increase was observed in the use of most radiation safety practices from 1945-1964 to 2000-2009 (e.g., use of lead-shielded vials during diagnostic radiopharmaceutical preparation increased from 56 to 96%), although lead apron use dramatically decreased (e.g., during diagnostic imaging procedures, from 81 to 7%). These data describe historical practices in nuclear medicine and can be used to support studies of health risks for nuclear medicine technologists. C1 [Van Dyke, Miriam E.; Drozdovitch, Vladimir; Doody, Michele M.; Lim, Hyeyeun; Simon, Steven L.; Kitahara, Cari M.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bolus, Norman E.] Univ Alabama Birmingham, Dept Clin & Diagnost Sci, Sch Hlth Profess, Birmingham, AL USA. [Alexander, Bruce H.] Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Sci, Minneapolis, MN USA. RP Kitahara, CM (reprint author), NCI, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM meinholdc@mail.nih.gov RI Kitahara, Cari/R-8267-2016 FU Division of Cancer Epidemiology and Genetics of the National Cancer Institute FX We thank the participants of the U.S. Radiologic Technologists Study, Jerry Reid of the American Registry of Radiologic Technologists for continued support, Diane Kampa and Allison Iwan of the University of Minnesota for study management and data collection, and Jeremy Miller of Information Management Services for data preparation. This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute. NR 24 TC 0 Z9 0 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JUL PY 2016 VL 111 IS 1 BP 37 EP 46 DI 10.1097/HP.0000000000000519 PG 10 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 DP3XM UT WOS:000378429300006 PM 27218293 ER PT J AU Canepa, M Pozios, I Vianello, PF Ameri, P Brunelli, C Ferrucci, L Abraham, TP AF Canepa, Marco Pozios, Iraklis Vianello, Pier Filippo Ameri, Pietro Brunelli, Claudio Ferrucci, Luigi Abraham, Theodore P. TI Distinguishing ventricular septal bulge versus hypertrophic cardiomyopathy in the elderly SO HEART LA English DT Review ID CARDIOVASCULAR MAGNETIC-RESONANCE; OUTFLOW TRACT OBSTRUCTION; CLINICAL PRESENTATION; FUNCTIONAL IMPACT; TASK-FORCE; PREVALENCE; ECHOCARDIOGRAPHY; PATTERNS; AGE; HYPERTENSION AB The burgeoning evidence of patients diagnosed with sigmoidal hypertrophic cardiomyopathy (HCM) later in life has revived the quest for distinctive features that may help discriminate it from more benign forms of isolated septal hypertrophy often labelled ventricular septal bulge (VSB). HCM is diagnosed less frequently than VSB at older ages, with a reversed female predominance. Most patients diagnosed with HCM at older ages suffer from hypertension, similar to those with VSB. A positive family history of HCM and/or sudden cardiac death and the presence of exertional symptoms usually support HCM, though they are less likely in older patients with HCM, and poorly investigated in individuals with VSB. A more severe hypertrophy and the presence of left ventricular outflow obstruction are considered diagnostic of HCM, though stress echocardiography has not been consistently used in VSB. Mitral annulus calcification is very prevalent in both conditions, whereas a restrictive filling pattern is found in a minority of older patients with HCM. Genetic testing has low applicability in this differential diagnosis at the current time, given that a causative mutation is found in less than 10% of elderly patients with suspected HCM. Emerging imaging modalities that allow non-invasive detection of myocardial fibrosis and disarray may help, but have not been fully investigated. Nonetheless, there remains a considerable morphological overlap between the two conditions. Comprehensive studies, particularly imaging based, are warranted to offer a more evidence-based approach to elderly patients with focal septal thickening. C1 [Canepa, Marco; Pozios, Iraklis; Abraham, Theodore P.] Johns Hopkins Hypertroph Cardiomyopathy Ctr Excel, 600 North Wolfe St,Blalock 910F, Baltimore, MD USA. [Canepa, Marco; Vianello, Pier Filippo; Ameri, Pietro; Brunelli, Claudio] Univ Genoa, IRCCS AOU San Martino IST, Dept Internal Med, Cardiovasc Dis Unit, Genoa, Italy. [Canepa, Marco; Ferrucci, Luigi] NIA, Translat Gerontol Branch, NIH, Baltimore, MD USA. RP Abraham, TP (reprint author), Johns Hopkins Hypertroph Cardiomyopathy Ctr Excel, 600 North Wolfe St,Blalock 910F, Baltimore, MD USA. EM tabraha3@jhmi.edu NR 48 TC 2 Z9 2 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 EI 1468-201X J9 HEART JI Heart PD JUL PY 2016 VL 102 IS 14 BP 1087 EP 1094 DI 10.1136/heartjnl-2015-308764 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DP7ZB UT WOS:000378716600006 PM 27122487 ER PT J AU Hinnebusch, BJ Chouikha, I Sun, YC AF Hinnebusch, B. Joseph Chouikha, Iman Sun, Yi-Cheng TI Ecological Opportunity, Evolution, and the Emergence of Flea-Borne Plague SO INFECTION AND IMMUNITY LA English DT Review ID EARLY-PHASE TRANSMISSION; YERSINIA MURINE TOXIN; CYCLIC DI-GMP; BIOFILM FORMATION; RCS PHOSPHORELAY; PLASMINOGEN-ACTIVATOR; INFECTIOUS-DISEASES; ADAPTIVE EVOLUTION; ESCHERICHIA-COLI; GENOME SEQUENCES AB The plague bacillus Yersinia pestis is unique among the pathogenic Enterobacteriaceae in utilizing an arthropod-borne transmission route. Transmission by fleabite is a recent evolutionary adaptation that followed the divergence of Y. pestis from the closely related food- and waterborne enteric pathogen Yersinia pseudotuberculosis. A combination of population genetics, comparative genomics, and investigations of Yersinia-flea interactions have disclosed the important steps in the evolution and emergence of Y. pestis as a flea-borne pathogen. Only a few genetic changes, representing both gene gain by lateral transfer and gene loss by loss-of-function mutation (pseudogenization), were fundamental to this process. The emergence of Y. pestis fits evolutionary theories that emphasize ecological opportunity in adaptive diversification and rapid emergence of new species. C1 [Hinnebusch, B. Joseph; Chouikha, Iman] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT USA. [Sun, Yi-Cheng] Chinese Acad Med Sci, MOH Key Lab Syst Biol Pathogens, Inst Pathogen Biol, Beijing 100730, Peoples R China. [Sun, Yi-Cheng] Peking Union Med Coll, Beijing 100021, Peoples R China. RP Hinnebusch, BJ (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT USA. EM jhinnebusch@niaid.nih.gov FU NIH, NIAID [1 ZIA AI000796-19]; National Basic Research Program of China (973) [2015CB554200] FX This work was funded by NIH, NIAID (1 ZIA AI000796-19; B.J.H.), and by the National Basic Research Program of China (973 no. 2015CB554200; Y.-C.S.). NR 93 TC 0 Z9 0 U1 16 U2 17 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 JUL PY 2016 VL 84 IS 7 BP 1932 EP 1940 DI 10.1128/IAI.00188-16 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DP5IO UT WOS:000378529700001 PM 27160296 ER PT J AU Sidana, A Walton-Diaz, A Truong, H Siddiqui, MM Miao, N Shih, J Mannes, A Bratslavsky, G Linehan, WM Metwalli, AR AF Sidana, Abhinav Walton-Diaz, Annerleim Hong Truong Siddiqui, M. Minhaj Miao, Ning Shih, Johanna Mannes, Andrew Bratslavsky, Gennady Linehan, W. Marston Metwalli, Adam R. TI Postoperative elevation in creatine kinase and its impact on renal function in patients undergoing complex partial nephrectomy SO INTERNATIONAL UROLOGY AND NEPHROLOGY LA English DT Article DE Partial nephrectomy; Creatine kinase; Rhabdomyolysis; Renal cell cancer ID NEPHRON-SPARING SURGERY; LITHOTOMY POSITION; SURGICAL-PATIENTS; KIDNEY INJURY; RHABDOMYOLYSIS; FAILURE; RISK; OUTCOMES; TUMORS; COMPLICATIONS AB To identify the risk factors associated with development of postoperative elevation of creatine kinase (CK) and study its effect on renal function in patients who underwent complex multifocal partial nephrectomy (PN). Patients who underwent PN at National Cancer Institute between January 2007 and December 2012 were included in the study. Elevated serum CK was defined as > 2000 U/L. Kidney function was assessed using serum creatinine and estimated glomerular filtration rate (eGFR). Changes were reported as percent change from preoperative values and compared using the Wilcoxon test. Regression analysis was performed to identify the predictors of elevation in CK and decline in eGFR. From 407 total cases, 207 had adequate CK data for analysis. Median number of tumors removed was 3 (1-70). Median peak CK was 1458 (82-36,788). Forty-two percent developed CK elevation > 2000 U/L. Factors associated with postoperative elevation of CK > 2000 were young age (p = 0.009), high BMI (p = 0.003) and operating room time (p < 0.001). Although CK > 2000 was associated with significantly greater decline in eGFR (37.4 vs. 20.3 %, p < 0.001) in immediate postoperative period, this change largely resolved to a much less clinically relevant (9.2 vs 3.3 %, p = 0.040) change after 3 months. On multivariate analysis, postoperative elevation in CK was not found to be an independent factor determining renal function at 3 months. In our cohort, a significant proportion of patients developed CK elevations > 2000 U/L. While patients with elevated CK had more decline in eGFR in immediate postoperative period, postoperative elevations of CK did not appear to impact overall long-term renal function in patients undergoing PN. C1 [Sidana, Abhinav; Walton-Diaz, Annerleim; Hong Truong; Siddiqui, M. Minhaj; Linehan, W. Marston; Metwalli, Adam R.] NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,Rm 1-5940, Bethesda, MD 20892 USA. [Miao, Ning; Mannes, Andrew] NIH, Dept Perioperat Med, Clin Res Ctr, Bldg 10, Bethesda, MD 20892 USA. [Shih, Johanna] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. [Bratslavsky, Gennady] SUNY Upstate Med Univ, Dept Urol, Syracuse, NY 13210 USA. [Siddiqui, M. Minhaj] Univ Maryland, Div Urol, Dept Surg, Sch Med, Baltimore, MD 21201 USA. RP Metwalli, AR (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,Rm 1-5940, Bethesda, MD 20892 USA. EM adam.metwalli@nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 31 TC 2 Z9 2 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0301-1623 EI 1573-2584 J9 INT UROL NEPHROL JI Int. Urol. Nephrol. PD JUL PY 2016 VL 48 IS 7 BP 1047 EP 1053 DI 10.1007/s11255-016-1284-1 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA DQ0KV UT WOS:000378888900006 PM 27093966 ER PT J AU Sato, E Muto, J Zhang, LJ Adase, CA Sanford, JA Takahashi, T Nakatsuji, T Usdin, TB Gallo, RL AF Sato, Emi Muto, Jun Zhang, Ling-Juan Adase, Christopher A. Sanford, James A. Takahashi, Toshiya Nakatsuji, Teruaki Usdin, Ted B. Gallo, Richard L. TI The Parathyroid Hormone Second Receptor PTH2R and its Ligand Tuberoinfundibular Peptide of 39 Residues TIP39 Regulate Intracellular Calcium and Influence Keratinocyte Differentiation SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID TYPE-2 RECEPTOR; EXPRESSION; PROTEIN; SKIN; MICE; IDENTIFICATION; PROLIFERATION; LOCALIZATION; INFLAMMATION; HYALURONAN AB Genes related to the parathyroid hormone (PTH) influence cutaneous immune defense and development, but the full functions of the PTH family in cutaneous biology remain incompletely understood. In this study, we examined the expression and potential functions of the PTH second receptor (PTH2R) and its ligand, the tuberoinfundibular peptide of 39 residues (TIP39), in the skin. TIP39 and PTH2R mRNA and protein were detectable in both human and mouse skin, and in cultured keratinocytes and adipocytes. TIP39 was observed in the basal layer of human skin, whereas PTH2R was detected in the spinous to granular layer. The subcellular localization of TIP39 in keratinocytes changed during calcium-induced differentiation and shifted to colocalize with PTH2R at the membrane. The addition of recombinant TIP39 to normal human keratinocytes in culture induced an increase in intercellular calcium and triggered aspects of terminal differentiation including decreased keratin-14 and increased involucrin expression. Consistent with these observations, PTH2R(-/-) ice were observed to have increased epidermal thickness. In summary, identification of TIP39 and its receptor in the epidermis reveals an additional PTH family member that is expressed in the skin and may influence keratinocyte function. C1 [Sato, Emi; Zhang, Ling-Juan; Adase, Christopher A.; Sanford, James A.; Takahashi, Toshiya; Nakatsuji, Teruaki; Gallo, Richard L.] Univ Calif San Diego, Dept Dermatol, 9500 Gillman, La Jolla, CA 92093 USA. [Muto, Jun] Aichi Med Univ, Dept Dermatol, Nagakute, Aichi, Japan. [Usdin, Ted B.] NIMH, Sect Fundamental Neurosci, Bethesda, MD 20892 USA. RP Gallo, RL (reprint author), Univ Calif San Diego, Dept Dermatol, 9500 Gillman, La Jolla, CA 92093 USA. EM rgallo@ucsd.edu FU NIH [R01AI116576, R01AR064781, R01AI052453, R21AR0675478, U19AI117673, P01HL107150]; UCSD Dermatologist Investigator Training Program [T32AR062496] FX This work was supported in part by NIH grants R01AI116576, R01AR064781, R01AI052453, R21AR0675478, U19AI117673, and P01HL107150 (RLG) and the UCSD Dermatologist Investigator Training Program T32AR062496 (JAS, CA). NR 46 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2016 VL 136 IS 7 BP 1449 EP 1459 DI 10.1016/j.jid.2016.02.814 PG 11 WC Dermatology SC Dermatology GA DQ2FA UT WOS:000379016400022 PM 27000502 ER PT J AU van Leeuwen, EM Sabo, A Bis, JC Huffman, JE Manichaikul, A Smith, AV Feitosa, MF Demissie, S Joshi, PK Duan, Q Marten, J van Klinken, JB Surakka, I Nolte, IM Zhang, WH Mbarek, H Li-Gao, RF Trompet, S Verweij, N Evangelou, E Lyytikainen, LP Tayo, BO Deelen, J van der Most, PJ van der Laan, SW Arking, DE Morrison, A Dehghan, A Franco, OH Hofman, A Rivadeneira, F Sijbrands, EJ Uitterlinden, AG Mychaleckyj, JC Campbell, A Hocking, LJ Padmanabhan, S Brody, JA Rice, KM White, CC Harris, T Isaacs, A Campbell, H Lange, LA Rudan, I Kolcic, I Navarro, P Zemunik, T Salomaa, V Kooner, AS Kooner, JS Lehne, B Scott, WR Tan, ST de Geus, EJ Milaneschi, Y Penninx, BWJH Willemsen, G de Mutsert, R Ford, I Gansevoort, RT Segura-Lepe, MP Raitakari, OT Viikari, JS Nikus, K Forrester, T McKenzie, CA de Craen, AJM de Ruijter, HM Pasterkamp, G Snieder, H Oldehinkel, AJ Slagboom, PE Cooper, RS Kahonen, M Lehtimaki, T Elliott, P van der Harst, P Jukema, JW Mook-Kanamori, DO Boomsma, DI Chambers, JC Swertz, M Ripatti, S van Dijk, KW Vitart, V Polasek, O Hayward, C Wilson, JG Wilson, JF Gudnason, V Rich, SS Psaty, BM Borecki, IB Boerwinkle, E Rotter, JI Cupples, LA van Duijn, CM AF van Leeuwen, Elisabeth M. Sabo, Aniko Bis, Joshua C. Huffman, Jennifer E. Manichaikul, Ani Smith, Albert V. Feitosa, Mary F. Demissie, Serkalem Joshi, Peter K. Duan, Qing Marten, Jonathan van Klinken, Jan B. Surakka, Ida Nolte, Ilja M. Zhang, Weihua Mbarek, Hamdi Li-Gao, Ruifang Trompet, Stella Verweij, Niek Evangelou, Evangelos Lyytikainen, Leo-Pekka Tayo, Bamidele O. Deelen, Joris van der Most, Peter J. van der Laan, Sander W. Arking, Dan E. Morrison, Alanna Dehghan, Abbas Franco, Oscar H. Hofman, Albert Rivadeneira, Fernando Sijbrands, Eric J. Uitterlinden, Andre G. Mychaleckyj, Josyf C. Campbell, Archie Hocking, Lynne J. Padmanabhan, Sandosh Brody, Jennifer A. Rice, Kenneth M. White, Charles C. Harris, Tamara Isaacs, Aaron Campbell, Harry Lange, Leslie A. Rudan, Igor Kolcic, Ivana Navarro, Pau Zemunik, Tatijana Salomaa, Veikko Kooner, Angad S. Kooner, Jaspal S. Lehne, Benjamin Scott, William R. Tan, Sian-Tsung de Geus, Eco J. Milaneschi, Yuri Penninx, Brenda W. J. H. Willemsen, Gonneke de Mutsert, Renee Ford, Ian Gansevoort, Ron T. Segura-Lepe, Marcelo P. Raitakari, Olli T. Viikari, Jorma S. Nikus, Kjell Forrester, Terrence McKenzie, Colin A. de Craen, Anton J. M. de Ruijter, Hester M. Pasterkamp, Gerard Snieder, Harold Oldehinkel, Albertine J. Slagboom, P. Eline Cooper, Richard S. Kahonen, Mika Lehtimaki, Terho Elliott, Paul van der Harst, Pim Jukema, J. Wouter Mook-Kanamori, Dennis O. Boomsma, Dorret I. Chambers, John C. Swertz, Morris Ripatti, Samuli van Dijk, Ko Willems Vitart, Veronique Polasek, Ozren Hayward, Caroline Wilson, James G. Wilson, James F. Gudnason, Vilmundur Rich, Stephen S. Psaty, Bruce M. Borecki, Ingrid B. Boerwinkle, Eric Rotter, Jerome I. Cupples, L. Adrienne van Duijn, Cornelia M. CA CHARGE Lipids Working Grp TI Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID ELEMENT-BINDING PROTEIN; GENE-EXPRESSION; LIPID-SYNTHESIS; GLUCOSE; CHREBP; MUTATIONS; TRIGLYCERIDES; TRANSCRIPTION; SREBP-1C; DISEASE AB Background So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels. Methods We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from similar to 60 000 individuals in the discovery stage and similar to 90 000 samples in the replication stage. Results Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene. Conclusions This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels. C1 [van Leeuwen, Elisabeth M.; Dehghan, Abbas; Franco, Oscar H.; Hofman, Albert; Uitterlinden, Andre G.; Isaacs, Aaron; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Sabo, Aniko; Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Bis, Joshua C.; Brody, Jennifer A.; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Huffman, Jennifer E.; Marten, Jonathan; Navarro, Pau; Vitart, Veronique; Hayward, Caroline; Wilson, James F.] Univ Edinburgh, Inst Genet & Mol Med, Med Res Council Human Genet Unit, Edinburgh, Midlothian, Scotland. [Huffman, Jennifer E.; Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Cardiovasc Epidemiol & Human Genom Branch, Framingham, MA USA. [Manichaikul, Ani; Mychaleckyj, Josyf C.; Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Feitosa, Mary F.; Borecki, Ingrid B.; Cupples, L. Adrienne] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Demissie, Serkalem] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Joshi, Peter K.; Campbell, Harry; Wilson, James F.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland. Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [van Klinken, Jan B.; van Dijk, Ko Willems] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Surakka, Ida; Ripatti, Samuli] Univ Helsinki, Inst Mol Med, Human Genom Unit, Helsinki, Finland. [Nolte, Ilja M.; van der Most, Peter J.; Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Zhang, Weihua; Evangelou, Evangelos; Lehne, Benjamin; Scott, William R.; Segura-Lepe, Marcelo P.; Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Zhang, Weihua; Kooner, Jaspal S.; Scott, William R.; Chambers, John C.] Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England. [Mbarek, Hamdi; de Geus, Eco J.; Willemsen, Gonneke; Boomsma, Dorret I.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Mbarek, Hamdi; de Geus, Eco J.; Willemsen, Gonneke; Boomsma, Dorret I.] EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Li-Gao, Ruifang; de Mutsert, Renee; Mook-Kanamori, Dennis O.] Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Trompet, Stella; de Craen, Anton J. M.] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [Verweij, Niek; van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Evangelou, Evangelos] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Fimlab Labs, Dept Clin Chem, Tampere, Finland. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Univ Tampere, Sch Med, Dept Clin Chem, FIN-33101 Tampere, Finland. [Tayo, Bamidele O.; Cooper, Richard S.] Loyola Univ, Chicago Stritch Sch Med, Publ Hlth Sci, Maywood, IL 60153 USA. [Deelen, Joris; Slagboom, P. Eline] Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands. [van der Laan, Sander W.; de Ruijter, Hester M.; Pasterkamp, Gerard] Univ Med Ctr Utrecht, Lab Expt Cardiol, Utrecht, Netherlands. [Arking, Dan E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Morrison, Alanna; Boerwinkle, Eric] Univ Texas Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX USA. [Rivadeneira, Fernando; Sijbrands, Eric J.; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Campbell, Archie] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Generat Scotland, Edinburgh, Midlothian, Scotland. [Hocking, Lynne J.] Univ Aberdeen, Div Appl Med, Musculoskeletal Res Programme, Aberdeen, Scotland. [Padmanabhan, Sandosh] Univ Glasgow, British Heart Fdn Glasgow Cardiovasc Res Ctr, Inst Cardiovasc & Med Sci, Coll Med Vet & Life Sci, Glasgow, Lanark, Scotland. [Rice, Kenneth M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [White, Charles C.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Harris, Tamara] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. [Rudan, Igor] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Kolcic, Ivana; Zemunik, Tatijana; Polasek, Ozren] Univ Split, Fac Med, Split, Croatia. [Salomaa, Veikko] Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland. [Kooner, Angad S.; Kooner, Jaspal S.; Tan, Sian-Tsung] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Cardiovasc Sci, London, England. [Kooner, Jaspal S.; Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, Imperial Coll Healthcare NHS Trus, London, England. [Milaneschi, Yuri; Penninx, Brenda W. J. H.] Vrije Univ Amsterdam, Med Ctr Amsterdam GGZinGeest, Dept Psychiat, Amsterdam, Netherlands. [Milaneschi, Yuri; Penninx, Brenda W. J. H.] EMGO Inst Hlth & Care Res & Neurosci Campus Amste, Amsterdam, Netherlands. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Gansevoort, Ron T.] Univ Groningen, Univ Med Ctr Groningen, Dept Nephrol, Groningen, Netherlands. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol, FIN-20520 Turku, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Viikari, Jorma S.] Turku Univ Hosp, Div Med, FIN-20520 Turku, Finland. [Viikari, Jorma S.] Univ Turku, Dept Med, Turku, Finland. [Nikus, Kjell] Tampere Univ Hosp, Heart Hosp, Dept Cardiol, Tampere, Finland. [Nikus, Kjell] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Forrester, Terrence; McKenzie, Colin A.] Univ W Indies, Res Inst Trop Med, Trop Metab Res Unit, Monaco, Jamaica. [Pasterkamp, Gerard] Univ Med Ctr Utrecht, Lab Clin Chem & Hematol, Utrecht, Netherlands. [Oldehinkel, Albertine J.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland. [Kahonen, Mika] Univ Tampere, Sch Med, Dept Clin Physiol, FIN-33101 Tampere, Finland. [Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [van der Harst, Pim; Swertz, Morris] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Mook-Kanamori, Dennis O.] Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, Leiden, Netherlands. [Mook-Kanamori, Dennis O.] King Faisal Med Hosp & Res Ctr, Dept BESC, Epidemiol Sect, Riyadh, Saudi Arabia. [Swertz, Morris] Univ Groningen, Univ Med Ctr Groningen, Genom Coordinat Ctr, Groningen, Netherlands. [Ripatti, Samuli] Univ Helsinki, Publ Hlth, Helsinki, Finland. [Ripatti, Samuli] Wellcome Trust Sanger Inst, Hinxton, England. [van Dijk, Ko Willems] Leiden Univ, Med Ctr, Dept Gen Internal Med, Leiden, Netherlands. [Wilson, James G.] Univ Mississippi, Med Ctr, Physiol & Biophys, Jackson, MS 39216 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles BioMed Res Inst, Torrance, CA 90509 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Div Genom Outcomes, Torrance, CA 90509 USA. [Rotter, Jerome I.] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA. [Rotter, Jerome I.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Rotter, Jerome I.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA. RP van Duijn, CM (reprint author), Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Postbus 2040, NL-3000 CA Rotterdam, Netherlands. EM c.vanduijn@erasmusmc.nl RI Slagboom, P. Eline/R-4790-2016; Padmanabhan, Sandosh/S-3963-2016; Verweij, Niek/A-4499-2017; Polasek, Ozren/B-6002-2011; Kolcic, Ivana/E-2713-2017; Feitosa, Mary/K-8044-2012; Smith, Albert Vernon/K-5150-2015 OI de Geus, Eco/0000-0001-6022-2666; Dehghan, Abbas/0000-0001-6403-016X; Mbarek, Hamdi/0000-0002-1108-0371; Slagboom, P. Eline/0000-0002-2875-4723; Manichaikul, Ani/0000-0002-5998-795X; van der Laan, Sander W./0000-0001-6888-1404; Evangelou, Evangelos/0000-0002-5488-2999; Polasek, Ozren/0000-0002-5765-1862; Kolcic, Ivana/0000-0001-7918-6052; Feitosa, Mary/0000-0002-0933-2410; Hocking, Lynne J/0000-0002-2414-2826; Verweij, Niek/0000-0002-4303-7685; Smith, Albert Vernon/0000-0003-1942-5845 FU NIH [N01-AG-1-2100, HHSN271201200022C]; NIA Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); Home Office [780-TETRA]; National Institute for Health Research (NIHR) Imperial College Healthcare NHS Trust (ICHNT); Imperial College Biomedical Research Centre (BRC); ICHNT; Imperial College BRC; MRC-PHE Centre for Environment and Health; NIHR Health Protection Research Unit on Health Impact of Environmental Hazards; National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C]; NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393]; National Institute on Aging (NIA) [R01AG023629]; National Center for Advancing Translational Sciences; CTSI grant [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; Medical Research Council UK; Croatian Ministry of Science, Education and Sports [216-1080315-0302]; European Union [LSHG-CT-2006-018947, 259679, 279143]; Croatian Science Foundation [8875]; European Commission FP6 STRP grant [018947 (LSHG-CT-2006-01947)]; European Community [HEALTH-F4-2007-201413]; European Commission under the programme "Quality of Life and Management of the Living Resources" of 5th Framework Programme [QLG2-CT-2002-01254]; ENGAGE consortium; CMSB; Netherlands Organisation for Scientific Research [NWO-RFBR 047.017.043]; Russian Foundation for Basic Research [NWO-RFBR 047.017.043]; ZonMw grant [91111025]; National Heart, Lung, and Blood Institute [R01-HL-087700, R01-HL-088215, R01-HL-117078]; Chief Scientist Office of the Scottish Government Health Directorate [CZD/16/6]; Scottish Funding Council [HR03006]; UK's Medical Research Council; Netherlands Organization of Scientific Research NWO [175.010.2007.006]; Economic Structure Enhancing Fund (FES) of the Dutch government; Ministry of Economic Affairs; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; Northern Netherlands Collaboration of Provinces (SNN); Province of Groningen; University Medical Center Groningen; University of Groningen; Dutch Kidney Foundation; Dutch Diabetes Research Foundation; Innovation-Oriented Research Program on Genomics (SenterNovem) [IGE05007]; Centre for Medical Systems Biology; Netherlands Consortium for Healthy Ageing [050-060-810]; UnileverColworth; BBMRI-NL, a Research Infrastructure - Dutch government [NWO 184.021.007]; National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust; British Heart Foundation [SP/04/002]; Medical Research Council [G0601966, G0700931]; Wellcome Trust [084723/Z/08/Z]; NIHR [RP-PG-0407-10371]; Action on Hearing Loss [G51]; Division and the Board of Directors of the Leiden University Medical Center; Leiden University, Research Profile Area 'Vascular and Regenerative Medicine'; Dutch Science Organization (ZonMW-VENI Grant) [916.14.023]; Chief Scientist Office of the Scottish Government; Royal Society; MRC Human Genetics Unit; Arthritis Research UK; Bristol-Myers Squibb; Netherlands Heart Foundation [2001 D 032]; European commission [223004]; Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) [050-060-810]; Netherlands Organisation of Scientific Research NWO [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015, RIDE2]; Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) [050-060-810]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); European Commission (DG XII); Municipality of Rotterdam; University Medical Center, Netherlands; Erasmus University Medical Center Rotterdam, Netherlands; University of Utrecht, Netherlands; Radboud Medical Center Nijmegen, Netherlands; Parnassia Bavo group, Netherlands; University of Groningen, Netherlands; Netherlands Organization for Scientific Research NWO (Medical Research Council program) [GB-MW 940-38-011]; Netherlands Organization for Scientific Research NWO (ZonMW Brainpower grant) [100-001-004]; ZonMw Risk Behavior and Dependence grants [60-60600-97-118]; ZonMw Culture and Health grant [261-98-710]; Social Sciences Council [GB-MaGW 480-01-006, GB-MaGW 480-07-001, GB-MaGW 452-04-314, GB-MaGW 452-06-004]; NWO large-sized investment grant [175.010.2003.005]; NWO Longitudinal Survey and Panel Funding [481-08-013, 481-11-001]; Dutch Ministry of Justice (WODC); European Science Foundation [FP-006]; Biobanking and Biomolecular Resources Research Infrastructure BBMRI-NL [CP 32] FX The AGES Study has been funded by NIH contracts N01-AG-1-2100 and HHSN271201200022C, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament).; The Airwave Study is funded by the Home Office (grant number 780-TETRA) with additional support from the National Institute for Health Research (NIHR) Imperial College Healthcare NHS Trust (ICHNT) and Imperial College Biomedical Research Centre (BRC). PE is an NIHR Senior Investigator and is supported by the ICHNT and Imperial College BRC, the MRC-PHE Centre for Environment and Health and the NIHR Health Protection Research Unit on Health Impact of Environmental Hazards.; The ARIC Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C.; Cardiovascular Health Study: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; CROATIA-Korcula, CROATIA-Split and CROATIA-Vis (CR-Korcula, CR-Split, CR-Vis) were funded by the Medical Research Council UK, The Croatian Ministry of Science, Education and Sports (grant 216-1080315-0302), the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947) and the Croatian Science Foundation (grant 8875).; The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme "Quality of Life and Management of the Living Resources" of 5th Framework Programme (no. QLG2-CT-2002-01254). The ERF study was further supported by ENGAGE consortium and CMSB. High-throughput analysis of the ERF data was supported by joint grant from Netherlands Organisation for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). Exome sequencing in ERF was supported by the ZonMw grant (project 91111025).; The Family Heart Study was supported by the by grants R01-HL-087700, R01-HL-088215 and R01-HL-117078 from the National Heart, Lung, and Blood Institute.; Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6 and the Scottish Funding Council HR03006. Genotyping of the GS: SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the UK's Medical Research Council.; The LifeLines Cohort Study, and generation and management of GWAS genotype data for the LifeLines Cohort Study is supported by the Netherlands Organization of Scientific Research NWO (grant 175.010.2007.006), the Economic Structure Enhancing Fund (FES) of the Dutch government, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation and Dutch Diabetes Research Foundation.; The Leiden Longevity Study (LLS) has received funding from the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement no 259679. This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007), the Centre for Medical Systems Biology, and the Netherlands Consortium for Healthy Ageing (grant 050-060-810), all in the framework of the Netherlands Genomics Initiative, Netherlands Organization for Scientific Research (NWO), UnileverColworth and by BBMRI-NL, a Research Infrastructure financed by the Dutch government (NWO 184.021.007).; The LOLIPOP study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0601966,G0700931), the Wellcome Trust (084723/Z/08/Z) the NIHR (RP-PG-0407-10371), European Union FP7 (EpiMigrant, 279143) and Action on Hearing Loss (G51). The work was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility.; The NEO study is supported by the participating Departments, the Division and the Board of Directors of the Leiden University Medical Center, and by the Leiden University, Research Profile Area 'Vascular and Regenerative Medicine'. Dennis Mook-Kanamori is supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023).; ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh.; The PROSPER study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. JWJ is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810).; The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam.; Participating centres of TRAILS include the University Medical Center and University of Groningen, the Erasmus University Medical Center Rotterdam, the University of Utrecht, the Radboud Medical Center Nijmegen, and the Parnassia Bavo group, all in the Netherlands. TRAILS has been financially supported by various grants from the Netherlands Organization for Scientific Research NWO (Medical Research Council program grant GB-MW 940-38-011; ZonMW Brainpower grant 100-001-004; ZonMw Risk Behavior and Dependence grants 60-60600-97-118; ZonMw Culture and Health grant 261-98-710; Social Sciences Council medium-sized investment grants GB-MaGW 480-01-006 and GB-MaGW 480-07-001; Social Sciences Council project grants GB-MaGW 452-04-314 and GB-MaGW 452-06-004; NWO large-sized investment grant 175.010.2003.005; NWO Longitudinal Survey and Panel Funding 481-08-013 and 481-11-001), the Dutch Ministry of Justice (WODC), the European Science Foundation (EuroSTRESS project FP-006), Biobanking and Biomolecular Resources Research Infrastructure BBMRI-NL (CP 32), and the participating universities. NR 20 TC 1 Z9 1 U1 2 U2 6 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 EI 1468-6244 J9 J MED GENET JI J. Med. Genet. PD JUL PY 2016 VL 53 IS 7 BP 441 EP 449 DI 10.1136/jmedgenet-2015-103439 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA DP5KH UT WOS:000378534500003 PM 27036123 ER PT J AU Carr, W Olivera, A Harrell, M Milhorn, D Elliot, J Rogers, N Brodnick, R Gill, J AF Carr, Walter Olivera, Anlys Harrell, Misha Milhorn, Denise Elliot, Jonathan Rogers, Nicholas Brodnick, Robert Gill, Jessica TI AN EVALUATION OF ACUTE NEUROTRAUMA BIOMARKERS IN SERUM FOR CONCUSSED AND NON-CONCUSSED COMBAT ZONE COHORTS SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE military; acute; serum; UCH-L1 C1 [Carr, Walter] USAMRMC, Ft Detrick, MD USA. [Olivera, Anlys; Gill, Jessica] NINR, NIH, Bethesda, MD 20892 USA. [Harrell, Misha] 651st EAES, Camp Leatherneck, Afghanistan. [Carr, Walter; Milhorn, Denise; Elliot, Jonathan; Rogers, Nicholas; Brodnick, Robert] 1st MLG Fwd, Camp Leatherneck, Afghanistan. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL 1 PY 2016 VL 33 IS 13 MA PSB-240 BP A99 EP A99 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200269 ER PT J AU Cota, M Moses, A Diaz-Arrastia, R Latour, L Turtzo, LC AF Cota, Martin Moses, Anita Diaz-Arrastia, Ramon Latour, Lawrence Turtzo, L. Christine TI DISCORDANCE BETWEEN DOCUMENTED CRITERIA AND WRITTEN DIAGNOSIS OF TBI IN A LEVEL 1 TRAUMA HOSPITAL EMERGENCY DEPARTMENT SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE chart review; diagnosis C1 [Cota, Martin; Moses, Anita] NINDS, CNRM, NIH, Stroke Branch, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Cota, Martin; Moses, Anita; Latour, Lawrence; Turtzo, L. Christine] NINDS, NIH, Stroke Branch, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Diaz-Arrastia, Ramon] CNRM, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL 1 PY 2016 VL 33 IS 13 MA PSB-227 BP A94 EP A94 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200256 ER PT J AU Griffin, A Tolpygo, A Parikh, G Turtzo, C Moses, A Ray-Chaudhury, A Dardzinksi, B Mitra, P Latour, L AF Griffin, Allison Tolpygo, Alexander Parikh, Gunjan Turtzo, Christine Moses, Anita Ray-Chaudhury, Abhik Dardzinksi, Bernard Mitra, Partha Latour, Lawrence TI MRI EVALUATION OF MICROBLEEDS MAY REVEAL ONLY THE TIP OF THE ICEBERG: A 3D HISTOLOGICAL ANALYSIS SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY C1 [Griffin, Allison; Turtzo, Christine; Moses, Anita; Ray-Chaudhury, Abhik; Latour, Lawrence] NINDS, CNRM, HJF, NIH,SB, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Tolpygo, Alexander; Mitra, Partha] Cold Spring Harbor Lab, POB 100, Cold Spring Harbor, NY 11724 USA. [Parikh, Gunjan] Univ Maryland, Shock Trauma, Baltimore, MD 21201 USA. [Dardzinksi, Bernard] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL 1 PY 2016 VL 33 IS 13 MA PSA-132 BP A59 EP A59 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200160 ER PT J AU Haber, M Hutchinson, E Irfanoglu, O Cheng, T Namjoshi, D Cripton, P Sadeghi, N Wellington, C Diaz-Arrastia, R Pierpaoli, C AF Haber, Margalit Hutchinson, Elizabeth Irfanoglu, Okan Cheng, Tom Namjoshi, Dhananjay Cripton, Peter Sadeghi, Neda Wellington, Cheryl Diaz-Arrastia, Ramon Pierpaoli, Carlo TI DTI ABNORMALITIES IN THE CLOSED HEAD INJURY MODEL OF ENGINEERED ROTATIONAL ACCELERATION (CHIMERA) MOUSE MODEL SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE DTI; animal model; CHIMERA; diffuse axonal injury; diffusion MRI C1 [Haber, Margalit] Henry M Jackson Fdn Adv Mil Med, CNRM, Rockville, MD USA. [Haber, Margalit; Hutchinson, Elizabeth; Irfanoglu, Okan; Sadeghi, Neda; Pierpaoli, Carlo] NICHD, NIH, SQITS, Bethesda, MD USA. [Cheng, Tom; Namjoshi, Dhananjay; Wellington, Cheryl] Univ British Columbia, Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada. [Cripton, Peter] Univ British Columbia, Biomech Engn, Vancouver, BC V5Z 1M9, Canada. [Haber, Margalit; Diaz-Arrastia, Ramon] USUHS, Neurol, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL 1 PY 2016 VL 33 IS 13 MA PSB-270 BP A109 EP A110 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200299 ER PT J AU Kenney, K Amyot, F Turtzo, LC Haber, M Silverman, E Moore, C Shenouda, C Wasserman, E Diaz-Arrastia, R AF Kenney, Kimbra Amyot, Franck Turtzo, L. Christine Haber, Margalit Silverman, Erika Moore, Carol Shenouda, Christian Wasserman, Eric Diaz-Arrastia, Ramon TI CEREBROVASCULAR REACTIVITY IN CHRONIC TRAUMATIC BRAIN INJURY-THE SILDENAFIL EFFECT SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE cerebrovascular reactivity; traumatic vascular injury; biomarker; phosphodiesterase 5 (PDE5) inhibitor; sildenafil C1 [Kenney, Kimbra; Amyot, Franck; Haber, Margalit; Silverman, Erika; Moore, Carol; Diaz-Arrastia, Ramon] USUHS, Neurol, Bethesda, MD USA. [Turtzo, L. Christine; Wasserman, Eric] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Shenouda, Christian] NIH, Phys Med & Rehabil, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL 1 PY 2016 VL 33 IS 13 MA PSA-022 BP A21 EP A21 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200052 ER PT J AU Merchant-Borna, K Olivera, A Gill, J Bazarian, J AF Merchant-Borna, Kian Olivera, Anlys Gill, Jessica Bazarian, Jeffrey TI LONGITUDINAL TAU CONCENTRATIONS IN SWEAT FOLLOWING SPORT-RELATED CONCUSSION: A PILOT STUDY SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE tau; sports; sport related concussion; sweat C1 [Merchant-Borna, Kian; Bazarian, Jeffrey] Univ Rochester, Med Ctr, Emergency Med, Rochester, NY 14627 USA. [Olivera, Anlys; Gill, Jessica] NINR, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL 1 PY 2016 VL 33 IS 13 MA PSB-248 BP A101 EP A102 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200277 ER PT J AU Parikh, G Griffin, A Moses, A Edwards, N Cota, M Nair, G Turtzo, C Reich, D Armstrong, R Ray-Chaudury, A Perl, D Latour, L AF Parikh, Gunjan Griffin, Allison Moses, Anita Edwards, Nancy Cota, Martin Nair, Govind Turtzo, Christine Reich, Daniel Armstrong, Regina Ray-Chaudury, Abhik Perl, Daniel Latour, Lawrence TI A WINDOW INTO THE WHITE MATTER RESPONSE TO PRIMARY MICROVASCULAR INJURY-2D HISTOLOGICAL ANALYSIS OF ACUTE TRAUMATIC MICROBLEEDS SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE histology; MRI; microvascular; extracellular matrix; ischemia; human C1 [Parikh, Gunjan] Univ Maryland, Sch Med, R Adams Cowley Shock Trauma Ctr, Neurocrit Care, Baltimore, MD 21201 USA. [Parikh, Gunjan; Edwards, Nancy; Nair, Govind; Reich, Daniel; Ray-Chaudury, Abhik; Latour, Lawrence] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Griffin, Allison; Moses, Anita; Cota, Martin; Turtzo, Christine; Armstrong, Regina; Perl, Daniel; Latour, Lawrence] CNRM, Bethesda, MD USA. [Armstrong, Regina; Perl, Daniel] USUHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL 1 PY 2016 VL 33 IS 13 MA PSA-134 BP A60 EP A60 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200162 ER PT J AU Qu, BX Bogoslovsky, T Cota, M Latour, L Diaz-Arrastia, R AF Qu, Baoxi Bogoslovsky, Tanya Cota, Martin Latour, Lawrence Diaz-Arrastia, Ramon TI PHOSPHORYLATED NEUROFILAMENT HEAVY CHAIN (PNF-H), VON WILLEBRAND FACTOR (VWF), AND CELLULAR FIBRONECTIN (CFN) IN PLASMA AFTER MTBI SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE Von Willebrand factor; cellular fibronectin; phosphorylated neurofilament H; mild TBI C1 [Qu, Baoxi; Bogoslovsky, Tanya; Diaz-Arrastia, Ramon] Uniformed Serv Univ Hlth Sci, Neurol, Bethesda, MD 20814 USA. [Bogoslovsky, Tanya; Cota, Martin; Latour, Lawrence; Diaz-Arrastia, Ramon] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Qu, Baoxi; Bogoslovsky, Tanya; Cota, Martin; Latour, Lawrence; Diaz-Arrastia, Ramon] Ctr Neurosci & Regenerat Med, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL 1 PY 2016 VL 33 IS 13 MA PSA-019 BP A19 EP A20 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200049 ER PT J AU Tolpygo, A Lodato, Z Ferrante, D Chaudhury, AR Dardinski, B Griffin, A Moses, A Nair, G Parikh, G Perl, DP Mitra, PP Latour, L AF Tolpygo, Alexander Lodato, Z. Ferrante, D. Chaudhury, A. R. Dardinski, B. Griffin, A. Moses, A. Nair, G. Parikh, G. Perl, D. P. Mitra, P. P. Latour, L. TI ADVANCES TOWARD 3D HISTOLOGICAL RECONSTRUCTION OF TRAUMATIC VASCULAR INJURY SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE histology; digital; pathology; whole-slide imaging; TBI C1 [Tolpygo, Alexander; Lodato, Z.; Ferrante, D.; Mitra, P. P.] CSHL, Cold Spring Harbor, NY USA. [Griffin, A.; Moses, A.; Perl, D. P.; Latour, L.] CNRM, Bethesda, MD USA. [Dardinski, B.; Perl, D. P.] USUHS, Bethesda, MD USA. [Chaudhury, A. R.; Nair, G.; Parikh, G.; Latour, L.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Parikh, G.] Univ Maryland, College Pk, MD 20742 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL 1 PY 2016 VL 33 IS 13 MA PSB-308 BP A123 EP A123 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200337 ER PT J AU Tu, TW Papadakis, G Ibrahim, W Jikaria, N Reid, W Hammoud, D Frank, J AF Tu, Tsang-Wei Papadakis, Georgios Ibrahim, Wael Jikaria, Neekita Reid, William Hammoud, Dima Frank, Joseph TI SENSITIVITY COMPARISON BETWEEN GLUCOCEST, FDG-PET AND 2DG-AUTORADIOGRAPHY IN MEASURING GLUCOSE METABOLIC DISORDER IN MILD TBI SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE glucoCEST; FDG-PET; 2DG Autoradiography; diffuse axonal injury; diffusion tensor imaging C1 [Tu, Tsang-Wei; Papadakis, Georgios; Ibrahim, Wael; Jikaria, Neekita; Reid, William; Hammoud, Dima; Frank, Joseph] NIH, Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL 1 PY 2016 VL 33 IS 13 MA PSB-272 BP A110 EP A110 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200301 ER PT J AU Turtzo, L Parikh, G MacLaren, J Williford, J Moses, A Cota, M Latour, L AF Turtzo, L. Parikh, Gunjan MacLaren, Judy Williford, Josh Moses, Anita Cota, Martin Latour, Larry TI ISCHEMIA AND LATE BLOOD BRAIN BARRIER DISRUPTION DURING EVOLUTION OF WHITE MATTER MICROVASCULAR INJURY SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE traumatic microvascular injury C1 [Turtzo, L.; Latour, Larry] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Parikh, Gunjan] UMD, Shock Trauma, Baltimore, MD USA. [MacLaren, Judy; Williford, Josh] Suburban Hosp, Bethesda, MD USA. [Moses, Anita; Cota, Martin; Latour, Larry] CNRM, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL 1 PY 2016 VL 33 IS 13 MA PSB-273 BP A110 EP A111 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200302 ER PT J AU D'Angio, CT Ambalavanan, N Carlo, WA McDonald, SA Skogstrand, K Hougaard, DM Shankaran, S Goldberg, RN Ehrenkranz, RA Tyson, JE Stoll, BJ Das, A Higgins, RD AF D'Angio, Carl T. Ambalavanan, Namasivayam Carlo, Waldemar A. McDonald, Scott A. Skogstrand, Kristin Hougaard, David M. Shankaran, Seetha Goldberg, Ronald N. Ehrenkranz, Richard A. Tyson, Jon E. Stoll, Barbara J. Das, Abhik Higgins, Rosemary D. CA Eunice Kennedy Shriver Natl Inst C TI Blood Cytokine Profiles Associated with Distinct Patterns of Bronchopulmonary Dysplasia among Extremely Low Birth Weight Infants SO JOURNAL OF PEDIATRICS LA English DT Article ID CHRONIC LUNG-DISEASE; PREMATURE-INFANTS; PRETERM INFANTS; INFLAMMATORY MARKERS; PULMONARY; INTERLEUKIN-8; FLUID; EXPRESSION; HYPEROXIA; ASPIRATE AB Objective To explore differences in blood cytokine profiles among distinct bronchopulmonary dysplasia (BPD) patterns. Study design We evaluated blood spots collected from 943 infants born at <= 1000 g and surviving to 28 days on postnatal days 1, 3, 7, 14, and 21 for 25 cytokines. Infants were assigned to the following lung disease patterns: (1) no lung disease (NLD); (2) respiratory distress syndrome without BPD; (3) classic BPD (persistent exposure to supplemental oxygen until 28 days of age); or (4) atypical BPD (period without supplemental oxygen before 28 days). Median cytokine levels for infants with BPD were compared with the IQR of results among infants with NLD. Results The distribution of enrolled infants by group was as follows: 69 (NLD), 73 (respiratory distress syndrome), 381 (classic BPD), and 160 (atypical BPD). The remaining 260 infants could not be classified because of missing data (104) or not fitting a predefined pattern (156). Median levels of 3 cytokines (elevated interleukin [IL]-8, matrix metalloproteinase-9; decreased granulocyte macrophage colony-stimulating factor) fell outside the IQR for at least 2 time points in both infants with atypical and classic BPD. Profiles of 7 cytokines (IL-6, IL-10, IL-18, macrophage inflammatory protein-1a, C-reactive protein, brain-derived neurotrophic factor, regulated on activation, normal T cell expressed and secreted) differed between infants with classic and atypical BPD. Conclusions Blood cytokine profiles may differ between infants developing classic and atypical BPD. These dissimilarities suggest the possibility that differing mechanisms could explain the varied patterns of pathophysiology of lung disease in extremely premature infants. C1 [D'Angio, Carl T.] Univ Rochester, Sch Med & Dent, Strong Childrens Res Ctr, Rochester, NY 14642 USA. [Ambalavanan, Namasivayam; Carlo, Waldemar A.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [McDonald, Scott A.] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Skogstrand, Kristin; Hougaard, David M.] Statens Serum Inst, Dept Clin Biochem Immunol & Genet, Danish Ctr Neonatal Screening, DK-2300 Copenhagen, Denmark. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Goldberg, Ronald N.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Ehrenkranz, Richard A.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Tyson, Jon E.] Univ Texas Houston, Sch Med, Dept Pediat, Houston, TX USA. [Stoll, Barbara J.] Emory Univ, Sch Med, Dept Pediat, Childrens Healthcare Atlanta, Atlanta, GA USA. [Das, Abhik] RTI Int, Stat & Epidemiol Unit, Rockville, MD USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP D'Angio, CT (reprint author), Univ Rochester, Sch Med & Dent, Neonatol, Box 651,601 Elmwood Ave, Rochester, NY 14642 USA. EM carl_dangio@urmc.rochester.edu OI Ambalavanan, Namasivayam/0000-0003-0731-9092 FU National Institutes of Health (NIH) [M01 RR30, M01 RR32, M01 RR39, M01 RR70, M01 RR80, M01 RR633, M01 RR750, M01 RR997, M01 RR6022, M01 RR7122, M01 RR8084, M01 RR16587]; NICHD [U01 HD36790, U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21397, U10 HD21415, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27881, U10 HD27904, U10 HD34216, U10 HD40461, U10 HD40492, U10 HD40498, U10 HD40689, 1 U10 HD 068263]; Centers for Disease Control and Prevention (CDC) [Y1-HD-500001] FX The Neonatal Research Network's Cytokines Study was supported by the National Institutes of Health (NIH; M01 RR30, M01 RR32, M01 RR39, M01 RR70, M01 RR80, M01 RR633, M01 RR750, M01 RR997, M01 RR6022, M01 RR7122, M01 RR8084, M01 RR16587), the NICHD (U01 HD36790, U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21397, U10 HD21415, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27881, U10 HD27904, U10 HD34216, U10 HD40461, U10 HD40492, U10 HD40498, U10 HD40689), and the Centers for Disease Control and Prevention (CDC; Interagency Agreement Y1-HD-500001). C.D. is supported by NICHD (1 U10 HD 068263). Participating sites collected data and transmitted it to RTI International, the data coordinating center for the network, which stored, managed, and analyzed the data for this study. Although NICHD and CDC staff did have input into the study design, conduct, analysis, and manuscript drafting, the content is solely the responsibility of the authors and does not necessarily represent the official views of NICHD or CDC. The authors declare no conflicts of interest. NR 27 TC 2 Z9 2 U1 1 U2 5 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 JUL PY 2016 VL 174 BP 45 EP 51 DI 10.1016/j.jpeds.2016.03.058 PG 7 WC Pediatrics SC Pediatrics GA DP6PX UT WOS:000378620800011 PM 27117196 ER PT J AU Rice, CE Zablotsky, B Avila, RM Colpe, LJ Schieve, LA Pringle, B Blumberg, SJ AF Rice, Catherine E. Zablotsky, Benjamin Avila, Rosa M. Colpe, Lisa J. Schieve, Laura A. Pringle, Beverly Blumberg, Stephen J. TI Reported Wandering Behavior among Children with Autism Spectrum Disorder and/or Intellectual Disability SO JOURNAL OF PEDIATRICS LA English DT Article ID CHALLENGING BEHAVIORS; FUNCTIONAL-ANALYSIS; CARE NEEDS; ELOPEMENT; ADULTS; HEALTH; DEATH AB Objective To characterize wandering, or elopement, among children with autism spectrum disorder (ASD) and intellectual disability. Study design Questions on wandering in the previous year were asked of parents of children with ASD with and without intellectual disability and children with intellectual disability without ASD as part of the 2011 Survey of Pathways to Diagnosis and Services. The Pathways study sample was drawn from the much larger National Survey of Children with Special Health Care Needs conducted in 2009-2010. Results For children with special healthcare needs diagnosed with either ASD, intellectual disability, or both, wandering or becoming lost during the previous year was reported for more than 1 in 4 children. Wandering was highest among children with ASD with intellectual disability (37.7%) followed by children with ASD without intellectual disability (32.7%), and then children with intellectual disability without ASD (23.7%), though the differences between these groups were not statistically significant. Conclusions This study affirms that wandering among children with ASD, regardless of intellectual disability status, is relatively common. However, wandering or becoming lost in the past year was also reported for many children with intellectual disability, indicating the need to broaden our understanding of this safety issue to other developmental disabilities. C1 [Rice, Catherine E.; Schieve, Laura A.] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Baltimore, MD USA. [Rice, Catherine E.] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. [Zablotsky, Benjamin; Blumberg, Stephen J.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Avila, Rosa M.] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Colpe, Lisa J.; Pringle, Beverly] NIMH, NIH, Bethesda, MD 20892 USA. RP Rice, CE (reprint author), Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. EM cerice@emory.edu FU National Institute of Mental Health; American Recovery and Reinvestment Act (ARRA) [111-5] FX Funded by the National Institute of Mental Health with funds available from the American Recovery and Reinvestment Act of 2009 (ARRA) (Public Law 111-5). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease and Control and Prevention, Emory University, the University of Washington, or the National Institute of Mental Health. The authors declare no conflicts of interest. NR 28 TC 0 Z9 0 U1 2 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JUL PY 2016 VL 174 BP 232 EP 239 DI 10.1016/j.jpeds.2016.03.047 PG 8 WC Pediatrics SC Pediatrics GA DP6PX UT WOS:000378620800044 PM 27157446 ER PT J AU Bansal, N Carpenter, MA Weiner, DE Levey, AS Pfeffer, M Kusek, JW Cai, JW Hunsicker, LG Park, M Bennett, M Liu, KD Hsu, CY AF Bansal, Nisha Carpenter, Myra A. Weiner, Daniel E. Levey, Andrew S. Pfeffer, Marc Kusek, John W. Cai, Jianwen Hunsicker, Lawrence G. Park, Meyeon Bennett, Michael Liu, Kathleen D. Hsu, Chi-yuan TI Urine Injury Biomarkers and Risk of Adverse Outcomes in Recipients of Prevalent Kidney Transplants: The Folic Acid for Vascular Outcome Reduction in Transplantation Trial SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GELATINASE-ASSOCIATED LIPOCALIN; TYPE-1 DIABETIC-PATIENTS; GLOMERULAR-FILTRATION-RATE; DELAYED GRAFT FUNCTION; BINDING PROTEIN GENE; STAGE RENAL-DISEASE; FATTY-ACID; CARDIOVASCULAR-DISEASE; CARDIAC-SURGERY; PREDICTIVE BIOMARKERS AB Recipients of kidney transplants (KTR) are at increased risk for cardiovascular events, graft failure, and death. It is unknown whether urine kidney injury biomarkers are associated with poor outcomes among KTRs. We conducted a post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial using a case-cohort study design, selecting participants with adjudicated cardiovascular events, graft failure, or death. Urine neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), IL-18, and liver-type fatty acid binding protein (L-FABP) were measured in spot urine samples and standardized to urine creatinine concentration. We adjusted for demographics, cardiovascular risk factors, eGFR, and urine albumin-to-creatinine ratio. Patients had 291 cardiovascular events, 257 graft failure events, and 359 deaths. Each log increase in urine NGAL/creatinine independently associated with a 24% greater risk of cardiovascular events (adjusted hazard ratio [aHR], 1.24; 95% confidence interval [95% CI], 1.06 to 1.45), a 40% greater risk of graft failure (aHR, 1.40; 95% CI, 1.16 to 1.68), and a 44% greater risk of death (aHR, 1.44; 95% Cl, 1.26 to 1.65). Urine KIM-1/creatinine and IL-18/creatinine independently associated with greater risk of death (aHR, 1.29; 95% CI, 1.03 to 1.61 and aHR, 1.25; 95% CI, 1.04 to 1.49 per log increase, respectively) but not with risk of cardiovascular events or graft failure. Urine L-FABP did not associate with any study outcomes. In conclusion, among prevalent KTRs, higher urine NGAL, KIM-1, and IL-18 levels independently and differentially associated with greater risk of adverse outcomes. C1 [Bansal, Nisha] Univ Washington, Kidney Res Inst, Div Nephrol, Seattle, WA 98104 USA. [Carpenter, Myra A.; Cai, Jianwen] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Weiner, Daniel E.; Levey, Andrew S.] Tufts Med Ctr, Div Nephrol, Boston, MA USA. [Pfeffer, Marc] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA. [Kusek, John W.] NIDDK, NIH, Bethesda, MD 20892 USA. [Hunsicker, Lawrence G.] Univ Iowa, Coll Med, Dept Med, Iowa City, IA 52242 USA. [Park, Meyeon; Liu, Kathleen D.; Hsu, Chi-yuan] Univ Calif San Francisco, Div Nephrol, San Francisco, CA 94143 USA. [Bennett, Michael] Cincinnati Childrens Hosp, Dept Pediat, Cincinnati, OH USA. RP Bansal, N (reprint author), Univ Washington, Kidney Res Inst, 908 Jefferson St,3rd Floor, Seattle, WA 98104 USA. EM nbansal@nephrology.washington.edu FU National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [K23 DK088865, K24 DK92291]; CKD Biomarker Consortium [U01DK85649]; NIDDK [U01 DK61700-01]; Office of Dietary Supplements, Department of Health and Human Services, the NIH FX This work was supported by Grants K23 DK088865 (to N.B.) and K24 DK92291 (to C.-y.H.) from the National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). K.D.L. and C.-y.H. are also supported by Grant U01DK85649 as members of the CKD Biomarker Consortium. The Folic Acid for Vascular Outcome Reduction in Transplantation Study was supported by Cooperative Agreement U01 DK61700-01 from the NIDDK, and additional financial support was from the Office of Dietary Supplements, Department of Health and Human Services, the NIH. Vitamins were provided by Pamlab, LLC. NR 61 TC 3 Z9 3 U1 1 U2 3 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 JUL PY 2016 VL 27 IS 7 BP 2109 EP 2121 DI 10.1681/ASN.2015030292 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA DP9OD UT WOS:000378824800025 PM 26538631 ER PT J AU Brown, P Juarez, B AF Brown, Patricia Juarez, Bernadette TI A word from USDA and OLAW SO LAB ANIMAL LA English DT Editorial Material C1 [Brown, Patricia] NIH, OLAW, OER, OD,NIH, Bldg 10, Bethesda, MD 20892 USA. [Juarez, Bernadette] APHIS, USDA, AC, Riverdale Pk, MD USA. RP Brown, P (reprint author), NIH, OLAW, OER, OD,NIH, Bldg 10, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0093-7355 EI 1548-4475 J9 LAB ANIMAL JI Lab Anim. PD JUL PY 2016 VL 45 IS 7 BP 250 EP 250 DI 10.1038/laban.1058 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA DP8OQ UT WOS:000378757900014 PM 27327010 ER PT J AU Nou, E Lo, J Hadigan, C Grinspoon, SK AF Nou, Eric Lo, Janet Hadigan, Colleen Grinspoon, Steven K. TI Pathophysiology and management of cardiovascular disease in patients with HIV SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACUTE MYOCARDIAL-INFARCTION; CORONARY-HEART-DISEASE; T-CELL-ACTIVATION; INTIMA-MEDIA THICKNESS; C-REACTIVE PROTEIN; EPICARDIAL ADIPOSE-TISSUE; RANDOMIZED CLINICAL-TRIAL; PLACEBO-CONTROLLED TRIAL; MULTICENTER AIDS COHORT AB Results from several studies have suggested that people with HIV have an increased risk of cardiovascular disease, especially coronary heart disease, compared with people not infected with HIV. People living with HIV have an increased prevalence of traditional cardiovascular disease risk factors, and HIV-specific mechanisms such as immune activation. Although older, more metabolically harmful antiretroviral regimens probably contributed to the risk of cardiovascular disease, new data suggest that early and continuous use of modern regimens, which might have fewer metabolic effects, minimises the risk of myocardial infarction by maintaining viral suppression and decreasing immune activation. Even with antiretroviral therapy, however, immune activation persists in people with HIV and could contribute to accelerated atherosclerosis, especially of coronary lesions that are susceptible to rupture. Therefore, treatments that safely reduce inflammation in people with HIV could provide additional cardiovascular protection alongside treatment of both traditional and non-traditional risk factors. C1 [Nou, Eric; Lo, Janet; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Hadigan, Colleen] NIAID, NIH, Bethesda, MD USA. RP Grinspoon, SK (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM sgrinspoon@mgh.harvard.edu FU US National Institute of Allergies and Infectious Diseases Intramural Program FX This work was partly supported by the US National Institute of Allergies and Infectious Diseases Intramural Program. NR 137 TC 5 Z9 5 U1 3 U2 7 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 JUL PY 2016 VL 4 IS 7 BP 598 EP 610 DI 10.1016/S2213-8587(15)00388-5 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DQ0CD UT WOS:000378864700022 PM 26873066 ER PT J AU Wiestner, A AF Wiestner, Adrian TI Choosing frontline chemoimmunotherapy for CLL SO LANCET ONCOLOGY LA English DT Editorial Material ID CHRONIC LYMPHOCYTIC-LEUKEMIA; CYCLOPHOSPHAMIDE; FLUDARABINE; IBRUTINIB; THERAPY; TRIAL C1 [Wiestner, Adrian] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Wiestner, A (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM wiestnera@mail.nih.gov NR 10 TC 0 Z9 0 U1 6 U2 6 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 JUL PY 2016 VL 17 IS 7 BP 852 EP 854 DI 10.1016/S1470-2045(16)30118-8 PG 4 WC Oncology SC Oncology GA DQ1FO UT WOS:000378947100035 PM 27216275 ER PT J AU Straub, H Simon, C Plunkett, BA Endres, L Adam, EK Mckinney, C Hobel, CJ Thorp, JM Raju, T Shalowitz, M AF Straub, Heather Simon, Clarissa Plunkett, Beth A. Endres, Loraine Adam, Emma K. Mckinney, Chelsea Hobel, Calvin J. Thorp, John M. Raju, Tonse Shalowitz, Madeleine TI Evidence for a Complex Relationship Among Weight Retention, Cortisol and Breastfeeding in Postpartum Women SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Postpartum weight retention; Cortisol slope; Breast feeding; Stress ID PITUITARY-ADRENAL AXIS; BODY-FAT DISTRIBUTION; SALIVARY CORTISOL; OBESITY; SECRETION; RISK; MOTHERS; STRESS; ADULTS; GAIN AB Objective To assess the relationship between cortisol slope, a biologic marker of stress, and postpartum weight retention. Methods We included 696 women in a secondary analysis from a multi-site study conducted using principles of community-based participatory research to study multi-level sources of stress on pregnancy outcomes. As a stress marker, we included salivary cortisol slope; the rate of cortisol decline across the day. Pre-pregnancy weight and demographic data were obtained from the medical records. At 6 months postpartum, patients were weighed and returned saliva samples. We built stepwise regression models to assess the effect of demographic variables, cortisol slope and cortisol covariates (wake time, tobacco use and breastfeeding) on postpartum weight retention. Results 45.5 % of participants were African American, 29.2 % White, and 25.3 % Hispanic. Of the Hispanic women 62.5 % were Spanish speaking and 37.5 % were English speaking. In general, participants were young, multiparous, and overweight. Postpartum, almost half (47.6 %) of women studied retained > 10 lbs. In multivariable analysis including age, pre-pregnancy BMI and public insurance, cortisol slope was significantly associated with weight retention (beta = -1.90, 95 % CI = 0.22-3.58). However, when the model was adjusted for the cortisol covariates, breastfeeding (beta = -0.63, 95 % CI = -1.01 to -0.24) and public insurance (beta = 0.62, 95 % CI = 0.20-1.04) were the two strongest correlates of weight retention. Conclusions for Practice The association between cortisol slope and postpartum weight retention appears to be influenced breastfeeding status. C1 [Straub, Heather; Plunkett, Beth A.; Endres, Loraine] NorthShore Univ HealthSyst, Evanston Hosp, Dept Obstet & Gynecol, Evanston, IL 60201 USA. [Straub, Heather] MultiCare Reg Maternal Fetal Med, MS 1105-2-MFM,1105 Div Ave,Suite 201, Tacoma, WA 98403 USA. [Simon, Clarissa; Adam, Emma K.] Northwestern Univ, Inst Policy Res, Evanston, IL USA. [Mckinney, Chelsea; Shalowitz, Madeleine] NorthShore Univ HealthSyst, Res Inst, Evanston, IL USA. [Hobel, Calvin J.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA USA. [Thorp, John M.] Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. [Raju, Tonse] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Straub, H (reprint author), NorthShore Univ HealthSyst, Evanston Hosp, Dept Obstet & Gynecol, Evanston, IL 60201 USA.; Straub, H (reprint author), MultiCare Reg Maternal Fetal Med, MS 1105-2-MFM,1105 Div Ave,Suite 201, Tacoma, WA 98403 USA. EM HeatherStraubMD@gmail.com FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U HD44207, U HD44219, U HD44226, U HD44245, U HD44253, U HD54791, U HD54019, U HD44226-05S1, U HD44245-06S1, R03 HD59584]; National Institute for Nursing Research [U NR008929] FX The Community Child Health Network is 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, U HD44253, U HD54791, U HD54019, U HD44226-05S1, U HD44245-06S1, R03 HD59584) and the National Institute for Nursing Research (U NR008929). NR 31 TC 0 Z9 0 U1 2 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD JUL PY 2016 VL 20 IS 7 BP 1375 EP 1383 DI 10.1007/s10995-016-1934-z PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DP8MK UT WOS:000378752000008 PM 26968183 ER PT J AU Ochiai, E Sa, QL Perkins, S Grigg, ME Suzuki, Y AF Ochiai, Eri Sa, Qila Perkins, Sara Grigg, Michael E. Suzuki, Yasuhiro TI CD8(+) T cells remove cysts of Toxoplasma gondii from the brain mostly by recognizing epitopes commonly expressed by or cross-reactive between type II and type III strains of the parasite SO MICROBES AND INFECTION LA English DT Article DE Toxoplasma gondii; Cyst; Genotype; CD8(+) T cells; Perforin ID CLINICAL FINDINGS; INTERFERON-GAMMA; INFECTION; GENOTYPE; RESISTANCE; RESPONSES AB Our previous study demonstrated that CD8(+) T cells remove cysts of Toxoplasma gondii from the brain through perforin-mediated mechanisms. We here show that a transfer of CD8(+) immune T cells primed with a type II or a type III strain of T. gondii both efficiently removed cysts of a type II strain from infected SCID mice, although the former tended to be slightly more efficient than the latter. Similarly, a transfer of type II-primed CD8(+) T cells removed cysts of a type III strain. Therefore, CD8(+) T cells are capable of removing T. gondii cysts by recognizing epitopes commonly expressed in types II and III strains or cross-reactive between these two genotypes. (C) 2016 Published by Elsevier Masson SAS on behalf of Institut Pasteur. C1 [Ochiai, Eri; Sa, Qila; Perkins, Sara; Suzuki, Yasuhiro] Univ Kentucky, Coll Med, Dept Microbiol Immunol & Mol Genet, 800 Rose St, Lexington, KY 40536 USA. [Grigg, Michael E.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Ochiai, Eri] Tokyo Univ Agr & Technol, Dept Biotechnol & Life Sci, Tokyo, Japan. RP Suzuki, Y (reprint author), Univ Kentucky, Coll Med, Dept Microbiol Immunol & Mol Genet, 800 Rose St, Lexington, KY 40536 USA. EM yasu.suzuki@uky.edu FU NIH [AI095032, AI073576, AI078756]; Intramural Research Program of the National Institutes of Health, NIAID FX The studies are supported in part by NIH grants (AI095032, AI073576, and AI078756) (Y.S.). This work was also supported, in part, by the Intramural Research Program of the National Institutes of Health, NIAID (M.E.G.). M.E.G. is a Scholar of the Canadian Institute for Advanced Research (CIFAR) Integrated Microbial Biodiversity program. NR 21 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 EI 1769-714X J9 MICROBES INFECT JI Microbes Infect. PD JUL-AUG PY 2016 VL 18 IS 7-8 DI 10.1016/j.micinf.2016.03.013 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DP9WK UT WOS:000378848400009 ER PT J AU Johnson, AR Qin, YY Cozzo, AJ Freemerman, AJ Huang, MJ Zhao, LY Sampey, BP Milner, JJ Beck, MA Damania, B Rashid, N Galanko, JA Lee, DP Edin, ML Zeldin, DC Fueger, PT Dietz, B Stahl, A Wu, Y Mohlke, KL Makowski, L AF Johnson, Amy R. Qin, Yuanyuan Cozzo, Alyssa J. Freemerman, Alex J. Huang, Megan J. Zhao, Liyang Sampey, Brante P. Milner, J. Justin Beck, Melinda A. Damania, Blossom Rashid, Naim Galanko, Joseph A. Lee, Douglas P. Edin, Matthew L. Zeldin, Darryl C. Fueger, Patrick T. Dietz, Brittney Stahl, Andreas Wu, Ying Mohlke, Karen L. Makowski, Liza TI Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation SO MOLECULAR METABOLISM LA English DT Article DE Adipose tissue macrophage; M2 macrophage; Obesity; Glycolysis; Crown-like structures; Mitochondria ID TISSUE MACROPHAGES; INSULIN-RESISTANCE; BINDING PROTEINS; GENE-EXPRESSION; PROINFLAMMATORY PHENOTYPE; RHEUMATOID-ARTHRITIS; GLUCOSE-METABOLISM; DIABETES-MELLITUS; SKELETAL-MUSCLE; DENDRITIC CELL AB Objective: A novel approach to regulate obesity-asociated adipose inflammation may be through metabolic reprogramming of macrophages (M Phi s). Broadly speaking, M Phi s dependent on glucose are pro-inflammatory, clasically activated M Phi s (CAM), which contribute to adipose inflammation and insulin resistance. In contrast, M Phi s that primarily metabolize fatty acids are alternatively activated M Phi s (AAM) and maintain tisue insulin sensitivity. In actuality, there is much flexibility and overlap in the CAM-AAM spectrum in vivo dependent upon various stimuli in the microenvironment. We hypothesized that specific lipid trafficking proteins, e.g. fatty acid transport protein 1 (FATP1), would direct M Phi s fatty acid transport and metabolism to limit inflammation and contribute to the maintenance of adipose tisue homeostasis. Methods: Bone marrow derived M Phi s (BMDMs) from Fatp1(-/-) and Fatp1(+/+) mice were used to investigate FATP1-dependent substrate metabolism, bioenergetics, metabolomics, and inflammatory responses. We also generated C57BL/6J chimeric mice by bone marrow transplant specifically lacking hematopoetic FATP1 (Fatp1B(-/-)) and controls Fatp1B(+/+). Mice were challenged by high fat diet (HFD) or low fat diet (LFD) and analyses including MRI, glucose and insulin tolerance tests, flow cytometric, histologic, and protein quantification asays were conducted. Finally, an FATP1-overexpresing RAW 264.7 M Phi s cell line (FATP1-OE) and empty vector control (FATP1-EV) were developed as a gain of function model to test effects on substrate metabolism, bioenergetics, metabolomics, and inflammatory responses. Results: Fatp1 is downregulated with pro-inflammatory stimulation of M Phi s. Fatp1(-/-) BMDMs and FATP1-OE RAW 264.7 M Phi s demonstrated that FATP1 reciprocally controled metabolic flexibility, i.e. lipid and glucose metabolism, which was asociated with inflammatory response. Supporting our previous work demonstrating the positive relationship between glucose metabolism and inflammation, los of FATP1 enhanced glucose metabolism and exaggerated the pro-inflammatory CAM phenotype. Fatp1B(-/-) chimeras fed a HFD gained more epididymal white adipose mas, which was inflamed and oxidatively stresed, compared to HFD-fed Fatp1B(+/+) controls. Adipose tisue macrophages displayed a CAM-like phenotype in the absence of Fatp1. Conversely, functional overexpresion of FATP1 decreased many aspects of glucose metabolism and diminished CAM-stimulated inflammation in vitro. FATP1 displayed acyl-CoA synthetase activity for long chain fatty acids in M Phi s and modulated lipid mediator metabolism in M Phi s. Conclusion: Our findings provide evidence that FATP1 is a novel regulator of M Phi activation through control of substrate metabolism. Absence of FATP1 exacerbated pro-inflammatory activation in vitro and increased local and systemic components of the metabolic syndrome in HFD-fed Fatp1(B-/-) mice. In contrast, gain of FATP1 activity in M Phi s suggested that Fatp1-mediated activation of fatty acids, substrate switch to glucose, oxidative stress, and lipid mediator synthesis are potential mechanisms. We demonstrate for the first time that FATP1 provides a unique mechanism by which the inflammatory tone of adipose and systemic metabolism may be regulated. (C) 2016 The Authors. Published by Elsevier GmbH. C1 [Johnson, Amy R.; Qin, Yuanyuan; Cozzo, Alyssa J.; Freemerman, Alex J.; Huang, Megan J.; Zhao, Liyang; Sampey, Brante P.; Milner, J. Justin; Beck, Melinda A.; Makowski, Liza] Univ N Carolina, Dept Nutr, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Beck, Melinda A.; Galanko, Joseph A.; Makowski, Liza] Univ N Carolina, Sch Med, Dept Nutr, Chapel Hill, NC 27599 USA. [Damania, Blossom] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [Rashid, Naim] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Damania, Blossom; Rashid, Naim; Makowski, Liza] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Beck, Melinda A.; Galanko, Joseph A.; Makowski, Liza] Univ N Carolina, Nutr Obes Res Ctr, Chapel Hill, NC 27599 USA. [Lee, Douglas P.] Omic Insight Inc, Durham, NC 27713 USA. [Edin, Matthew L.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, POB 12233, Res Triangle Pk, NC 27709 USA. [Fueger, Patrick T.] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Fueger, Patrick T.] Indiana Univ Sch Med, Dept Cellular Physiol, Indianapolis, IN 46202 USA. [Fueger, Patrick T.] Indiana Univ Sch Med, Dept Integrat Physiol, Indianapolis, IN 46202 USA. [Dietz, Brittney; Stahl, Andreas] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA. [Wu, Ying; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Sampey, Brante P.] Roivant Sci Inc, Roviant, NC 27701 USA. [Milner, J. Justin] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA. RP Makowski, L (reprint author), Univ N Carolina, Dept Nutr, CB7461, Chapel Hill, NC 27599 USA. EM liza.makowski@unc.edu FU NCI NIH HHS [P50 CA058223, R01 CA096500]; NHGRI NIH HHS [Z01 HG000024]; NHLBI NIH HHS [F32 HL075970]; NIAAA NIH HHS [K99 AA017376, R00 AA017376]; NIDDK NIH HHS [R01 DK089202, P30 DK034987, P30 DK056350, R01 DK093757, R01 DK099311, U01 DK062370, P30 DK026743, R01 DK062370, R01 DK072193, R01 DK101293, R56 DK062370]; NIEHS NIH HHS [P30 ES010126, Z01 ES025034] NR 95 TC 2 Z9 2 U1 6 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2212-8778 J9 MOL METAB JI Mol. Metab. PD JUL PY 2016 VL 5 IS 7 BP 506 EP 526 DI 10.1016/j.molmet.2016.04.005 PG 21 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP6UK UT WOS:000378634300009 PM 27408776 ER PT J AU Lee, JG Takahama, S Zhang, GF Tomarev, SI Ye, YH AF Lee, Jin-Gu Takahama, Shokichi Zhang, Guofeng Tomarev, Stanislav I. Ye, Yihong TI Unconventional secretion of misfolded proteins promotes adaptation to proteasome dysfunction in mammalian cells SO NATURE CELL BIOLOGY LA English DT Article ID ENDOPLASMIC-RETICULUM; QUALITY CONTROL; NEURODEGENERATIVE DISEASES; UBIQUITIN LIGASE; ALPHA-SYNUCLEIN; USP19; DEGRADATION; TRANSMISSION; MECHANISMS; EXOSOMES AB To safeguard proteomic integrity, cells rely on the proteasome to degrade aberrant polypeptides, but it is unclear how cells remove defective proteins that have escaped degradation owing to proteasome insufficiency or dysfunction. Here we report a pathway termed misfolding-associated protein secretion, which uses the endoplasmic reticulum (ER)-associated deubiquitylase USP19 to preferentially export aberrant cytosolic proteins. Intriguingly, the catalytic domain of USP19 possesses an unprecedented chaperone activity, allowing recruitment of misfolded proteins to the ER surface for deubiquitylation. Deubiquitylated cargos are encapsulated into ER-associated late endosomes and secreted to the cell exterior. USP19-deficient cells cannot efficiently secrete unwanted proteins, and grow more slowly than wild-type cells following exposure to a proteasome inhibitor. Together, our findings delineate a protein quality control (PQC) pathway that, unlike degradation-based PQC mechanisms, promotes protein homeostasis by exporting misfolded proteins through an unconventional protein secretion process. C1 [Lee, Jin-Gu; Ye, Yihong] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Takahama, Shokichi; Tomarev, Stanislav I.] NEI, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Zhang, Guofeng] NIBIB, Biomed Engn & Phys Sci Shared Resource, NIH, Bethesda, MD 20892 USA. [Takahama, Shokichi] Kumamoto Univ, Matsushita Project Lab, Ctr AIDS Res, Kumamoto 8600811, Japan. RP Ye, YH (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM yihongy@mail.nih.gov NR 47 TC 13 Z9 13 U1 7 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD JUL PY 2016 VL 18 IS 7 BP 765 EP + DI 10.1038/ncb3372 PG 14 WC Cell Biology SC Cell Biology GA DP9TS UT WOS:000378840900009 PM 27295555 ER PT J AU Rich, SS Wang, ZY Sturcke, A Ziyabari, L Feolo, M O'Donnell, CJ Rice, K Bis, JC Psaty, BM AF Rich, Stephen S. Wang, Zeng Y. Sturcke, Anne Ziyabari, Lora Feolo, Mike O'Donnell, Christopher J. Rice, Ken Bis, Joshua C. Psaty, Bruce M. TI Rapid evaluation of phenotypes, SNPs and results through the dbGaP CHARGE Summary Results site SO NATURE GENETICS LA English DT Letter ID GENOME-WIDE ASSOCIATION; DESIGN C1 [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Wang, Zeng Y.; Sturcke, Anne; Ziyabari, Lora; Feolo, Mike] US Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Div Intramural Res, Framingham, MA USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Rice, Ken] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP Rich, SS (reprint author), Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. EM ssr4n@virginia.edu NR 8 TC 2 Z9 2 U1 2 U2 4 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 JUL PY 2016 VL 48 IS 7 BP 702 EP 703 DI 10.1038/ng.3582 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA DP9TK UT WOS:000378840100002 PM 27350599 ER PT J AU Platonov, FA Tyryshkin, K Tikhonov, DG Neustroyeva, TS Sivtseva, TM Yakovleva, NV Nikolaev, VP Sidorova, OG Kononova, SK Goldfarb, LG Renwick, NM AF Platonov, Fedor A. Tyryshkin, Kathrin Tikhonov, Dmitriy G. Neustroyeva, Tatyana S. Sivtseva, Tatyana M. Yakovleva, Natalya V. Nikolaev, Valerian P. Sidorova, Oksana G. Kononova, Sardana K. Goldfarb, Lev G. Renwick, Neil M. TI Genetic fitness and selection intensity in a population affected with high-incidence spinocerebellar ataxia type 1 SO NEUROGENETICS LA English DT Article DE Spinocerebellar ataxia type 1; ATXN1 gene; Northeast Siberia; Sakha(Yakut)population; Genetic fitness; Crow's index ID CAG-REPEAT; HIGH PREVALENCE; EXPANSION; SIBERIA; DISEASE; ONSET; SCA1; AGE AB Spinocerebellar ataxia type 1 (SCA1) is the major and likely the only type of autosomal dominant cerebellar ataxia in the Sakha (Yakut) people of Eastern Siberia. The prevalence rate of SCA1 has doubled over the past 21 years peaking at 46 cases per 100,000 rural population. The age at death correlates closely with the number of CAG triplet repeats in the mutant ATXN1 gene (r = -0.81); most patients with low-medium (39-55) repeat numbers survived until the end of reproductive age. The number of CAG repeats expands in meiosis, particularly in paternal transmissions; the average total increase in intergenerational transmissions in our cohort was estimated at 1.6 CAG repeats. The fertility rates of heterozygous carriers of 39-55 CAG repeats in women were no different from those of the general Sakha population. Overall, the survival of mutation carriers through reproductive age, unaltered fertility rates, low childhood mortality in SCA1-affected families, and intergenerational transmission of increasing numbers of CAG repeats in the ATXN1 gene indicate that SCA1 in the Sakha population will be maintained at high prevalence levels. The low (0.19) Crow's index of total selection intensity in our SCA1 cohort implies that this mutation is unlikely to be eliminated through natural selection alone. C1 [Platonov, Fedor A.; Tikhonov, Dmitriy G.; Neustroyeva, Tatyana S.; Sivtseva, Tatyana M.; Yakovleva, Natalya V.; Nikolaev, Valerian P.] MK Ammosov North Eastern Fed Univ, Inst Hlth, Yakutsk 677010, Russia. [Tyryshkin, Kathrin; Renwick, Neil M.] Queens Univ, Dept Pathol & Mol Med, Kingston, ON K7L 3N6, Canada. [Sidorova, Oksana G.; Kononova, Sardana K.] Acad Med Sci, Ctr Integrated Med Res, Yakutsk 677010, Russia. [Goldfarb, Lev G.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Goldfarb, LG (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM GoldfarbL@ninds.nih.gov FU Ministry of Education and Science of the Russian Federation [1742, 18.1742.2014/K, 6.656.2014/K]; Department of Pathology and Molecular Medicine, Queen's University; Intramural Research Programs of the National Institute of Neurological Disorders and Stroke; SEAMO New Clinician-Scientist Investigator Award; Queen's University Principal's Development Fund FX The study was funded in part by the Ministry of Education and Science of the Russian Federation through individual or group projects: PFA-project 1742, TDG, NTS, YNV, and NVP-project 18.1742.2014/K and KSK-project 6.656.2014/K. KT was supported by the Department of Pathology and Molecular Medicine, Queen's University. GLG was funded in part by the Intramural Research Programs of the National Institute of Neurological Disorders and Stroke. NR was funded through a SEAMO New Clinician-Scientist Investigator Award and the Queen's University Principal's Development Fund. The authors wish to thank Dr. A. L. Suhomasova for helpful advice. NR 28 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1364-6745 EI 1364-6753 J9 NEUROGENETICS JI Neurogenetics PD JUL PY 2016 VL 17 IS 3 BP 179 EP 185 DI 10.1007/s10048-016-0481-5 PG 7 WC Genetics & Heredity; Clinical Neurology SC Genetics & Heredity; Neurosciences & Neurology GA DP5NI UT WOS:000378543900005 PM 27106293 ER PT J AU Ghassabian, A Sundaram, R Bell, E Bello, SC Kus, C Yeung, E AF Ghassabian, Akhgar Sundaram, Rajeshwari Bell, Erin Bello, Scott C. Kus, Christopher Yeung, Edwina TI Gross Motor Milestones and Subsequent Development SO PEDIATRICS LA English DT Article ID AUTISM SPECTRUM DISORDERS; INFANT MOTOR; COGNITIVE FUNCTION; GENERATION R; BIRTH COHORT; SCHOOL-AGE; ATTAINMENT; LANGUAGE; ABILITIES; TODDLERS AB OBJECTIVE: We examined the longitudinal associations of age at achieving gross motor milestones and children's development in a US cohort of singletons and twins. METHODS: In the Upstate KIDS study, a population-based study of children born between 2008 and 2010, information on age at achievement of motor milestones and developmental skills was available in 599 children (314 singletons, 259 twins, and 26 triplets). Mothers reported their children's major motor milestones at similar to 4, 8, 12, 18, and 24 months. At age 4 years, children's development was clinically assessed by using the Battelle Developmental Inventory, Second Edition (BDI-2). Primary analyses by using multivariate linear regressions were conducted in singletons. We also examined the associations in twins. RESULTS: Later achievement of standing with assistance predicted lower BDI-2 scores in singletons in adjusted models (B per SD of age at achievement, -21.9 [95% confidence interval (CI), -41.5 to -2.2]). Post hoc analysis on age of standing with assistance showed that associations were driven by differences in adaptive skills (B = -5.3 [95% CI, -9.0 to -1.6]) and cognitive skills (B = -5.9 [95% CI, -11.5 to -0.4]). Analyses restricted to twins suggested no association between the age at achievement of milestones and total BDI- 2 score after adjustment for gestational age and birth weight. CONCLUSIONS: This study provides evidence that the age of achieving motor milestones may be an important basis for various aspects of later child development. In twins, key predictors of later development (eg, perinatal factors) overshadow the predictive role of milestones in infancy. C1 [Ghassabian, Akhgar; Yeung, Edwina] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. [Sundaram, Rajeshwari] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. [Bell, Erin] SUNY Albany, Dept Environm Hlth Sci, Sch Publ Hlth, Albany, NY 12222 USA. [Bell, Erin] SUNY Albany, Dept Epidemiol & Biostat, Sch Publ Hlth, Albany, NY 12222 USA. [Bello, Scott C.] CapitalCare Pediat Troy, Troy, NY USA. [Kus, Christopher] New York State Dept Hlth, Div Family Hlth, Albany, NY USA. RP Yeung, E (reprint author), 6100 Execut Blvd,7B03, Bethesda, MD 20892 USA. EM yeungedw@mail.nih.gov OI Yeung, Edwina/0000-0002-3851-2613; Sundaram, Rajeshwari/0000-0002-6918-5002 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN275201200005C, HHSN267200700019C]; National Institutes of Health (NIH) FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HHSN275201200005C and HHSN267200700019C). Funded by the National Institutes of Health (NIH). NR 30 TC 0 Z9 0 U1 8 U2 14 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 JUL PY 2016 VL 138 IS 1 AR e20154372 DI 10.1542/peds.2015-4372 PG 8 WC Pediatrics SC Pediatrics GA DP9YD UT WOS:000378853100023 ER PT J AU Levy, SJL Williams, JF Ryan, SA Gonzalez, PK Patrick, SW Quigley, J Siqueira, L Walker, LR Faden, VB Tau, G Jarrett, R AF Levy, Sharon J. L. Williams, Janet F. Ryan, Sheryl A. Gonzalez, Pamela K. Patrick, Stephen W. Quigley, Joanna Siqueira, Lorena Walker, Leslie R. Faden, Vivian B. Tau, Gregory Jarrett, Renee CA Comm Subst Use & Prevention TI Substance Use Screening, Brief Intervention, and Referral to Treatment SO PEDIATRICS LA English DT Article AB The enormous public health impact of adolescent substance use and its preventable morbidity and mortality show the need for the health care sector, including pediatricians and the medical home, to increase its capacity related to substance use prevention, detection, assessment, and intervention. The American Academy of Pediatrics published its policy statement "Substance Use Screening, Brief Intervention, and Referral to Treatment for Pediatricians" in 2011 to introduce the concepts and terminology of screening, brief intervention, and referral to treatment (SBIRT) and to offer clinical guidance about available substance use screening tools and intervention procedures. This policy statement is a revision of the 2011 SBIRT statement. An accompanying clinical report updates clinical guidance for adolescent SBIRT. C1 [Faden, Vivian B.] NIAAA, Bethesda, MD 20892 USA. [Tau, Gregory] Amer Acad Child & Adolescent Psychiat, Washington, DC USA. NR 9 TC 0 Z9 0 U1 2 U2 2 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 JUL PY 2016 VL 138 IS 1 AR e20161210 DI 10.1542/peds.2016-1210 PG 3 WC Pediatrics SC Pediatrics GA DP9YD UT WOS:000378853100059 ER PT J AU Lowry, JA Ahdoot, S Baum, CR Bernstein, AS Bole, A Brumberg, HL Campbell, CC Lanphear, BP Pacheco, SE Spanier, AJ Trasande, L Osterhoudt, KC Paulson, JA Sandel, MT Rogers, PT Balbus, JM Brubaker, TA DeNicola, NG Etzel, RA Mortensen, ME Ward, MH Spire, P AF Lowry, Jennifer A. Ahdoot, Samantha Baum, Carl R. Bernstein, Aaron S. Bole, Aparna Brumberg, Heather Lynn Campbell, Carla C. Lanphear, Bruce Perrin Pacheco, Susan E. Spanier, Adam J. Trasande, Leonardo Osterhoudt, Kevin C. Paulson, Jerome A. Sandel, Megan T. Rogers, Paul Thomas Balbus, John M. Brubaker, Todd A. DeNicola, Nathaniel G. Etzel, Ruth Ann Mortensen, Mary Ellen Ward, Mary H. Spire, Paul TI Prevention of Childhood Lead Toxicity SO PEDIATRICS LA English DT Article ID ELEVATED BLOOD LEAD; US CHILDREN; EARLY ADULTHOOD; INFANT FORMULA; UNITED-STATES; EXPOSURE; LEVEL; WATER; DUST; RISK AB Blood lead concentrations have decreased dramatically in US children over the past 4 decades, but too many children still live in housing with deteriorated lead-based paint and are at risk for lead exposure with resulting lead-associated cognitive impairment and behavioral problems. Evidence continues to accrue that commonly encountered blood lead concentrations, even those below 5 mu g/dL (50 ppb), impair cognition; there is no identified threshold or safe level of lead in blood. From 2007 to 2010, approximately 2.6% of preschool children in the United States had a blood lead concentration >= 5 mu g/dL (>= 50 ppb), which represents about 535 000 US children 1 to 5 years of age. Evidence-based guidance is available for managing increased lead exposure in children, and reducing sources of lead in the environment, including lead in housing, soil, water, and consumer products, has been shown to be cost-beneficial. Primary prevention should be the focus of policy on childhood lead toxicity. C1 [DeNicola, Nathaniel G.] Amer Coll Obstetricians & Gynecologists, Washington, DC 20024 USA. [Etzel, Ruth Ann] US Environm Protect Agcy, Washington, DC 20004 USA. [Mortensen, Mary Ellen] CDC, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. [Ward, Mary H.] NCI, Bethesda, MD 20892 USA. NR 71 TC 0 Z9 0 U1 11 U2 15 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 JUL PY 2016 VL 138 IS 1 AR e20161493 DI 10.1542/peds.2016-1493 PG 15 WC Pediatrics SC Pediatrics GA DP9YD UT WOS:000378853100071 ER PT J AU Moeller, SJ Konova, AB Tomasi, D Parvaz, MA Goldstein, RZ AF Moeller, Scott J. Konova, Anna B. Tomasi, Dardo Parvaz, Muhammad A. Goldstein, Rita Z. TI Abnormal response to methylphenidate across multiple fMRI procedures in cocaine use disorder: feasibility study SO PSYCHOPHARMACOLOGY LA English DT Article DE Addiction; ADHD; Brain imaging; Cerebral cortex; Cocaine; Dopamine; FMRI; Inhibition; Psychostimulant; Working memory ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; DORSOLATERAL PREFRONTAL CORTEX; TRAUMATIC BRAIN-INJURY; WORKING-MEMORY; FUNCTIONAL CONNECTIVITY; INHIBITORY CONTROL; DEPENDENT PATIENTS; INTERFERENCE TASK; ADDICTION AB Rationale The indirect dopamine agonist methylphenidate remediates cognitive deficits in psychopathology, but the individual characteristics that determine its effects on the brain are not known. Objectives We aimed to determine whether targeted dopaminergically modulated traits and individual differences could predict neural response to methylphenidate across multiple functional magnetic resonance imaging (fMRI) procedures. Methods We combined neural measures from three separate procedures (two inhibitory control tasks differing in their degree of emotional salience and resting-state functional connectivity) during methylphenidate (20 mg oral, versus randomized and counterbalanced placebo) and correlated these aggregated responses with cocaine use disorder diagnosis (22 cocaine abusers, 21 controls), symptoms of attention deficit hyperactivity disorder, and working memory capacity. Results Cocaine abusers, relative to controls, had a lower response in the dorsolateral prefrontal cortex to methylphenidate across all three procedures, driven by responses to the two inhibitory control tasks; reduced methylphenidate fMRI response in this region further correlated with more frequent cocaine use. Conclusions Cocaine abuse (and its frequency), associated with lower tonic dopamine levels, correlated with a reduction in activation to methylphenidate (versus placebo). These initial results provide feasibility to the idea that multimodal fMRI tasks can be meaningfully aggregated, and that these aggregated procedures show a common disruption in addiction in a highly anticipated region relevant to cognitive control. Results also suggest that drug use frequency may represent an important modulatory variable in interpreting the efficacy of pharmacologically enhanced cognitive interventions in addiction. C1 [Moeller, Scott J.; Parvaz, Muhammad A.; Goldstein, Rita Z.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Moeller, Scott J.; Parvaz, Muhammad A.; Goldstein, Rita Z.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Moeller, Scott J.] 1470 Madison Ave Room 9-115, New York, NY 10029 USA. [Konova, Anna B.] NYU, Ctr Neural Sci, New York, NY 10003 USA. [Tomasi, Dardo] NIAAA, Bethesda, MD 20892 USA. [Goldstein, Rita Z.] One Gustave L Levy Pl,Box 1230, New York, NY 10029 USA. RP Moeller, SJ; Goldstein, RZ (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA.; Moeller, SJ; Goldstein, RZ (reprint author), Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA.; Moeller, SJ (reprint author), 1470 Madison Ave Room 9-115, New York, NY 10029 USA.; Goldstein, RZ (reprint author), One Gustave L Levy Pl,Box 1230, New York, NY 10029 USA. EM scott.moeller@mssm.edu; rita.goldstein@mssm.edu RI Moeller, Scott/L-5549-2016; OI Moeller, Scott/0000-0002-4449-0844; Parvaz, Muhammad/0000-0002-2671-2327 FU National Institute on Drug Abuse [R01DA023579, F32DA030017, K01DA037452, F32DA039648, F32DA033088] FX This study was supported by grants from the National Institute on Drug Abuse (to RZG: R01DA023579; to SJM: F32DA030017, K01DA037452; to ABK: F32DA039648; to MAP: F32DA033088). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We also thank Dr. Elena Shumay, whom the scientific community has lost too prematurely, for help with analyses in earlier versions of this manuscript. NR 68 TC 0 Z9 0 U1 1 U2 1 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 JUL PY 2016 VL 233 IS 13 BP 2559 EP 2569 DI 10.1007/s00213-016-4307-9 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DP5ZE UT WOS:000378575900014 PM 27150080 ER PT J AU Sampath, SC Sampath, SC Bredella, MA Cypess, AM Torriani, M AF Sampath, Srihari C. Sampath, Srinath C. Bredella, Miriam A. Cypess, Aaron M. Torriani, Martin TI Imaging of Brown Adipose Tissue: State of the Art SO RADIOLOGY LA English DT Article ID IN-VIVO; GLUCOSE-UPTAKE; COLD-EXPOSURE; ADULT HUMANS; ENERGY-EXPENDITURE; BLOOD-FLOW; FDG UPTAKE; CONTRAST ULTRASOUND; BEIGE ADIPOCYTES; FAT-CELLS AB The rates of diabetes, obesity, and metabolic disease have reached epidemic proportions worldwide. In recent years there has been renewed interest in combating these diseases not only by modifying energy intake and lifestyle factors, but also by inducing endogenous energy expenditure. This approach has largely been stimulated by the recent recognition that brown adipose tissue (BAT)-long known to promote heat production and energy expenditure in infants and hibernating mammals-also exists in adult humans. This landmark finding relied on the use of clinical fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography, and imaging techniques continue to play a crucial and increasingly central role in understanding BAT physiology and function. Herein, the authors review the origins of BAT imaging, discuss current preclinical and clinical strategies for imaging BAT, and discuss imaging methods that will provide crucial insight into metabolic disease and how it may be treated by modulating BAT activity. (C) RSNA, 2016 C1 [Sampath, Srihari C.; Sampath, Srinath C.] Novartis Res Fdn, Genom Inst, Dept Pharmacol, Musculoskeletal Biol & Bioimaging, San Diego, CA USA. [Bredella, Miriam A.; Torriani, Martin] Massachusetts Gen Hosp, Div Musculoskeletal Imaging & Intervent, 55 Fruit St,Yawkey 6E, Boston, MA 02114 USA. [Bredella, Miriam A.; Torriani, Martin] Harvard Univ, Sch Med, 55 Fruit St,Yawkey 6E, Boston, MA 02114 USA. [Cypess, Aaron M.] NIDDK, Translat Physiol Sect, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Torriani, M (reprint author), Massachusetts Gen Hosp, Div Musculoskeletal Imaging & Intervent, 55 Fruit St,Yawkey 6E, Boston, MA 02114 USA.; Torriani, M (reprint author), Harvard Univ, Sch Med, 55 Fruit St,Yawkey 6E, Boston, MA 02114 USA. EM mtor-riani@mgh.harvard.edu FU Chugai Pharma; Molecular Metabolism; Pfizer FX Srihari C. Sampath Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: is an employee of the Genomics Institute of the Novartis Research Foundation, part of the Novartis Institutes for Biomedical Research. Other relationships: disclosed no relevant relationships. Srinath C. Sampath Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: is an employee of the Genomics Institute of the Novartis Research Foundation, part of the Novartis Institutes for Biomedical Research. Other relationships: disclosed no relevant relationships. M.B. disclosed no relevant relationships. A.M.C. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: received grants from Chugai Pharma and Molecular Metabolism; received personal fees from Pfizer. Other relationships: disclosed no relevant relationships. M.T. disclosed no relevant relationships. NR 100 TC 1 Z9 1 U1 11 U2 11 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 JUL PY 2016 VL 280 IS 1 BP 4 EP 19 DI 10.1148/radiol.2016150390 PG 16 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DP8BC UT WOS:000378721900002 PM 27322970 ER PT J AU Gibson, BA Zhang, YJ Jiang, H Hussey, KM Shrimp, JH Lin, HN Schwede, F Yu, YH Kraus, WL AF Gibson, Bryan A. Zhang, Yajie Jiang, Hong Hussey, Kristine M. Shrimp, Jonathan H. Lin, Hening Schwede, Frank Yu, Yonghao Kraus, W. Lee TI Chemical genetic discovery of PARP targets reveals a role for PARP-1 in transcription elongation SO SCIENCE LA English DT Article ID ADP-RIBOSYLATION; RNA; POLY(ADP-RIBOSE); LOCI; PROMOTERS; BINDING AB Poly[adenosine diphosphate (ADP)-ribose] polymerases (PARPs) are a family of enzymes that modulate diverse biological processes through covalent transfer of ADP-ribose from the oxidized form of nicotinamide adenine dinucleotide (NAD(+)) onto substrate proteins. Here we report a robust NAD(+) analog-sensitive approach for PARPs, which allows PARP-specific ADP-ribosylation of substrates that is suitable for subsequent copper-catalyzed azide-alkyne cycloaddition reactions. Using this approach, we mapped hundreds of sites of ADP-ribosylation for PARPs 1, 2, and 3 across the proteome, as well as thousands of PARP-1-mediated ADP-ribosylation sites across the genome. We found that PARP-1 ADP-ribosylates and inhibits negative elongation factor (NELF), a protein complex that regulates promoter-proximal pausing by RNA polymerase II (Pol II). Depletion or inhibition of PARP-1 or mutation of the ADP-ribosylation sites on NELF-E promotes Pol II pausing, providing a clear functional link between PARP-1, ADP-ribosylation, and NELF. This analog-sensitive approach should be broadly applicable across the PARP family and has the potential to illuminate the ADP-ribosylated proteome and the molecular mechanisms used by individual PARPs to mediate their responses to cellular signals. C1 [Gibson, Bryan A.; Kraus, W. Lee] Univ Texas SW Med Ctr Dallas, Lab Signaling & Gene Express, Cecil H & Ida Green Ctr Reprod Biol Sci, Dallas, TX 75390 USA. [Gibson, Bryan A.; Kraus, W. Lee] Univ Texas SW Med Ctr Dallas, Basic Res Div, Dept Obstet & Gynecol, Dallas, TX 75390 USA. [Zhang, Yajie; Yu, Yonghao] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Jiang, Hong; Shrimp, Jonathan H.; Lin, Hening] Cornell Univ, Howard Hughes Med Inst, Ithaca, NY 14850 USA. [Jiang, Hong; Shrimp, Jonathan H.; Lin, Hening] Cornell Univ, Dept Chem, Ithaca, NY 14850 USA. [Hussey, Kristine M.] Sarepta Therapeut, Cambridge, MA 02142 USA. [Schwede, Frank] Biolog Life Sci Inst, D-28199 Bremen, Germany. [Jiang, Hong] Chinese Acad Sci, Shanghai Inst Organ Chem, Interdisciplinary Res Ctr Biol & Chem, Shanghai 201203, Peoples R China. [Shrimp, Jonathan H.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Kraus, WL (reprint author), Univ Texas SW Med Ctr Dallas, Lab Signaling & Gene Express, Cecil H & Ida Green Ctr Reprod Biol Sci, Dallas, TX 75390 USA.; Kraus, WL (reprint author), Univ Texas SW Med Ctr Dallas, Basic Res Div, Dept Obstet & Gynecol, Dallas, TX 75390 USA. EM lee.kraus@utsouthwestern.edu FU American Heart Association; Cancer Prevention and Research Institute of Texas [CPRIT R1103]; Welch Foundation [I-1800]; UT Southwestern Endowed Scholars Program; NIH National Institute of General Medical Sciences [GM086703]; NIH National Institute of Diabetes and Digestive and Kidney Diseases [DK069710]; Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowments FX We thank M. Chae, Q. Liang, J. DeBrabander, U. Havemann, and D. Imren for technical assistance and members of the Kraus laboratory for helpful discussions about this project. The asPARP expression constructs and the NAD+ analogs can be obtained from University of Texas (UT) Southwestern Medical Center and Biolog Life Science Institute, respectively, under a material transfer agreement. W.L.K., B.A.G., F.S., and H.L. are inventors on U.S. patent application no. 62/144,711, filed by UT Southwestern Medical Center, related to the asPARP technology. W.L.K. and B.A.G. are inventors on U.S. patent application nos. 62/009,955 and PCT/US2015/034852, filed by UT Southwestern Medical Center, related to the ADP-ribose detection reagents. Y.Y. is an inventor on U.S. patent no. 8828672 B2, filed by UT Southwestern Medical Center, related to technology for the determination of D/E-ADP-ribosylation sites. This work was supported by a predoctoral fellowship from the American Heart Association to B.A.G.; grants from the Cancer Prevention and Research Institute of Texas (CPRIT R1103), the Welch Foundation (I-1800), and the UT Southwestern Endowed Scholars Program to Y.Y., who is the Virginia Murchison Linthicum Scholar in Medical Research and a CPRIT Scholar in Cancer Research; a grant from the NIH National Institute of General Medical Sciences (GM086703) to H.L.; and a grant from the NIH National Institute of Diabetes and Digestive and Kidney Diseases (DK069710) and support from the Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowments to W.L.K. W.L.K. is a founder and consultant for Ribon Therapeutics. The genomic data sets from this study are available from the National Center for Biotechnology Information Gene Expression Omnibus database under accession numbers GSE74141 (ChIP-seq) and GSE74142 (GRO-seq and RNA-seq). The proteomic data sets generated for these studies are available in table S1. Author contributions: On the basis of (7), B.A.G. conceived the asPARP concept, with input from W.L.K. W.L.K. conceived the Click-ChIP-seq method, which was further developed by B.A.G. B.A.G. performed all experiments and computational analyses, except as follows: H. J., J. H. S., H.L., and F.S. synthesized all precursors and NAD+ analogs used in this study. B.A.G. and H. J. performed the enzyme kinetics assays. B.A.G., Y.Z., and Y.Y. prepared the samples and ran the LC-MS/MS analysis. K.M.H. made the PARP-1 knockdown MCF-7 cells and prepared the GRO-seq samples. W.L.K. secured funding to support this project and provided intellectual support for all aspects of the work. B.A.G. and W.L.K. prepared the figures and wrote the paper. NR 19 TC 19 Z9 19 U1 13 U2 20 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JUL 1 PY 2016 VL 353 IS 6294 BP 45 EP 50 DI 10.1126/science.aaf7865 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP9KX UT WOS:000378816200031 PM 27256882 ER PT J AU Kim, S Zhao, YY Lee, JM Kim, WR Gorivodsky, M Westphal, H Geum, D AF Kim, Soojin Zhao, Yangu Lee, Ja-myong Kim, Woon Ryoung Gorivodsky, Marat Westphal, Heiner Geum, Dongho TI Ldb1 Is Essential for the Development of Isthmic Organizer and Midbrain Dopaminergic Neurons SO STEM CELLS AND DEVELOPMENT LA English DT Article ID LIM-HOMEODOMAIN PROTEINS; EMBRYONIC STEM-CELLS; INT-1 PROTOONCOGENE; CHOLINERGIC NEURONS; WNT1 EXPRESSION; LMX1B; MOUSE; DIFFERENTIATION; GENE; CEREBELLUM AB LIM domain-binding protein 1 (Ldb1) is a nuclear cofactor that interacts with LIM homeodomain proteins to form multiprotein complexes that are important for transcription regulation. Ldb1 has been shown to play essential roles in various processes during mouse embryogenesis. To determine the role of Ldb1 in mid-and hindbrain development, we have generated a conditional mutant with a specific deletion of the Ldb1 in the Engrailed-1-expressing region of the developing mid-and hindbrain. Our study showed that the deletion impaired the expression of signaling molecules, such as fibroblast growth factor 8 (FGF8) and Wnt1, in the isthmic organizer and the expression of Shh in the ventral midbrain. The midbrain and the cerebellum were severely reduced in size, and the midbrain dopaminergic (mDA) neurons were missing in the mutant. These defects are identical to the phenotype that has been observed previously in mice with a deletion of the LIM homeodomain gene Lmx1b. Our results thus provide genetic evidence supporting that Ldb1 and Lmx1b function cooperatively to regulate mid-and hindbrain development. In addition, we found that mouse embryonic stem cells lacking Ldb1 failed to generate several types of differentiated neurons, including the mDA neurons, serotonergic neurons, cholinergic neurons, and olfactory bulb neurons, indicating an essential cell-autonomous role for Ldb1 in the development of these neurons. C1 [Kim, Soojin; Lee, Ja-myong; Kim, Woon Ryoung; Geum, Dongho] Korea Univ, Sch Med, Dept Biomed Sci, Seoul 136705, South Korea. [Zhao, Yangu; Gorivodsky, Marat; Westphal, Heiner] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD USA. [Zhao, Yangu] NIDDK, Lab Cellular Dev Biol, NIH, Bethesda, MD 20892 USA. RP Geum, D (reprint author), Korea Univ, Sch Med, Dept Biomed Sci, Seoul 136705, South Korea.; Zhao, YY (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. EM zhaoyang@mail.nih.gov; geumd@korea.ac.kr FU Korea Health Technology R&D Project through the Korea Health Industry Development Institute - Ministry of Health & Welfare, Republic of Korea [HI14C3347]; National Research Foundation of Korea [NRF-2012M3A9C7050135]; NICHD/NIH FX The authors would like to thank Dr. Wolfgang Wurst for providing the En1Cre mice, Dr. Andrew McMahon for providing the probes of Shh and Wnt1 for in situ hybridization, and Dr. Paul Love for providing the Ldb1 antibody. This work was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (grant number HI14C3347), the National Research Foundation of Korea (NRF-2012M3A9C7050135), and the Intramural Research Program of the NICHD/NIH. NR 40 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 EI 1557-8534 J9 STEM CELLS DEV JI Stem Cells Dev. PD JUL 1 PY 2016 VL 25 IS 13 BP 986 EP 994 DI 10.1089/scd.2015.0307 PG 9 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA DP7BP UT WOS:000378654300003 PM 27171818 ER PT J AU Kringelbach, ML Stark, EA Alexander, C Bornstein, MH Stein, A AF Kringelbach, Morten L. Stark, Eloise A. Alexander, Catherine Bornstein, Marc H. Stein, Alan TI On Cuteness: Unlocking the Parental Brain and Beyond SO TRENDS IN COGNITIVE SCIENCES LA English DT Review ID HUMAN ORBITOFRONTAL CORTEX; INFANT FACES; POSTNATAL DEPRESSION; BABY SCHEMA; FUNCTIONAL NEUROANATOMY; POSTPARTUM DEPRESSION; MATERNAL SENSITIVITY; PERCEIVED CUTENESS; ATTACHMENT; RESPONSES AB Cuteness in offspring is a potent protective mechanism that ensures survival for otherwise completely dependent infants. Previous research has linked cuteness to early ethological ideas of a 'Kindchenschema' (infant schema) where infant facial features serve as 'innate releasing mechanisms' for instinctual caregiving behaviours. We propose extending the concept of cuteness beyond visual features to include positive infant sounds and smells. Evidence from behavioural and neuroimaging studies links this extended concept of cuteness to simple 'instinctual' behaviours and to caregiving, protection, and complex emotions. We review how cuteness supports key parental capacities by igniting fast privileged neural activity followed by slower processing in large brain networks also involved in play, empathy, and perhaps even higher-order moral emotions. C1 [Kringelbach, Morten L.; Stark, Eloise A.; Alexander, Catherine; Stein, Alan] Univ Oxford, Dept Psychiat, Oxford OX3 7JX, England. [Kringelbach, Morten L.; Alexander, Catherine] Aarhus Univ, Ctr Mus Brain MIB, Aarhus, Denmark. [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. RP Kringelbach, ML (reprint author), Univ Oxford, Dept Psychiat, Oxford OX3 7JX, England.; Kringelbach, ML (reprint author), Aarhus Univ, Ctr Mus Brain MIB, Aarhus, Denmark. EM morten.kringelbach@psych.ox.ac.uk OI Kringelbach, Morten/0000-0002-3908-6898 FU ERC [615539]; MRC; Wellcome Trust [090139]; Intramural Research Program of the NIH, NICHD; Barclay Foundation; Center for Music in the Brain at Aarhus University - Danish National Research Foundation [DNRF117] FX The research was supported by an ERC Consolidator Grant CAREGIVING (No. 615539) to M.L.K.; an MRC Studentship awarded to E.A.S.; a Wellcome Trust Grant (No. 090139) to A.S. M.H.B. was supported by the Intramural Research Program of the NIH, NICHD. Furthermore the research was supported by the Barclay Foundation to M.L.K. and A.S., as well as the Center for Music in the Brain at Aarhus University funded by the Danish National Research Foundation (DNRF117) to M.L.K. NR 114 TC 2 Z9 2 U1 22 U2 35 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 JUL PY 2016 VL 20 IS 7 BP 545 EP 558 DI 10.1016/j.tics.2016.05.003 PG 14 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA DQ3MJ UT WOS:000379106100009 PM 27211583 ER PT J AU Wu, J Liu, Q Tang, P Mikkelsen, JD Shen, JX Whiteaker, P Yakel, JL AF Wu, Jie Liu, Qiang Tang, Pei Mikkelsen, Jens D. Shen, Jianxin Whiteaker, Paul Yakel, Jerrel L. TI Heteromeric alpha 7 beta 2 Nicotinic Acetylcholine Receptors in the Brain SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID XENOPUS-LAEVIS OOCYTES; ALPHA-BUNGAROTOXIN; PHARMACOLOGICAL CHARACTERIZATION; HIPPOCAMPAL-NEURONS; CHOLINERGIC NEURONS; HIGH-SENSITIVITY; BETA-2 SUBUNITS; ACH RECEPTORS; BINDING-SITE; RAT-BRAIN AB The alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR) is highly expressed in the brain, where it maintains various neuronal functions including (but not limited to) learning and memory. In addition, the protein expression levels of alpha 7 nAChRs are altered in various brain disorders. The classic rule governing alpha 7 nAChR assembly in the mammalian brain was that it was assembled from five alpha 7 subunits to form a homomeric receptor pentamer. However, emerging evidence demonstrates the presence of heteromeric alpha 7 nAChRs in heterologously expressed systems and naturally in brain neurons, where alpha 7 subunits are co-assembled with beta 2 subunits to form a novel type of alpha 7 beta 2 nAChR. Interestingly, the alpha 7 beta 2 nAChR exhibits distinctive function and pharmacology from traditional homomeric alpha 7 nAChRs. We review recent advances in probing the distribution, function, pharmacology, pathophysiology, and stoichiometry of the heteromeric alpha 7 beta 2 nAChR, which have provided, new insights into the understanding of a novel target of cholinergic signaling. C1 [Wu, Jie; Shen, Jianxin] Shantou Univ, Dept Physiol, Coll Med, Shantou, Guangdong, Peoples R China. [Wu, Jie; Liu, Qiang; Whiteaker, Paul] St Josephs Hosp, Barrow Neurol Inst, Div Neurol, Phoenix, AZ 85013 USA. [Wu, Jie; Liu, Qiang; Whiteaker, Paul] St Josephs Hosp, Barrow Neurol Inst, Div Neurobiol, Phoenix, AZ 85013 USA. [Tang, Pei] Univ Pittsburgh, Sch Med, Dept Anesthesiol, Pittsburgh, PA 15260 USA. [Mikkelsen, Jens D.] Rigshosp, Univ Copenhagen Hosp, Neurobiol Res Unit, Copenhagen, Denmark. [Yakel, Jerrel L.] NIEHS, Neurobiol Lab, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. RP Wu, J (reprint author), Shantou Univ, Dept Physiol, Coll Med, Shantou, Guangdong, Peoples R China.; Wu, J (reprint author), St Josephs Hosp, Barrow Neurol Inst, Div Neurol, Phoenix, AZ 85013 USA.; Wu, J (reprint author), St Josephs Hosp, Barrow Neurol Inst, Div Neurobiol, Phoenix, AZ 85013 USA. EM jie.wu@dignityhealth.org FU Barrow Neuroscience Foundation; Arizona Alzheimer Disease Consortium; NIH [R01GM66358, R01GM56257, R21DA026627]; Intramural Research Program, NIEHS/NIH; Innovation Fund in Denmark, COGNITO; National Natural Science Foundation of China [31171089] FX This work was supported by grants from the Barrow Neuroscience Foundation to J.W. and P.W., Arizona Alzheimer Disease Consortium to J.W. and Q.L., NIH (R01GM66358 and R01GM56257) to P.T., NIH (R21DA026627) to P.W., the Intramural Research Program, NIEHS/NIH to J.L.Y., the Innovation Fund in Denmark, COGNITO to J.D.M., and National Natural Science Foundation of China (No. 31171089) to J.X.S. NR 66 TC 6 Z9 7 U1 3 U2 10 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD JUL PY 2016 VL 37 IS 7 BP 562 EP 574 DI 10.1016/j.tips.2016.03.005 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DQ1LC UT WOS:000378961500005 PM 27179601 ER PT J AU Brennan, CW Kelly, B Skarf, LM Tellem, R Dunn, KM Poswolsky, S AF Brennan, Caitlin W. Kelly, Brittany Skarf, Lara Michal Tellem, Rotem Dunn, Kathleen M. Poswolsky, Sheila TI Improving Palliative Care Team Meetings: Structure, Inclusion, and "Team Care" SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Article DE palliative care; interprofessional; team meeting; quality improvement; model for improvement; efficiency ID COMMUNICATION AB Increasing demands on palliative care teams point to the need for continuous improvement to ensure teams are working collaboratively and efficiently. This quality improvement initiative focused on improving interprofessional team meeting efficiency and subsequently patient care. Meeting start and end times improved from a mean of approximately 9 and 6 minutes late in the baseline period, respectively, to a mean of 4.4 minutes late (start time) and ending early in our sustainability phase. Mean team satisfaction improved from 2.4 to 4.5 on a 5-point Likert-type scale. The improvement initiative clarified communication about patients' plans of care, thus positively impacting team members' ability to articulate goals to other professionals, patients, and families. We propose several recommendations in the form of a team meeting toolkit. C1 [Brennan, Caitlin W.] NIH, Ctr Clin, Dept Nursing, Res & Practice Dev Sect, 10 Ctr Dr,Suite 2B,Room 08, Bethesda, MD 20892 USA. [Brennan, Caitlin W.; Kelly, Brittany; Skarf, Lara Michal; Tellem, Rotem; Dunn, Kathleen M.; Poswolsky, Sheila] Vet Affairs Boston Healthcare Syst, Jamaica Plain, MA USA. RP Brennan, CW (reprint author), NIH, Ctr Clin, Dept Nursing, Res & Practice Dev Sect, 10 Ctr Dr,Suite 2B,Room 08, Bethesda, MD 20892 USA. EM caitlin.brennan@nih.gov NR 11 TC 0 Z9 0 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-9091 EI 1938-2715 J9 AM J HOSP PALLIAT ME JI Am. J. Hosp. Palliat. Med. PD JUL PY 2016 VL 33 IS 6 BP 585 EP 593 DI 10.1177/1049909115577049 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DP3NJ UT WOS:000378401100010 PM 25794871 ER PT J AU Goldberg, RB Bittner, VA Dunbar, RL Fleg, JL Grunberger, G Guyton, JR Leiter, LA McBride, R Robinson, JG Simmons, DL Wysham, C Xu, P Boden, WE AF Goldberg, Ronald B. Bittner, Vera A. Dunbar, Richard L. Fleg, Jerome L. Grunberger, George Guyton, John R. Leiter, Lawrence A. McBride, Ruth Robinson, Jennifer G. Simmons, Debra L. Wysham, Carol Xu, Ping Boden, William E. TI Effects of Extended-Release Niacin Added to Simvastatin/Ezetimibe on Glucose and Insulin Values in AIM-HIGH SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Clinical trial; Diabetes; Extended release niacin; Glucose and insulin; Heart disease; Impaired fasting glucoses ID IMPAIRED FASTING GLUCOSE; CORONARY-ARTERY-DISEASE; CARDIOVASCULAR EVENTS; METABOLIC SYNDROME; NICOTINIC-ACID; THERAPY; TRIAL; CHOLESTEROL; TOLERANCE; HEALTH AB BACKGROUND: Niacin is an antidyslipidemic agent that may cause blood sugar elevation in patients with diabetes, but its effects on glucose and insulin values in nondiabetic statin-treated subjects with cardiovascular disease and at high risk for diabetes are less well known. METHODS: This was a prespecified, intent-to-treat analysis of the Atherothrombosis Intervention in Metabolic syndrome with low high-density lipoprotein/high triglycerides: Impact on Global Health outcomes trial which randomized 3,414 participants at 92 centers in the US and Canada to extended-release niacin (ERN) plus simvastatin/ezetimibe (ERN) or simvastatin/ezetimibe plus placebo (Placebo). Baseline and annual fasting glucose and insulin values were measured. Those experiencing an adverse event indicative of diabetes or starting medications for diabetes were considered to have confirmed diabetes. In addition, nondiabetic subjects with 2 annual follow-up glucose measurements were categorized into normal, impaired fasting glucose or newly diagnosed diabetes (presumed or confirmed) states. RESULTS: Compared with placebo, ERN increased annual fasting glucose from baseline to 1 year in both those with normal (7.9 +/- 15.8 vs 4.3 +/- 10.3 mg/dL; P < .001) and impaired fasting glucose (4.1 +/- 18.7 vs 1.4 +/- 14.9; P < .02) and increased insulin levels. Both effectswaned over the next 2 years. There were less consistent effects in those with baseline diabetes. There was an increased risk of progressing from normal to presumed or confirmed impaired fasting glucose (ERN 197/336) cases (58.6%) vs placebo 135/325 cases (41.5%; P < .001) over time, but no difference in diabetes development in the 2 treatment groups except in those with normal fasting glucose at baseline. CONCLUSIONS: The addition of ERN to simvastatin/ezetimibe had marginal effects on glycemia in those with diabetes at baseline, and there was a trend toward increased development of new-onset diabetes. In addition, ERN increased the risk of developing impaired fasting glucose, which may have deleterious consequences over time and warrants further study. (C) 2016 Elsevier Inc. All rights reserved. C1 [Goldberg, Ronald B.] Univ Miami, Miller Sch Med, Div Endocrinol Metab & Diabet, Coral Gables, FL 33124 USA. [Bittner, Vera A.] Univ Alabama, Birmingham Sch Med, Dept Med, Div Cardiovasc Dis, Tuscaloosa, AL 35487 USA. [Dunbar, Richard L.] Univ Penn, Perelman Sch Med, Dept Med, Div Translat Med & Human Genet, Philadelphia, PA 19104 USA. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Grunberger, George] Grunberger Diabet Inst, Bloomfield Hills, MI USA. [Guyton, John R.] Duke Univ, Med Ctr, Durham, NC USA. [Leiter, Lawrence A.] St Michaels Hosp, Keenan Res Ctr, Li Ka Shing Knowledge Inst, Div Endocrinol & Metab, 30 Bond St, Toronto, ON M5B 1W8, Canada. [McBride, Ruth] Axio Res LLC, 2601 Fourth Ave,Suite 200, Seattle, WA 98121 USA. [Robinson, Jennifer G.] Univ Iowa, Coll Publ Hlth, Iowa City, IA USA. [Robinson, Jennifer G.] Univ Iowa, Carver Coll Med, Iowa City, IA USA. [Simmons, Debra L.] Univ Utah, Dept Internal Med, Div Endocrinol, Salt Lake City, UT 84112 USA. [Wysham, Carol] Rockwood Diabet & Endocrinol, Spokane, WA USA. [Xu, Ping] PPD, Wilmington, NC USA. [Boden, William E.] Albany VA Med Ctr, Dept Med, Albany, NY 12208 USA. RP McBride, R (reprint author), Axio Res LLC, 2601 Fourth Ave,Suite 200, Seattle, WA 98121 USA. EM ruthm@axioresearch.com FU National Heart, Lung, and Blood Institute [U01 HL081616, U01 HL081649]; AbbVie, Inc. FX The Atherothrombosis Intervention in Metabolic syndrome with low high-density lipoprotein/high triglycerides: Impact on Global Health (AIM-HIGH) study was supported by the National Heart, Lung, and Blood Institute (U01 HL081616 and U01 HL081649) and by an unrestricted grant from AbbVie, Inc. AbbVie donated the extended-release niacin, the matching placebo, and the ezetimibe; Merck donated the simvastatin. Neither of these companies had any role in the oversight or design of the study or in the analysis or interpretation of the data. NR 21 TC 0 Z9 0 U1 5 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD JUL PY 2016 VL 129 IS 7 AR 753.e13 DI 10.1016/j.amjmed.2016.02.039 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DO8WJ UT WOS:000378065800049 PM 27036394 ER PT J AU Lichtveld, M Kennedy, S Krouse, RZ Grimsley, F El-Dahr, J Bordelon, K Sterling, Y White, L Barlow, N DeGruy, S Paul, D Denham, S Hayes, C Sanders, M Mvula, MM Thornton, E Chulada, P Mitchell, H Martin, WJ Stephens, KU Cohn, RD AF Lichtveld, Maureen Kennedy, Suzanne Krouse, Rebecca Z. Grimsley, Faye El-Dahr, Jane Bordelon, Keith Sterling, Yvonne White, LuAnn Barlow, Natasha DeGruy, Shannon Paul, Dorothy Denham, Stacey Hayes, Claire Sanders, Margaret Mvula, Mosanda M. Thornton, Eleanor Chulada, Patricia Mitchell, Herman Martin, William J., II Stephens, Kevin U. Cohn, Richard D. TI From Design to Dissemination: Implementing Community-Based Participatory Research in Postdisaster Communities SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID OFF ENVIRONMENTAL ASTHMA; KATRINA NEW-ORLEANS; LOUISIANA HEAL; CHILDREN; EXPOSURES AB Objectives. To review how disasters introduce unique challenges to conducting population-based research and community-based participatory research (CBPR). Methods. From 2007-2009, we conducted the Head-off Environmental Asthma in Louisiana (HEAL) Study in the aftermath of Hurricane Katrina in a Gulf Coast community facing an unprecedented triple burden: Katrina's and other disasters' impact on the environment and health, historic health disparities, and persistent environmental health threats. Results. The unique triple burden influenced every research component; still, most existing CBPR principles were applicable, even though full adherence was not always feasible and additional tailored principles govern postdisaster settings. Conclusions. Even in the most challenging postdisaster conditions, CBPR can be successfully designed, implemented, and disseminated while adhering to scientific rigor. C1 [Lichtveld, Maureen; Grimsley, Faye; White, LuAnn; Barlow, Natasha; DeGruy, Shannon; Paul, Dorothy] Tulane Univ, Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Kennedy, Suzanne; Krouse, Rebecca Z.; Mitchell, Herman] Rho Fed Syst Div Inc, Chapel Hill, NC USA. [El-Dahr, Jane] Tulane Univ, Sch Med, Dept Pediat, New Orleans, LA 70112 USA. [Bordelon, Keith; Cohn, Richard D.] Constella Grp LLC, Durham, NC USA. [Sterling, Yvonne] Louisiana State Univ, Hlth Sci Ctr, Sch Nursing, New Orleans, LA USA. [Denham, Stacey; Hayes, Claire; Sanders, Margaret; Mvula, Mosanda M.; Stephens, Kevin U.] New Orleans Hlth Dept, New Orleans, LA USA. [Thornton, Eleanor] Visionary Consulting Partners LLC, Fairfax, VA USA. [Chulada, Patricia; Martin, William J., II] NIEHS, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. RP Lichtveld, M (reprint author), 1440 Canal St,Suite 2100, New Orleans, LA 70112 USA. EM mlichtve@tulane.edu FU National Center of Minority Health and Health Disparities (NCMHD); National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) [NO1-ES-55553]; Merck Childhood Asthma Network, Inc (MCAN); NIH; Foundation for the National Institutes of Health; Louisiana Board of Regents RC/EEP FX This project was funded by the National Center of Minority Health and Health Disparities (NCMHD, now the NIMHD); the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH; contract NO1-ES-55553); and the Merck Childhood Asthma Network, Inc (MCAN). Public-private funding provided by the NIH and MCAN was managed under the auspices of the Foundation for the National Institutes of Health. Other organizations that contributed include the National Toxicology Program (NIEHS), the US Environmental Protection Agency (Cincinnati, OH), and the de Laski Family Foundation. The Clinical and Translational Research Center of Tulane and Louisiana State Universities Schools of Medicine was supported in whole or in part by funds provided through the Louisiana Board of Regents RC/EEP. NR 22 TC 0 Z9 0 U1 2 U2 7 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 JUL PY 2016 VL 106 IS 7 BP 1235 EP 1242 DI 10.2105/AJPH.2016.303169 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DO7CL UT WOS:000377939700044 PM 27196662 ER PT J AU Assadipour, Y Azoury, SC Schaub, NN Hong, Y Eil, R Inchauste, SM Steinberg, SM Venkatesan, AM Libutti, SK Hughes, MS AF Assadipour, Yasmine Azoury, Said C. Schaub, Nicholas N. Hong, Young Eil, Robert Inchauste, Suzanne M. Steinberg, Seth M. Venkatesan, Aradhana M. Libutti, Steven K. Hughes, Marybeth S. TI Significance of preoperative radiographic pancreatic density in predicting pancreatic fistula after surgery for pancreatic neuroendocrine tumors SO AMERICAN JOURNAL OF SURGERY LA English DT Article DE Pancreatic fistula; Neuroendocrine tumors; Pancreaticoduo denectomy; Pancreatic resection; Pancreatic enucleation ID INTERNATIONAL STUDY-GROUP; RISK-FACTORS; PROPHYLACTIC OCTREOTIDE; PANCREATICODUODENECTOMY; COMPLICATIONS; RESECTION; OUTCOMES AB BACKGROUND: Postoperative pancreatic fistula remains the most severe and worrisome complication after surgery. Predictive preoperative assessment remains challenging. The authors examine the role of pancreatic computed tomography density in predicting postoperative pancreatic fistula after surgery for pancreatic neuroendocrine tumors. METHODS: A single institutional retrospective review of pancreatic surgery for neuroendocrine tumors between 1998 and 2010 was conducted. Preoperative contrast-enhanced computed tomography scans were reviewed, with mean region of interest measurements of pancreatic parenchymal density obtained from 10-mm thick axial computed tomography images. RESULTS: A total of 119 patients were identified: 59 with enucleations and 60 with resections. Decreased preoperative pancreatic density was significantly associated with an increased grade of postoperative pancreatic fistula (P < .01). Subgroup analyses revealed that decreased gland density was associated with increased grade of postoperative pancreatic fistula in the resection (P < .01) but not in the enucleation group (P = .34). CONCLUSIONS: A significant association between postoperative pancreatic fistula grade and preoperative pancreatic computed tomography density is observed in patients undergoing resection for pancreatic neuroendocrine tumors. Published by Elsevier Inc. C1 [Assadipour, Yasmine; Azoury, Said C.; Schaub, Nicholas N.; Hong, Young; Eil, Robert; Inchauste, Suzanne M.; Hughes, Marybeth S.] NCI, Surg Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Azoury, Said C.; Hughes, Marybeth S.] NCI, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Venkatesan, Aradhana M.] NIH, Radiol & Imaging Sci NIH Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. [Libutti, Steven K.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Surg, Bronx, NY 10467 USA. RP Hughes, MS (reprint author), NCI, Surg Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA.; Hughes, MS (reprint author), NCI, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM hughesm@mail.nih.gov FU Intramural Program of the National Cancer Institute FX All funding is provided by the Intramural Program of the National Cancer Institute; this did not create a conflict of interest. NR 23 TC 0 Z9 0 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9610 EI 1879-1883 J9 AM J SURG JI Am. J. Surg. PD JUL PY 2016 VL 212 IS 1 BP 40 EP 46 DI 10.1016/j.amjsurg.2015.07.031 PG 7 WC Surgery SC Surgery GA DO8VM UT WOS:000378063100006 PM 26782807 ER PT J AU Wilson, CJ Mitchelson, AJ Tzeng, TH El-Othmani, MM Saleh, J Vasdev, S LaMontagne, HJ Saleh, KJ AF Wilson, Craig J. Mitchelson, Andrew J. Tzeng, Tony H. El-Othmani, Mouhanad M. Saleh, Jasmine Vasdev, Sonia LaMontagne, Hillary J. Saleh, Khaled J. TI Caring for the surgically anxious patient: a review of the interventions and a guide to optimizing surgical outcomes SO AMERICAN JOURNAL OF SURGERY LA English DT Review DE Preoperative anxiety; Perioperative anxiety; Psychiatric anxiety survey; Patient education; Surgical anxiety intervention; Preoperative anxiolytics ID AMSTERDAM PREOPERATIVE ANXIETY; RANDOMIZED CONTROLLED-TRIAL; TOTAL HIP-REPLACEMENT; ARTERY-BYPASS GRAFT; SURGERY PATIENTS; REDUCE ANXIETY; CLINICAL-TRIAL; CARDIAC-CATHETERIZATION; PERIOPERATIVE ANXIETY; POSTOPERATIVE ANXIETY AB BACKGROUND: Preoperative surgical anxiety is an unpleasant and common reaction exhibited by patients who are scheduled for surgical procedures. Beyond emotional effects on the patient, it can also have negative repercussions on the surgery including longer hospital stays and poorer outcomes. Given the widespread impacts of preoperative anxiety, it is critical for surgeons to gain a better understanding of how to identify and reduce surgical anxiety in their patients. DATA SOURCES: This study used the PubMed database to review the current literature to evaluate screening tools and interventions for surgically anxious patients. CONCLUSIONS: Psychiatric anxiety surveys are currently the most appropriate form of assessment for surgical anxiety. Patient education is important for preventing and reducing anxiety levels in patients. Both nonpharmacological and pharmacological interventions have been shown to be effective in reducing patient anxiety and treatment should be based on patient preference, resources available, and the surgeon's experience. (C) 2015 Elsevier Inc. All rights reserved. C1 [Wilson, Craig J.; Mitchelson, Andrew J.; Tzeng, Tony H.; El-Othmani, Mouhanad M.; Vasdev, Sonia; Saleh, Khaled J.] So Illinois Univ, Sch Med, Dept Surg, Div Orthopaed & Rehabil, Springfield, IL 62794 USA. [Saleh, Jasmine] Natl Inst Deafness & Other Communicable Disorders, NIH, Bethesda, MD USA. [LaMontagne, Hillary J.] So Illinois Univ, Sch Med, Dept Psychiat, Springfield, IL USA. RP El-Othmani, MM (reprint author), So Illinois Univ, Sch Med, Dept Surg, Div Orthopaed & Rehabil, Springfield, IL 62794 USA. EM mohannad.othmani@gmail.com OI Mitchelson, Andrew/0000-0001-5348-6495; El-Othmani, Mouhanad/0000-0001-7211-4072 NR 110 TC 0 Z9 0 U1 1 U2 4 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9610 EI 1879-1883 J9 AM J SURG JI Am. J. Surg. PD JUL PY 2016 VL 212 IS 1 BP 151 EP 159 DI 10.1016/j.amjsurg.2015.03.023 PG 9 WC Surgery SC Surgery GA DO8VM UT WOS:000378063100021 PM 26138522 ER PT J AU Gaskell, J Blanchette, RA Stewart, PE BonDurant, SS Adams, M Sabat, G Kersten, P Cullen, D AF Gaskell, Jill Blanchette, Robert A. Stewart, Philip E. BonDurant, Sandra Splinter Adams, Marie Sabat, Grzegorz Kersten, Phil Cullen, Dan TI Transcriptome and Secretome Analyses of the Wood Decay Fungus Wolfiporia cocos Support Alternative Mechanisms of Lignocellulose Conversion SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID BASIDIOMYCETE PHANEROCHAETE-CHRYSOSPORIUM; BROWN-ROT; POSTIA-PLACENTA; GLOEOPHYLLUM-TRABEUM; DEGRADATION; CELLULOSE; DATABASE; GENOMES; OXIDASE; IRON AB Certain wood decay basidiomycetes, collectively referred to as brown rot fungi, rapidly depolymerize cellulose while leaving behind the bulk of cell wall lignin as a modified residue. The mechanism(s) employed is unclear, but considerable evidence implicates the involvement of diffusible oxidants generated via Fenton-like chemistry. Toward a better understanding of this process, we have examined the transcriptome and secretome of Wolfiporia cocos when cultivated on media containing glucose, purified crystalline cellulose, aspen (Populus grandidentata), or lodgepole pine (Pinus contorta) as the sole carbon source. Compared to the results obtained with glucose, 30, 183, and 207 genes exhibited 4-fold increases in transcript levels in cellulose, aspen, and lodgepole pine, respectively. Mass spectrometry identified peptides corresponding to 64 glycoside hydrolase (GH) proteins, and of these, 17 corresponded to transcripts upregulated on one or both woody substrates. Most of these genes were broadly categorized as hemicellulases or chitinases. Consistent with an important role for hydroxyl radical in cellulose depolymerization, high transcript levels and upregulation were observed for genes involved in iron homeostasis, iron reduction, and extracellular peroxide generation. These patterns of regulation differ markedly from those of the closely related brown rot fungus Postia placenta and expand the number of enzymes potentially involved in the oxidative depolymerization of cellulose. C1 [Gaskell, Jill; Kersten, Phil; Cullen, Dan] USDA, Forest Prod Lab, Madison, WI 53705 USA. [Blanchette, Robert A.] Univ Minnesota, Dept Plant Pathol, St Paul, MN USA. [Stewart, Philip E.] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [BonDurant, Sandra Splinter; Adams, Marie; Sabat, Grzegorz] Univ Wisconsin, Madison Biotechnol Ctr, Madison, WI USA. RP Cullen, D (reprint author), USDA, Forest Prod Lab, Madison, WI 53705 USA. EM dcullen@wisc.edu FU National Research Initiative of the U.S. Department of Agriculture Cooperative State, Research Education and Extension Service grant [2007 35504 18257] FX This work was supported in part by the National Research Initiative of the U.S. Department of Agriculture Cooperative State, Research Education and Extension Service grant 2007 35504 18257, to D.C. and R.A.B. NR 47 TC 1 Z9 1 U1 8 U2 17 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 JUL PY 2016 VL 82 IS 13 BP 3979 EP 3987 DI 10.1128/AEM.00639-16 PG 9 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DO8QP UT WOS:000378048800030 PM 27107121 ER PT J AU Schiller, CE Johnson, SL Abate, AC Schmidt, PJ Rubinow, DR AF Schiller, Crystal Edler Johnson, Sarah L. Abate, Anna C. Schmidt, Peter J. Rubinow, David R. TI Reproductive Steroid Regulation of Mood and Behavior SO COMPREHENSIVE PHYSIOLOGY LA English DT Article ID PREMENSTRUAL DYSPHORIC DISORDER; MAJOR DEPRESSIVE DISORDER; DEFAULT-MODE NETWORK; STRESS-INDUCED ANHEDONIA; ESTROGEN-RECEPTOR-ALPHA; FRONTAL EEG ASYMMETRY; MENSTRUAL-CYCLE PHASE; DORSOLATERAL PREFRONTAL CORTEX; POSTMENOPAUSAL HORMONE-THERAPY; STATE FUNCTIONAL CONNECTIVITY AB In this article, we examine evidence supporting the role of reproductive steroids in the regulation of mood and behavior in women and the nature of that role. In the first half of the article, we review evidence for the following: (i) the reproductive system is designed to regulate behavior; (ii) from the subcellular to cellular to circuit to behavior, reproductive steroids are powerful neuroregulators; (iii) affective disorders are disorders of behavioral state; and (iv) reproductive steroids affect virtually every system implicated in the pathophysiology of depression. In the second half of the article, we discuss the diagnosis of the three reproductive endocrine-related mood disorders (premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression) and present evidence supporting the relevance of reproductive steroids to these conditions. Existing evidence suggests that changes in reproductive steroid levels during specific reproductive states (i.e., the premenstrual phase of the menstrual cycle, pregnancy, parturition, and the menopause transition) trigger affective dysregulation in susceptible women, thus suggesting the etiopathogenic relevance of these hormonal changes in reproductive mood disorders. Understanding the source of individual susceptibility is critical to both preventing the onset of illness and developing novel, individualized treatments for reproductive-related affective dysregulation. (C) 2016 American Physiological Society. C1 [Schiller, Crystal Edler; Johnson, Sarah L.; Abate, Anna C.; Rubinow, David R.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27514 USA. [Schmidt, Peter J.] NIMH, Sect Behav Endocrinol, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Rubinow, DR (reprint author), Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27514 USA. EM david_rubinow@med.unc.edu NR 366 TC 1 Z9 1 U1 16 U2 21 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2040-4603 J9 COMPR PHYSIOL JI Compr. Physiol. PD JUL PY 2016 VL 6 IS 3 BP 1135 EP 1160 DI 10.1002/cphy.c150014 PG 26 WC Physiology SC Physiology GA DP1EB UT WOS:000378232200001 PM 27347888 ER PT J AU Eriksson, O Laughlin, M Brom, M Nuutila, P Roden, M Hwa, A Bonadonna, R Gotthardt, M AF Eriksson, Olof Laughlin, Maren Brom, Maarten Nuutila, Pirjo Roden, Michael Hwa, Albert Bonadonna, Riccardo Gotthardt, Martin TI In vivo imaging of beta cells with radiotracers: state of the art, prospects and recommendations for development and use SO DIABETOLOGIA LA English DT Review DE Beta cell; Beta cell imaging; Diabetes; Exendin; Islet imaging; Islets of Langerhans; PET; Review; SPECT ID POSITRON-EMISSION-TOMOGRAPHY; HUMAN PANCREAS; RECEPTOR EXPRESSION; PEPTIDE-1 RECEPTOR; ENDOCRINE PANCREAS; EUROPEAN SUBJECTS; VMAT2 EXPRESSION; GLP-1 RECEPTOR; ADULT PATIENTS; RAT PANCREAS AB Radiotracer imaging is characterised by high in vivo sensitivity, with a detection limit in the lower picomolar range. Therefore, radiotracers represent a valuable tool for imaging pancreatic beta cells. High demands are made of radiotracers for in vivo imaging of beta cells. Beta cells represent only a small fraction of the volume of the pancreas (usually 1-3%) and are scattered in the tiny islets of Langerhans throughout the organ. In order to be able to measure a beta cell-specific signal, one has to rely on highly specific tracer molecules because current in vivo imaging technologies do not allow the resolution of single islets in humans non-invasively. Currently, a considerable amount of preclinical data are available for several radiotracers and three are under clinical evaluation. We summarise the current status of the evaluation of these tracer molecules and put forward recommendations for their further evaluation. C1 [Eriksson, Olof] Uppsala Univ, Dept Med Chem, Preclin PET Platform, Dag Hammarskjolds Vag 14C,3tr, SE-75183 Uppsala, Sweden. [Eriksson, Olof; Nuutila, Pirjo] Univ Turku, Turku PET Ctr, Turku, Finland. [Eriksson, Olof] Abo Akad Univ, Dept Biosci, Turku, Finland. [Laughlin, Maren] NIDDK, NIH, Bethesda, MD 20892 USA. [Brom, Maarten; Gotthardt, Martin] Radboud Univ Nijmegen, Dept Radiol & Nucl Med, Med Ctr, POB 9101, NL-6500 HB Nijmegen, Netherlands. [Roden, Michael] Univ Dusseldorf, Fac Med, Dept Endocrinol & Diabetol, Dusseldorf, Germany. [Roden, Michael] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany. [Hwa, Albert] JDRF, Discovery Res, New York, NY USA. [Bonadonna, Riccardo] Univ Parma, Dept Clin & Expt Med, Div Endocrinol, I-43100 Parma, Italy. [Bonadonna, Riccardo] AOU Parma, Parma, Italy. RP Eriksson, O (reprint author), Uppsala Univ, Dept Med Chem, Preclin PET Platform, Dag Hammarskjolds Vag 14C,3tr, SE-75183 Uppsala, Sweden.; Eriksson, O (reprint author), Univ Turku, Turku PET Ctr, Turku, Finland.; Eriksson, O (reprint author), Abo Akad Univ, Dept Biosci, Turku, Finland.; Gotthardt, M (reprint author), Radboud Univ Nijmegen, Dept Radiol & Nucl Med, Med Ctr, POB 9101, NL-6500 HB Nijmegen, Netherlands. EM olof.eriksson@pet.medchem.uu.se; martin.gotthardt@radboudumc.nl RI Brom, Maarten/J-1953-2014; OI Brom, Maarten/0000-0001-5755-1477; Bonadonna, Riccardo/0000-0002-9809-1005 NR 57 TC 2 Z9 2 U1 3 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD JUL PY 2016 VL 59 IS 7 BP 1340 EP 1349 DI 10.1007/s00125-016-3959-7 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DO8QH UT WOS:000378047800002 PM 27094935 ER PT J AU Zhang, CL Rawal, S Chong, YS AF Zhang, Cuilin Rawal, Shristi Chong, Yap Seng TI Risk factors for gestational diabetes: is prevention possible? SO DIABETOLOGIA LA English DT Review DE Diet; Gestational diabetes; Intervention; Lifestyle; Prevention; Review; Risk factors ID RANDOMIZED CONTROLLED-TRIAL; OBESE PREGNANT-WOMEN; PHYSICAL-ACTIVITY INTERVENTIONS; MELLITUS PROSPECTIVE COHORT; HEALTHY LIFE-STYLE; WEIGHT-GAIN; DIETARY PATTERNS; EXERCISE; METAANALYSIS; ASSOCIATION AB Gestational diabetes mellitus (GDM), a common pregnancy complication, continues to be a significant public health and clinical problem. It carries significant short-term and long-term adverse health outcomes for both mother and offspring, which reinforces the significance of understanding risk factors, in particular modifiable factors, for GDM and of preventing the condition. Research in the past decade from observational studies has identified a few diet and lifestyle factors that are associated with GDM risk and demonstrated that time frames both before and during pregnancy may be relevant to the development of GDM. Findings from intervention studies on the effect of diet and lifestyle on the prevention of GDM have been largely controversial and inconsistent. Variations in study population, types of intervention, timing and duration of intervention and diagnostic criteria for GDM may all at least partly account for the large heterogeneity in the findings from these intervention studies. This review provides an overview of emerging diet, lifestyle, and other factors that may help to prevent GDM, and the challenges associated with prevention. It also discusses major methodological concerns about the available epidemiological studies on GDM risk factors. Findings from both observational and intervention studies are discussed. This review summarises a presentation given at the 'Gestational diabetes: what's up?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Peter Damm and Colleagues, DOI: 10.1007/s00125-016-3985-5, and by Marja Vaarasmaki, DOI: 10.1007/s00125-016-3976-6<) and an overview by the Session Chair, Kerstin Berntorp (DOI: 10.1007/s00125-016-3975-7). C1 [Zhang, Cuilin; Rawal, Shristi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. [Chong, Yap Seng] Agcy Sci Technol & Res, Singapore Inst Clin Sci, Singapore, Singapore. [Chong, Yap Seng] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Obstet & Gynaecol, Singapore 117595, Singapore. 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 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health FX CZ and SR are supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health. NR 49 TC 1 Z9 1 U1 18 U2 23 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD JUL PY 2016 VL 59 IS 7 BP 1385 EP 1390 DI 10.1007/s00125-016-3979-3 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DO8QH UT WOS:000378047800010 PM 27165093 ER PT J AU Xing, CH Huang, J Hsu, YH DeStefano, AL Heard-Costa, NL Wolf, PA Seshadri, S Kiel, DP Cupples, LA Dupuis, J AF Xing, Chuanhua Huang, Jie Hsu, Yi-Hsiang DeStefano, Anita L. Heard-Costa, Nancy L. Wolf, Philip A. Seshadri, Sudha Kiel, Douglas P. Cupples, L. Adrienne Dupuis, Josee TI Evaluation of power of the Illumina HumanOmni5M-4v1 BeadChip to detect risk variants for human complex diseases SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; LINKAGE DISEQUILIBRIUM; GENOTYPE IMPUTATION; COVERAGE; EXTENT AB Although emerging sequencing technologies can characterize all genetic variants, the cost is still high. Illumina released the HumanOmni5M-4v1 (Omni5) genotype array with similar to 4.3M assayed SNPs, a much denser array compared with other available arrays. The Omni5 balances both cost and array density. In this article, we illustrate the power of Omni5 to detect genetic associations. The Omni5 includes variants with a wide range of minor allele frequencies down to <1%. The theoretical power calculation examples indicate the increased power of the Omni5 array compared with other arrays with lower density when evaluating associations with some known loci, although there are exceptions. We further evaluate the genetic associations between known loci and several quantitative traits in the Framingham Heart Study: femoral neck bone mineral density, lumbar spine bone mineral density and hippocampal volume. Finally, we search genome wide for novel associations using the Omni5 genotypes. We compare our association results from Affymetrix 500K+MIPS 50K arrays and two imputed data sets: (1) HapMap Phase II and (2) 1000 Genomes reference panel. We observed increased evidence for genotype-phenotype associations with smaller P-values for selected known loci using the Omni5 genotypes. With limited sample sizes, we identify novel variants with genome-wide significant P-values. Our observations support the notion that dense genotyping using the Omni5 can be powerful in detecting novel associated variants. Comparison with imputed data with higher density also suggests that imputation helps but cannot replace genotyping, especially when imputation quality is low. C1 [Xing, Chuanhua; DeStefano, Anita L.; Cupples, L. Adrienne; Dupuis, Josee] Boston Univ, Dept Biostat, Sch Publ Hlth, Third Floor,801 Massachusetts Ave, Boston, MA 02118 USA. [Huang, Jie] Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, England. [Hsu, Yi-Hsiang; Kiel, Douglas P.] Hebrew SeniorLife, Inst Aging Res, Boston, MA USA. [Hsu, Yi-Hsiang; Kiel, Douglas P.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Hsu, Yi-Hsiang; Kiel, Douglas P.] Harvard Univ, Sch Med, Boston, MA USA. [Hsu, Yi-Hsiang] Harvard Univ, Sch Publ Hlth, Mol & Integrat Physiol Sci Program, 665 Huntington Ave, Boston, MA 02115 USA. [DeStefano, Anita L.; Heard-Costa, Nancy L.; Wolf, Philip A.; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Third Floor,801 Massachusetts Ave, Boston, MA 02118 USA. [DeStefano, Anita L.; Heard-Costa, Nancy L.; Wolf, Philip A.; Seshadri, Sudha; Cupples, L. Adrienne; Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. RP Dupuis, J (reprint author), Boston Univ, Dept Biostat, Sch Publ Hlth, Third Floor,801 Massachusetts Ave, Boston, MA 02118 USA.; Xing, CH (reprint author), Boston Univ, Dept Biostat, POB 152, Gaithersburg, MD 20884 USA. EM chuanhua.xing@gmail.com; dupuis@bu.edu OI Kiel, Douglas/0000-0001-8474-0310 FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; NINDS [NS17950]; NHLBI [HL102419, HL096917]; NIA [AG08122, AG16495, AG033193]; NIAMS [R01 AR/AG 41398] FX We would like to acknowledge the work of Larry Atwood for his early efforts in connecting Illumina and Boston University. Genotyping of similar to 4.3M SNPs was conducted in subset of 2500 Framingham Offspring Cohort participants using the Illumina HumanOmni5M-4v1 array designed to target variation down to 1% minor allele frequency. This genotyping was produced at no charge by Illumina under an agreement between Illumina and Boston University. This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract no. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract no. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This study was also supported by grants from the NINDS (NS17950), the NHLBI (HL102419, HL096917) and the NIA (AG08122, AG16495, AG033193). Additional support for the skeletal phenotypes was obtained from NIAMS (R01 AR/AG 41398). NR 16 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD JUL PY 2016 VL 24 IS 7 BP 1029 EP 1034 DI 10.1038/ejhg.2015.244 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DO9IA UT WOS:000378098000014 PM 26577045 ER PT J AU Paredes, A Saenz, P Marzal, MW Orrego, MA Castillo, Y Rivera, A Mahanty, S Guerra-Giraldez, C Garcia, HH Nash, TE AF Paredes, Adriana Saenz, Patricia Marzal, Miguel W. Orrego, Miguel A. Castillo, Yesenia Rivera, Andrea Mahanty, Siddhartha Guerra-Giraldez, Cristina Garcia, Hector H. Nash, Theodore E. CA Cysticercosis Working Grp Peru TI Anti-Taenia solium monoclonal antibodies for the detection of parasite antigens in body fluids from patients with neurocysticercosis SO EXPERIMENTAL PARASITOLOGY LA English DT Article DE Taenia solium; Monoclonal antibodies; Capture ELISA; Neurocysticercosis; Diagnosis ID HP10 ANTIGEN; FOLLOW-UP; DIAGNOSIS; CYSTICERCOSIS; SERUM; ELISA AB Neurocysticercosis (NCC), an infection of the brain by Taenia solium (Ts) cysts, is the most common cause of adult-onset epilepsy in developing countries. Serological testing consists primarily of varying methods to detect antibodies in body fluids and more recently antigen (Ag) detection assays to identify individuals or animals with viable parasites. Antigen assays currently in use employ monoclonal antibodies (mAbs) raised against T. saginata, which have known cross reactivity to animal cestodes but are highly specific in human samples. We produced, characterized and tested 21 mAbs raised against T. solium whole cyst antigens, vesicular fluid or excretory secretory products. Reactivity of the TsmAbs against specific cyst structures was determined using immunofluorescence and immunohistochemistry on histological sections of Ts muscle cysts. Four TsmAbs reacted to vesicular space alone, 9 to the neck and cyst wall, one to the neck and vesicular space and 7 to the neck, cyst wall and vesicular space. An in-house ELISA assay to detect circulating Ts antigen, using the TsmAbs as capture antibodies and a rabbit polyclonal anti-Ts whole cyst antibody as a detector antibody demonstrated that eight of the 21 TsmAbs detected antigens in known NCC-positive human sera and three of these also in urine samples. Reactivity was expressed as normalized ratios of optical densities (OD positive control/OD negative control). Three TsmAbs had ratios >10 and five between 2 and 10. The TsmAbs have potential utility for the diagnosis and post-treatment monitoring of patients with viable NCC infections. (C) 2016 Elsevier Inc. All rights reserved. C1 [Paredes, Adriana; Saenz, Patricia; Marzal, Miguel W.; Orrego, Miguel A.; Rivera, Andrea; Mahanty, Siddhartha; Guerra-Giraldez, Cristina; Nash, Theodore E.] Univ Peruana Cayetano Heredia, Fac Ciencias & Filosofia, Lab Inmunopatol Neurocisticercosis, Lima, Peru. [Castillo, Yesenia; Garcia, Hector H.] Univ Peruana Cayetano Heredia, Fac Ciencias & Filosofia, Lab Inmunol Parasitaria, Lima, Peru. [Mahanty, Siddhartha; Nash, Theodore E.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. [Guerra-Giraldez, Cristina; Garcia, Hector H.] Univ Peruana Cayetano Heredia, Fac Ciencias & Filosofia, Dept Ciencias Celulares & Mol, Lima, Peru. [Garcia, Hector H.] Inst Nacl Ciencias Neurol, Unidad Cisticercosis, Lima, Peru. RP Guerra-Giraldez, C (reprint author), Univ Peruana Cayetano Heredia, Fac Ciencias & Filosofia, Dept Ciencias Celulares & Mol, Lima, Peru. EM cristina.guerra@upch.pe OI Guerra-Giraldez, Cristina/0000-0002-9287-9838; Mahanty, Siddhartha/0000-0003-1068-0524 FU Innovate Peru [FINCyT-IA-231-2013]; NIH/FIC Training grant [TW001140]; National Institutes of Allergy and Infectious Diseases FX This work was supported partially by Innovate Peru, project FINCyT-IA-231-2013, by NIH/FIC Training grant TW001140, and by an intramural research program of the National Institutes of Allergy and Infectious Diseases. NR 20 TC 1 Z9 1 U1 3 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4894 EI 1090-2449 J9 EXP PARASITOL JI Exp. Parasitol. PD JUL PY 2016 VL 166 BP 37 EP 43 DI 10.1016/j.exppara.2016.03.025 PG 7 WC Parasitology SC Parasitology GA DP4JK UT WOS:000378462000006 PM 27018063 ER PT J AU Verma, M AF Verma, Mukesh TI Genome-wide association studies and epigenome-wide association studies go together in cancer control SO FUTURE ONCOLOGY LA English DT Review DE biomarkers; cancer; epidemiology; epigenetics; genomics; omics technologies; outcome; personalized medicine; pharmacogenomics ID SQUAMOUS-CELL CARCINOMA; DNA METHYLATION ANALYSIS; HUMAN-PAPILLOMAVIRUS 16; COPY NUMBER VARIATION; COLORECTAL-CANCER; BREAST-CANCER; PROSTATE-CANCER; LUNG-CANCER; PANCREATIC-CANCER; SUSCEPTIBILITY LOCI AB Completion of the human genome a decade ago laid the foundation for: using genetic information in assessing risk to identify individuals and populations that are likely to develop cancer, and designing treatments based on a person's genetic profiling ( precision medicine). Genome-wide association studies (GWAS) completed during the past few years have identified risk-associated single nucleotide polymorphisms that can be used as screening tools in epidemiologic studies of a variety of tumor types. This led to the conduct of epigenome-wide association studies (EWAS). This article discusses the current status, challenges and research opportunities in GWAS and EWAS. Information gained from GWAS and EWAS has potential applications in cancer control and treatment. C1 [Verma, Mukesh] NCI, Methods & Technol Branch, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci,NIH, 9609 Med Ctr Dr,Suite 4E102, Rockville, MD 20850 USA. RP Verma, M (reprint author), NCI, Methods & Technol Branch, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci,NIH, 9609 Med Ctr Dr,Suite 4E102, Rockville, MD 20850 USA. EM vermam@mail.nih.gov NR 149 TC 0 Z9 0 U1 11 U2 19 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1479-6694 EI 1744-8301 J9 FUTURE ONCOL JI Future Oncol. PD JUL PY 2016 VL 12 IS 13 BP 1645 EP 1664 DI 10.2217/fon-2015-0035 PG 20 WC Oncology SC Oncology GA DP3RS UT WOS:000378413200011 PM 27079684 ER PT J AU Sei, Y Feng, JY Zhao, XL Forbes, J Tang, D Nagashima, K Hanson, J Quezado, MM Hughes, MS Wank, SA AF Sei, Yoshitatsu Feng, Jianying Zhao, Xilin Forbes, Joanne Tang, Derek Nagashima, Kunio Hanson, Jeffrey Quezado, Martha M. Hughes, Marybeth S. Wank, Stephen A. TI Polyclonal Crypt Genesis and Development of Familial Small Intestinal Neuroendocrine Tumors SO GASTROENTEROLOGY LA English DT Article DE Small Intestine; Cancer; Malignancy; Gene Expression ID MITOCHONDRIAL-DNA MUTATIONS; STEM-CELL POPULATIONS; ILEAL CARCINOIDS; PROGENITOR CELLS; IN-VIVO; LGR5; MARKER; TUMORIGENESIS; ORIGIN; CANCER AB BACKGROUND & AIMS: Small intestinal neuroendocrine tumors (SI-NETs) are serotonin-secreting well-differentiated neuroendocrine tumors believed to originate from entero-chromaffin (EC) cells. Intestinal stem cell (ISC) are believed to contribute to the formation of SI-NETs, although little is known about tumor formation or development. We investigated the relationship between EC cells, ISCs, and SI-NETs. METHODS: We analyzed jejuno-ileal tissue specimens from 14 patients with familial SI-NETs enrolled in the Natural History of Familial Carcinoid Tumor study at the National Institutes of Health from January 2009 to December 2014. Frozen and paraffin-embedded tumor tissues of different stages and isolated crypts were analyzed by in situ hybridization and immunohistochemistry. Tumor clonality was assessed by analyses of mitochondrial DNA. RESULTS: We identified multifocal aberrant crypt-containing endocrine cell clusters (ACECs) that contain crypt EC cell microtumors in patients with familial SI-NETs. RNA in situ hybridization revealed expression of the EC cell and reserve stem cell genes TPH1, BMI1, HOPX, and LGR5(low), in the ACECs and more advanced extraepithelial tumor nests. This expression pattern resembled that of reserve EC cells that express reserve ISC genes; most reside at the +4 position in normal crypts. The presence of multifocal ACECs from separate tumors and in the macroscopic tumor-free mucosa indicated widespread, independent, multifocal tumorigenesis. Analyses of mitochondrial DNA confirmed the independent origin of the ACECs. CONCLUSIONS: Familial SI-NETs originate from a subset of EC cells (reserve EC cells that express reserve ISC genes) via multifocal and polyclonal processes. Increasing our understanding of the role of these reserve EC cells in the genesis of multifocal SI-NETs could improve diagnostic and therapeutic strategies for this otherwise intractable disease. C1 [Sei, Yoshitatsu; Feng, Jianying; Zhao, Xilin; Forbes, Joanne; Tang, Derek; Wank, Stephen A.] NIDDKD, Digest Dis Branch, NIH, 10 Ctr Dr,Bldg 10,Room 9C-101,MSC1804, Bethesda, MD 20892 USA. [Nagashima, Kunio] Frederick Natl Lab Canc Res, Electron Microscopy Lab, Frederick, MD USA. [Hanson, Jeffrey; Quezado, Martha M.] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Hughes, Marybeth S.] NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Wank, SA (reprint author), NIDDKD, Digest Dis Branch, 10 Ctr Dr,Bldg 10,Room 9C-101,MSC1804, Bethesda, MD 20892 USA. EM stevew@mail.nih.gov OI Tang, Derek/0000-0002-9419-1869 FU National Institute of Diabetes, Digestive and Kidney Diseases; Clinical Research Center; Frederick National Laboratory for Cancer Research; National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Institute of Diabetes, Digestive and Kidney Diseases, Clinical Research Center, Frederick National Laboratory for Cancer Research and National Cancer Institute, National Institutes of Health. NR 35 TC 2 Z9 2 U1 6 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 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD JUL PY 2016 VL 151 IS 1 BP 140 EP 151 DI 10.1053/j.gastro.2016.03.007 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DP5QD UT WOS:000378551400030 PM 27003604 ER PT J AU Wong, RP Tinsley, EA Waclawiw, MA Krull, HK Lathrop, DA AF Wong, Renee P. Tinsley, Emily A. Waclawiw, Myron A. Krull, Holly K. Lathrop, David A. TI National, Heart, Lung, and Blood Institute support of cardiac arrhythmia research SO HEART RHYTHM LA English DT Editorial Material C1 [Wong, Renee P.; Tinsley, Emily A.; Waclawiw, Myron A.; Krull, Holly K.; Lathrop, David A.] NHLBI, Heart Failure & Arrhythmias Branch, Adult & Pediat Cardiac Res Program, Div Cardiovasc Sci,NIH, Bldg 10, Bethesda, MD 20892 USA. RP Lathrop, DA (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Room 8170, Bethesda, MD 20892 USA. EM lathropd@nhlbi.nih.gov NR 4 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 EI 1556-3871 J9 HEART RHYTHM JI Heart Rhythm PD JUL PY 2016 VL 13 IS 7 BP 1570 EP 1572 DI 10.1016/j.hrthm.2016.03.001 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO9FK UT WOS:000378090000030 PM 26945850 ER PT J AU Choi, H Chung, H Muntaner, C Lee, M Kim, Y Barry, CE Cho, SN AF Choi, H. Chung, H. Muntaner, C. Lee, M. Kim, Y. Barry, C. E., III Cho, S-N. TI The impact of social conditions on patient adherence to pulmonary tuberculosis treatment SO INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE LA English DT Article DE TB; socio-economic position; adherence; loss to follow-up; infectious epidemiology ID SOUTH-AFRICA; ANTITUBERCULOSIS TREATMENT; DEFAULT; INTERVENTIONS; NONADHERENCE; PREDICTORS; MORTALITY; EDUCATION; BARRIERS; RISK AB SETTING: Tuberculosis (TB) remains one of the main concerns in global health. One of the main threats to treatment success is patient non-adherence to anti-tuberculosis treatment. OBJECTIVE: To identify the relation between social conditions and treatment adherence in a prospective cohort setting in an intermediate TB burden country. DESIGN: To identify associations between poor adherence and social conditions, including educational level, type of residence and occupation, we constructed hierarchical logistic regression models. RESULTS: A total of 551 participants were included in the study. Low educational levels, poor housing and occupations in the construction and manufacturing industries and service sectors were associated with poor adherence; this association was likely to be differentiated by previous history of anti-tuberculosis treatment. CONCLUSION: Policy making should focus on improving the social conditions of patients by working towards better housing conditions and providing health promoting working conditions to enable treatment adherence. C1 [Choi, H.; Lee, M.; Kim, Y.; Cho, S-N.] Int TB Res Ctr, Clin Res Sect, Chang Won, South Korea. [Choi, H.] Korean Inst TB, Dept Res & Dev, Cheongju, South Korea. [Chung, H.] Korea Univ, Grad Sch, Dept Publ Hlth Sci, Program Embodiment Hlth Soc Interact BK21PLUS, Seoul, South Korea. [Chung, H.] Korea Univ, Coll Hlth Sci, Sch Hlth Policy & Management, Seoul, South Korea. [Muntaner, C.] Univ Toronto, DaIla Lana Sch Publ Hlth, Bloomberg Fac Nursing, Toronto, ON, Canada. [Barry, C. E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Cho, S-N.] Yonsei Univ, Coll Med, Project Med Sci BK21PLUS, Dept Microbiol, Seoul, South Korea. [Cho, S-N.] Yonsei Univ, Coll Med, Project Med Sci BK21PLUS, Inst Immunol & Immunol Dis, Seoul, South Korea. RP Chung, H (reprint author), B-365,Hana Sci Hall,145 Anam Ro, Seoul, South Korea. EM hpolicy@korea.ac.kr FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), US National Institutes of Health (NIH), Bethesda, MD, USA; Korean Centers for Disease Control of the Korean Ministry of Health and Welfare, Seoul; Social Science Korea Program through the National Research Foundation of Korea, Daejeon; Ministry of Education, Seoul, South Korea [NRF-2012S1A5A8022889] FX This study was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), US National Institutes of Health (NIH), Bethesda, MD, USA, in part by continuous support from the Korean Centers for Disease Control of the Korean Ministry of Health and Welfare, Seoul, to the International Tuberculosis Research Center, Masan, and in part by the Social Science Korea Program through the National Research Foundation of Korea, Daejeon, funded by the Ministry of Education, Seoul, South Korea, (NRF-2012S1A5A8022889). The authors would like to thank the patients who enrolled in this research study and the clinical staff who supported the trial. NR 33 TC 1 Z9 1 U1 4 U2 5 PU INT UNION AGAINST TUBERCULOSIS LUNG DISEASE (I U A T L D) PI PARIS PA 68 BOULEVARD SAINT-MICHEL,, 75006 PARIS, FRANCE SN 1027-3719 EI 1815-7920 J9 INT J TUBERC LUNG D JI Int. J. Tuberc. Lung Dis. PD JUL PY 2016 VL 20 IS 7 BP 948 EP 954 DI 10.5588/ijtld.15.0759 PG 7 WC Infectious Diseases; Respiratory System SC Infectious Diseases; Respiratory System GA DP0ON UT WOS:000378189200019 PM 27287649 ER PT J AU Kacanek, D Malee, K Mellins, CA Tassiopoulos, K Smith, R Grant, M Lee, S Siddiqui, DQ Puga, A AF Kacanek, Deborah Malee, Kathleen Mellins, Claude A. Tassiopoulos, Katherine Smith, Renee Grant, Mitzie Lee, Sonia Siddiqui, Danish Q. Puga, Ana TI Exposure to Violence and Virologic and Immunological Outcomes Among Youth With Perinatal HIV in the Pediatric HIV/AIDS Cohort Study SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Violence; Adolescents; Gender; Virologic suppression; Adherence ID INTIMATE PARTNER VIOLENCE; HUMAN-IMMUNODEFICIENCY-VIRUS; NEGATIVE LIFE EVENTS; OF-THE-LITERATURE; CHILDHOOD ADVERSITIES; DOMESTIC VIOLENCE; INFECTION; CHILDREN; ADOLESCENTS; ABUSE AB Purpose: Exposure to violence in childhood has been linked to adverse health outcomes. Little is known about the prevalence and relationship of youth and caregiver violence exposure to clinical outcomes among youth with perinatal human immunodeficiency virus (HIV) infection (PHIV). We evaluated associations of youth and caregiver violence exposure with unsuppressed viral load (VL) (HIV RNA > 400 copies/mL) and CD4% < 25% among 8- to 15-year-old participants with PHIV in the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol. Methods: Annual clinical examination, record abstraction, and interview data were collected, including youth report of recent exposure to violence and caregivers' self-report of being assaulted/abused in adulthood. Multivariable logistic regression methods were used to calculate adjusted odds ratios for unsuppressed VL and CD4% < 25%, controlling for sociodemographic characteristics. Results: Among 268 youth with PHIV (53% girls, mean age 12.8 years, 21% white, 42% with household income <$ 20,000/year), 34% reported past year violence exposure; 30% had a caregiver who reported being assaulted in adulthood. One quarter of youth (24%) had unsuppressed VL and 22% had CD4% < 25%. Youth who were exposed to violence in the past year versus those who were not had elevated odds of unsuppressed VL. Youth with indirect exposure to violence in the past year versus those without had elevated odds of unsuppressed VL and CD4% < 25% in adjusted models. Conclusions: Youth with PHIV report a high prevalence of recent violence exposure, which was associated with poor virologic and immunologic outcomes. Reducing violence and providing support to youth with violence exposure and PHIV may improve health outcomes. (C) 2016 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved. C1 [Kacanek, Deborah] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Malee, Kathleen] Northwestern Univ, Feinberg Sch Med, Dept Psychiat & Behav Sci, Chicago, IL 60611 USA. [Mellins, Claude A.] Columbia Univ, Dept Psychiat, Med Ctr, HIV Ctr Clin & Behav Studies, New York, NY USA. [Tassiopoulos, Katherine] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Smith, Renee] Univ Illinois, Dept Pediat, Chicago, IL USA. [Grant, Mitzie] Drexel Univ, Coll Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Grant, Mitzie] St Christophers Hosp Children, Philadelphia, PA 19133 USA. [Lee, Sonia] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, Bethesda, MD USA. [Siddiqui, Danish Q.] Tulane Sch Med, Dept Pediat Infect Dis, New Orleans, LA USA. [Puga, Ana] Childrens Diagnost & Treatment Ctr, Ft Lauderdale, FL USA. RP Kacanek, D (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Ctr Biostat AIDS Res, 665 Huntington Ave,FXB 505, Boston, MA 02115 USA. EM dkacanek@sdac.harvard.edu FU NICHD NIH HHS [U01 HD052102, U01 HD052104] NR 39 TC 2 Z9 2 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X EI 1879-1972 J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD JUL PY 2016 VL 59 IS 1 BP 30 EP 37 DI 10.1016/j.jadohealth.2016.03.004 PG 8 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA DP0TL UT WOS:000378202300007 PM 27089837 ER PT J AU Hinkle, SN Albert, PS Sjaarda, LA Grewal, J Grantz, KL AF Hinkle, Stefanie N. Albert, Paul S. Sjaarda, Lindsey A. Grewal, Jagteshwar Grantz, Katherine L. TI Trajectories of maternal gestational weight gain and child cognition assessed at 5 years of age in a prospective cohort study SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Article ID BRAIN-DEVELOPMENT; PREGNANCY; ASSOCIATIONS; ADOLESCENCE; OUTCOMES; MOTHERS; GROWTH; MODELS; BIRTH; WOMEN AB Background There has been concern that low gestational weight gain may cause poor fetal neurodevelopment. Methods The association between maternal weight gain and child IQ was examined using serial antenatal weight measurements (median 12) from a prospective cohort of non-obese Scandinavian women (1986-1988). Linear mixed models with piecewise regression were used to estimate participants' (n = 552) trimester-specific average rate of weight gain. Linear regression was used to assess the association between weight gain and children's (n= 344) full-scale, performance and verbal IQ measured at age 5 using the Wechsler Preschool and Primary Scales of Intelligence-Revised. Results Children born to mothers who gained below versus within the 2nd trimester 2009 recommendations tended to have lower IQ scores (Full-scale: 106.6 (SD 15.1) vs 110.2 (15.2), p = 0.04; verbal: 102.5 (14.3) vs 105.0 (14.9), p = 0.10; performance: 109.5 (15.4) vs 113.4 (14.5), p = 0.03). After adjustment there were no differences in child IQ by weight gain adequacy (full-scale: beta(below)=-1.1 (95% CI -5.1 to 2.9), beta(above) = 1.5 (-3.8 to 6.8); verbal: beta(below) =-0.2 (-3.1 to 2.6), beta(above) = 1.8 (-3.6 to 7.3); performance beta(below) =-1.2 (-4.6 to 2.2), beta(above) = 1.0 (-4.6 to 6.7)). No differences were observed based on 3rd trimester adequacy. No differences were observed in IQ scores by quintile of weight gain for any trimester, particularly after adjustment for maternal IQ. Conclusions Our findings are reassuring that among normal weight women, pregnancy weight gain is not associated with child cognitive development. Further investigation should be conducted in contemporary cohorts that also include obese mothers, who are at the greatest risk for low weight gain. C1 [Hinkle, Stefanie N.; Sjaarda, Lindsey A.; Grantz, Katherine L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd Room 7B03, Bethesda, MD 20892 USA. [Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd Room 7B03, Bethesda, MD 20892 USA. [Grewal, Jagteshwar] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Off Director, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd Room 7B03, Bethesda, MD 20892 USA. RP Hinkle, SN (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd Room 7B03, Bethesda, MD 20892 USA. EM hinklesn@mail.nih.gov OI Hinkle, Stefanie/0000-0003-4312-708X; Sjaarda, Lindsey/0000-0003-0539-8110; Grewal, Jagteshwar/0000-0002-0141-4876; Grantz, Katherine/0000-0003-0276-8534 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health 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. NR 32 TC 1 Z9 1 U1 2 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X EI 1470-2738 J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD JUL PY 2016 VL 70 IS 7 BP 696 EP 703 DI 10.1136/jech-2014-205108 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DO8UY UT WOS:000378061200010 PM 26759126 ER PT J AU Roche, J Ying, JF Shen, Y Torchia, DA Bax, A AF Roche, Julien Ying, Jinfa Shen, Yang Torchia, Dennis A. Bax, Ad TI ARTSY-J: Convenient and precise measurement of (3)J(HNH alpha) couplings in medium-size proteins from TROSY-HSQC spectra SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Backbone torsion angle; Gly; Karplus equation; TROSY; GB3; HIV-1 Protease; Protein NMR ID RESIDUAL DIPOLAR COUPLINGS; CHEMICAL-SHIFT PREDICTION; RESOLVED NMR-SPECTROSCOPY; HIV-1 PROTEASE; PERDEUTERATED PROTEINS; ACCURATE MEASUREMENTS; KARPLUS EQUATIONS; CONSTANTS; RELAXATION; DYNAMICS AB A new and convenient method, named ARTSY-j, is introduced that permits extraction of the (3)J(HNH alpha) couplings in proteins from the relative intensities in a pair of N-15-H-1 TROSY-HSQC spectra. The pulse scheme includes (3)J(HNH alpha) dephasing of the narrower TROSY H-1(N)-{N-15) doublet component during a delay, integrated into the regular two-dimensional TROSY-HSQC pulse scheme, and compares the obtained intensity with a reference spectrum where (3)J(HNH alpha) dephasing is suppressed. The effect of passive H-1(alpha) spin flips downscales the apparent (3)J(HNH alpha) coupling by a uniform factor that depends approximately linea(r)ly on both the duration of the (3)J(HNH alpha) dephasing delay and the H-1-H-1 cross relaxation rate. Using such a correction factor, which accounts for the effects of both inhomogeneity of the radiofrequency field and H-1(alpha) spin flips, agreement between prior and newly measured values for the small model protein GB3 is better than 0.3 Hz. Measurement for the HIV-1 protease homodimer (22 kDa) yields (3)J(HNH alpha) values that agree to better than 0.7 Hz with predictions made on the basis of a previously parameterized Karplus equation. Although for Gly residues the two individual (3)J(HNH alpha) couplings cannot be extracted from a single set of ARTSY-J spectra, the measurement provides valuable phi angle information. Published by Elsevier Inc. C1 [Roche, Julien; Ying, Jinfa; Shen, Yang; Torchia, Dennis A.; Bax, Ad] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM bax@nih.gov RI Shen, Yang/C-3064-2008 OI Shen, Yang/0000-0003-1408-8034 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Intramural Antiviral Target Program of the Office of the Director, NIH FX We thank John Louis for preparing the protease sample, and Fang Li for the GB3 sample. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and the Intramural Antiviral Target Program of the Office of the Director, NIH. NR 47 TC 0 Z9 0 U1 4 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 EI 1096-0856 J9 J MAGN RESON JI J. Magn. Reson. PD JUL PY 2016 VL 268 BP 73 EP 81 DI 10.1016/j.jmr.2016.05.001 PG 9 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA DP0NG UT WOS:000378185900009 PM 27179455 ER PT J AU Therkelsen, KE Preis, SR Beiser, A DeCarli, C Seshadri, S Wolf, P Au, R Fox, CS AF Therkelsen, Kate E. Preis, Sarah R. Beiser, Alexa DeCarli, Charles Seshadri, Sudha Wolf, Philip Au, Rhoda Fox, Caroline S. TI Neck Circumference, Brain Imaging Measures, and Neuropsychological Testing Measures SO JOURNAL OF STROKE & CEREBROVASCULAR DISEASES LA English DT Article DE Epidemiology; population studies; cognition; adiposity ID OBSTRUCTIVE SLEEP-APNEA; BODY-MASS INDEX; INTIMA-MEDIA THICKNESS; COGNITIVE PERFORMANCE; CENTRAL OBESITY; FRAMINGHAM; RISK; DEMENTIA; VOLUME; IMPAIRMENT AB Background: Perivascular fat may have direct effects on local vascularity. Neck fat is associated with carotid intimal thickness, a predictor of brain aging outcomes. This study investigated whether neck circumference, an estimation of neck fat, has unique associations with brain aging outcomes. Methods: The study sample (n = 2082, 53.5% women, mean age 60.9 years) was derived from Framingham Heart Study participants with brain magnetic resonance imaging (MRI) and neuropsychological (NP) test measures. Multivariable-adjusted regressions examined crosssectional associations of neck circumference with brain MRI and NP test measures. Models were also constructed with waist circumference and body mass index (BMI) as exposures. Results: A 1 standard deviation (2.8 cm [women]; 2.9 cm [men]) increment in neck circumference was associated with lower total cerebral brain volume (beta = -.22, P = .0006) and lower frontal brain volume (beta = -.55, P < .0001). However, a similar association was observed for both waist circumference and BMI. There were no associations between neck circumference and NP test measures after full covariate adjustment. Conclusions: There were no unique associations between neck circumference and brain MRI or NP measures. Consistent with prior observations, all adiposity measures showed associations with more adverse brain MRI and NP measures, suggesting a global association of generalized adiposity. C1 [Therkelsen, Kate E.; Fox, Caroline S.] NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. [Therkelsen, Kate E.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Preis, Sarah R.; Beiser, Alexa] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Beiser, Alexa; Seshadri, Sudha; Wolf, Philip; Au, Rhoda] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Fox, Caroline S.] Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA. [Fox, Caroline S.] Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95817 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol & Metab, 75 Francis St, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Beiser, Alexa/0000-0001-8551-7778 FU Framingham Heart Study of the National Heart, Lungand Blood Institute [N01-HC-25195] FX The Framingham Heart Study of the National Heart, Lungand Blood Institute is supported by contract N01-HC-25195. NR 33 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1052-3057 EI 1532-8511 J9 J STROKE CEREBROVASC JI J. Stroke Cerebrovasc. Dis. PD JUL PY 2016 VL 25 IS 7 BP 1570 EP 1581 DI 10.1016/j.jstrokecerebrovasdis.2016.02.016 PG 12 WC Neurosciences; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DO7ZW UT WOS:000378002800003 PM 27056441 ER PT J AU Kwon, YD Georgiev, IS Ofek, G Zhang, BS Asokan, M Bailer, RT Bao, A Caruso, W Chen, XJ Choe, M Druz, A Ko, SY Louder, MK McKee, K O'Dell, S Pegu, A Rudicell, RS Shi, W Wang, KY Yang, YP Alger, M Bender, MF Carlton, K Cooper, JW Blinn, J Eudailey, J Lloyd, K Parks, R Alam, SM Haynes, BF Padte, NN Yu, J Ho, DD Huang, JH Connors, M Schwartz, RM Mascola, JR Kwong, PD AF Kwon, Young D. Georgiev, Ivelin S. Ofek, Gilad Zhang, Baoshan Asokan, Mangaiarkarasi Bailer, Robert T. Bao, Amy Caruso, William Chen, Xuejun Choe, Misook Druz, Aliaksandr Ko, Sung-Youl Louder, Mark K. McKee, Krisha O'Dell, Sijy Pegu, Amarendra Rudicell, Rebecca S. Shi, Wei Wang, Keyun Yang, Yongping Alger, Mandy Bender, Michael F. Carlton, Kevin Cooper, Jonathan W. Blinn, Julie Eudailey, Joshua Lloyd, Krissey Parks, Robert Alam, S. Munir Haynes, Barton F. Padte, Neal N. Yu, Jian Ho, David D. Huang, Jinghe Connors, Mark Schwartz, Richard M. Mascola, John R. Kwong, Peter D. TI Optimization of the Solubility of HIV-1-Neutralizing Antibody 10E8 through Somatic Variation and Structure-Based Design SO JOURNAL OF VIROLOGY LA English DT Article ID PROXIMAL EXTERNAL REGION; MONOCLONAL-ANTIBODIES; HIV-1 NEUTRALIZATION; POTENT NEUTRALIZATION; IMPROVES PROTECTION; GLYCOPROTEIN GP41; ENVELOPE TRIMER; IN-VIVO; MEMBRANE; BROAD AB Extraordinary antibodies capable of near pan-neutralization of HIV-1 have been identified. One of the broadest is antibody 10E8, which recognizes the membrane-proximal external region (MPER) of the HIV-1 envelope and neutralizes > 95% of circulating HIV-1 strains. If delivered passively, 10E8 might serve to prevent or treat HIV-1 infection. Antibody 10E8, however, is markedly less soluble than other antibodies. Here, we describe the use of both structural biology and somatic variation to develop optimizedversions of 10E8 with increased solubility. From the structure of 10E8, we identified a prominent hydrophobic patch; reversion of four hydrophobic residues in this patch to their hydrophilic germ line counterparts resulted in an similar to 10-fold decrease in turbidity. We also used somatic variants of 10E8, identified previously by next-generation sequencing, to optimize heavy and light chains; this process yielded several improved variants. Of these, variant 10E8v4 with 26 changes versus the parent 10E8 was the most soluble, with a paratope we showed crystallographically to be virtually identical to that of 10E8, a potency on a panel of 200 HIV-1 isolates also similar to that of 10E8, and a half-life in rhesus macaques of similar to 10 days. An anomaly in 10E8v4 size exclusion chromatography that appeared to be related to conformational isomerization was resolved by engineering an interchain disulfide. Thus, by combining a structure-based approach with natural variation in potency and solubility from the 10E8 lineage, we successfully created variants of 10E8 which retained the potency and extraordinary neutralization breadth of the parent 10E8 but with substantially increased solubility. IMPORTANCE Antibody 10E8 could be used to prevent HIV-1 infection, if manufactured and delivered economically. It suffers, however, from issues of solubility, which impede manufacturing. We hypothesized that the physical characteristic of 10E8 could be improved through rational design, without compromising breadth and potency. We used structural biology to identify hydrophobic patches on 10E8, which did not appear to be involved in 10E8 function. Reversion of hydrophobic residues in these patches to their hydrophilic germ line counterparts increased solubility. Next, clues from somatic variants of 10E8, identified by next-generation sequencing, were incorporated. A combination of structure-based design and somatic variant optimization led to 10E8v4, with substantially improved solubility and similar potency compared to the parent 10E8. The cocrystal structure of antibody 10E8v4 with its HIV-1 epitope was highly similar to that with the parent 10E8, despite 26 alterations in sequence and substantially improved solubility. Antibody 10E8v4 may be suitable for manufacturing. C1 [Kwon, Young D.; Georgiev, Ivelin S.; Ofek, Gilad; Zhang, Baoshan; Asokan, Mangaiarkarasi; Bailer, Robert T.; Bao, Amy; Caruso, William; Chen, Xuejun; Choe, Misook; Druz, Aliaksandr; Ko, Sung-Youl; Louder, Mark K.; McKee, Krisha; O'Dell, Sijy; Pegu, Amarendra; Rudicell, Rebecca S.; Shi, Wei; Wang, Keyun; Yang, Yongping; Alger, Mandy; Bender, Michael F.; Carlton, Kevin; Cooper, Jonathan W.; Schwartz, Richard M.; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Blinn, Julie; Eudailey, Joshua; Lloyd, Krissey; Parks, Robert; Alam, S. Munir; Haynes, Barton F.] Duke Univ, Sch Med, Dept Med, Duke Human Vaccine Inst, Durham, NC 27706 USA. [Blinn, Julie; Eudailey, Joshua; Lloyd, Krissey; Parks, Robert; Alam, S. Munir; Haynes, Barton F.] Duke Univ, Sch Med, Dept Surg, Duke Human Vaccine Inst, Durham, NC USA. [Blinn, Julie; Eudailey, Joshua; Lloyd, Krissey; Parks, Robert; Alam, S. Munir; Haynes, Barton F.] Duke Univ, Dept Pediat, Sch Med, Duke Human Vaccine Inst, Durham, NC 27706 USA. [Blinn, Julie; Eudailey, Joshua; Lloyd, Krissey; Parks, Robert; Alam, S. Munir; Haynes, Barton F.] Duke Univ, Sch Med, Dept Immunol, Duke Human Vaccine Inst, Durham, NC USA. [Blinn, Julie; Eudailey, Joshua; Lloyd, Krissey; Parks, Robert; Alam, S. Munir; Haynes, Barton F.] Duke Univ, Ctr HIV AIDS Vaccine Immunol Immunogen Discovery, Durham, NC USA. [Padte, Neal N.; Yu, Jian; Ho, David D.] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, 1230 York Ave, New York, NY 10021 USA. [Huang, Jinghe; Connors, Mark] NIAID, HIV Specif Immun Sect, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Mascola, JR; Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jmascola@mail.nih.gov; pdkwong@nih.gov RI Kwon, Young Do/A-6957-2010 FU Bill and Melinda Gates Foundation [OPP1039775]; Intramural Research Program, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (VRC, NIAID) [ZIA AI005022-15] FX This work, including the efforts of John R. Mascola and Peter D. Kwong, was funded by Bill and Melinda Gates Foundation (OPP1039775). This work, including the efforts of Peter D. Kwong, was funded by Intramural Research Program, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (VRC, NIAID) (ZIA AI005022-15). NR 44 TC 7 Z9 7 U1 2 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUL PY 2016 VL 90 IS 13 BP 5899 EP 5914 DI 10.1128/JVI.03246-15 PG 16 WC Virology SC Virology GA DP2SA UT WOS:000378340300006 PM 27053554 ER PT J AU Lavender, KJ Gibbert, K Peterson, KE Van Dis, E Francois, S Woods, T Messer, RJ Gawanbacht, A Muller, JA Munch, J Phillips, K Race, B Harper, MS Guo, KJ Lee, EJ Trilling, M Hengel, H Piehler, J Verheyen, J Wilson, CC Santiago, ML Hasenkrug, KJ Dittmer, U AF Lavender, Kerry J. Gibbert, Kathrin Peterson, Karin E. Van Dis, Erik Francois, Sandra Woods, Tyson Messer, Ronald J. Gawanbacht, Ali Mueller, Janis A. Muench, Jan Phillips, Katie Race, Brent Harper, Michael S. Guo, Kejun Lee, Eric J. Trilling, Mirko Hengel, Hartmut Piehler, Jacob Verheyen, Jens Wilson, Cara C. Santiago, Mario L. Hasenkrug, Kim J. Dittmer, Ulf TI Interferon Alpha Subtype-Specific Suppression of HIV-1 Infection In Vivo SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HIGH-DOSE INTERFERON; T-CELL-ACTIVATION; HEPATITIS-C VIRUS; PEGYLATED INTERFERON; PHASE-II; ANTIRETROVIRAL THERAPY; MEDIATED SUPPRESSION; DISEASE PROGRESSION; DNA DEAMINATION AB Although all 12 subtypes of human interferon alpha (IFN-alpha) bind the same receptor, recent results have demonstrated that they elicit unique host responses and display distinct efficacies in the control of different viral infections. The IFN-alpha 2 subtype is currently in HIV-1 clinical trials, but it has not consistently reduced viral loads in HIV-1 patients and is not the most effective subtype against HIV-1 in vitro. We now demonstrate in humanized mice that, when delivered at the same high clinical dose, the human IFN-alpha 14 subtype has very potent anti-HIV-1 activity whereas IFN-alpha 2 does not. In both postexposure prophylaxis and treatment of acute infections, IFN-alpha 14, but not IFN-alpha 2, significantly suppressed HIV-1 replication and proviral loads. Furthermore, HIV-1- induced immune hyperactivation, which is a prognosticator of disease progression, was reduced by IFN-alpha 14 but not IFN-alpha 2. Whereas ineffective IFN-alpha 2 therapy was associated with CD8(+) T cell activation, successful IFN-alpha 14 therapy was associated with increased intrinsic and innate immunity, including significantly higher induction of tetherin and MX2, increased APOBEC3G signature mutations in HIV-1 proviral DNA, and higher frequencies of TRAIL(+) NK cells. These results identify IFN-alpha 14 as a potent new therapeutic that operates via mechanisms distinct from those of antiretroviral drugs. The ability of IFN-alpha 14 to reduce both viremia and proviral loads in vivo suggests that it has strong potential as a component of a cure strategy for HIV-1 infections. The broad implication of these results is that the antiviral efficacy of each individual IFN-alpha subtype should be evaluated against the specific virus being treated. IMPORTANCE The naturally occurring antiviral protein IFN-alpha 2 is used to treat hepatitis viruses but has proven rather ineffective against HIV in comparison to triple therapy with the antiretroviral (ARV) drugs. Although ARVs suppress the replication of HIV, they fail to completely clear infections. Since IFN-alpha acts by different mechanism than ARVs and has been shown to reduce HIV proviral loads, clinical trials are under way to test whether IFN-alpha 2 combined with ARVs might eradicate HIV-1 infections. IFN-alpha is actually a family of 12 distinct proteins, and each IFN-alpha subtype has different efficacies toward different viruses. Here, we use mice that contain a human immune system, so they can be infected with HIV. With this model, we demonstrate that while IFN-alpha 2 is only weakly effective against HIV, IFN-alpha 14 is extremely potent. This discovery identifies IFN-alpha 14 as a more powerful IFN-alpha subtype for use in combination therapy trials aimed toward an HIV cure. C1 [Lavender, Kerry J.; Peterson, Karin E.; Van Dis, Erik; Woods, Tyson; Messer, Ronald J.; Phillips, Katie; Race, Brent; Hasenkrug, Kim J.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Gibbert, Kathrin; Francois, Sandra; Trilling, Mirko; Verheyen, Jens; Dittmer, Ulf] Univ Duisburg Essen, Univ Hosp Essen, Inst Virol, Essen, Germany. [Gawanbacht, Ali; Mueller, Janis A.; Muench, Jan] Univ Ulm, Inst Mol Virol, D-89069 Ulm, Germany. [Hengel, Hartmut] Univ Freiburg, Inst Virol, Univ Med Ctr, Hugstetter Str 55, D-79106 Freiburg, Germany. [Piehler, Jacob] Univ Osnabruck, Dept Biol, Osnabruck, Germany. [Harper, Michael S.; Guo, Kejun; Lee, Eric J.; Wilson, Cara C.; Santiago, Mario L.] Univ Colorado Denver, Dept Med, Aurora, CO USA. RP Hasenkrug, KJ (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA.; Dittmer, U (reprint author), Univ Duisburg Essen, Univ Hosp Essen, Inst Virol, Essen, Germany. EM khasenkrug@nih.gov; ulf.dittmer@uni-due.de OI Trilling, Mirko/0000-0003-3659-3541 FU HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [ZIA A1001141, R56 AI116271]; Deutsche Forschungsgemeinschaft (DFG) [DFG TRR60, GRK 1949/1]; International Graduate School in Molecular Medicine Ulm (fellowship) FX This work, including the efforts of Kim J. Hasenkrug, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (ZIA A1001141). This work, including the efforts of Ulf Dittmer, Kathrin Gibbert, and Mirko Trilling, was funded by Deutsche Forschungsgemeinschaft (DFG) (DFG TRR60 and GRK 1949/1). This work, including the efforts of Mario L. Santiago, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (R56 AI116271). This work, including the efforts of Janis A. Mueller, was funded by International Graduate School in Molecular Medicine Ulm (fellowship). NR 86 TC 7 Z9 7 U1 2 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUL PY 2016 VL 90 IS 13 BP 6001 EP 6013 DI 10.1128/JVI.00451-16 PG 13 WC Virology SC Virology GA DP2SA UT WOS:000378340300014 PM 27099312 ER PT J AU Rhein, BA Brouillette, RB Schaack, GA Chiorini, JA Maury, W AF Rhein, Bethany A. Brouillette, Rachel B. Schaack, Grace A. Chiorini, John A. Maury, Wendy TI Characterization of Human and Murine T-Cell Immunoglobulin Mucin Domain 4 (TIM-4) IgV Domain Residues Critical for Ebola Virus Entry SO JOURNAL OF VIROLOGY LA English DT Article ID APOPTOTIC CELLS; PHOSPHATIDYLSERINE RECEPTOR; ZAIRE-EBOLAVIRUS; MEMBRANE PHOSPHATIDYLSERINE; MARBURG VIRUSES; LIPID RAFTS; GLYCOPROTEIN; ACTIVATION; IDENTIFICATION; BINDING AB Phosphatidylserine (PtdSer) receptors that are responsible for the clearance of dying cells have recently been found to mediate enveloped virus entry. Ebola virus (EBOV), a member of the Filoviridae family of viruses, utilizes PtdSer receptors for entry into target cells. The PtdSer receptors human and murine T-cell immunoglobulin mucin (TIM) domain proteins TIM-1 and TIM-4 mediate filovirus entry by binding to PtdSer on the virion surface via a conserved PtdSer binding pocket within the amino-terminal IgV domain. While the residues within the TIM-1 IgV domain that are important for EBOV entry are characterized, the molecular details of virion-TIM-4 interactions have yet to be investigated. As sequences and structural alignments of the TIM proteins suggest distinct differences in the TIM-1 and TIM-4 IgV domain structures, we sought to characterize TIM-4 IgV domain residues required for EBOV entry. Using vesicular stomatitis virus pseudovirions bearing EBOV glycoprotein (EBOV GP/VSV Delta G), we evaluated virus binding and entry into cells expressing TIM-4 molecules mutated within the IgV domain, allowing us to identify residues important for entry. Similar to TIM-1, residues in the PtdSer binding pocket of murine and human TIM-4 (mTIM-4 and hTIM-4) were found to be important for EBOV entry. However, additional TIM-4-specific residues were also found to impact EBOV entry, with a total of 8 mTIM-4 and 14 hTIM-4 IgV domain residues being critical for virion binding and internalization. Together, these findings provide a greater understanding of the interaction of TIM-4 with EBOV virions. C1 [Rhein, Bethany A.; Brouillette, Rachel B.; Schaack, Grace A.; Maury, Wendy] Univ Iowa, Dept Microbiol, Iowa City, IA 52242 USA. [Chiorini, John A.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. RP Maury, W (reprint author), Univ Iowa, Dept Microbiol, Iowa City, IA 52242 USA. EM wendy-maury@uiowa.edu FU HHS \ National Institutes of Health (NIH); HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [R01AI077519, U54 AI057160] FX This work, including the efforts of John A. Chiorini, was funded by HHS vertical bar National Institutes of Health (NIH) (intramural funds). This work, including the efforts of Wendy Maury, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (R01AI077519 and U54 AI057160). NR 59 TC 1 Z9 1 U1 6 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUL PY 2016 VL 90 IS 13 BP 6097 EP 6111 DI 10.1128/JVI.00100-16 PG 15 WC Virology SC Virology GA DP2SA UT WOS:000378340300022 PM 27122575 ER PT J AU Belsher, BE Jaycox, LH Freed, MC Evatt, DP Liu, X Novak, LA Zatzick, D Bray, RM Engel, CC AF Belsher, Bradley E. Jaycox, Lisa H. Freed, Michael C. Evatt, Daniel P. Liu, Xian Novak, Laura A. Zatzick, Douglas Bray, Robert M. Engel, Charles C. TI Mental Health Utilization Patterns During a Stepped, Collaborative Care Effectiveness Trial for PTSD and Depression in the Military Health System SO MEDICAL CARE LA English DT Article DE service utilization; collaborative care; stepped-care; mental health ID POSTTRAUMATIC-STRESS-DISORDER; INTERVENTION; METAANALYSIS; DEPLOYMENT; VALIDITY; MODELS; SAMPLE AB Background: Integrated health care models aim to improve access and continuity of mental health services in general medical settings. STEPS-UP is a stepped, centrally assisted collaborative care model designed to improve posttraumatic stress disorder (PTSD) and depression care by providing the appropriate intensity and type of care based on patient characteristics and clinical complexity. STEPS-UP demonstrated improved PTSD and depression outcomes in a large effectiveness trial conducted in the Military Health System. The objective of this study was to examine differences in mental health utilization patterns between patients in the stepped, centrally assisted collaborative care model relative to patients in the collaborative care as usual-treatment arm. Methods: Patients with probable PTSD and/or depression were recruited at 6 large military treatment facilities, and 666 patients were enrolled and randomized to STEPS-UP or usual collaborative care. Utilization data acquired from Military Health System administrative datasets were analyzed to determine mental health service use and patterns. Clinical complexity and patient characteristics were based on self-report questionnaires collected at baseline. Results: Compared with the treatment as usual arm, STEPS-UP participants received significantly more mental health services and psychiatric medications across primary and specialty care settings during the year of their participation. Patterns of service use indicated that greater clinical complexity was associated with increased service use in the STEPS-UP group, but not in the usual care group. Conclusions: Results suggest that stepped, centrally assisted collaborative care models may increase the quantity of mental health services patients receive, while efficiently matching care on the basis of the clinical complexity of patients. C1 [Belsher, Bradley E.; Evatt, Daniel P.; Liu, Xian; Novak, Laura A.] Def Ctr Excellence Psychol Hlth & Traumat Brain I, Deployment Hlth Clin Ctr, 1335 East West Highway,3rd Floor,Suite 3-100, Silver Spring, MD 20910 USA. [Belsher, Bradley E.; Liu, Xian; Engel, Charles C.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Jaycox, Lisa H.; Engel, Charles C.] RAND Corp, Arlington, VA USA. [Freed, Michael C.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Zatzick, Douglas] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Bray, Robert M.] RTI Int, Res Triangle Pk, NC USA. RP Belsher, BE (reprint author), Def Ctr Excellence Psychol Hlth & Traumat Brain I, Deployment Hlth Clin Ctr, 1335 East West Highway,3rd Floor,Suite 3-100, Silver Spring, MD 20910 USA. EM bradley.e.belsher.civ@mail.mil FU US Department of Defense Deployment Related Medical Research Program award [DR080409]; [W81XWH-09-2-0077]; [W81XWH-09-2-0078]; [W81XWH-09-2-0079] FX Supported by a US Department of Defense Deployment Related Medical Research Program award (Grant DR080409). The award was a joint award to the Henry M. Jackson Foundation for the Advancement of Military Medicine Inc. (award W81XWH-09-2-0077), Research Triangle Institute (award W81XWH-09-2-0078), and RAND Corporation (award W81XWH-09-2-0079). The sponsor had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Defense, the US Government, or any other organization or agency, public or private. NR 37 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 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD JUL PY 2016 VL 54 IS 7 BP 706 EP 713 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DO8UW UT WOS:000378061000010 PM 27111751 ER PT J AU Demidowich, AP Davis, AI Dedhia, N Yanovski, JA AF Demidowich, Andrew P. Davis, Angela I. Dedhia, Nicket Yanovski, Jack A. TI Colchicine to decrease NLRP3-activated inflammation and improve obesity-related metabolic dysregulation SO MEDICAL HYPOTHESES LA English DT Article ID C-REACTIVE PROTEIN; FAMILIAL MEDITERRANEAN FEVER; NECROSIS-FACTOR-ALPHA; NF-KAPPA-B; ISLET AMYLOID POLYPEPTIDE; LIFE-STYLE INTERVENTION; DIET-INDUCED OBESITY; ASPIRIN-LIKE DRUGS; INSULIN-RESISTANCE; ADIPOSE-TISSUE AB Obesity is a major risk-factor for the development of insulin resistance, type 2 diabetes, and cardiovascular disease. Circulating molecules associated with obesity, such as saturated fatty acids and cholesterol crystals, stimulate the innate immune system to incite a chronic inflammatory state. Studies in mouse models suggest that suppressing the obesity-induced chronic inflammatory state may prevent or reverse obesity-associated metabolic dysregulation. Human studies, however, have been far less positive, possibly because targeted interventions were too far downstream of the inciting inflammatory events. Recently, it has been shown that, within adipose tissue macrophages, assembly of a multi-protein member of the innate immune system, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, is essential for the induction of this inflammatory state. Microtubules enable the necessary spatial arrangement of the components of the NLRP3 inflammasome in the cell, leading to its activation and propagation of the inflammatory cascade. Colchicine, a medication classically used for gout, mediates its anti-inflammatory effect by inhibiting tubulin polymerization, and has been shown to attenuate macrophage NLRP3 inflammasome arrangement and activation in vitro and in vivo. Given these findings, we hypothesize that, in at-risk individuals (those with obesity-induced inflammation and metabolic dysregulation), long-term colchicine use will lead to suppression of inflammation and thus cause improvements in insulin sensitivity and other obesity-related metabolic impairments. Published by Elsevier Ltd. C1 [Demidowich, Andrew P.; Davis, Angela I.; Dedhia, Nicket; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Div Translat Med, NIH,DHHS, Bethesda, MD 20892 USA. RP Demidowich, AP (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, NIH, Hatfield Clin Res Ctr CRC, 10 Ctr Dr,Room 1-3330,MSC 1103, Bethesda, MD 20892 USA. EM andrew.demidowich@nih.gov FU Division of Intramural Research of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH [ZIAHD00641]; NICHD Director's Investigator Award; Zafgen Inc. FX This research was supported by the Division of Intramural Research of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH ZIAHD00641 (to JAY) with supplemental funding from an NICHD Director's Investigator Award (to JAY and APD). Dr. Yanovski reports receiving grant funding from Zafgen Inc. for a clinical trial of pharmacotherapy to treat obesity and hyperphagia in patients with the Prader-Willi syndrome. No sponsors were involved in the collection, analysis, or interpretation of data; writing of the manuscript; or decision to submit the manuscript for publication. NR 100 TC 2 Z9 2 U1 1 U2 4 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0306-9877 EI 1532-2777 J9 MED HYPOTHESES JI Med. Hypotheses PD JUL PY 2016 VL 92 BP 67 EP 73 DI 10.1016/j.mehy.2016.04.039 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DP0LZ UT WOS:000378182600018 PM 27241260 ER PT J AU Fishman, EI Steeves, JA Zipunnikov, V Koster, A Berrigan, D Harris, TA Murphy, R AF Fishman, Ezra I. Steeves, Jeremy A. Zipunnikov, Vadim Koster, Annemarie Berrigan, David Harris, Tamara A. Murphy, Rachel TI Association between Objectively Measured Physical Activity and Mortality in NHANES SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE ACCELEROMETER; LIGHT ACTIVITY; MODERATETO-VIGOROUS PHYSICAL ACTIVITY; PROSPECTIVE COHORT STUDY; SEDENTARY ID ALL-CAUSE MORTALITY; SEDENTARY BEHAVIOR; US ADULTS; OLDER-ADULTS; TIME; ACCELEROMETER; INTENSITY; METAANALYSIS; HEALTH; RISK AB Purpose: We examined total activity, light activity, and moderate-to-vigorous physical activity (MVPA) as predictors of mortality in a nationally representative sample of older adults. Then we explored the theoretical consequences of replacing sedentary time with the same duration of light activity or MVPA. Methods: Using accelerometer-measured activity, the associations between total activity, light activity (100-2019 counts per minute), and MVPA (92019 counts per minute) counts and mortality were examined in adults age 50 to 79 yr in the National Health and Nutrition Examination Survey, 2003-2006 (n = 3029), with mortality follow-up through December 2011. Cox proportional hazard models were fitted to estimate mortality risks. An isotemporal substitution model was used to examine the theoretical consequences of replacing sedentary time with light activity or MVPA on mortality. Results: After adjusting for potential confounders, including age, sex, race/ethnicity, education, BMI, and the presence of comorbid conditions, those in the highest tertile of total activity counts had one fifth the risk of death of those in the lowest tertile (hazard ratio [HR] = 0.21, 95% confidence interval [CI] = 0.12-0.38), and those in the middle tertile had one third the risk of death (HR = 0.36, 95% CI = 0.30-0.44). In addition, replacing 30 min of sedentary time with light activity was associated with significant reduction in mortality risk (after 5 yr of follow-up: HR = 0.80, 95% CI = 0.75-0.85). Replacing 30 min of sedentary time with MVPA was also associated with reduction in mortality risk (HR = 0.49, 95% CI = 0.25-0.97). Conclusions: Greater total activity is associated with lower all-cause mortality risk. Replacing sedentary time with light activity or MVPA may reduce mortality risk for older adults. C1 [Fishman, Ezra I.] Univ Penn, Ctr Populat Studies, 239 McNeil Bldg,3718 Locust Walk, Philadelphia, PA 19104 USA. [Steeves, Jeremy A.] Maryville Coll, Div Educ, Maryville, TN USA. [Zipunnikov, Vadim] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Koster, Annemarie] Maastricht Univ, Dept Social Med, NL-6200 MD Maastricht, Netherlands. [Berrigan, David] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Harris, Tamara A.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Murphy, Rachel] Univ British Columbia, Fac Med, Vancouver, BC, Canada. RP Fishman, EI (reprint author), Univ Penn, Ctr Populat Studies, 239 McNeil Bldg,3718 Locust Walk, Philadelphia, PA 19104 USA. EM fishmane@sas.upenn.edu RI Koster, Annemarie/E-7438-2010 FU National Institute on Aging, National Institutes of Health; National Institute on Aging [R01AG040212] FX This work was supported by the Intramural Research Program at the National Institute on Aging, National Institutes of Health, and by the National Institute on Aging (grant no. R01AG040212). NR 40 TC 5 Z9 5 U1 1 U2 6 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 JUL PY 2016 VL 48 IS 7 BP 1303 EP 1311 DI 10.1249/MSS.0000000000000885 PG 9 WC Sport Sciences SC Sport Sciences GA DO9CQ UT WOS:000378082300011 PM 26848889 ER PT J AU Kumar, A Leinisch, F Kadiiska, MB Corbett, J Mason, RP AF Kumar, Ashutosh Leinisch, Fabian Kadiiska, Maria B. Corbett, Jean Mason, Ronald P. TI Formation and Implications of Alpha-Synuclein Radical in Maneb- and Paraquat-Induced Models of Parkinson's Disease SO MOLECULAR NEUROBIOLOGY LA English DT Article DE Protein radicals; Peroxynitrite; Parkinson's disease; Immuno-spin trapping; DMPO ID NITRIC-OXIDE; DOPAMINERGIC NEUROTOXICITY; SUPEROXIDE-DISMUTASE; PROTEIN RADICALS; NADPH OXIDASE; IN-VIVO; 2 PARTS; PEROXYNITRITE; NITRATION; INACTIVATION AB Parkinson's disease (PD) is a debilitating, progressive, neurodegenerative disorder characterized by progressive loss of dopaminergic neurons and motor deficits. Alpha-synuclein-containing aggregates represent a feature of a variety of neurodegenerative disorders, including PD; however, the mechanism that initiates and promotes intraneuronal alpha-synuclein aggregation remains unknown. We hypothesized protein radical formation as an initiating mechanism for alpha-synuclein aggregation. Therefore, we used the highly sensitive immuno-spin trapping technique to investigate protein radical formation as a possible mechanism of alpha-synuclein aggregation as well as to investigate the source of protein radical formation in the midbrains of Maneb- and paraquat-coexposed mice. Coexposure to Maneb and paraquat for 6 weeks resulted in active microgliosis, NADPH oxidase activation, and inducible nitric oxide synthase (iNOS) induction, which culminated in protein radical formation in the midbrains of mice. Results obtained with immuno-spin trapping and immunoprecipitation experiments confirmed formation of alpha-synuclein radicals in dopaminergic neurons of exposed mice. Free radical formation requires NADPH oxidase and iNOS, as indicated by decreased protein radical formation in knockout mice (P47phox(-/-) and iNOS(-/-)) and in mice treated with inhibitors such as FeTPPS (a peroxynitrite decomposition catalyst), 1400 W (an iNOS inhibitor), or apocynin (a NADPH oxidase inhibitor). Concurrence of protein radical formation with dopaminergic neuronal death indicated a link between protein radicals and disease progression. Taken together, these results show for the first time the formation and detection of the alpha-synuclein radical and suggest that NADPH oxidase and iNOS play roles in peroxynitrite-mediated protein radical formation and subsequent neuronal death in the midbrains of Maneb- and paraquat-coexposed mice. C1 [Kumar, Ashutosh; Leinisch, Fabian; Kadiiska, Maria B.; Corbett, Jean; Mason, Ronald P.] NIEHS, Free Radical Metab Grp, Immun Inflammat & Dis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Kumar, A (reprint author), NIEHS, Free Radical Metab Grp, Immun Inflammat & Dis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM kumara10@niehs.nih.gov FU National Institutes of Health; National Institute of Environmental Health Sciences FX The authors gratefully acknowledge Dr. Ann Motten and Mary Mason for their valuable help in the preparation of the manuscript. We are very thankful to Dr. Thomas van't Erve and Dr. Birandra Sinha for reviewing the manuscript. This work has been supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Environmental Health Sciences. NR 45 TC 2 Z9 2 U1 6 U2 12 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 EI 1559-1182 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD JUL PY 2016 VL 53 IS 5 BP 2983 EP 2994 DI 10.1007/s12035-015-9179-1 PG 12 WC Neurosciences SC Neurosciences & Neurology GA DO7AU UT WOS:000377935400024 PM 25952542 ER PT J AU Murase, S Lantz, CL Kim, E Gupta, N Higgins, R Stopfer, M Hoffman, DA Quinlan, EM AF Murase, Sachiko Lantz, Crystal L. Kim, Eunyoung Gupta, Nitin Higgins, Richard Stopfer, Mark Hoffman, Dax A. Quinlan, Elizabeth M. TI Matrix Metalloproteinase-9 Regulates Neuronal Circuit Development and Excitability SO MOLECULAR NEUROBIOLOGY LA English DT Article DE Extracellular matrix; Cell death; Dendritic morphology; Spontaneous activity; Kainate-induced seizure ID TEMPORAL-LOBE EPILEPSY; LONG-TERM POTENTIATION; CA1 PYRAMIDAL NEURONS; OCCURRING CELL-DEATH; FRAGILE-X-SYNDROME; MATRIX METALLOPROTEINASES; HIPPOCAMPAL-NEURONS; EXTRACELLULAR-MATRIX; NEWBORN HIPPOCAMPUS; SYNAPTIC PLASTICITY AB In early postnatal development, naturally occurring cell death, dendritic outgrowth, and synaptogenesis sculpt neuronal ensembles into functional neuronal circuits. Here, we demonstrate that deletion of the extracellular proteinase matrix metalloproteinase-9 (MMP-9) affects each of these processes, resulting in maladapted neuronal circuitry. MMP-9 deletion increases the number of CA1 pyramidal neurons but decreases dendritic length and complexity. Parallel changes in neuronal morphology are observed in primary visual cortex and persist into adulthood. Individual CA1 neurons in MMP-9(-/-) mice have enhanced input resistance and a significant increase in the frequency, but not amplitude, of miniature excitatory postsynaptic currents (mEPSCs). Additionally, deletion of MMP-9 significantly increases spontaneous neuronal activity in awake MMP-9(-/-) mice and enhances response to acute challenge by the excitotoxin kainate. Our data document a novel role for MMP-9-dependent proteolysis: the regulation of several aspects of circuit maturation to constrain excitability throughout life. C1 [Murase, Sachiko] NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Murase, Sachiko; Lantz, Crystal L.; Higgins, Richard; Quinlan, Elizabeth M.] Univ Maryland, Dept Biol, College Pk, MD 20742 USA. [Murase, Sachiko; Lantz, Crystal L.; Higgins, Richard; Quinlan, Elizabeth M.] Univ Maryland, Neurosci & Cognit Sci Program, College Pk, MD 20742 USA. [Kim, Eunyoung; Hoffman, Dax A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurophysiol & Biophys Sect, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Gupta, Nitin; Stopfer, Mark] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Murase, S (reprint author), NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA.; Murase, S (reprint author), Univ Maryland, Dept Biol, College Pk, MD 20742 USA.; Murase, S (reprint author), Univ Maryland, Neurosci & Cognit Sci Program, College Pk, MD 20742 USA. EM smurase@umd.edu OI Gupta, Nitin/0000-0002-8408-3848; Hoffman, Dax/0000-0001-6999-2157 FU NIH; NICHD; NINDS; [R01EY016431] FX This work was supported by the Intramural Research Program of the NIH, NICHD and NINDS, and R01EY016431 to EMQ. NR 75 TC 3 Z9 3 U1 2 U2 7 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 EI 1559-1182 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD JUL PY 2016 VL 53 IS 5 BP 3477 EP 3493 DI 10.1007/s12035-015-9295-y PG 17 WC Neurosciences SC Neurosciences & Neurology GA DO7AU UT WOS:000377935400065 PM 26093382 ER PT J AU Filardy, AA He, J Bennink, J Yewdell, J Kelsall, BL AF Filardy, A. A. He, J. Bennink, J. Yewdell, J. Kelsall, B. L. TI Posttranscriptional control of NLRP3 inflammasome activation in colonic macrophages SO MUCOSAL IMMUNOLOGY LA English DT Article ID CHRONIC INTESTINAL INFLAMMATION; REGULATORY T-CELLS; INTERLEUKIN-10 RECEPTOR; BOWEL-DISEASE; PROTEASOME INHIBITORS; DENDRITIC CELLS; LY6C(HI) MONOCYTES; CROHNS-DISEASE; IN-VIVO; EXPRESSION AB Colonic macrophages (cMPs) are important for intestinal homeostasis as they kill microbes and yet produce regulatory cytokines. Activity of the NLRP3 (nucleotide-binding leucine-rich repeat-containing pyrin receptor 3) inflammasome, a major sensor of stress and microorganisms that results in pro-inflammatory cytokine production and cell death, must be tightly controlled in the intestine. We demonstrate that resident cMPs are hyporesponsive to NLRP3 inflammasome activation owing to a remarkable level of posttranscriptional control of NLRP3 and pro-interleukin-1 beta (proIL-1 beta) protein expression, which was also seen for tumor necrosis factor-alpha and IL-6, but lost during experimental colitis. Resident cMPs rapidly degraded NLRP3 and proIL-1 beta proteins by the ubiquitin/proteasome system. Finally, blocking IL-10R-signaling in vivo enhanced NLRP3 and proIL-1 beta protein but not mRNA levels in resident cMPs, implicating a role for IL-10 in environmental conditioning of cMPs. These data are the first to show dramatic posttranscriptional control of inflammatory cytokine production by a relevant tissue-derived macrophage population and proteasomal degradation of proIL-1 beta and NLRP3 as a mechanism to control inflammasome activation, findings which have broad implications for our understanding of intestinal and systemic inflammatory diseases. C1 [Filardy, A. A.; He, J.; Kelsall, B. L.] NIAID, Mucosal Immunobiol Sect, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Bennink, J.; Yewdell, J.] NIAID, Cellular Biol Sect, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Bennink, J.; Yewdell, J.] NIAID, Viral Immunol Sect, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Kelsall, BL (reprint author), NIAID, Mucosal Immunobiol Sect, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bkelsall@niaid.nih.gov FU Division of Intramural Research, NIAID, NIH; Brazilian National Council for Scientific and Technological Development/Science Without Borders Program (CNPq/CsF) postdoctoral fellowship FX This work was supported by the Division of Intramural Research, NIAID, NIH. A.A.F. was a recipient of the Brazilian National Council for Scientific and Technological Development/Science Without Borders Program (CNPq/CsF) postdoctoral fellowship. We thank Alan Sher, Dan Barber, Dragana Jankovic, and Katrin Meyer-Barber for their helpful discussion, Elina Stregevsky from NIAID FACS sorting facility, and the members of the NIAID Comparative Medicine Branch animal facilities for technical assistance. NR 42 TC 4 Z9 4 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 EI 1935-3456 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD JUL PY 2016 VL 9 IS 4 BP 850 EP 858 DI 10.1038/mi.2015.109 PG 9 WC Immunology SC Immunology GA DP2TW UT WOS:000378346800002 PM 26627461 ER PT J AU Veenbergen, S van Berkel, LA du Pre, MF He, J Karrich, JJ Costes, LMM Luk, F Simons-Oosterhuis, Y Raatgeep, HC Cerovic, V Cupedo, T Mowat, AM Kelsall, BL Samsom, JN AF Veenbergen, S. van Berkel, L. A. du Pre, M. F. He, J. Karrich, J. J. Costes, L. M. M. Luk, F. Simons-Oosterhuis, Y. Raatgeep, H. C. Cerovic, V. Cupedo, T. Mowat, A. M. Kelsall, B. L. Samsom, J. N. TI Colonic tolerance develops in the iliac lymph nodes and can be established independent of CD103(+) dendritic cells SO MUCOSAL IMMUNOLOGY LA English DT Article ID REGULATORY T-CELLS; INTESTINAL IMMUNE-SYSTEM; RETINOIC-ACID; INTEGRIN ALPHA-V-BETA-8; ORAL TOLERANCE; IN-VIVO; ANTIGEN; GENERATION; DIFFERENTIATION; HOMEOSTASIS AB Tolerance to harmless exogenous antigens is the default immune response in the gastrointestinal tract. Although extensive studies have demonstrated the importance of the mesenteric lymph nodes (MLNs) and intestinal CD103(+) dendritic cells (DCs) in driving small intestinal tolerance to protein antigen, the structural and immunological basis of colonic tolerance remain poorly understood. We show here that the caudal and iliac lymph nodes (ILNs) are inductive sites for distal colonic immune responses and that colonic T cell-mediated tolerance induction to protein antigen is initiated in these draining lymph nodes and not in MLNs. In agreement, colonic tolerance induction was not altered by mesenteric lymphadenectomy. Despite tolerance development, CD103(-)CD11b(+) DCs, which are the major migratory DC population in the MLNs, and the tolerance-related retinoic acid-generating enzyme RALDH2 were virtually absent from the ILNs. Administration of ovalbumin (OVA) to the distal colon did increase the number of CD11c(+)MHCII(hi) migratory CD103(-)CD11b(+) DCs and CD103(-)CD11b(+) DCs in the ILNs. Strikingly, colonic tolerance was intact in Batf3-deficient mice specifically lacking CD103(-)CD11b(+) DCs, suggesting that CD103(-) DCs in the ILNs are sufficient to drive tolerance induction after protein antigen encounter in the distal colon. Altogether, we identify different inductive sites for small intestinal and colonic T-cell responses and reveal that distinct cellular mechanisms are operative to maintain tolerance at these sites. C1 [Veenbergen, S.; van Berkel, L. A.; du Pre, M. F.; Costes, L. M. M.; Luk, F.; Simons-Oosterhuis, Y.; Raatgeep, H. C.; Samsom, J. N.] Erasmus Univ, Med Ctr, Div Gastroenterol & Nutr, Pediat Lab, Rotterdam, Netherlands. [He, J.; Kelsall, B. L.] NIAID, Mucosal Immunobiol Sect, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Karrich, J. J.; Cupedo, T.] Erasmus Univ, Med Ctr, Dept Hematol, Rotterdam, Netherlands. [Cerovic, V.] Rhein Westfal TH Aachen, Inst Mol Med, D-52062 Aachen, Germany. [Mowat, A. M.] Univ Glasgow, Inst Infect Immun & Inflammat, Ctr Immunobiol, Glasgow, Lanark, Scotland. RP Samsom, JN (reprint author), Erasmus Univ, Med Ctr, Div Gastroenterol & Nutr, Pediat Lab, Rotterdam, Netherlands. EM j.samsom@erasmusmc.nl FU Dutch Digestive Foundation [WO 10-37]; Sophia Foundation [470] FX We gratefully acknowledge E. Stregevsky from the National Institute of Allergy and Infectious Diseases (NIAID) sorting facility, I. Hekking, M. Muijtjens, E. Fijneman from the ErasmusMC SkillsLab, and the animal caretakers at the Erasmus University Medical Center Rotterdam. This work was supported by the Dutch Digestive Foundation grant (WO 10-37) and Sophia Foundation grant 470. NR 46 TC 0 Z9 0 U1 3 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 EI 1935-3456 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD JUL PY 2016 VL 9 IS 4 BP 894 EP 906 DI 10.1038/mi.2015.118 PG 13 WC Immunology SC Immunology GA DP2TW UT WOS:000378346800006 PM 26577569 ER PT J AU Jung, Y Hsieh, LS Lee, AM Zhou, ZF Coman, D Heath, CJ Hyder, F Mineur, YS Yuan, QP Goldman, D Bordey, A Picciotto, MR AF Jung, Yonwoo Hsieh, Lawrence S. Lee, Angela M. Zhou, Zhifeng Coman, Daniel Heath, Christopher J. Hyder, Fahmeed Mineur, Yann S. Yuan, Qiaoping Goldman, David Bordey, Angelique Picciotto, Marina R. TI An epigenetic mechanism mediates developmental nicotine effects on neuronal structure and behavior SO NATURE NEUROSCIENCE LA English DT Article ID TRITHORAX GROUP PROTEIN; FETAL AUDITORY-CORTEX; ACETYLCHOLINE-RECEPTORS; TRANSCRIPTION FACTOR; PRENATAL NICOTINE; EXPOSURE; MEF2; DROSOPHILA; GENES; DIFFERENTIATION AB Developmental nicotine exposure causes persistent changes in cortical neuron morphology and in behavior. We used microarray screening to identify master transcriptional or epigenetic regulators mediating these effects of nicotine and discovered increases in Ash2I mRNA, encoding a component of a histone methyltransferase complex. We therefore examined genome-wide changes in trimethylation of histone H3 on Lys4 (H3K4me3), a mark induced by the Ash2I complex associated with increased gene transcription. A large proportion of regulated promoter sites were involved in synapse maintenance. We found that Mef2c interacts with Ash2I and mediates changes in H3K4me3. Knockdown of Ash2I or Mef2c abolished nicotine-mediated alterations of dendritic complexity in vitro and in vivo, and attenuated nicotine-dependent changes in passive avoidance behavior. In contrast, overexpression mimicked nicotine-mediated alterations of neuronal structure and passive avoidance behavior. These studies identify Ash2I as a target induced by nicotinic stimulation that couples developmental nicotine exposure to changes in brain epigenetic marks, neuronal structure and behavior. C1 [Jung, Yonwoo; Lee, Angela M.; Heath, Christopher J.; Mineur, Yann S.; Picciotto, Marina R.] Yale Univ, Sch Med, Div Mol Psychiat, New Haven, CT USA. [Jung, Yonwoo; Lee, Angela M.; Heath, Christopher J.; Picciotto, Marina R.] Yale Univ, Sch Med, Interdept Neurosci Program, New Haven, CT USA. [Hsieh, Lawrence S.; Bordey, Angelique] Yale Univ, Sch Med, Dept Neurosurg, New Haven, CT USA. [Hsieh, Lawrence S.; Bordey, Angelique] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA. [Zhou, Zhifeng; Yuan, Qiaoping; Goldman, David] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. [Coman, Daniel; Hyder, Fahmeed] Yale Univ, Sch Med, Dept Radiol, New Haven, CT 06510 USA. [Coman, Daniel; Hyder, Fahmeed] Yale Univ, Sch Med, Biomed Imaging Magnet Resonance Res Ctr, New Haven, CT USA. [Coman, Daniel; Hyder, Fahmeed] Yale Univ, Sch Med, Magnet Resonance Res Ctr, New Haven, CT USA. [Heath, Christopher J.] Open Univ, Dept Life Hlth & Chem Sci, Milton Keynes MK7 6AA, Bucks, England. [Hyder, Fahmeed] Yale Univ, Sch Appl Sci & Engn, Dept Biomed Engn, New Haven, CT USA. RP Picciotto, MR (reprint author), Yale Univ, Sch Med, Div Mol Psychiat, New Haven, CT USA.; Picciotto, MR (reprint author), Yale Univ, Sch Med, Interdept Neurosci Program, New Haven, CT USA. EM marina.picciotto@yale.edu RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU National Institutes of Health [DA14241, DA10455, NS052519, NS086329]; State of Connecticut; Department of Mental Health and Addiction Services; Kavli Institute for Neuroscience at Yale FX This work was supported by grants DA14241 (M.R.P.), DA10455 (M.R.P.), NS052519 (RH.) and NS086329 (EH.) from the National Institutes of Health, the State of Connecticut, Department of Mental Health and Addiction Services and the Kavli Institute for Neuroscience at Yale. NR 43 TC 4 Z9 4 U1 5 U2 6 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 JUL PY 2016 VL 19 IS 7 BP 905 EP 914 DI 10.1038/nn.4315 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DP8PH UT WOS:000378759600009 PM 27239938 ER PT J AU Gupta, S Kaplan, MJ AF Gupta, Sarthak Kaplan, Mariana J. TI The role of neutrophils and NETosis in autoimmune and renal diseases SO NATURE REVIEWS NEPHROLOGY LA English DT Review ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; PEPTIDYLARGININE DEIMINASE INHIBITION; ANCA-ASSOCIATED VASCULITIS; CYTOPLASMIC ANTIBODY VASCULITIS; EXTRACELLULAR TRAP FORMATION; ARTHRITIS SYNOVIAL-FLUID; SMALL-VESSEL VASCULITIS; T-CELL RESPONSES; RHEUMATOID-ARTHRITIS; ANTIPHOSPHOLIPID SYNDROME AB Systemic autoimmune diseases are a group of disorders characterized by a failure in self-tolerance to a wide variety of autoantigens. In genetically predisposed individuals, these diseases occur as a multistep process in which environmental factors have key roles in the development of abnormal innate and adaptive immune responses. Experimental evidence collected in the past decade suggests that neutrophils-the most abundant type of white blood cell-might have an important role in the pathogenesis of these diseases by contributing to the initiation and perpetuation of immune dysregulation through the formation of neutrophil extracellular traps (NETs), synthesis of proinflammatory cytokines and direct tissue damage. Many of the molecules externalized through NET formation are considered to be key autoantigens and might be involved in the generation of autoimmune responses in predisposed individuals. In several systemic autoimmune diseases, the imbalance between NET formation and degradation might increase the half-life of these lattices, which could enhance the exposure of the immune system to modified autoantigens and increase the capacity for NET-induced organ damage. This Review details the role of neutrophils and NETs in the pathophysiology of systemic autoimmune diseases, including their effect on renal damage, and discusses neutrophil targets as potential novel therapies for these diseases. C1 [Gupta, Sarthak; Kaplan, Mariana J.] NIAMSD, System Autoimmun Branch, Intramural Res Program, NIH, Room 6D 47C,10 Ctr Dr, Bethesda, MD 20892 USA. RP Kaplan, MJ (reprint author), NIAMSD, System Autoimmun Branch, Intramural Res Program, NIH, Room 6D 47C,10 Ctr Dr, Bethesda, MD 20892 USA. EM mariana.kaplan@nih.gov NR 163 TC 3 Z9 3 U1 3 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5061 EI 1759-507X J9 NAT REV NEPHROL JI Nat. Rev. Nephrol. PD JUL PY 2016 VL 12 IS 7 BP 402 EP 413 DI 10.1038/nrneph.2016.71 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA DO9EU UT WOS:000378088100004 PM 27241241 ER PT J AU Bilgel, M Prince, JL Wong, DF Resnick, SM Jedynak, BM AF Bilgel, Murat Prince, Jerry L. Wong, Dean F. Resnick, Susan M. Jedynak, Bruno M. TI A multivariate nonlinear mixed effects model for longitudinal image analysis: Application to amyloid imaging SO NEUROIMAGE LA English DT Article DE Longitudinal image analysis; Progression score; Amyloid imaging ID PRECLINICAL ALZHEIMERS-DISEASE; MILD COGNITIVE IMPAIRMENT; BIOMARKER CHANGES; BETA DEPOSITION; PROGRESSION; BRAIN; REGISTRATION; TRAJECTORIES; ROBUST; COHORT AB It is important to characterize the temporal trajectories of disease-related biomarkers in order to monitor progression and identify potential points of intervention. These are especially important for neurodegenerative diseases, as therapeutic intervention is most likely to be effective in the preclinical disease stages prior to significant neuronal damage. Neuroimaging allows for the measurement of structural, functional, and metabolic integrity of the brain at the level of voxels, whose volumes are on the order of mm(3). These voxelwise measurements provide a rich collection of disease indicators. Longitudinal neuroimaging studies enable the analysis of changes in these voxelwise measures. However, commonly used longitudinal analysis approaches, such as linear mixed effects models, do not account for the fact that individuals enter a study at various disease stages and progress at different rates, and generally consider each voxelwise measure independently. We propose a multivariate nonlinear mixed effects model for estimating the trajectories of voxelwise neuroimaging biomarkers from longitudinal data that accounts for such differences across individuals. The method involves the prediction of a progression score for each visit based on a collective analysis of voxelwise biomarker data within an expectation-maximization framework that efficiently handles large amounts of measurements and variable number of visits per individual, and accounts for spatial correlations among voxels. This score allows individuals with similar progressions to be aligned and analyzed together, which enables the construction of a trajectory of brain changes as a function of an underlying progression or disease stage. We apply our method to studying cortical beta-amyloid deposition, a hallmark of preclinical Alzheimer's disease, as measured using positron emission tomography. Results on 104 individuals with a total of 300 visits suggest that precuneus is the earliest cortical region to accumulate amyloid, closely followed by the cingulate and frontal cortices, then by the lateral parietal cortex. The extracted progression scores reveal a pattern similar to mean cortical distribution volume ratio (DVR), an index of global brain amyloid levels. The proposed method can be applied to other types of longitudinal imaging data, including metabolism, blood flow, tau, and structural imaging-derived measures, to extract individualized summary scores indicating disease progression and to provide voxelwise trajectories that can be compared between brain regions. Published by Elsevier Inc. C1 [Bilgel, Murat; Prince, Jerry L.] Johns Hopkins Univ, Sch Engn, Image Anal & Commun Lab, Baltimore, MD USA. [Bilgel, Murat; Prince, Jerry L.] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA. [Bilgel, Murat; Resnick, Susan M.] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Prince, Jerry L.] Johns Hopkins Univ, Dept Elect & Comp Engn, Sch Engn, Baltimore, MD 21218 USA. [Prince, Jerry L.; Wong, Dean F.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Jedynak, Bruno M.] Portland State Univ, Dept Math & Stat, Portland, OR 97207 USA. RP Bilgel, M (reprint author), NIA, Lab Behav Neurosci, 251 Bayview Blvd,Suite 100,Rm 04B316, Baltimore, MD 21224 USA. EM murat.bilgel@nih.gov OI Bilgel, Murat/0000-0001-5042-7422 FU Intramural Research Program of National Institutes of Health; Michael J. Fox Foundation for Parkinson's Research [9310] FX We thank Kalyani Kansal for her thorough review of the mathematical derivations and assistance with code testing. This research was supported in part by the Intramural Research Program of the National Institutes of Health and by the Michael J. Fox Foundation for Parkinson's Research, MJFF Research Grant ID: 9310. NR 45 TC 0 Z9 0 U1 2 U2 6 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 JUL 1 PY 2016 VL 134 BP 658 EP 670 DI 10.1016/j.neuroimage.2016.04.001 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DO8PP UT WOS:000378045900061 PM 27095307 ER PT J AU Fisher, DE Jonasson, F Klein, R Jonsson, PV Eiriksdottir, G Launer, LJ Gudnason, V Cotch, MF AF Fisher, Diana E. Jonasson, Fridbert Klein, Ronald Jonsson, Palmi V. Eiriksdottir, Gudny Launer, Lenore J. Gudnason, Vilmundur Cotch, Mary Frances TI Mortality in Older Persons with Retinopathy and Concomitant Health Conditions The Age, Gene/Environment Susceptibility-Reykjavik Study SO OPHTHALMOLOGY LA English DT Article ID CORONARY-HEART-DISEASE; CHRONIC KIDNEY-DISEASE; ALL-CAUSE MORTALITY; RETINAL MICROVASCULAR ABNORMALITIES; CARDIOVASCULAR-DISEASE; DIABETIC-RETINOPATHY; HYPERTENSIVE RETINOPATHY; RISK-FACTORS; POPULATION; COHORT AB Purpose: To assess the impact of retinopathy on mortality in older persons with concomitant health conditions. Design: Population-based prospective cohort study. Participants: A total of 4966 individuals aged 67 to 96 years (43.2% were male) from the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-RS). Methods: Retinopathy was evaluated from digital fundus images (2002-2006) using the modified Airlie House adaptation of the Early Treatment Diabetic Retinopathy Study protocol. Mortality was assessed through September 2013 (cause of death assigned through 2009). Cox proportional hazards regression models, with age as the time scale, estimated the association between retinopathy and death while controlling for risk factors and the presence of concomitant health conditions. Main Outcome Measures: Mortality from all causes and cardiovascular disease (CVD). Results: Among the 4966 participants, 503 (10.1%) had diabetes and 614 (12.4%) had retinopathy at baseline. A subset of these (136 [2.7%]) had both diabetes and retinopathy. After a median follow-up of 8.6 years, 1763 persons died, 276 (45.0%) with retinopathy and 1487 (34.2%) without retinopathy, of whom 76 and 162 persons, respectively, also had diabetes. There were 366 deaths from CVD through 2009, 72 (11.7%) in persons with retinopathy and 294 (6.8%) in those without retinopathy. In multivariable analyses, retinopathy was significantly associated with all-cause mortality (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.10-1.43; P < 0.01) and CVD-related mortality (HR, 1.57; 95% CI, 1.20-2.06; P < 0.01). Findings were more striking in men: all-cause HR, 1.33 (95% CI, 1.11-1.60) and CVD HR, 1.81 (95% CI, 1.25-2.63). Risk of mortality was further increased among those with retinopathy concomitant with microalbuminuria (all-cause HR, 1.70; 95% CI, 1.03-2.23, and CVD HR, 2.04; 95% CI, 1.27-3.28) and those with retinopathy, microalbuminuria, and diabetes (all-cause HR, 2.01; 95% CI, 1.22-3.31, and CVD HR, 5.24; 95% CI, 1.91-14.42). History of clinical stroke increased the risk of CVD-related mortality among persons with retinopathy (HR, 3.30; 95% CI, 2.05-5.32), particularly those with retinopathy and diabetes (HR, 5.38; 95% CI, 1.80-16.06). Conclusions: Even minimal retinopathy was a significant predictor of increased mortality in older persons, particularly men, irrespective of diabetes status. Persons with retinopathy may warrant closer clinical management of general health. (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. [Jonasson, Fridbert; Jonsson, Palmi V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Jonasson, Fridbert] Landspitali Univ Hosp, Dept Ophthalmol, Reykjavik, Iceland. [Klein, Ronald] Univ Wisconsin, Ophthalmol & Visual Sci, Madison, WI USA. [Jonsson, Palmi V.] Landspitali Univ Hosp, Dept Geriatr, Reykjavik, Iceland. [Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, NIH, Bethesda, MD 20892 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 Institutes of Health (Intramural Research Programs of the National Institute of Aging and the National Eye Institute) [ZIAEY00401]; National Institutes of Health [N01-AG-1-2100]; IHA; Icelandic Parliament; Helga Jonsdottir and Sigurlidi Kristjansson Research Fund; University of Iceland Research Fund FX Supported by the National Institutes of Health (Intramural Research Programs of the National Institute of Aging and the National Eye Institute, ZIAEY00401), National Institutes of Health Contract Number N01-AG-1-2100, the IHA, the Icelandic Parliament, the University of Iceland Research Fund, and the Helga Jonsdottir and Sigurlidi Kristjansson Research Fund. The funders had no role in data collection, management, analysis, and interpretation of the data, preparation, writing, and approval of the manuscript, and decision to submit the manuscript for publication. NR 38 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD JUL PY 2016 VL 123 IS 7 BP 1570 EP 1580 DI 10.1016/j.ophtha.2016.02.045 PG 11 WC Ophthalmology SC Ophthalmology GA DP3KC UT WOS:000378391100029 PM 27067925 ER PT J AU Gibbins, KJ Silver, RM Pinar, H Reddy, UM Parker, CB Thorsten, V Willinger, M Dudley, DJ Bukowski, R Saade, GR Koch, MA Conway, D Hogue, CJ Stoll, BJ Goldenberg, RL AF Gibbins, Karen J. Silver, Robert M. Pinar, Halit Reddy, Uma M. Parker, Corette B. Thorsten, Vanessa Willinger, Marian Dudley, Donald J. Bukowski, Radek Saade, George R. Koch, Matthew A. Conway, Deborah Hogue, Carol J. Stoll, Barbara J. Goldenberg, Robert L. TI Stillbirth, hypertensive disorders of pregnancy, and placental pathology SO PLACENTA LA English DT Article DE Placental pathology; Preeclampsia; Stillbirth ID LATE-ONSET PREECLAMPSIA; FETAL-GROWTH RESTRICTION; RISK-FACTORS; MATERNAL UNDERPERFUSION; GESTATIONAL-AGE; UNITED-STATES; LESIONS; DEATH; SEVERITY; TRENDS AB Introduction: Stillbirth, preeclampsia, and gestational hypertension (PE/GH) have similar clinical risk factors and redundant placental pathology. We aim to discern if stillbirth with PE/GH has a particular phenotype by comparing stillbirths with and without PE/GH. Methods: Secondary analysis of the Stillbirth Collaborative Research Network, a population-based cohort study of all stillbirths and a sample of live births from 2006 to 2008 in five catchment areas. We compared placental pathology between stillbirths and with and without PE/GH, stratified by term or preterm. We also compared placental pathology between stillbirths and live births with PE/GH. Results: 79/518 stillbirths and 140/1200 live births had PE/GH. Amongst preterm stillbirths, there was higher feto-placental ratio in PE/GH pregnancies (OR 1.24 [1.11, 1.37] per unit increase), and there were more parenchymal infarctions (OR 5.77 [3.18, 10.47]). Among PE/GH pregnancies, stillbirths had increased maternal and fetal vascular lesions, including retroplacental hematoma, parenchymal infarction, fibrin deposition, fetal vascular thrombi, and avascular villi. Discussion: Stillbirth pregnancies are overwhelmingly associated with placental lesions. Parenchymal infarctions are more common in PE/GH preterm stillbirths, but there is significant overlap in lesions found in stillbirths and PE/GH. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Gibbins, Karen J.; Silver, Robert M.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Pinar, Halit] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Reddy, Uma M.; Willinger, Marian; Koch, Matthew A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Parker, Corette B.; Thorsten, Vanessa] RTI Int, Durham, NC USA. [Dudley, Donald J.] Univ Virginia, Charlottesville, VA 22903 USA. [Bukowski, Radek] Yale New Haven Med Ctr, 20 York St, New Haven, CT 06504 USA. [Saade, George R.] Univ Texas Med Branch, Galveston, TX 77555 USA. [Conway, Deborah] Univ Texas San Antonio, San Antonio, TX USA. [Hogue, Carol J.; Stoll, Barbara J.] Emory Univ, Atlanta, GA 30322 USA. [Goldenberg, Robert L.] Columbia Univ, Sch Med, New York, NY USA. RP Gibbins, KJ (reprint author), Univ Utah, Hlth Sci Ctr, Dept OB GYN, Div Maternal Fetal Med, Suite 2B200,30 North Med Dr, Salt Lake City, UT 84132 USA. EM Karen.gibbins@hsc.utah.edu OI Gibbins, Karen/0000-0002-7431-3451 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD45925, HD45944, HD45952, HD45953, HD45954] FX Supported by grants (HD45925, HD45944, HD45952, HD45953, HD45954, and HD45925) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 34 TC 0 Z9 0 U1 2 U2 9 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 EI 1532-3102 J9 PLACENTA JI Placenta PD JUL PY 2016 VL 43 BP 61 EP 68 DI 10.1016/j.placenta.2016.04.020 PG 8 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA DP1VY UT WOS:000378278700010 PM 27324101 ER PT J AU Yadav, BK Neelavalli, J Krishnamurthy, U Szalai, G Shen, YM Nayak, NR Chaiworapongsa, T Hernandez-Andrade, E Than, NG Haacke, EM Romero, R AF Yadav, Brijesh Kumar Neelavalli, Jaladhar Krishnamurthy, Uday Szalai, Gabor Shen, Yimin Nayak, Nihar R. Chaiworapongsa, Tinnakorn Hernandez-Andrade, Edgar Than, Nandor Gabor Haacke, E. Mark Romero, Roberto TI A longitudinal study of placental perfusion using dynamic contrast enhanced magnetic resonance imaging in murine pregnancy SO PLACENTA LA English DT Article DE Labyrinth zone; Junctional zone; Contrast enhanced; Central canal; Mice ID DCE-MRI DATA; ARTERIAL INPUT FUNCTION; REFERENCE REGION MODEL; MOUSE PLACENTA; BLOOD-FLOW; FETOPLACENTAL VASCULATURE; JUNCTIONAL ZONE; MICE; GESTATION; QUANTIFICATION AB Introduction: To evaluate changes in placental perfusion with advancing gestation in normal murine pregnancy using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). Methods: Seven timed-pregnant CD-1 mice underwent DCE-MRI scanning longitudinally on gestational days (GD) 13, 15 and 17. Placentas were segmented into high (HPZ) and low perfusion zones (LPZ) using tissue similarity mapping. Blood perfusion of the respective regions and the whole placenta was quantified using the steepest slope method. The diameter of the maternal central canal (CC) was also measured. Results: An increase in perfusion was observed between GD13 and GD17 in the overall placenta (p = 0.04) and in the HPZ (p = 0.02). Although perfusion in the LPZ showed a slight increasing trend, it was not significant (p = 0.07). Perfusion, in units of ml/min/100 ml, in the overall placenta and the HPZ was respectively 61.2 +/- 31.2 and 106.2 +/- 56.3 at GD13 (n = 19 placentas); 90.3 +/- 43.7 and 139 +/- 55.4 at GD15 (n = 20); and 104.9 +/- 76.1 and 172.2 +/- 85.6 at GD17 (n = 14). The size of the CC increased with advancing gestation (p < 0.05). Discussion: Using longitudinal DCE-MRI, the gestational age-dependent perfusion change in the normal murine placenta and in its regional compartments was quantified. In mid and late gestations, placental constituent regions differ significantly in their perfusion rates. The CC diameter also showed increase with advancing gestation, which may be playing an important role toward the gestational age-dependent increase in placental perfusion. (C) 2016 Published by Elsevier Ltd. C1 [Yadav, Brijesh Kumar; Neelavalli, Jaladhar; Krishnamurthy, Uday; Shen, Yimin; Haacke, E. Mark] Wayne State Univ, Sch Med, Dept Radiol, 4201 St Antoine, Detroit, MI 48201 USA. [Yadav, Brijesh Kumar; Neelavalli, Jaladhar; Krishnamurthy, Uday; Haacke, E. Mark] Wayne State Univ, Coll Engn, Dept Biomed Engn, Detroit, MI USA. [Szalai, Gabor; Chaiworapongsa, Tinnakorn; Hernandez-Andrade, Edgar; Than, Nandor Gabor; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Szalai, Gabor; Chaiworapongsa, Tinnakorn; Hernandez-Andrade, Edgar; Than, Nandor Gabor; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Nayak, Nihar R.; Chaiworapongsa, Tinnakorn; Hernandez-Andrade, Edgar; Than, Nandor Gabor] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Than, Nandor Gabor] Hungarian Acad Sci, Res Ctr Nat Sci, Inst Enzymol, Lendulet Reprod Res Grp, Budapest, Hungary. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. RP Neelavalli, J (reprint author), Wayne State Univ, Sch Med, Dept Radiol, 4201 St Antoine, Detroit, MI 48201 USA. EM jneelava@med.wayne.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Health and Human Services (DHHS); NICHD (NIH, DHHS) [HHSN275201300006C]; Small Business Technology Transfer (STTR) grant from the National Heart, Lung, and Blood Institute (NHLBI, NIH, DHHS) [1R42HL112580-01A1]; Wayne State University's Perinatal Research Initiative; Perinatology Virtual Discovery Grant (by the W.K. Kellogg Foundation award) [P3018205] FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Health and Human Services (DHHS); and, in part, with Federal funds from NICHD (NIH, DHHS) under Contract No. HHSN275201300006C. The authors are grateful to Dr. Theodore Price (Perinatology Research Branch), Dr. Lisa J. Brossia-Root, Laura Lee McIntyre, and all personnel involved in the Division of Laboratory Animal Resources (Wayne State University). This work was also supported, in part, by a Small Business Technology Transfer (STTR) grant from the National Heart, Lung, and Blood Institute (NHLBI, NIH, DHHS; 1R42HL112580-01A1), by Wayne State University's Perinatal Research Initiative and by the Perinatology Virtual Discovery Grant to J.N. (made possible by the W.K. Kellogg Foundation award P3018205). NR 58 TC 0 Z9 0 U1 3 U2 3 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 EI 1532-3102 J9 PLACENTA JI Placenta PD JUL PY 2016 VL 43 BP 90 EP 97 DI 10.1016/j.placenta.2015.12.019 PG 8 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA DP1VY UT WOS:000378278700015 PM 26947613 ER PT J AU Marceau, LD Welch, LC Pemberton, VL Pearson, GD AF Marceau, Lisa D. Welch, Lisa C. Pemberton, Victoria L. Pearson, Gail D. TI Educating Parents About Pediatric Research: Children and Clinical Studies Website Qualitative Evaluation SO QUALITATIVE HEALTH RESEARCH LA English DT Article DE children; education, patient; health information seeking; qualitative analysis; research, qualitative methods; technology, use in research; New England region ID RANDOMIZED CONTROLLED-TRIALS; INFORMED-CONSENT; ATTITUDES; DECISIONS; LEUKEMIA; PARTICIPATE; DISTRUST; MEDICINE; MOTHERS; ENROLL AB A gap in information about pediatric clinical trials exists, and parents remain uncertain about what is involved in research studies involving children. We aimed to understand parent perspectives about pediatric clinical research after viewing the online Children and Clinical Studies (CaCS) program. Using a qualitative descriptive study design, we conducted focus groups with parents and phone interviews with physicians. Three themes emerged providing approaches to improve parent's understanding of clinical research by including strategies where parents (a) hear from parents like themselves to learn about pediatric research, (b) receive general clinical research information to complement study-specific details, and (c) are provided more information about the role of healthy child volunteers. Parents found the website a valuable tool that would help them make a decision about what it means to participate in research. This tool can assist parents, providers, and researchers by connecting general information with study-specific information. C1 [Marceau, Lisa D.] New England Res Inst, 480 Pleasant St,Suite A100, Watertown, MA 02472 USA. [Welch, Lisa C.] Tufts Univ, Boston, MA 02111 USA. [Pemberton, Victoria L.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Pearson, Gail D.] NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Pearson, Gail D.] NHLBI, Adult & Pediat Cardiac Res Program, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Marceau, LD (reprint author), New England Res Inst, 480 Pleasant St,Suite A100, Watertown, MA 02472 USA. EM LMarceau@neriscience.com FU National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) [U01 HL68270]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Best Pharmaceuticals for Children Act (BPCA); National Marfan Foundation (NMF); National Center for Research Resources (NCRR); Gerber Foundation; Booz Allen Hamilton; Foundation for the National Institutes of Health; NIH FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This article was primarily supported by Award Number U01 HL68270 from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH). Other support for the Children and Clinical Studies Web program was provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the Best Pharmaceuticals for Children Act (BPCA), the National Marfan Foundation (NMF), the National Center for Research Resources (NCRR), the Gerber Foundation, Booz Allen Hamilton, and the Foundation for the National Institutes of Health. The role of the funding sources was financial support for the project and ensuring study compliance with NIH regulations. NR 33 TC 0 Z9 0 U1 5 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-7323 EI 1552-7557 J9 QUAL HEALTH RES JI Qual. Health Res. PD JUL PY 2016 VL 26 IS 8 SI SI BP 1114 EP 1122 DI 10.1177/1049732315616620 PG 9 WC Information Science & Library Science; Social Sciences, Interdisciplinary; Social Sciences, Biomedical SC Information Science & Library Science; Social Sciences - Other Topics; Biomedical Social Sciences GA DP3WU UT WOS:000378427400009 PM 26711142 ER PT J AU Markmann, JF Bartlett, ST Johnson, P Korsgren, O Hering, BJ Scharp, D Kay, TWH Bromberg, J Odorico, JS Weir, GC Bridges, N Kandaswamy, R Stock, P Friend, P Gotoh, M Cooper, DKC Park, CG O'Connell, PJ Stabler, C Matsumoto, S Ludwig, B Choudhary, P Khovatchev, B Rickels, MR Sykes, M Wood, K Kraemer, K Hwa, A Stanley, E Ricordi, C Zimmerman, M Greenstein, J Montanya, E Otonkoski, T AF Markmann, James F. Bartlett, Stephen T. Johnson, Paul Korsgren, Olle Hering, Bernhard J. Scharp, David Kay, Thomas W. H. Bromberg, Jonathan Odorico, Jon S. Weir, Gordon C. Bridges, Nancy Kandaswamy, Raja Stock, Peter Friend, Peter Gotoh, Mitsukazu Cooper, David K. C. Park, Chung-Gyu O'Connell, Philip J. Stabler, Cherie Matsumoto, Shinichi Ludwig, Barbara Choudhary, Pratik Khovatchev, Boris Rickels, Michael R. Sykes, Megan Wood, Kathryn Kraemer, Kristy Hwa, Albert Stanley, Edward Ricordi, Camillo Zimmerman, Mark Greenstein, Julia Montanya, Eduard Otonkoski, Timo TI Executive Summary of IPITA-TTS Opinion Leaders Report on the Future of beta-Cell Replacement SO TRANSPLANTATION LA English DT Review ID PORCINE ISLET XENOTRANSPLANTATION; MEDIATED INFLAMMATORY REACTION; NONHUMAN-PRIMATES; CYNOMOLOGUS MONKEYS; PIG ISLETS; REVERSAL; TRANSPLANTATION; SURVIVAL; IMMUNOSUPPRESSION; AUTOIMMUNITY AB The International Pancreas and Islet Transplant Association (IPITA), in conjunction with the Transplantation Society (TTS), convened a workshop to consider the future of pancreas and islet transplantation in the context of potential competing technologies that are under development, including the artificial pancreas, transplantation tolerance, xenotransplantation, encapsulation, stem cell derived beta cells, beta cell proliferation, and endogenous regeneration. Separate workgroups for each topic and then the collective group reviewed the state of the art, hurdles to application, and proposed research agenda for each therapy that would allow widespread application. Herein we present the executive summary of this workshop that focuses on obstacles to application and the research agenda to overcome them; the full length article with detailed background for each topic is published as an online supplement to Transplantation. C1 [Markmann, James F.] Massachusetts Gen Hosp, Div Transplantat, Boston, MA 02114 USA. [Bartlett, Stephen T.; Bromberg, Jonathan] Univ Maryland, Sch Med, Dept Surg, Baltimore, MD 21201 USA. [Johnson, Paul; Friend, Peter; Wood, Kathryn] Univ Oxford, Nuffield Dept Surg Sci, Oxford, England. [Johnson, Paul; Friend, Peter; Wood, Kathryn] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Korsgren, Olle] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Hering, Bernhard J.; Kandaswamy, Raja] Univ Minnesota, Dept Surg, Schulze Diabet Inst, Box 242 UMHC, Minneapolis, MN 55455 USA. [Scharp, David] Prodo Labs LLC, Irvine, CA USA. [Scharp, David] Scharp Lacy Res Inst, Irvine, CA USA. [Kay, Thomas W. H.] St Vincents Inst Med Res, 41 Victoria Parade, Fitzroy, Vic 3065, Australia. [Kay, Thomas W. H.] Univ Melbourne, St Vincents Hosp, Dept Med, Melbourne, Vic 3010, Australia. [Odorico, Jon S.] Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, Div Transplantat, Madison, WI USA. [Weir, Gordon C.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Weir, Gordon C.] Harvard Univ, Sch Med, Boston, MA USA. [Bridges, Nancy; Kraemer, Kristy] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Stock, Peter] Univ San Francisco, Med Ctr, Div Transplantat, San Francisco, CA 94117 USA. [Gotoh, Mitsukazu] Fukushima Med Univ, Dept Surg, Fukushima, Japan. [Cooper, David K. C.] Univ Pittsburgh, Thomas E Starzl Transplantat Inst, Pittsburgh, PA USA. [Park, Chung-Gyu] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Xenotransplantat Res Ctr,Dept Microbiol & Immunol, Seoul, South Korea. [O'Connell, Philip J.] Univ Sydney, Westmead Hosp, Ctr Transplant & Renal Res, Westmead Millennium Inst, Westmead, NSW 2145, Australia. [Stabler, Cherie] Univ Florida, Dept Biomed Engn, Gainesville, FL USA. [Matsumoto, Shinichi] Otsuka Pharmaceut Factory Inc, Naruto, Japan. [Matsumoto, Shinichi] Natl Ctr Global Hlth & Med, Tokyo, Japan. [Ludwig, Barbara] Tech Univ Dresden, Dept Med 3, D-01062 Dresden, Germany. [Ludwig, Barbara] Tech Univ Dresden, Univ Clin Carl Gustav Carus, Helmholtz Ctr Munich, Paul Langerhans Inst Dresden, Dresden, Germany. [Ludwig, Barbara] DZD German Ctr Diabet Res, Dresden, Germany. [Choudhary, Pratik] Kings Coll London, Weston Educ Ctr, Diabet Res Grp, London WC2R 2LS, England. [Khovatchev, Boris] Univ Virginia, Ctr Diabet Technol, Charlottesville, VA USA. [Rickels, Michael R.] Univ Penn, Dept Med, Perelman Sch Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Sykes, Megan] Columbia Univ, Med Ctr, Columbia Ctr Translat Immunol, New York, NY USA. [Hwa, Albert] Juvenile Diabet Res Fdn, New York, NY USA. [Stanley, Edward] Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Stanley, Edward] Monash Univ, Melbourne, Vic 3004, Australia. [Ricordi, Camillo] Univ Miami, Diabet Res Inst, Coral Gables, FL 33124 USA. [Zimmerman, Mark] BetaLogics, Raritan, NJ USA. [Greenstein, Julia] Juvenile Diabet Res Fdn, Discovery Res, New York, NY USA. [Montanya, Eduard] Univ Barcelona, Hosp Univ Bellvitge, CIBERDEM, Bellvitge Biomed Res Inst IDIBELL, Barcelona, Spain. [Otonkoski, Timo] Univ Helsinki, Childrens Hosp, Helsinki, Finland. [Otonkoski, Timo] Univ Helsinki, Biomedicum Stem Cell Ctr, Helsinki, Finland. RP Markmann, JF (reprint author), Massachusetts Gen Hosp, 55 Fruit St,WHT 517, Boston, MA 02114 USA. EM jmarkmann@partners.org RI Stabler, Cherie/E-8227-2011 NR 32 TC 3 Z9 3 U1 1 U2 6 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 JUL PY 2016 VL 100 IS 7 BP E25 EP E31 DI 10.1097/TP.0000000000001054 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DP0AG UT WOS:000378149300001 PM 27082827 ER PT J AU Ferreira, M Firmino, MJ Marques, EA Santos, PC Duarte, JA AF Ferreira, Margarida Firmino, Machado J. Marques, Elisa A. Santos, Paula C. Duarte, Jose A. TI Are corticosteroids useful in all degrees of severity and rapid recovery of Bell's palsy? SO ACTA OTO-LARYNGOLOGICA LA English DT Article DE Facial palsy; medical therapy; muscular training; Sunnybrook Facial Grading System; House-Brackmann Facial Grading System ID NEUROMUSCULAR REEDUCATION; GRADING SYSTEM; REHABILITATION; TRIAL AB Conclusions The results provide preliminary evidence that corticosteroids were not effective in all grades of dysfunction and for achieving a rapid remission in the early phase of BP, highlighting the need to define standard and rigorous criteria to prescribe corticosteroids in these patients. Objectives The main aim of this study was to investigate whether the use of corticosteroids better associated than paralleled with neuromuscular training (C+FNT) is more effective than facial neuromuscular training (FNT) applied alone, in terms of recovery degree and facial symmetry during the early phase of Bell's palsy (BP). Patients and methods A prospective single-blinded study involved 73 patients: the C+FNT group (n=42; median age = 37.5 years) and FNT group (n=31; median age = 49.0 years). Patients were assessed before and 6 weeks after treatment by House-Brackmann (HB-FGS) and Sunnybrook Facial Grading System (SB-FGS). Results Recovery degree and facial symmetry improved significantly in both groups (p<0.001), without differences between groups (p>0.05). However, the C+FNT group displayed better outcomes for cheek (p=0.004) and mouth (p=0.022) resting symmetry at SB-FGS, instead of compared to the FNT group. The corticosteroids had no significant effect on all recovery degrees (p=0.992) and rapid remission (p=0.952). Multiple linear regression analysis showed that the type of intervention was not a significant predictor for recovery degree (p=0.917). C1 [Ferreira, Margarida; Santos, Paula C.; Duarte, Jose A.] Univ Porto, Fac Sport, Res Ctr Phys Act Hlth & Leisure, P-914200 Oporto, Portugal. [Ferreira, Margarida] CESPU, North Polytech Inst Hlth, Dept Physiotherapy Paredes & Vila Nova De Famalic, Gandra, Portugal. [Firmino, Machado J.] Dept Publ Hlth Occidental, Oporto, Portugal. [Marques, Elisa A.] Univ Inst Maia ISMAI, Res Ctr Sports Sci Hlth & Human Dev CIDESD, Maia, Portugal. [Marques, Elisa A.] NIA, NIH, Bethesda, MD 20892 USA. [Santos, Paula C.] Polytech Inst Porto, Sch Hlth Technol, Dept Phys Therapy, Vila Nova De Gaia, Portugal. RP Ferreira, M (reprint author), Univ Porto, Fac Sport, Res Ctr Phys Act Hlth & Leisure, P-914200 Oporto, Portugal. EM margasufer@gmail.com NR 20 TC 0 Z9 0 U1 1 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0001-6489 EI 1651-2251 J9 ACTA OTO-LARYNGOL JI Acta Oto-Laryngol. PD JUL PY 2016 VL 136 IS 7 BP 736 EP 741 DI 10.3109/00016489.2016.1154604 PG 6 WC Otorhinolaryngology SC Otorhinolaryngology GA DO6ZQ UT WOS:000377932400017 PM 27003272 ER PT J AU Zhang, YS McNerny, EG Terajima, M Raghavan, M Romanowicz, G Zhang, ZP Zhang, HH Kamiya, N Tantillo, M Zhu, PZ Scott, GJ Ray, MK Lynch, M Ma, PX Morris, MD Yamauchi, M Kohn, DH Mishina, Y AF Zhang, Yanshuai McNerny, Erin Gatenby Terajima, Masahiko Raghavan, Mekhala Romanowicz, Genevieve Zhang, Zhanpeng Zhang, Honghao Kamiya, Nobuhiro Tantillo, Margaret Zhu, Peizhi Scott, Gregory J. Ray, Manas K. Lynch, Michelle Ma, Peter X. Morris, Michael D. Yamauchi, Mitsuo Kohn, David H. Mishina, Yuji TI Loss of BMP signaling through BMPR1A in osteoblasts leads to greater collagen cross-link maturation and material-level mechanical properties in mouse femoral trabecular compartments SO BONE LA English DT Article DE BMP receptor type 1A; Collagen cross-links; Cortical geometry; Bone quality; Biomechanical properties ID INCREASES BONE MASS; IA RECEPTOR BMPRIA; MINERAL-TO-MATRIX; CORTICAL BONE; FRAGILITY; MICE; FRACTURE; STRENGTH; TISSUE; NANOINDENTATION AB Bone morphogenetic protein (BMP) signaling pathways play critical roles in skeletal development and new bone formation. Our previous study, however, showed a negative impact of BMP signaling on bone mass because of the osteoblast-specific loss of a BMP receptor (i.e. BMPR1A) showing increased trabecular bone volume and mineral density in mice. Here, we investigated the bone quality and biomechanical properties of the higher bone mass associated with BMPR1A deficiency using the osteoblast-specific Bmpr 1a conditional knockout (cKO) mouse model. Collagen biochemical analysis revealed greater levels of the mature cross-link pyridinoline in the cKO bones, in parallel with upregulation of collagen modifying enzymes. Raman spectroscopy distinguished increases in the mature to immature cross-link ratio and mineral to matrix ratio in the trabecular compartments of cKO femora, but not in the cortical compartments. The mineral crystallinity was unchanged in the cKO in either the trabecular or cortical compartments. Further, we tested the intrinsic material properties by nanoindentation and found significantly higher hardness and elastic modulus in the cKO trabecular compartments, but not in the cortical compartments. Four point bending tests of cortical compartments showed lower structural biomechanical properties (i.e. strength and stiffness) in the cKO bones due to the smaller cortical areas. However, there were no significant differences in biomechanical performance at the material level, which was consistent with the nanoindentation test results on the cortical compartment These studies emphasize the pivotal role of BMPR1A in the determination of bone quality and mechanical integrity under physiological conditions, with different impact on femoral cortical and trabecular compartments. (C) 2016 Elsevier Inc. All rights reserved. C1 [Zhang, Yanshuai; Romanowicz, Genevieve; Zhang, Zhanpeng; Zhang, Honghao; Kamiya, Nobuhiro; Tantillo, Margaret; Ma, Peter X.; Kohn, David H.; Mishina, Yuji] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, 1011 N Univ Ave, Ann Arbor, MI 48109 USA. [McNerny, Erin Gatenby; Kohn, David H.] Univ Michigan, Coll Engn, Biomed Engn, Ann Arbor, MI 48109 USA. [Raghavan, Mekhala; Zhu, Peizhi; Morris, Michael D.] Univ Michigan, Coll Literature Sci & Arts, Dept Chem, Ann Arbor, MI 48109 USA. [Terajima, Masahiko; Yamauchi, Mitsuo] Univ N Carolina, Sch Dent, Chapel Hill, NC USA. [Kamiya, Nobuhiro; Mishina, Yuji] NIEHS, Reprod & Dev Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Scott, Gregory J.; Ray, Manas K.; Mishina, Yuji] NIEHS, Knock Out Core, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Kamiya, Nobuhiro] Texas Scottish Rite Hosp Children, Ctr Excellence Hip Disorders, Dallas, TX 75219 USA. [Kamiya, Nobuhiro] Tenri Univ, Fac Budo & Sport Studies, Nara, Japan. [Lynch, Michelle] Univ Michigan, Sch Dent, Res Off, Ann Arbor, MI 48109 USA. RP Mishina, Y (reprint author), Univ Michigan, Sch Dent, Dept Biol & Mat Sci, 1011 N Univ Ave, Ann Arbor, MI 48109 USA. EM mishina@umich.edu FU National Institutes of Health [R01DE020843, E5071003-11, R01ARAR047969]; Department of Defense [DOD W81XWH-12-2-0008]; NIH/NCRR [S10RR026475-01] FX We thank Drs. Hank Kronenberg and Tatsuya Kobayashi for providing Col1CreERTM mice; Dr. Gurjit Mandair for advice on Raman analyses, Drs. Kenneth Kozloff and Joseph Perosky for advice on nano indentation; Ms. Toni Ward, Ms. Kelly McCann and Ms. Xixi Wang for maintaining mouse colonies; Ms. Caitlyn Molloy for excellent technical assistance; and Dr. Judith Connett for critical reading and editing of this manuscript. This study is supported by the National Institutes of Health (R01DE020843 and E5071003-11 to YM, R01ARAR047969 to MDM) and Department of Defense (DOD W81XWH-12-2-0008 to MXP). The mu CT core at the School of Dentistry, University of Michigan is funded in part by NIH/NCRR S10RR026475-01. NR 61 TC 1 Z9 1 U1 3 U2 8 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 JUL PY 2016 VL 88 BP 74 EP 84 DI 10.1016/j.bone.2016.04.022 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DO6WV UT WOS:000377925100010 PM 27113526 ER PT J AU Chu, CH Wang, SJ Li, CL Chen, SH Hu, CF Chung, YL Chen, SL Wang, QS Lu, RB Gao, HM Hong, JS AF Chu, Chun-Hsien Wang, Shijun Li, Chia-Ling Chen, Shih-Heng Hu, Chih-Fen Chung, Yi-Lun Chen, Shiou-Lan Wang, Qingshan Lu, Ru-Band Gao, Hui-Ming Hong, Jau-Shyong TI Neurons and astroglia govern microglial endotoxin tolerance through macrophage colony-stimulating factor receptor-mediated ERK1/2 signals SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Microglia; Endotoxin tolerance; Neurons; Astroglia; M-CSF; CSF1R; ERK1/2; M2-like microglia; Neuroprotection ID LANGERHANS CELLS; IN-VITRO; PROGENITOR-CELL; GENE-EXPRESSION; NERVOUS-SYSTEM; LIPOPOLYSACCHARIDE; BRAIN; CSF-1; BETA; NEURODEGENERATION AB Endotoxin tolerance (ET) is a reduced responsiveness of innate immune cells like macrophages/monocytes to an endotoxin challenge following a previous encounter with the endotoxin. Although ET in peripheral systems has been well studied, little is known about ET in the brain. The present study showed that brain immune cells, microglia, being different from peripheral macrophages, displayed non-cell autonomous mechanisms in ET formation. Specifically, neurons and astroglia were indispensable for microglial ET. Macrophage colony-stimulating factor (M-CSF) secreted from these non-immune cells was essential for governing microglial ET. Neutralization of M-CSF deprived the neuron-glia conditioned medium of its ability to enable microglia to form ET when microglia encountered two lipopolysaccharide (LPS) treatments. Recombinant M-CSF protein rendered enriched microglia refractory to the second LPS challenge leading to microglial ET. Activation of microglial M-CSF receptor (M-CSFR; also known as CSF1R) and the downstream ERK1/2 signals was responsible for M-CSF-mediated microglial ET. Endotoxin-tolerant microglia in neuron-glia cultures displayed M2-like polarized phenotypes, as shown by upregulation of M2 marker Arg-1, elevated production of anti-inflammatory cytokine interleukin 10, and decreased secretion of pro-inflammatory mediators (tumor necrosis factor a, nitric oxide, prostaglandin E2 and interleukin 1(3). Endotoxin-tolerant microglia protected neurons against LPS-elicited inflammatory insults, as shown by reduced neuronal damages in LPS pre-treatment group compared with the group without LPS pre-treatment. Moreover, while neurons and astroglia became injured during chronic neuroinflammation, microglia failed to form ET. Thus, this study identified a distinct non-cell autonomous mechanism of microglial ET. Interactions of M-CSF secreted by neurons and astroglia with microglial M-CSFR programed microglial ET. Loss of microglial ET could be an important pathogenetic mechanism of inflammation-associated neuronal damages. (C) 2016 Elsevier Inc. All rights reserved. C1 [Chu, Chun-Hsien; Wang, Shijun; Chen, Shih-Heng; Hu, Chih-Fen; Wang, Qingshan; Hong, Jau-Shyong] NIEHS, Neurobiol Lab, Div Intramural Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Chu, Chun-Hsien] Natl Cheng Kung Univ, Natl Cheng Kung Univ Hosp, Inst Mol Med, Coll Med, Tainan 70101, Taiwan. [Li, Chia-Ling; Lu, Ru-Band] Natl Cheng Kung Univ, Natl Cheng Kung Univ Hosp, Dept Psychiat, Coll Med, Tainan 70101, Taiwan. [Hu, Chih-Fen] Triserv Gen Hosp, Grad Inst Med Sci, Dept Pediat, Natl Def Med Ctr, Taipei 11401, Taiwan. [Chung, Yi-Lun] Natl Cheng Kung Univ, Inst Basic Med Sci, Tainan 70101, Taiwan. [Chen, Shiou-Lan] Kaohsiung Med Univ, Sch Med, Dept Neurol, Kaohsiung 80780, Taiwan. [Lu, Ru-Band] Natl Cheng Kung Univ, Inst Behav Med, Tainan 70101, Taiwan. [Lu, Ru-Band] Natl Cheng Kung Univ, Inst Allied Hlth Sci, Tainan 70101, Taiwan. [Lu, Ru-Band] Natl Cheng Kung Univ, Addict Res Ctr, Tainan 70101, Taiwan. [Gao, Hui-Ming] Nanjing Univ, Model Anim Res Ctr, 12 Xuefu Rd, Nanjing 210061, Jiangsu, Peoples R China. [Gao, Hui-Ming] Nanjing Univ, MOE Key Lab Model Anim Dis Study, 12 Xuefu Rd, Nanjing 210061, Jiangsu, Peoples R China. [Gao, Hui-Ming] Nanjing Univ, Nanjing Biomed Res Inst, Nanjing 210061, Jiangsu, Peoples R China. RP Gao, HM (reprint author), Nanjing Univ, Model Anim Res Ctr, 12 Xuefu Rd, Nanjing 210061, Jiangsu, Peoples R China.; Gao, HM (reprint author), Nanjing Univ, MOE Key Lab Model Anim Dis Study, 12 Xuefu Rd, Nanjing 210061, Jiangsu, Peoples R China. EM gaohm@nju.edu.cn FU Intramural Research Program of the NIH/NIEHS in the United States [ES090082]; National Natural Science Foundation of China [31471006, 21577004]; national high technology research and development program of China (863 program) [2014 AA021601]; award to high-level innovative and entrepreneurial talents of Jiangsu Province of China FX This work was supported by the Intramural Research Program of the NIH/NIEHS in the United States (ES090082) to J.-S.H., the National Natural Science Foundation of China (Nos. 31471006 and 21577004), the national high technology research and development program of China (863 program; No. 2014 AA021601), and the award to high-level innovative and entrepreneurial talents of Jiangsu Province of China to H.-M.G. We thank Anthony Lockhart for the assistance with animal colony management and maintenance of the timed pregnant mice. NR 56 TC 2 Z9 2 U1 3 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 EI 1090-2139 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD JUL PY 2016 VL 55 SI SI BP 260 EP 272 DI 10.1016/j.bbi.2016.04.015 PG 13 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DO8FT UT WOS:000378019100024 PM 27132056 ER PT J AU Chen, Q Shou, P Zheng, C Jiang, M Cao, G Yang, Q Cao, J Xie, N Velletri, T Zhang, X Xu, C Zhang, L Yang, H Hou, J Wang, Y Shi, Y AF Chen, Q. Shou, P. Zheng, C. Jiang, M. Cao, G. Yang, Q. Cao, J. Xie, N. Velletri, T. Zhang, X. Xu, C. Zhang, L. Yang, H. Hou, J. Wang, Y. Shi, Y. TI Fate decision of mesenchymal stem cells: adipocytes or osteoblasts? SO CELL DEATH AND DIFFERENTIATION LA English DT Review ID FIBROBLAST-GROWTH-FACTOR; HUMAN ADIPOSE-TISSUE; THERAPY POSITION STATEMENT; MARROW STROMAL CELLS; OSTEOGENIC DIFFERENTIATION; BONE-MARROW; ADIPOGENIC DIFFERENTIATION; PROGENITOR CELLS; TGF-BETA; IN-VITRO AB Mesenchymal stem cells (MSCs), a non-hematopoietic stem cell population first discovered in bone marrow, are multipotent cells capable of differentiating into mature cells of several mesenchymal tissues, such as fat and bone. As common progenitor cells of adipocytes and osteoblasts, MSCs are delicately balanced for their differentiation commitment. Numerous in vitro investigations have demonstrated that fat-induction factors inhibit osteogenesis, and, conversely, bone-induction factors hinder adipogenesis. In fact, a variety of external cues contribute to the delicate balance of adipo-osteogenic differentiation of MSCs, including chemical, physical, and biological factors. These factors trigger different signaling pathways and activate various transcription factors that guide MSCs to commit to either lineage. The dysregulation of the adipo-osteogenic balance has been linked to several pathophysiologic processes, such as aging, obesity, osteopenia, osteopetrosis, and osteoporosis. Thus, the regulation of MSC differentiation has increasingly attracted great attention in recent years. Here, we review external factors and their signaling processes dictating the reciprocal regulation between adipocytes and osteoblasts during MSC differentiation and the ultimate control of the adipo-osteogenic balance. C1 [Chen, Q.; Zhang, L.; Yang, H.; Hou, J.; Shi, Y.] Soochow Univ, Inst Translat Med, Affiliated Hosp 1, Suzhou 215006, Peoples R China. [Chen, Q.; Shou, P.; Zheng, C.; Jiang, M.; Cao, G.; Yang, Q.; Cao, J.; Xie, N.; Velletri, T.; Zhang, X.; Xu, C.; Wang, Y.; Shi, Y.] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Key Lab Stem Cell Biol, Shanghai 200031, Peoples R China. [Zhang, L.; Shi, Y.] Rutgers Robert Wood Johnson Med Sch, Child Hlth Inst New Jersey, New Brunswick, NJ 08901 USA. [Chen, Q.] NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Shi, Y (reprint author), Soochow Univ, Inst Translat Med, Affiliated Hosp 1, Suzhou 215006, Peoples R China.; Wang, Y (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Shanghai 200025, Peoples R China. EM yingwang@sibs.ac.cn; yfshi@suda.edu.cn OI Shou, Peishun/0000-0001-7685-7471 FU Scientific Innovation Project of the Chinese Academy of Sciences [XDA01040107]; Ministry of Science and Technology of China [2015CB964500]; National Natural Science Foundation of China [81330046, 81530043, 81273316, 81571612]; Shanghai Rising-Star Program [14QA1404200] FX We are indebted to those whose work is not discussed due to space limitations. This work is supported by grants from Scientific Innovation Project of the Chinese Academy of Sciences (XDA01040107), the Ministry of Science and Technology of China (2015CB964500), National Natural Science Foundation of China (81330046, 81530043, 81273316, 81571612), and Shanghai Rising-Star Program (14QA1404200). NR 154 TC 21 Z9 21 U1 19 U2 38 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD JUL PY 2016 VL 23 IS 7 BP 1128 EP 1139 DI 10.1038/cdd.2015.168 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DO6YN UT WOS:000377929500005 PM 26868907 ER PT J AU Balkus, JE Brown, ER Hillier, SL Coletti, A Ramjee, G Mgodi, N Makanani, B Reid, C Martinson, F Soto-Torres, L Karim, SSA Chirenje, ZM AF Balkus, Jennifer E. Brown, Elizabeth R. Hillier, Sharon L. Coletti, Anne Ramjee, Gita Mgodi, Nyaradzo Makanani, Bonus Reid, Cheri Martinson, Francis Soto-Torres, Lydia Karim, Salim S. Abdool Chirenje, Zvavahera M. TI oral and injectable contraceptive use and HIV acquisition risk among women in four African countries: a secondary analysis of data from a microbicide trial (vol 93, pg 25, 2016) SO CONTRACEPTION LA English DT Correction C1 [Balkus, Jennifer E.; Brown, Elizabeth R.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. [Hillier, Sharon L.] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Hillier, Sharon L.] Univ Pittsburgh, Magee Womens Res Inst, Sch Med, Pittsburgh, PA USA. [Coletti, Anne] FHI360, Durham, NC USA. [Ramjee, Gita] South Africa Med Res Council, HIV Prevent Res Unit, Durban, South Africa. [Mgodi, Nyaradzo; Chirenje, Zvavahera M.] Univ Zimbabwe Univ Calif San Francisco Res Progra, Harare, Zimbabwe. [Makanani, Bonus] Univ Malawi, Coll Med, Blantyre, Malawi. [Reid, Cheri] Ctr Infect Dis Res Zambia, Lusaka, Zambia. [Martinson, Francis] Univ North Carolina Project, Kamuzu Cent Hosp, Lilongwe, Malawi. [Soto-Torres, Lydia] NIH, Bldg 10, Bethesda, MD 20892 USA. [Karim, Salim S. Abdool] Univ KwaZulu Natal, Nelson R Mandela Sch Med, Doris Duke Med Res Inst, Ctr AIDS Program Res South Africa, Congella, South Africa. [Karim, Salim S. Abdool] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. RP Balkus, JE (reprint author), Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. EM jbalkus@fhcrc.org NR 1 TC 0 Z9 0 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0010-7824 EI 1879-0518 J9 CONTRACEPTION JI Contraception PD JUL PY 2016 VL 94 IS 1 BP 95 EP 95 DI 10.1016/j.contraception.2016.03.018 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DO2TG UT WOS:000377632400018 ER PT J AU Graham, AL Nussey, DH Lloyd-Smith, JO Longbottom, D Maley, M Pemberton, JM Pilkington, JG Prager, KC Smith, L Watt, KA Wilson, K McNeilly, TN Brulisauer, F AF Graham, A. L. Nussey, D. H. Lloyd-Smith, J. O. Longbottom, D. Maley, M. Pemberton, J. M. Pilkington, J. G. Prager, K. C. Smith, L. Watt, K. A. Wilson, K. McNeilly, T. N. Brulisauer, F. TI Exposure to viral and bacterial pathogens among Soay sheep (Ovis aries) of the St Kilda archipelago SO EPIDEMIOLOGY AND INFECTION LA English DT Article DE Epidemiology; parasites ID INTERROGANS SEROVAR HARDJO; LINKED-IMMUNOSORBENT-ASSAY; ENZOOTIC ABORTION; MAINTENANCE HOST; POPULATION; ANTIBODIES; DISEASE; DIAGNOSIS; VIRUSES; ISLAND AB We assessed evidence of exposure to viruses and bacteria in an unmanaged and long-isolated population of Soay sheep (Ovis aries) inhabiting Hirta, in the St Kilda archipelago, 65 km west of Benbecula in the Outer Hebrides of Scotland. The sheep harbour many metazoan and protozoan parasites but their exposure to viral and bacterial pathogens is unknown. We tested for herpes viral DNA in leucocytes and found that 21 of 42 tested sheep were infected with ovine herpesvirus 2 (OHV-2). We also tested 750 plasma samples collected between 1997 and 2010 for evidence of exposure to seven other viral and bacterial agents common in domestic Scottish sheep. We found evidence of exposure to Leptospira spp., with overall seroprevalence of 6.5%. However, serological evidence indicated that the population had not been exposed to border disease, parainfluenza, maedi-visna, or orf viruses, nor to Chlamydia abortus. Some sheep tested positive for antibodies against Mycobacterium avium subsp. paratuberculosis (MAP) but, in the absence of retrospective faecal samples, the presence of this infection could not be confirmed. The roles of importation, the pathogen-host interaction, nematode co-infection and local transmission warrant future investigation, to elucidate the transmission ecology and fitness effects of the few viral and bacterial pathogens on Hirta. C1 [Graham, A. L.] Princeton Univ, Dept Ecol & Evolutionary Biol, 106a Guyot Hall, Princeton, NJ 08544 USA. [Graham, A. L.; Lloyd-Smith, J. O.; Prager, K. C.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Nussey, D. H.; Pemberton, J. M.; Pilkington, J. G.; Watt, K. A.] Univ Edinburgh, Sch Biol Sci, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Lloyd-Smith, J. O.; Prager, K. C.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA USA. [Longbottom, D.; Maley, M.; McNeilly, T. N.] Moredun Res Inst, Pentlands Sci Pk, Penicuik, Midlothian, Scotland. [Smith, L.] Anim & Plant Hlth Agcy, Addlestone, Surrey, England. [Wilson, K.] Univ Lancaster, Lancaster Environm Ctr, Lancaster, England. [Brulisauer, F.] Scotlands Rural Coll, SAC Consulting Vet Serv, Inverness, Scotland. RP Graham, AL (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, 106a Guyot Hall, Princeton, NJ 08544 USA.; Brulisauer, F (reprint author), Scotlands Rural Coll, SAC Consulting Vet Serv, Inverness, Scotland. EM algraham@princeton.edu; Franz.Brulisauer@sruc.ac.uk RI APHA, Staff publications/E-6082-2010; Pemberton, Josephine/F-3100-2010; Graham, Andrea/A-8808-2010; Nussey, Daniel/F-4155-2010; Lloyd-Smith, James/K-4080-2012 OI Graham, Andrea/0000-0002-6580-2755; Lloyd-Smith, James/0000-0001-7941-502X FU U.K. Natural Environment and Biotechnology & Biological Sciences Research Councils (including BBSRC Fellowships); Wellcome Trust; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, U.S. Department of Homeland Security; Fogarty International Center of the National Institutes of Health FX This work was supported by the U.K. Natural Environment and Biotechnology & Biological Sciences Research Councils (including BBSRC Fellowships to A.L.G. and D.H.N.), the Wellcome Trust, and the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, U.S. Department of Homeland Security, and the Fogarty International Center of the National Institutes of Health. NR 40 TC 0 Z9 0 U1 3 U2 10 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0950-2688 EI 1469-4409 J9 EPIDEMIOL INFECT JI Epidemiol. Infect. PD JUL PY 2016 VL 144 IS 9 BP 1879 EP 1888 DI 10.1017/S0950268816000017 PG 10 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA DO5JV UT WOS:000377820300010 PM 26829883 ER PT J AU Kwon, J Wang, AB Burke, DJ Boudreau, HE Lekstrom, KJ Korzeniowska, A Sugamata, R Kim, YS Yi, L Ersoy, I Jaeger, S Palaniappan, K Ambruso, DR Jackson, SH Leto, TL AF Kwon, Jaeyul Wang, Aibing Burke, Devin J. Boudreau, Howard E. Lekstrom, Kristen J. Korzeniowska, Agnieszka Sugamata, Ryuichi Kim, Yong-Soo Yi, Liang Ersoy, Ilker Jaeger, Stefan Palaniappan, Kannappan Ambruso, Daniel R. Jackson, Sharon H. Leto, Thomas L. TI Peroxiredoxin 6 (Prdx6) supports NADPH oxidase1 (Nox1)-based superoxide generation and cell migration SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Nox1; NADPH oxidase; Peroxiredoxin 6; Prdx 6; Phospholipase A(2); Peroxidase; Cell migration ID PHOSPHOLIPASE A(2) ACTIVITY; COLON EPITHELIAL-CELLS; OXYGEN SPECIES GENERATION; FORMYL PEPTIDE RECEPTOR; INNATE IMMUNE-RESPONSE; SMOOTH-MUSCLE-CELLS; GLUTATHIONE-PEROXIDASE; NAD(P)H OXIDASE-1; ARACHIDONIC-ACID; KINASE-C AB Nox1 is an abundant source of reactive oxygen species (ROS) in colon epithelium recently shown to function in wound healing and epithelial homeostasis. We identified Peroxiredoxin 6 (Prdx6) as a novel binding partner of Nox activator 1 (Noxa1) in yeast two-hybrid screening experiments using the Noxa1 SH3 domain as bait. Prdx6 is a unique member of the Prdx antioxidant enzyme family exhibiting both glutathione peroxidase and phospholipase A(2) activities. We confirmed this interaction in cells over expressing both proteins, showing Prdx6 binds to and stabilizes wild type Noxal, but not the SH3 domain mutant form, Noxa1 W436R. We demonstrated in several cell models that Prdx6 knockdown suppresses Nox1 activity, whereas enhanced Prdx6 expression supports higher Nox1-derived superoxide production. Both peroxidase- and lipase-deficient mutant forms of Prdx6 (Prdx6 C47S and S32A, respectively) failed to bind to or stabilize Nox1 components or support Nox1-mediated superoxide generation. Furthermore, the transition-state substrate analogue inhibitor of Prdx6 phospholipase A(2) activity (MJ-33) was shown to suppress Nox1 activity, suggesting Nox1 activity is regulated by the phospholipase activity of Prdx6. Finally, wild type Prdx6, but not lipase or peroxidase mutant forms, supports Nox1-mediated cell migration in the HCT-116 colon epithelial cell model of wound closure. These findings highlight a novel pathway in which this antioxidant enzyme positively regulates an oxidant-generating system to support cell migration and wound healing. Published by Elsevier Inc. C1 [Kwon, Jaeyul; Burke, Devin J.; Boudreau, Howard E.; Lekstrom, Kristen J.; Korzeniowska, Agnieszka; Sugamata, Ryuichi; Leto, Thomas L.] NIAID, Host Def Lab, NIH, Rockville, MD USA. [Kwon, Jaeyul] Chungnam Natl Univ, Sch Med, Dept Med Educ, Daejeon 301747, South Korea. [Wang, Aibing; Yi, Liang; Jackson, Sharon H.] Natl Inst Minor Hlth & Hlth Disparities, Diabet Cluster, NIH, Bethesda, MD USA. [Kim, Yong-Soo] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Ersoy, Ilker] Univ Missouri, Sch Med, Dept Pathol & Anant Sci, Columbia, MO USA. [Jaeger, Stefan] NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. [Palaniappan, Kannappan] Univ Missouri, Dept Comp Sci, Columbia, MO USA. [Ambruso, Daniel R.] Univ Colorado, Sch Med, Dept Pediat, Denver, CO 80202 USA. RP Leto, TL (reprint author), NIAID, Host Def Lab, NIH, Rockville, MD USA. EM tleto@nih.gov RI Ersoy, Ilker/N-2116-2016 OI Ersoy, Ilker/0000-0003-2650-4496 FU Intramural Research Program of NIH, USA; National Institute of Allergy and Infectious Diseases [ZO1-AI-000614]; Chungnam National University, South Korea FX This work was supported by funds from the Intramural Research Program of the NIH, USA, National Institute of Allergy and Infectious Diseases (ZO1-AI-000614) and, in part, by research funds from Chungnam National University, South Korea. The authors are grateful to Dr. Miklos Geiszt (Semmelweis University) for providing antibodies against Noxal and Dr. Gary M. Bokoch (deceased, Scripps Research Institute) for providing the Myc-tagged Noxal cDNA. NR 67 TC 2 Z9 2 U1 2 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 JUL PY 2016 VL 96 BP 99 EP 115 DI 10.1016/j.freeradbiomed.2016.04.009 PG 17 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DO2OO UT WOS:000377619600010 PM 27094494 ER PT J AU Mattson, MP AF Mattson, Mark P. TI Intermittent bioenergetic and oxidative challenges promote optimal brain function SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract CT Conference of the Society-for-Free-Radical-Research-Europe (SFRR-E) CY JUN 08-11, 2016 CL Budapest, HUNGARY SP Soc Free Rad Res Europe C1 [Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUL PY 2016 VL 96 SU 1 MA A-03 BP S1 EP S2 DI 10.1016/j.freeradbiomed.2016.04.164 PG 2 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DO2NY UT WOS:000377617900004 ER PT J AU Tran, AH Best, BM Stek, A Wang, JJ Capparelli, EV Burchett, SK Kreitchmann, R Rungruengthanakit, K George, K Cressey, TR Chakhtoura, N Smith, E Shapiro, DE Mirochnick, M AF Tran, Anna H. Best, Brookie M. Stek, Alice Wang, Jiajia Capparelli, Edmund V. Burchett, Sandra K. Kreitchmann, Regis Rungruengthanakit, Kittipong George, Kathleen Cressey, Tim R. Chakhtoura, Nahida Smith, Elizabeth Shapiro, David E. Mirochnick, Mark CA IMPAACT P1026s Protocol Team TI Pharmacokinetics of Rilpivirine in HIV-Infected Pregnant Women SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE rilpivirine; pregnancy; HIV; pharmacokinetics ID STEADY-STATE PHARMACOKINETICS; DRUG-METABOLISM; EFAVIRENZ; EXPOSURE; PHARMACOGENETICS; ANTIRETROVIRALS; POSTPARTUM; INHIBITOR; SAFETY; TWICE AB Background: Rilpivirine pharmacokinetics is defined by its absorption, distribution, metabolism, and excretion. Pregnancy can affect these factors by changes in cardiac output, protein binding, volume of distribution, and cytochrome P450 (CYP) 3A4 activity. Rilpivirine is metabolized by CYP3A4. The impact of pregnancy on rilpivirine pharmacokinetics is largely unknown. Methods: International Maternal Pediatric Adolescent AIDS Clinical Trials P1026s is a multicenter, nonblinded, prospective study evaluating antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving rilpivirine 25 mg once daily as part of their combination antiretrovirals for clinical care. Thirty-two women were enrolled in this study. Intensive pharmacokinetic sampling was performed at steady state during the second trimester, the third trimester, and postpartum. Maternal and umbilical cord blood samples were obtained at delivery. Plasma rilpivirine concentration was measured using liquid chromatography-mass spectrometry; lower limit of quantitation was 10 ng/mL. Results: Median (range) AUC(0-24) were 1969 (867-4987, n = 15), 1669 (556-4312, n = 28), and 2387 (188-6736, n = 28) ng.h/mL in the second trimester, the third trimester, and postpartum, respectively (P < 0.05 for either trimester vs postpartum). Median (range) C-24 were 63 (37-225, n = 17), 56 (<10-181, n = 30), and 81 (<10-299, n = 28) ng/mL (P < 0.05 for either trimester vs postpartum). High variability in pharmacokinetic parameters was observed between subjects. Median (range) cord blood/maternal concentration ratio was 0.55 (0.3-0.8, n = 21). Delivery HIV-1 RNA was <= 50 copies per milliliter in 70% and <= 400 copies per milliliter in 90% of women. C-min were significantly lower at 15 visits with detectable HIV-1 RNA compared with 61 visits with undetectable HIV-1 RNA, 29 (<10-93) vs 63 (15-200) ng/mL (P = 0.0001). C-min was below the protein binding-adjusted EC90 concentration (12.2 ng/mL) at 4 visits in 3 of 31 women (10%). Conclusions: Rilpivirine exposure is lower during pregnancy compared with postpartum and highly variable. Ninety percent of women had minimum concentrations above the protein binding-adjusted EC90 for rilpivirine. C1 [Tran, Anna H.] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, San Diego, CA 92103 USA. [Best, Brookie M.; Capparelli, Edmund V.] Univ Calif San Diego, Dept Pediat, Skaggs Sch Pharm & Pharmaceut Sci, Rady Childrens Hosp, San Diego, CA 92103 USA. [Stek, Alice] Univ So Calif, Dept Obstet & Gynecol, Los Angeles, CA 90089 USA. [Wang, Jiajia; Shapiro, David E.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Burchett, Sandra K.] Childrens Hosp Boston, Dept Med, Boston, MA USA. [Kreitchmann, Regis] Irmandade Santa Casa de Misericordia Porto Alegre, HIV AIDS Res Dept, Porto Alegre, RS, Brazil. [Rungruengthanakit, Kittipong] Chiang Mai Univ, Res Inst Hlth Sci, Chiang Mai 50000, Thailand. [George, Kathleen] FHI 360, IMPAACT Operat Off, Durham, NC USA. [Cressey, Tim R.] Chiang Mai Univ, Program HIV Prevent & Treatment, Dept Med Technol, Fac Associated Med Sci, Chiang Mai 50000, Thailand. [Chakhtoura, Nahida] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, DHHS, Bethesda, MD USA. [Smith, Elizabeth] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Mirochnick, Mark] Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. RP Best, BM (reprint author), Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, Dept Pediat, Rady Childrens Hosp San Diego, 9500 Gilman Dr,MC 0657, La Jolla, CA 92093 USA. EM brookie@ucsd.edu FU National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) [UM1AI068632, UM1AI068616, UM1AI106716]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH); Eunice Kennedy Shriver National Institute of Child Health and Human Development [T35HD064385]; ViiV; Merck FX Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC), and UM1AI106716 (IMPAACT LC), with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH). A.T. was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development award number T35HD064385. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.; M.M. is a member of a DSMB for studies funded by ViiV and Merck and is a member of an advisory board for Merck. The authors have no funding or conflicts of interest to disclose. NR 27 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUL 1 PY 2016 VL 72 IS 3 BP 289 EP 296 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DO8UM UT WOS:000378059800015 PM 26918544 ER PT J AU Gross, C Akoth, E Price, A Kattakuzhy, S Silk, R Rosenthal, E AF Gross, Chloe Akoth, Elizabeth Price, Angie Kattakuzhy, Sarah Silk, Rachel Rosenthal, Elana TI HIV/HCV Co-infection: Overcoming Barriers to Treatment SO JANAC-JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE LA English DT Article DE direct-acting antivirals; HCV; HIV; managed care organizations; sustained virologic response; underserved population ID HEPATITIS-C AB A critical step in the eradication of hepatitis C virus (HCV) infection is access to effective therapy. With the advent of interferon-free regimens, HCV providers and patients gained hope that the success seen in clinical trials could be translated to the real world. However, the exorbitant cost of the new direct-acting antivirals limits access to these medications to the general HCV population, especially underserved patients with public insurance. We used a descriptive qualitative approach to detail the measures necessary and challenges faced by an inner-city nursing team in Washington, DC to obtain the new direct-acting antivirals. Significant time and dedication on the part of providers and staff was required to assist patients with the process of obtaining direct-acting antivirals. Copyright (C) 2016 Association of Nurses in AIDS Care C1 [Gross, Chloe; Akoth, Elizabeth; Price, Angie; Silk, Rachel] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Gross, Chloe; Akoth, Elizabeth; Price, Angie; Kattakuzhy, Sarah; Silk, Rachel] NIH, Bldg 10, Bethesda, MD 20892 USA. [Kattakuzhy, Sarah] Univ Maryland, Sch Med, Div Infect Dis, Inst Human Virol, Baltimore, MD 21201 USA. [Rosenthal, Elana] Leidos Biomed Res Inc, Clin Monitoring Res Program, Bethesda, MD USA. RP Gross, C (reprint author), Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA.; Gross, C (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM chloe.gross@nih.gov OI Rosenthal, Elana/0000-0001-7234-4871 NR 13 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1055-3290 EI 1552-6917 J9 J ASSOC NURSE AIDS C JI J. Assoc. Nurses Aids Care PD JUL-AUG PY 2016 VL 27 IS 4 BP 524 EP 529 DI 10.1016/j.jana.2016.02.009 PG 6 WC Nursing SC Nursing GA DO4WK UT WOS:000377785400017 PM 26996983 ER PT J AU Scheidweiler, KB Newmeyer, MN Barnes, AJ Huestis, MA AF Scheidweiler, Karl B. Newmeyer, Matthew N. Barnes, Allan J. Huestis, Marilyn A. TI Quantification of cannabinoids and their free and glucuronide metabolites in whole blood by disposable pipette extraction and liquid chromatography-tandem mass spectrometry SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Cannabinoids; Whole blood; Recent use markers; Disposable pipette extraction ID SOLID-PHASE EXTRACTION; CONTROLLED SMOKED CANNABIS; GAS-CHROMATOGRAPHY; DELTA-9-TETRAHYDROCANNABINOLIC ACID; ORAL FLUID; LC-MS/MS; HUMAN URINE; GC-MS; DELTA(9)-TETRAHYDROCANNABINOL; TETRAHYDROCANNABINOL AB Identifying recent cannabis intake is confounded by prolonged cannabinoid excretion in chronic frequent cannabis users. We previously observed detection times <= 2.1 h for cannabidiol (CBD) and cannabinol (CBN) and Delta(9)-tetrahydrocannabinol (THC)-glucuronide in whole blood after smoking, suggesting their applicability for identifying recent intake. However, whole blood collection may not occur for up to 4h during driving under the influence of drugs investigations, making a recent-use marker with a 6-8 h detection window helpful for improving whole blood cannabinoid interpretation. Other minor cannabinoids cannabigerol (CBG), Delta 9-tetrahydrocannabivarin (THCV), and its metabolite 11-nor-9-carboxy-THCV (THCVCOOH) might also be useful. We developed and validated a sensitive and specific liquid chromatography-tandem mass spectrometry method for quantification of THC, its phase I and glucuronide phase II metabolites, and 5 five minor cannabinoids. Cannabinoids were extracted from 200 mu L whole blood via disposable pipette extraction, separated on a C-18 column, and detected via electrospray ionization in negative mode with scheduled multiple reaction mass spectrometric monitoring. Linear ranges were 0.5-100 mu g/L for THC and 11-nor-9-carboxy-THC (THCCOOH); 0.5-50 mu g/L for 11-hydroxy-THC (11-OH-THC), CBD, CBN, and THC-glucuronide; 1-50 mu g/L for CBG, THCV, and THCVCOOH; and 5-500 mu g/L for THCCOOH-glucuronide. Inter-day accuracy and precision at low, mid and high quality control (QC) concentrations were 95.1-113% and 2.4-8.5%, respectively (n =25). Extraction recoveries and matrix effects at low and high QC concentrations were 54.0-84.4% and -25.8-30.6%, respectively. By simultaneously monitoring multiple cannabinoids and metabolites, identification of recent cannabis administration or discrimination between licit medicinal and illicit recreational cannabis use can be improved. Published by Elsevier B.V. C1 [Scheidweiler, Karl B.; Newmeyer, Matthew N.; Barnes, Allan J.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, IRP, NIH, Baltimore, MD 21224 USA. [Newmeyer, Matthew N.] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. RP Scheidweiler, KB (reprint author), NIDA, Chem & Drug Metab, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200 Room 05A-721, Baltimore, MD 21224 USA. EM KScheidweiler@intra.nida.nih.gov OI Newmeyer, Matthew/0000-0002-0653-1553 FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. MNN acknowledges the Graduate Partnership Program, NIH. The authors thank William E. Brewer (DPX Laboratories) for his technical assistance. NR 32 TC 2 Z9 2 U1 13 U2 31 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD JUL 1 PY 2016 VL 1453 BP 34 EP 42 DI 10.1016/j.chroma.2016.05.024 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DP0MB UT WOS:000378182800004 PM 27236483 ER PT J AU Kitson, AP Metherel, AH Chen, CT Domenichiello, AF Trepanier, MO Berger, A Bazinet, RP AF Kitson, Alex P. Metherel, Adam H. Chen, Chuck T. Domenichiello, Anthony F. Trepanier, Marc-Olivier Berger, Alvin Bazinet, Richard P. TI Effect of dietary docosahexaenoic acid (DHA) in phospholipids or triglycerides on brain DHA uptake and accretion SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE Docosahexaenoic acid; Brain; Triacylglycerol; Phospholipid; Serum; Uptake ID POLYUNSATURATED FATTY-ACIDS; POSTMORTEM ORBITOFRONTAL CORTEX; MAJOR DEPRESSIVE DISORDER; ALPHA-LINOLENIC ACID; DENSITY-LIPOPROTEIN RECEPTOR; CAPILLARY ENDOTHELIAL-CELLS; COMPARING KRILL OIL; FISH-OIL; RAT-BRAIN; ALZHEIMERS-DISEASE AB Tracer studies suggest that phospholipid DHA (PL-DHA) more effectively targets the brain than triglyceride DHA (TAG-DHA), although the mechanism and whether this translates into higher brain DHA concentrations are not clear. Rats were gavaged with [U-H-3]PL-DHA and [U-H-3]TAG-DHA and blood sampled over 6 h prior to collection of brain regions and other tissues. In another experiment, rats were supplemented for 4 weeks with TAG-DHA (fish oil), PL-DHA (roe PL) or a mixture of both for comparison to a low-omega-3 diet. Brain regions and other tissues were collected, and blood was sampled weekly. DHA accretion rates were estimated using the balance method. [U-H-3]PL-DHA rats had higher radioactivity in cerebellum, hippocampus and remainder of brain, with no differences in other tissues despite higher serum lipid radioactivity in [U-H-3]TAG-DHA rats. TAG-DHA, PL-DHA or a mixture were equally effective at increasing brain DHA. There were no differences between DHA-supplemented groups in brain region, whole-body, or tissue DHA accretion rates except heart and serum TAG where the PL-DHA/TAG-DHA blend was higher than TAG-DHA. Apparent DHA beta-oxidation was not different between DHA-supplemented groups. This indicates that more labeled DHA enters the brain when consumed as PL; however, this may not translate into higher brain DHA concentrations. (C) 2016 The Authors. Published by Elsevier Inc. C1 [Kitson, Alex P.; Metherel, Adam H.; Chen, Chuck T.; Domenichiello, Anthony F.; Trepanier, Marc-Olivier; Bazinet, Richard P.] Univ Toronto, Dept Nutr Sci, Fitzgerald Bldg,150 Coll St Room 306, Toronto, ON M5S 3E2, Canada. [Berger, Alvin] Arctic Nutr AS, NO-6155 Orsta, Norway. [Berger, Alvin] Univ Minnesota, Dept Food Sci & Nutr, St Paul, MN 55108 USA. [Chen, Chuck T.] NIAAA, NIH, Bethesda, MD 20892 USA. RP Bazinet, RP (reprint author), Univ Toronto, Dept Nutr Sci, Fitzgerald Bldg,150 Coll St Room 306, Toronto, ON M5S 3E2, Canada. EM richard.bazinet@utoronto.ca FU Arctic Nutrition AS, Orsta, Norway [NO-6155]; Canadian Institutes of Health Research FX This work was funded by Arctic Nutrition AS, NO-6155 Orsta, Norway. Funding source was involved in study design, but not in analysis, data handling or manuscript preparation. Alex P. Kitson received a fellowship from the Canadian Institutes of Health Research. Richard P. Bazinet holds a Canada Research Chair in Brain Lipid Metabolism. NR 95 TC 2 Z9 2 U1 8 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-2863 EI 1873-4847 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD JUL PY 2016 VL 33 BP 91 EP 102 DI 10.1016/j.jnutbio.2016.02.009 PG 12 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA DO8CY UT WOS:000378011400011 PM 27135386 ER PT J AU Katz, JL Hiranita, T Kopajtic, TA Rice, KC Mesangeau, C Narayanan, S Abdelazeem, AH McCurdy, CR AF Katz, Jonathan L. Hiranita, Takato Kopajtic, Theresa A. Rice, Kenner C. Mesangeau, Christophe Narayanan, Sanju Abdelazeem, Ahmed H. McCurdy, Christopher R. TI Blockade of Cocaine or sigma Receptor Agonist Self Administration by Subtype-Selective sigma Receptor Antagonists SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID ANTIPSYCHOTIC-DRUGS; PGRMC1 PROTEIN; HIGH-AFFINITY; DOPAMINE; RATS; BINDING; LIGANDS; INHIBITION; ANALOGS AB The identification of sigma receptor (sigma R) subtypes has been based on radioligand binding and, despite progress with sigma R-1 cellular function, less is known about sigma R subtype functions in vivo. Recent findings that cocaine self administration experience will trigger sigma R agonist self administration was used in this study to assess the in vivo receptor subtype specificity of the agonists (+)-pentazocine, PRE-084 [2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate hydrochloride], and 1,3-di-o-tolylguanidine (DTG) and several novel putative sigma R antagonists. Radioligand binding studies determined in vitro sigma R selectivity of the novel compounds, which were subsequently studied for self administration and antagonism of cocaine, (+)-pentazocine, PRE-084, or DTG self administration. Across the dose ranges studied, none of the novel compounds were self administered, nor did they alter cocaine self administration. All compounds blocked DTG self administration, with a subset also blocking (+)-pentazocine and PRE-084 self administration. The most selective of the compounds in binding sigma 1Rs blocked cocaine self administration when combined with a dopamine transport inhibitor, either methylphenidate or nomifensine. These drug combinations did not decrease rates of responding maintained by food reinforcement. In contrast, the most selective of the compounds in binding sigma 2Rs had no effect on cocaine self administration in combination with either dopamine transport inhibitor. Thus, these results identify subtype-specific in vivo antagonists, and the utility of sigma R agonist substitution for cocaine self administration as an assay capable of distinguishing sigma R subtype selectivity in vivo. These results further suggest that effectiveness of dual sigma R antagonism and dopamine transport inhibition in blocking cocaine self administration is specific for sigma 1Rs and further support this dual targeting approach to development of cocaine antagonists. C1 [Katz, Jonathan L.; Hiranita, Takato; Kopajtic, Theresa A.] NIDA, Psychobiol Sect, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. [Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Intramural Res Program, NIH, Baltimore, MD USA. [Rice, Kenner C.] NIAAA, Baltimore, MD USA. [Mesangeau, Christophe; Narayanan, Sanju; Abdelazeem, Ahmed H.; McCurdy, Christopher R.] Univ Mississippi, Sch Pharm, Dept Biomol Sci, University, MS 38677 USA. RP Katz, JL (reprint author), NIDA, Psychobiol Sect, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM jkatz@intra.nida.nih.gov FU National Institutes of Health National Institute on Drug Abuse [R01-DA023205]; National Institutes of Health National Institute of General Medical Sciences [P20-GM104932]; Intramural Research Program of the National Institutes of Health National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX This research was supported by the National Institutes of Health National Institute on Drug Abuse [Grant R01-DA023205 (to C.R.M.)] and the National Institutes of Health National Institute of General Medical Sciences [Grant P20-GM104932 (to C.R.M.)]. This research was supported [in part] by the Intramural Research Program of the National Institutes of Health National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. NR 37 TC 1 Z9 1 U1 2 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUL PY 2016 VL 358 IS 1 BP 109 EP 124 DI 10.1124/jpet.116.232728 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DO3OQ UT WOS:000377691300013 PM 27189970 ER PT J AU Chelluri, R Kilchevsky, A George, AK Sidana, A Frye, TP Su, D Fascelli, M Ho, R Abboud, SF Turkbey, B Merino, MJ Choyke, PL Wood, BJ Pinto, PA AF Chelluri, Raju Kilchevsky, Amichai George, Arvin K. Sidana, Abhinav Frye, Thomas P. Su, Daniel Fascelli, Michele Ho, Richard Abboud, Steven F. Turkbey, Baris Merino, Maria J. Choyke, Peter L. Wood, Bradford J. Pinto, Peter A. TI Prostate Cancer Diagnosis on Repeat Magnetic Resonance Imaging-Transrectal Ultrasound Fusion Biopsy of Benign Lesions: Recommendations for Repeat Sampling SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; magnetic resonance imaging; ultrasound, high-intensity focused, transrectal; image-guided biopsy; watchful waiting ID GUIDED BIOPSY; MULTIPARAMETRIC MRI; ACTIVE SURVEILLANCE; NATURAL-HISTORY; NEGATIVE BIOPSY; FOLLOW-UP; PATHOLOGY; RISK AB Purpose: Urologists face a dilemma when a lesion identified on multiparametric magnetic resonance imaging is benign on image guided fusion biopsy. We investigated the detection rate of prostate cancer on repeat fusion biopsy in multiparametric magnetic resonance imaging lesions initially found to be pathologically benign on fusion biopsy. Materials and Methods: We reviewed the records of all patients from 2007 to 2014 who underwent multiparametric magnetic resonance imaging and image guided fusion biopsy. We identified men who underwent rebiopsy of the same discrete lesion after initial fusion biopsy results were benign. Data were documented on a per lesion basis. We manually reviewed UroNav system (Invivo, Gainesville, Florida) needle tracking to verify accurate image registration. Multivariate analysis was used to identify clinical and imaging factors predictive of prostate cancer detection at repeat fusion biopsy. Results: A total of 131 unique lesions were rebiopsied in 90 patients. Of these 131 resampled lesions 21 (16%) showed prostate cancer, which in 13 (61.9%) was Gleason 3 + 3. On multivariate analysis only lesion growth on repeat multiparametric magnetic resonance imaging was significantly associated with prostate cancer detection at repeat biopsy (HR 3.274, 95% CI 1.205-8.896, p = 0.02). Conclusions: Pathologically benign multiparametric magnetic resonance imaging lesions on initial image guided fusion biopsy are rarely found to harbor clinically significant prostate cancer on repeat biopsy. When prostate cancer was identified, most disease was low risk. An increase in lesion diameter was an independent predictor of prostate cancer detection. While these data are retrospective, they may provide some confidence in the reliability of negative initial image guided fusion biopsies despite a positive multiparametric magnetic resonance imaging finding. C1 [Chelluri, Raju; Kilchevsky, Amichai; George, Arvin K.; Sidana, Abhinav; Frye, Thomas P.; Su, Daniel; Fascelli, Michele; Ho, Richard; Abboud, Steven F.; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Wood, Bradford J.] NCI, Ctr Intervent Oncol, NIH, Bethesda, MD 20892 USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, 9000 Rockville Pike,Bldg 10,Room 1-5940, Bethesda, MD 20892 USA. EM pintop@mail.nih.gov NR 24 TC 3 Z9 3 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD JUL PY 2016 VL 196 IS 1 BP 62 EP 67 DI 10.1016/j.juro.2016.02.066 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA DO7HY UT WOS:000377954400023 PM 26880408 ER PT J AU Yang, CC Weinfurt, KP Merion, RM Kirkali, Z AF Yang, Claire C. Weinfurt, Kevin P. Merion, Robert M. Kirkali, Ziya CA LURN Study Grp TI Symptoms of Lower Urinary Tract Dysfunction Research Network SO JOURNAL OF UROLOGY LA English DT Article DE lower urinary tract symptoms; research; government agencies ID OVERACTIVE BLADDER; INCONTINENCE; WOMEN; MEN AB Purpose: To address gaps in understanding and treating lower urinary tract symptoms, the NIDDK created the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN). The goals of LURN are to work collaboratively to 1) identify and explain the important subtypes of lower urinary tract symptoms; 2) improve the measurement of patient experiences of lower urinary tract symptoms; 3) disseminate novel findings to researchers, clinicians and patients; and 4) generate data, research tools and biological samples for future studies. Materials and Methods: As a first step in understanding subtypes of lower urinary tract symptoms, LURN will focus on disorders of urinary sensation (eg urgency) and their causes. These are being examined with respect to patient experience, organism or systemic factors, genitourinary organs and tissues, and cellular/molecular factors. This is being achieved via an observational cohort study that is currently enrolling patients with lower urinary tract symptoms (target number 1,000) and that will extensively characterize patients with lower urinary tract symptoms. Future studies embedded within the observational cohort study will focus on neuroimaging and sensory testing, biomarkers and organ based factors. To advance the science of measurement of lower urinary tract symptoms, LURN is also developing and evaluating a comprehensive set of self-report questions to provide more granular assessments of lower urinary tract symptoms. Results: LURN has taken its first steps by developing a framework for studying lower urinary tract symptom subtypes. Conclusions: In developing this framework, LURN is choosing an initial domain on which to focus (sensory experiences), and creating and executing protocols designed to improve measurement of self-reported symptoms and identify patient subtypes. C1 [Yang, Claire C.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Weinfurt, Kevin P.] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA. [Merion, Robert M.] Univ Michigan, Arbor Res Collaborat Hlth, Ann Arbor, MI 48109 USA. [Merion, Robert M.] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA. [Kirkali, Ziya] NIDDK, NIH, Bethesda, MD 20892 USA. RP Kirkali, Z (reprint author), Div Kidney Urol & Hematol, Two Democracy Plaza,Room 627,6707 Democracy Blvd, Bethesda, MD 20892 USA. EM ziya.kirkali@nih.gov OI Flynn, Kathryn/0000-0002-4427-3583 FU Intramural NIH HHS [Z99 DK999999]; NIDDK NIH HHS [U01 DK097776, K12 DK100024, U01 DK097772, U01 DK097779, U01 DK097780, U01 DK099879, U01 DK099932, U01 DK100011, U01 DK100017] NR 12 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD JUL PY 2016 VL 196 IS 1 BP 146 EP 152 DI 10.1016/j.juro.2016.01.007 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA DO7HY UT WOS:000377954400063 PM 26784646 ER PT J AU Osafo, C Raji, YR Olanrewaju, T Mamven, M Arogundade, F Ajayi, S Ulasi, I Salako, B Plange-Rhule, J Mengistu, Y Mc'Ligeyo, SO Moturi, G Winkler, CA Moxey-Mims, MM Rasooly, RS Kimmel, P Adu, D Ojo, A Parekh, RS AF Osafo, Charlotte Raji, Yemi R. Olanrewaju, Timothy Mamven, Manmak Arogundade, Fatiu Ajayi, Samuel Ulasi, Ifeoma Salako, Babatunde Plange-Rhule, Jacob Mengistu, Yewondwossen Mc'Ligeyo, S. O. Moturi, George Winkler, Cheryl A. Moxey-Mims, Marva M. Rasooly, Rebekah S. Kimmel, Paul Adu, Dwomoa Ojo, Akinlolu Parekh, Rulan S. CA H3Africa Kidney Disease Res TI Genomic approaches to the burden of kidney disease in Sub-Saharan Africa: the Human Heredity and Health in Africa (H3Africa) Kidney Disease Research Network SO KIDNEY INTERNATIONAL LA English DT News Item DE Africa; APOL 1; chronic kidney disease; genomics ID APOL1 RISK VARIANTS C1 [Osafo, Charlotte; Adu, Dwomoa] Univ Ghana, Sch Med & Dent, Accra, Ghana. [Raji, Yemi R.; Salako, Babatunde] Univ Ibadan, Dept Med, Ibadan, Nigeria. [Olanrewaju, Timothy] Univ Ilorin, Dept Med, Ilorin, Nigeria. [Mamven, Manmak; Ajayi, Samuel] Univ Abuja, Dept Med, Teaching Hosp, Abuja, Nigeria. [Arogundade, Fatiu] Obafemi Awolowo Univ, Dept Med, Ife, Nigeria. [Ulasi, Ifeoma] Univ Nigeria, Dept Med, Enugu, Nigeria. [Plange-Rhule, Jacob] Kwame Nkrumah Univ Sci & Technol, Dept Med, Kumasi, Ghana. [Mengistu, Yewondwossen] Univ Addis Ababa, Dept Med, Addis Ababa, Ethiopia. [Mc'Ligeyo, S. O.; Moturi, George] Univ Nairobi, Dept Med, Nairobi, Kenya. [Winkler, Cheryl A.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Moxey-Mims, Marva M.; Rasooly, Rebekah S.; Kimmel, Paul] NIDDK, NIH, Bethesda, MD 20892 USA. [Ojo, Akinlolu] Univ Michigan, Sch Med, Dept Med, Ann Arbor, MI 48104 USA. [Parekh, Rulan S.] Univ Toronto, Hosp Sick Children, Dept Pediat, Univ Hlth Network, Toronto, ON M5G 1X8, Canada. [Parekh, Rulan S.] Univ Toronto, Hosp Sick Children, Dept Med, Univ Hlth Network, Toronto, ON M5G 1X8, Canada. RP Osafo, C (reprint author), Univ Ghana, POB 4236, Accra, Ghana. EM ceyosafo@gmail.com FU NHGRI NIH HHS [U54 HG006939] NR 9 TC 3 Z9 3 U1 3 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD JUL PY 2016 VL 90 IS 1 BP 2 EP 5 DI 10.1016/j.kint.2015.12.059 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA DO6YM UT WOS:000377929400001 PM 27312436 ER PT J AU Acuna-Villaorduna, C White, LF Fennelly, KP Jones-Lopez, EC AF Acuna-Villaorduna, Carlos White, Laura F. Fennelly, Kevin P. Jones-Lopez, Edward C. TI Tuberculosis transmission: sputum vs aerosols SO LANCET INFECTIOUS DISEASES LA English DT Letter ID MYCOBACTERIUM-TUBERCULOSIS C1 [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. [White, Laura F.] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA USA. [Fennelly, Kevin P.] NHLBI, Pulm Clin Med Sect, Cardiovasc & Pulm Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Fennelly, Kevin P.] 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-lopez@bmc.org NR 5 TC 0 Z9 0 U1 5 U2 5 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 JUL PY 2016 VL 16 IS 7 BP 770 EP 771 PG 4 WC Infectious Diseases SC Infectious Diseases GA DP2LH UT WOS:000378319600019 PM 27352747 ER PT J AU Cnops, L van Griensven, J Honko, AN Bausch, DG Sprecher, A Hill, CE Colebunders, R Johnson, JC Griffiths, A Palacios, GF Kraft, CS Kobinger, G Hewlett, A Norwood, DA Sabeti, P Jahrling, PB Formenty, P Kuhn, JH Arien, KK AF Cnops, Lieselotte van Griensven, Johan Honko, Anna N. Bausch, Daniel G. Sprecher, Armand Hill, Charles E. Colebunders, Robert Johnson, Joshua C. Griffiths, Anthony Palacios, Gustavo F. Kraft, Colleen S. Kobinger, Gary Hewlett, Angela Norwood, David A. Sabeti, Pardis Jahrling, Peter B. Formenty, Pierre Kuhn, Jens H. Arien, Kevin K. TI Essentials of filoviral load quantification SO LANCET INFECTIOUS DISEASES LA English DT Article ID EBOLA-VIRUS DISEASE; REVERSE TRANSCRIPTION-PCR; POINT-OF-CARE; VIRAL LOAD; INFECTIOUS-DISEASES; HEMORRHAGIC-FEVER; MARBURG VIRUS; SIERRA-LEONE; INTERNATIONAL STANDARD; SEXUAL TRANSMISSION AB Quantitative measurement of viral load is an important parameter in the management of filovirus disease outbreaks because viral load correlates with severity of disease, survival, and infectivity. During the ongoing Ebola virus disease outbreak in parts of Western Africa, most assays used in the detection of Ebola virus disease by more than 44 diagnostic laboratories yielded qualitative results. Regulatory hurdles involved in validating quantitative assays and the urgent need for a rapid Ebola virus disease diagnosis precluded development of validated quantitative assays during the outbreak. Because of sparse quantitative data obtained from these outbreaks, opportunities for study of correlations between patient outcome, changes in viral load during the course of an outbreak, disease course in asymptomatic individuals, and the potential for virus transmission between infected patients and contacts have been limited. We strongly urge the continued development of quantitative viral load assays to carefully evaluate these parameters in future outbreaks of filovirus disease. C1 [Cnops, Lieselotte; van Griensven, Johan] Inst Trop Med, Dept Clin Sci, B-2000 Antwerp, Belgium. [Honko, Anna N.; Johnson, Joshua C.; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, Div Clin Res, NIH, Frederick, MD USA. [Bausch, Daniel G.; Formenty, Pierre] WHO, CH-1211 Geneva, Switzerland. [Sprecher, Armand] Medecins Sans Frontieres Operat Ctr Brussels, Brussels, Belgium. [Hill, Charles E.] Emory Univ Hosp, Mol Diagnost Lab, 1364 Clifton Rd NE, Atlanta, GA 30322 USA. [Colebunders, Robert] Univ Antwerp, Fac Med & Hlth Sci, Global Hlth Inst, Int Hlth Unit, B-2020 Antwerp, Belgium. [Griffiths, Anthony] Texas Biomed Res Inst, Dept Virol & Immunol, San Antonio, TX USA. [Palacios, Gustavo F.; Norwood, David A.] US Army, Med Res Inst Infect Dis, Frederick, MD USA. [Kraft, Colleen S.] Emory Univ, Sch Med, Pathol & Lab Med, Atlanta, GA USA. [Kobinger, Gary] Univ Manitoba, Publ Hlth Agcy Canada, Natl Microbiol Lab, Winnipeg, MB, Canada. [Hewlett, Angela] Univ Nebraska Med Ctr, Omaha, NE USA. [Sabeti, Pardis] Harvard Univ, Dept Organism & Evolutionary Biol, FAS Ctr Syst Biol, Cambridge, MA 02138 USA. [Arien, Kevin K.] Inst Trop Med, Dept Biomed Sci, B-2000 Antwerp, Belgium. RP Arien, KK (reprint author), Inst Trop Med, Dept Biomed Sci, B-2000 Antwerp, Belgium. EM karien@itg.be RI Palacios, Gustavo/I-7773-2015; OI Palacios, Gustavo/0000-0001-5062-1938; Honko, Anna/0000-0001-9165-148X FU Battelle Memorial Institute; US National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200700016I]; European Union's Horizon research and innovation programme [666094] FX We thank Laura Bollinger (Battelle Memorial Institute, USA) for editing this paper. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, the US Department of Defense, the US Department of the Army, WHO, or the institutions and companies affiliated with the authors. This work was funded in part through Battelle Memorial Institute's prime contract with the US National Institute of Allergy and Infectious Diseases (NIAID) under Contract No. HHSN272200700016I. JCJ is an employee of Battelle Memorial Institute. A subcontractor to Battelle Memorial Institute who performed this work is: JHK, an employee of Tunnell Government Services Inc. LC holds an innovation mandate from the Agency for Innovation by Science and Technology (IWT) from the Flemish Government. JVG is supported by the European Union's Horizon 2020 research and innovation programme (grant agreement number 666094). NR 56 TC 2 Z9 2 U1 1 U2 6 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 JUL PY 2016 VL 16 IS 7 BP E134 EP E138 DI 10.1016/S1473-3099(16)30063-9 PG 5 WC Infectious Diseases SC Infectious Diseases GA DP2LH UT WOS:000378319600004 PM 27296694 ER PT J AU Lai, SJ Qin, Y Cowling, BJ Ren, X Wardrop, NA Gilbert, M Tsang, TK Wu, P Feng, LZ Jiang, H Peng, ZB Zheng, JD Liao, QH Li, S Horby, PW Farrar, JJ Gao, GF Tatem, AJ Yu, HJ AF Lai, Shengjie Qin, Ying Cowling, Benjamin J. Ren, Xiang Wardrop, Nicola A. Gilbert, Marius Tsang, Tim K. Wu, Peng Feng, Luzhao Jiang, Hui Peng, Zhibin Zheng, Jiandong Liao, Qiaohong Li, Sa Horby, Peter W. Farrar, Jeremy J. Gao, George F. Tatem, Andrew J. Yu, Hongjie TI Global epidemiology of avian influenza A H5N1 virus infection in humans, 1997-2015: a systematic review of individual case data SO LANCET INFECTIOUS DISEASES LA English DT Review ID TO-PERSON TRANSMISSION; RISK-FACTORS; A(H5N1) VIRUS; SUBTYPE H5N1; HONG-KONG; MAINLAND CHINA; H7N9 VIRUS; EGYPT; VACCINES; VIETNAM AB Avian influenza A H5N1 viruses have caused many, typically severe, human infections since the first human case was reported in 1997. However, no comprehensive epidemiological analysis of global human cases of H5N1 from 1997 to 2015 exists. Moreover, few studies have examined in detail the changing epidemiology of human H5N1 cases in Egypt, especially given the outbreaks since November, 2014, which have the highest number of cases ever reported worldwide in a similar period. Data on individual patients were collated from different sources using a systematic approach to describe the global epidemiology of 907 human H5N1 cases between May, 1997, and April, 2015. The number of affected countries rose between 2003 and 2008, with expansion from east and southeast Asia, then to west Asia and Africa. Most cases (67.2%) occurred from December to March, and the overall case-fatality risk was 483 (53.5%) of 903 cases which varied across geographical regions. Although the incidence in Egypt has increased dramatically since November, 2014, compared with the cases beforehand, there were no significant differences in the fatality risk, history of exposure to poultry, history of patient contact, and time from onset to hospital admission in the recent cases. C1 [Lai, Shengjie; Qin, Ying; Ren, Xiang; Feng, Luzhao; Jiang, Hui; Peng, Zhibin; Zheng, Jiandong; Liao, Qiaohong; Li, Sa; Yu, Hongjie] Chinese Ctr Dis Control & Prevent, Div Infect Dis, Key Lab Surveillance & Early Warning Infect Dis, Beijing, Peoples R China. [Lai, Shengjie; Wardrop, Nicola A.; Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. [Lai, Shengjie; Wardrop, Nicola A.] Flowminder Fdn, Stockholm, Sweden. [Cowling, Benjamin J.; Tsang, Tim K.; Wu, Peng] Univ Hong Kong, Li Ka Shing Fac Med, Sch Publ Hlth, WHO Collaborating Ctr Infect Dis Epidemiol & Cont, Hong Kong, Hong Kong, Peoples R China. [Gilbert, Marius] Univ Libre Bruxelles, Biol Control & Spatial Ecol, Brussels, Belgium. [Gilbert, Marius] Fonds Natl Rech Sci, Brussels, Belgium. [Horby, Peter W.; Farrar, Jeremy J.] Univ Oxford, Clin Res Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam. [Horby, Peter W.; Farrar, Jeremy J.] Univ Oxford, Dept Clin Med, Ctr Trop Med Nuffield, Oxford, England. [Horby, Peter W.; Farrar, Jeremy J.] Singapore Infect Dis Initiat, Singapore, Singapore. [Farrar, Jeremy J.] Univ Oxford, Churchill Hosp, Int Severe Acute Resp & Emerging Infect Consortiu, Ctr Trop Med, Oxford, England. [Gao, George F.] Chinese Acad Sci, Inst Microbiol, Key Lab Pathogen Microbiol & Immunol, Beijing, Peoples R China. [Gao, George F.] Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Yu, Hongjie] Fudan Univ, Sch Publ Hlth, Minist Educ, Key Lab Publ Hlth Safety, Shanghai 200032, Peoples R China. RP Yu, HJ (reprint author), Fudan Univ, Sch Publ Hlth, Minist Educ, Key Lab Publ Hlth Safety, Shanghai 200032, Peoples R China. EM cfetpyhj@vip.sina.com OI ren, xiang/0000-0001-5020-5838; Wu, Peng/0000-0003-1157-9401 FU National Science Fund for Distinguished Young Scholars [81525023]; US National Institutes of Health (Comprehensive International Program for Research on AIDS) [U19 AI51915]; Ministry of Science and Technology of China [2012 ZX10004-201, 2014BAI13B05]; Ministry of Health of China [201202006]; China CDCs Key Laboratory of Surveillance and Early-warning on Infectious Disease; Harvard Center for Communicable Disease Dynamics from the National Institute of General Medical Sciences [U54 GM088558]; Health and Medical Research Fund of the Health, Welfare and Food Bureau of the Hong Kong Government; University Grants Committee of Hong Kong, China [T11-705/14N]; Flowminder Foundation; University of Hong Kong; UK Medical Research Council [MR/J012343/1]; Wellcome Trust [089276/Z/09/Z, 089276/B/09/Z]; EU FP7 project PREPARE [602525]; National Institutes of Health National Institute of Allergy and Infectious Diseases [U19AI089674]; Bill & Melinda Gates Foundation [OPP1106427, 1032350]; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX We thank staff members at county-level, district-level, prefecture-level, and provincial-level Centers for Disease Control and Prevention at the provinces with human H5N1 cases for providing assistance with field investigation, administration, and data collection in China; and staff members from WHO, the Ministry of Health of Azerbaijan, and the Vietnam National Institute of Hygiene and Epidemiology for assistance in coordination of data collection. This study was supported by grants from the National Science Fund for Distinguished Young Scholars (81525023); the US National Institutes of Health (Comprehensive International Program for Research on AIDS grant U19 AI51915); the Ministry of Science and Technology of China (2012 ZX10004-201, 2014BAI13B05); the Ministry of Health of China (201202006); China CDCs Key Laboratory of Surveillance and Early-warning on Infectious Disease; the Harvard Center for Communicable Disease Dynamics from the National Institute of General Medical Sciences (U54 GM088558); a commissioned grant from the Health and Medical Research Fund of the Health, Welfare and Food Bureau of the Hong Kong Government; and the University Grants Committee of Hong Kong, China (project number T11-705/14N). SLa is supported by the Flowminder Foundation and the University of Hong Kong for his postgraduate research on population movement and infectious disease dynamics at the University of Southampton. NAW is supported by the UK Medical Research Council (MR/J012343/1). PWH is funded by the Wellcome Trust (grants 089276/Z/09/Z and 089276/B/09/Z) and the EU FP7 project PREPARE (602525). AJT is supported by funding from National Institutes of Health National Institute of Allergy and Infectious Diseases (U19AI089674); the Bill & Melinda Gates Foundation (OPP1106427, 1032350); the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; and the Fogarty International Center, National Institutes of Health. The funder of the study had no role in the study design, data collection, data analysis, data interpretation, writing of the report, or the decision to publish. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. The views expressed are those of the authors and do not necessarily represent the policy of the China CDC or the institutions with which the authors are affiliated. NR 97 TC 6 Z9 7 U1 15 U2 27 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 JUL PY 2016 VL 16 IS 7 BP E108 EP E118 DI 10.1016/S1473-3099(16)00153-5 PG 11 WC Infectious Diseases SC Infectious Diseases GA DP2LH UT WOS:000378319600001 PM 27211899 ER PT J AU Baltos, JA Paoletta, S Nguyen, ATN Gregory, KJ Tosh, DK Christopoulos, A Jacobson, KA May, LT AF Baltos, Jo-Anne Paoletta, Silvia Nguyen, Anh T. N. Gregory, Karen J. Tosh, Dilip K. Christopoulos, Arthur Jacobson, Kenneth A. May, Lauren T. TI Structure-Activity Analysis of Biased Agonism at the Human Adenosine A(3) Receptor SO MOLECULAR PHARMACOLOGY LA English DT Article ID FUNCTIONAL SELECTIVITY; INTERNATIONAL UNION; DRUG DISCOVERY; LIGANDS; EFFICACY; SUBSTITUTIONS; NUCLEOSIDES; MODULATION; ACTIVATION; QUANTIFICATION AB Biased agonism at G protein-coupled receptors (GPCRs) has significant implications for current drug discovery, but molecular determinants that govern ligand bias remain largely unknown. The adenosine A3 GPCR (A(3)AR) is a potential therapeutic target for various conditions, including cancer, inflammation, and ischemia, but for which biased agonism remains largely unexplored. We now report the generation of bias "fingerprints" for prototypical ribose containing A(3)AR agonists and rigidified (N)-methanocarba 5'-N-methyluronamide nucleoside derivatives with regard to their ability to mediate different signaling pathways. Relative to the reference prototypical agonist IB-MECA, (N)-methanocarba 5'-N-methyluronamide nucleoside derivatives with significant N-6 or C2 modifications, including elongated aryl-ethynyl groups, exhibited biased agonism. Significant positive correlation was observed between the C2 substituent length (in angstrom) and bias toward cell survival. Molecular modeling suggests that extended C2 substituents on (N)-methanocarba 5'-N-methyluronamide nucleosides promote a progressive outward shift of the A(3)AR transmembrane domain 2, which may contribute to the subset of A(3)AR conformations stabilized on biased agonist binding. C1 [Baltos, Jo-Anne; Nguyen, Anh T. N.; Gregory, Karen J.; Christopoulos, Arthur; May, Lauren T.] Monash Univ, Drug Discovery Biol, Monash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia. [Baltos, Jo-Anne; Nguyen, Anh T. N.; Gregory, Karen J.; Christopoulos, Arthur; May, Lauren T.] Monash Univ, Dept Pharmacol, Parkville, Vic 3052, Australia. [Paoletta, Silvia; Tosh, Dilip K.; Jacobson, Kenneth A.] Natl Inst Diabet & Digest & Kidney Dis, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD USA. RP May, LT (reprint author), Monash Univ, Drug Discovery Biol, 399 Royal Parade, Parkville, Vic 3052, Australia.; May, LT (reprint author), Monash Univ, Monash Inst Pharmaceut Sci, Dept Pharmacol, 399 Royal Parade, Parkville, Vic 3052, Australia. EM lauren.may@monash.edu RI Jacobson, Kenneth/A-1530-2009; OI Jacobson, Kenneth/0000-0001-8104-1493; Christopoulos, Arthur/0000-0003-4442-3294 FU National Institute of Diabetes and Digestive and Kidney Intramural Research Program FX The authors thank Drs. Michael Crouch and Ron Osmond for providing the ERK 1/2 phosphorylation assay kit. K.A.J., D.K.T., and S.P. thank the National Institute of Diabetes and Digestive and Kidney Intramural Research Program for support. NR 53 TC 1 Z9 1 U1 1 U2 9 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUL PY 2016 VL 90 IS 1 BP 12 EP 22 DI 10.1124/mol.116.103283 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DO9EQ UT WOS:000378087600002 PM 27136943 ER PT J AU Frank, GA Shukla, S Rao, P Borgnia, MJ Bartesaghi, A Merk, A Mobin, A Esser, L Earl, LA Gottesman, MM Xia, D Ambudkar, SV Subramaniam, S AF Frank, Gabriel A. Shukla, Suneet Rao, Prashant Borgnia, Mario J. Bartesaghi, Alberto Merk, Alan Mobin, Aerfa Esser, Lothar Earl, Lesley A. Gottesman, Michael M. Xia, Di Ambudkar, Suresh V. Subramaniam, Sriram TI Cryo-EM Analysis of the Conformational Landscape of Human P-glycoprotein (ABCB1) During its Catalytic Cycle SO MOLECULAR PHARMACOLOGY LA English DT Article ID BINDING CASSETTE TRANSPORTER; ATP HYDROLYSIS; MULTIDRUG TRANSPORTER; ELECTRON-MICROSCOPY; NUCLEOTIDE; EXPRESSION; TURNOVER; SYSTEM; CELLS; STATE AB The multidrug transporter P-glycoprotein (P-gp, ABCB1) is an ATP-dependent pump that mediates the efflux of structurally diverse drugs and xenobiotics across cell membranes, affecting drug pharmacokinetics and contributing to the development of multidrug resistance. Structural information about the conformational changes in human P-gp during the ATP hydrolysis cycle has not been directly demonstrated, although mechanistic information has been inferred from biochemical and biophysical studies conducted with P-gp and its orthologs, or from structures of other ATP-binding cassette transporters. Using single-particle cryo-electron microscopy, we report the surprising discovery that, in the absence of the transport substrate and nucleotides, human P-gp can exist in both open [nucleotide binding domains (NBDs) apart; inwardfacing] and closed (NBDs close; outward-facing) conformations. We also probe conformational states of human P-gp during the catalytic cycle, and demonstrate that, following ATP hydrolysis, P-gp transitions through a complete closed conformation to a complete open conformation in the presence of ADP. C1 [Frank, Gabriel A.; Shukla, Suneet; Rao, Prashant; Borgnia, Mario J.; Bartesaghi, Alberto; Merk, Alan; Mobin, Aerfa; Esser, Lothar; Earl, Lesley A.; Gottesman, Michael M.; Xia, Di; Ambudkar, Suresh V.; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. RP Ambudkar, SV (reprint author), 37 Convent Dr,Rm 2120,MSC 4256, Bethesda, MD 20892 USA.; Subramaniam, S (reprint author), 50 South Dr,Rm 4306,MSC 8008, Bethesda, MD 20892 USA. EM ambudkar@helix.nih.gov; ss1@nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; NIH-FEI Living Laboratory for Structural Biology; Center for Cancer Research Center for Molecular Microscopy FX This work was supported by funds from the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, the NIH-FEI Living Laboratory for Structural Biology, and the Center for Cancer Research Center for Molecular Microscopy. NR 37 TC 4 Z9 4 U1 2 U2 8 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUL PY 2016 VL 90 IS 1 BP 35 EP 41 DI 10.1124/mol.116.104190 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DO9EQ UT WOS:000378087600004 PM 27190212 ER PT J AU Chuang, YF An, Y Bilgel, M Wong, DF Troncoso, JC O'Brien, RJ Breitner, JC Ferruci, L Resnick, SM Thambisetty, M AF Chuang, Y-F An, Y. Bilgel, M. Wong, D. F. Troncoso, J. C. O'Brien, R. J. Breitner, J. C. Ferruci, L. Resnick, S. M. Thambisetty, M. TI Midlife adiposity predicts earlier onset of Alzheimer's dementia, neuropathology and presymptomatic cerebral amyloid accumulation SO MOLECULAR PSYCHIATRY LA English DT Article ID BODY-MASS INDEX; MILD COGNITIVE IMPAIRMENT; OLDER-ADULTS; LATE-LIFE; MEDITERRANEAN DIET; GLOBAL BURDEN; RISK-FACTOR; AGING BLSA; DISEASE; OBESITY AB Understanding how midlife risk factors influence age at onset (AAO) of Alzheimer's disease (AD) may provide clues to delay disease expression. Although midlife adiposity predicts increased incidence of AD, it is unclear whether it affects AAO and severity of Alzheimer's neuropathology. Using a prospective population-based cohort, Baltimore Longitudinal Study of Aging (BLSA), this study aims to examine the relationships between midlife body mass index (BMI) and (1) AAO of AD (2) severity of Alzheimer's neuropathology and (3) fibrillar brain amyloid deposition during aging. We analyzed data on 1394 cognitively normal individuals at baseline (8643 visits; average follow-up interval 13.9 years), among whom 142 participants developed incident AD. In two subsamples of BLSA, 191 participants underwent autopsy and neuropathological assessment, and 75 non-demented individuals underwent brain amyloid imaging. Midlife adiposity was derived from BMI data at 50 years of age. We find that each unit increase in midlife BMI predicts earlier onset of AD by 6.7 months (P = 0.013). Higher midlife BMI was associated with greater Braak neurofibrillary but not CERAD (Consortium to Establish a Registry for Alzheimer's Disease) neuritic plaque scores at autopsy overall. Associations between midlife BMI and brain amyloid burden approached statistical significance. Thus, higher midlife BMI was also associated with greater fibrillar amyloid measured by global mean cortical distribution volume ratio (P = 0.075) and within the precuneus (left, P = 0.061; right, P = 0.079). In conclusion, midlife overweight predicts earlier onset of AD and greater burden of Alzheimer's neuropathology. A healthy BMI at midlife may delay the onset of AD. C1 [Chuang, Y-F; Thambisetty, M.] NIA, Clin & Translat Neurosci Unit, Lab Behav Neurosci, NIH, Room 4B-311,251 Bayview Blvd, Baltimore, MD 21224 USA. [Chuang, Y-F] Natl Yang Ming Univ, Inst Publ Hlth, Taipei 112, Taiwan. [Chuang, Y-F] Far Eastern Mem Hosp, Dept Psychiat, New Taipei, Taiwan. [An, Y.; Bilgel, M.; Ferruci, L.; Resnick, S. M.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Bilgel, M.] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA. [Wong, D. F.] Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA. [Wong, D. F.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci & Neurosci, Baltimore, MD USA. [Troncoso, J. C.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [O'Brien, R. J.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Breitner, J. C.] Douglas Mental Hlth Univ Inst, Res Ctr, Ctr Studies Prevent Alzheimers Dis, Montreal, PQ, Canada. RP Thambisetty, M (reprint author), NIA, Clin & Translat Neurosci Unit, Lab Behav Neurosci, NIH, Room 4B-311,251 Bayview Blvd, Baltimore, MD 21224 USA. EM thambisettym@mail.nih.gov FU Intramural Research Program, National Institute on Aging, National Institutes of Health; [HHSN-260-2004-00012C] FX We are grateful to the Baltimore Longitudinal Study of Aging participants and neuroimaging staff for their dedication to these studies and the staff of the Johns Hopkins University PET facility for their assistance. This work was supported in part by research and development contract HHSN-260-2004-00012C and the Intramural Research Program, National Institute on Aging, National Institutes of Health. NR 48 TC 4 Z9 4 U1 4 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUL PY 2016 VL 21 IS 7 BP 910 EP 915 DI 10.1038/mp.2015.129 PG 6 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DO9DX UT WOS:000378085600007 PM 26324099 ER PT J AU Rennekamp, AJ Huang, XP Wang, Y Patel, S Lorello, PJ Cade, L Gonzales, APW Yeh, JRJ Caldarone, BJ Roth, BL Kokel, D Peterson, RT AF Rennekamp, Andrew J. Huang, Xi-Ping Wang, You Patel, Samir Lorello, Paul J. Cade, Lindsay Gonzales, Andrew P. W. Yeh, Jing-Ruey Joanna Caldarone, Barbara J. Roth, Bryan L. Kokel, David Peterson, Randall T. TI sigma(1) receptor ligands control a switch between passive and active threat responses SO NATURE CHEMICAL BIOLOGY LA English DT Article ID ZEBRAFISH DANIO-RERIO; FORCED SWIMMING TEST; DEPRESSIVE-LIKE; KNOCKOUT MICE; SCHIZOPHRENIA; FEAR; MODULATION; AGONISTS; AMYGDALA; BIOLOGY AB Humans and many animals show 'freezing' behavior in response to threatening stimuli. In humans, inappropriate threat responses are fundamental characteristics of several mental illnesses. To identify small molecules that modulate threat responses, we developed a high-throughput behavioral assay in zebrafish (Danio rerio) and evaluated 10,000 compounds for their effects on freezing behavior. We found three classes of compounds that switch the threat response from freezing to escape-like behavior. We then screened these for binding activity across 45 candidate targets. Using target profile clustering, we identified the sigma-1 (sigma(1)) receptor as having a role in the mechanism of behavioral switching and confirmed that known ligands also disrupt freezing behavior. Furthermore, mutation of the gene encoding sigma(1) prevented the behavioral effect of escape-inducing compounds. One compound, which we call finazine, potently bound mammalian sigma(1) and altered threat-response behavior in mice. Thus, pharmacological and genetic interrogation of the freezing response revealed sigma(1) as a mediator of threat responses in vertebrates. C1 [Rennekamp, Andrew J.; Wang, You; Patel, Samir; Cade, Lindsay; Gonzales, Andrew P. W.; Yeh, Jing-Ruey Joanna; Peterson, Randall T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Rennekamp, Andrew J.; Wang, You; Patel, Samir; Cade, Lindsay; Gonzales, Andrew P. W.; Yeh, Jing-Ruey Joanna; Peterson, Randall T.] Massachusetts Gen Hosp, Dept Med, Charlestown, MA USA. [Rennekamp, Andrew J.; Wang, You; Patel, Samir; Cade, Lindsay; Gonzales, Andrew P. W.; Yeh, Jing-Ruey Joanna; Peterson, Randall T.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Rennekamp, Andrew J.; Wang, You; Patel, Samir; Cade, Lindsay; Gonzales, Andrew P. W.; Peterson, Randall T.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. [Rennekamp, Andrew J.; Wang, You; Patel, Samir; Cade, Lindsay; Gonzales, Andrew P. W.; Peterson, Randall T.] Broad Inst, Cambridge, MA USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, NIMH, Psychoact Drug Screening Program, Chapel Hill, NC USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC USA. [Lorello, Paul J.; Caldarone, Barbara J.] Brigham & Womens Hosp, Neurobehav Lab, Harvard NeuroDiscovery Ctr, 75 Francis St, Boston, MA 02115 USA. [Lorello, Paul J.; Caldarone, Barbara J.] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Roth, Bryan L.] Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC USA. [Kokel, David] Univ Calif San Francisco, Dept Physiol, Box 0444, San Francisco, CA USA. RP Peterson, RT (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA.; Peterson, RT (reprint author), Massachusetts Gen Hosp, Dept Med, Charlestown, MA USA.; Peterson, RT (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA USA.; Peterson, RT (reprint author), Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA.; Peterson, RT (reprint author), Broad Inst, Cambridge, MA USA. EM peterson@cvrc.mgh.harvard.edu OI Rennekamp , Andrew /0000-0001-6174-7253 FU US National Institutes of Health (NIH) Psychoactive Drug Screening Program [HHSN-271-2008-025C]; NIH [T32 HL 007208, R01 MH 086867, R01 GM 088040, U01 MH 105027]; Charles and Ann Sanders MGH Research Scholar Award; Harvard NeuroDiscovery Center FX We thank C. Brady, J.J. Colund, I.T. Helenius, Y.N. Jin and A. Nath for helpful comments. Receptor binding profiles and Ki data were provided by the US National Institutes of Health (NIH) Psychoactive Drug Screening Program, contract HHSN-271-2008-025C. This work was supported by NIH grants T32 HL 007208 (A.J.R.), R01 MH 086867 (R.T.P.), R01 GM 088040 (R.T.P.) and U01 MH 105027 (D.K. and J.-R.J.Y.); the Charles and Ann Sanders MGH Research Scholar Award (R.T.P.); and the Harvard NeuroDiscovery Center. NR 37 TC 3 Z9 3 U1 5 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD JUL PY 2016 VL 12 IS 7 BP 552 EP + DI 10.1038/NCHEMBIO.2089 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DO9EP UT WOS:000378087500016 PM 27239788 ER PT J AU Bruni, G Rennekamp, AJ Velenich, A McCarroll, M Gendelev, L Fertsch, E Taylor, J Lakhani, P Lensen, D Evron, T Lorello, PJ Huang, XP Kolczewski, S Carey, G Caldarone, BJ Prinssen, E Roth, BL Keiser, MJ Peterson, RT Kokel, D AF Bruni, Giancarlo Rennekamp, Andrew J. Velenich, Andrea McCarroll, Matthew Gendelev, Leo Fertsch, Ethan Taylor, Jack Lakhani, Parth Lensen, Dennis Evron, Tama Lorello, Paul J. Huang, Xi-Ping Kolczewski, Sabine Carey, Galen Caldarone, Barbara J. Prinssen, Eric Roth, Bryan L. Keiser, Michael J. Peterson, Randall T. Kokel, David TI Zebrafish behavioral profiling identifies multitarget antipsychotic-like compounds SO NATURE CHEMICAL BIOLOGY LA English DT Article ID PSYCHIATRIC DRUG DISCOVERY; LARVAL ZEBRAFISH; SMALL MOLECULES; CNS DISORDERS; IN-VIVO; CLOZAPINE; PHENCYCLIDINE; SCHIZOPHRENIA; SEROTONIN; DOPAMINE AB Many psychiatric drugs act on multiple targets and therefore require screening assays that encompass a wide target space. With sufficiently rich phenotyping and a large sampling of compounds, it should be possible to identify compounds with desired mechanisms of action on the basis of behavioral profiles alone. Although zebrafish (Danio rerio) behavior has been used to rapidly identify neuroactive compounds, it is not clear what types of behavioral assays would be necessary to identify multitarget compounds such as antipsychotics. Here we developed a battery of behavioral assays in larval zebrafish to determine whether behavioral profiles can provide sufficient phenotypic resolution to identify and classify psychiatric drugs. Using the antipsychotic drug haloperidol as a test case, we found that behavioral profiles of haloperidol-treated zebrafish could be used to identify previously uncharacterized compounds with desired antipsychotic-like activities and multitarget mechanisms of action. C1 [Bruni, Giancarlo; Rennekamp, Andrew J.; Peterson, Randall T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Bruni, Giancarlo; Velenich, Andrea; Lensen, Dennis; Evron, Tama; Carey, Galen] Teleos Therapeut, Medford, MA USA. [Rennekamp, Andrew J.; Peterson, Randall T.] Massachusetts Gen Hosp, Div Cardiol, Dept Med, Charlestown, MA USA. [Rennekamp, Andrew J.; Peterson, Randall T.] Harvard Univ, Sch Med, Dept Syst Biol, Charlestown, MA USA. [Rennekamp, Andrew J.; Peterson, Randall T.] Broad Inst, Cambridge, MA USA. [McCarroll, Matthew; Fertsch, Ethan; Taylor, Jack; Lakhani, Parth; Kokel, David] Univ Calif San Francisco, Dept Physiol, Box 0444, San Francisco, CA USA. [McCarroll, Matthew; Gendelev, Leo; Fertsch, Ethan; Taylor, Jack; Lakhani, Parth; Keiser, Michael J.; Kokel, David] Univ Calif San Francisco, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA. [Gendelev, Leo; Keiser, Michael J.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA USA. [Gendelev, Leo; Keiser, Michael J.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Lorello, Paul J.; Caldarone, Barbara J.] Brigham & Womens Hosp, Neurobehav Lab, Harvard NeuroDiscovery Ctr, 75 Francis St, Boston, MA 02115 USA. [Lorello, Paul J.; Caldarone, Barbara J.] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, NIMH Psychoact Drug Screening Program, Chapel Hill, NC USA. [Kolczewski, Sabine; Prinssen, Eric] Roche Innovat Ctr Basel, Roche Pharmaceut Res & Early Dev, Basel, Switzerland. RP Kokel, D (reprint author), Univ Calif San Francisco, Dept Physiol, Box 0444, San Francisco, CA USA.; Kokel, D (reprint author), Univ Calif San Francisco, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA. EM david.kokel@ucsf.edu OI Keiser, Michael/0000-0002-1240-2192; Bruni, Giancarlo/0000-0003-2850-4633; Rennekamp , Andrew /0000-0001-6174-7253 FU US National Institutes of Health (NIH) [K01MH091449, U01MH105027, R01AA022583, R44GM093456, T32EB009383, T32GM008284, R01MH086867, R21MH085205]; Charles and Ann Sanders MGH Research Scholar Award; Glenn Foundation Award for Research in Biological Mechanisms of Aging FX We thank members of our research groups for helpful advice. This work was supported by US National Institutes of Health (NIH) grants K01MH091449, U01MH105027 and R01AA022583 (D.K.); R44GM093456 (M.J.K.), T32EB009383 and T32GM008284 (L.G.) and R01MH086867 and R21MH085205 (R.T.P.); the Charles and Ann Sanders MGH Research Scholar Award (R.T.P.); and the Glenn Foundation Award for Research in Biological Mechanisms of Aging (D.K. and M.J.K.). NR 52 TC 3 Z9 3 U1 6 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD JUL PY 2016 VL 12 IS 7 BP 559 EP + DI 10.1038/NCHEMBIO.2097 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DO9EP UT WOS:000378087500017 PM 27239787 ER PT J AU Roychoudhuri, R Clever, D Li, P Wakabayashi, Y Quinn, KM Klebanoff, CA Ji, Y Sukumar, M Eil, RL Yu, ZY Spolski, R Palmer, DC Pan, JH Patel, SJ Macallan, DC Fabozzi, G Shih, HY Kanno, Y Muto, A Zhu, J Gattinoni, L O'Shea, JJ Okkenhaug, K Igarashi, K Leonard, WJ Restifo, NP AF Roychoudhuri, Rahul Clever, David Li, Peng Wakabayashi, Yoshiyuki Quinn, Kylie M. Klebanoff, Christopher A. Ji, Yun Sukumar, Madhusudhanan Eil, Robert L. Yu, Zhiya Spolski, Rosanne Palmer, Douglas C. Pan, Jenny H. Patel, Shashank J. Macallan, Derek C. Fabozzi, Giulia Shih, Han-Yu Kanno, Yuka Muto, Akihiko Zhu, Jun Gattinoni, Luca O'Shea, John J. Okkenhaug, Klaus Igarashi, Kazuhiko Leonard, Warren J. Restifo, Nicholas P. TI BACH2 regulates CD8(+) T cell differentiation by controlling access of AP-1 factors to enhancers SO NATURE IMMUNOLOGY LA English DT Article ID TRANSCRIPTION FACTORS; EXPRESSION ANALYSIS; MEMORY PHENOTYPE; REPRESSOR BACH2; C-JUN; EFFECTOR; LYMPHOCYTES; GENE; DNA; ACTIVATION AB T cell antigen receptor (TCR) signaling drives distinct responses depending on the differentiation state and context of CD8(+) T cells. We hypothesized that access of signal-dependent transcription factors (TFs) to enhancers is dynamically regulated to shape transcriptional responses to TCR signaling. We found that the TF BACH2 restrains terminal differentiation to enable generation of long-lived memory cells and protective immunity after viral infection. BACH2 was recruited to enhancers, where it limited expression of TCR-driven genes by attenuating the availability of activator protein-1 (AP-1) sites to Jun family signal-dependent TFs. In naive cells, this prevented TCR-driven induction of genes associated with terminal differentiation. Upon effector differentiation, reduced expression of BACH2 and its phosphorylation enabled unrestrained induction of TCR-driven effector programs. C1 [Roychoudhuri, Rahul; Clever, David; Klebanoff, Christopher A.; Ji, Yun; Sukumar, Madhusudhanan; Eil, Robert L.; Yu, Zhiya; Palmer, Douglas C.; Pan, Jenny H.; Patel, Shashank J.; Fabozzi, Giulia; Gattinoni, Luca; Restifo, Nicholas P.] NCI, NIH, Bethesda, MD 20892 USA. [Roychoudhuri, Rahul; Okkenhaug, Klaus] Babraham Inst, Lab Lymphocyte Signalling & Dev, Cambridge, England. [Clever, David] Ohio State Univ, Coll Med, Med Scientist Training Program, Columbus, OH 43210 USA. [Li, Peng; Spolski, Rosanne; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. [Li, Peng; Spolski, Rosanne; Leonard, Warren J.] NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. [Wakabayashi, Yoshiyuki; Zhu, Jun] NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Quinn, Kylie M.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD USA. [Macallan, Derek C.] St Georges Univ London, Inst Infect & Immun, London, England. [Shih, Han-Yu; Kanno, Yuka; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Muto, Akihiko; Igarashi, Kazuhiko] Tohoku Univ, Dept Biochem, Grad Sch Med, Sendai, Miyagi 980, Japan. [Muto, Akihiko; Igarashi, Kazuhiko] Japan Agcy Med Res & Dev, AMED CREST, Tokyo, Japan. [Restifo, Nicholas P.] Georgetown Univ, Med Ctr, Grad Program Microbiol & Immunol, Washington, DC 20007 USA. RP Roychoudhuri, R; Restifo, NP (reprint author), NCI, NIH, Bethesda, MD 20892 USA.; Roychoudhuri, R (reprint author), Babraham Inst, Lab Lymphocyte Signalling & Dev, Cambridge, England.; Restifo, NP (reprint author), Georgetown Univ, Med Ctr, Grad Program Microbiol & Immunol, Washington, DC 20007 USA. EM rahul.roychoudhuri@babraham.ac.uk; restifo@nih.gov RI Gattinoni, Luca/A-2281-2008; Roychoudhuri, Rahul/A-7442-2010; Ji, Yun/B-7245-2009; OI Gattinoni, Luca/0000-0003-2239-3282; Roychoudhuri, Rahul/0000-0002-5392-1853; Ji, Yun/0000-0001-6340-7009; Igarashi, Kazuhiko/0000-0002-2470-2475; Okkenhaug, Klaus/0000-0002-9432-4051 FU Intramural Research Program of the NCI; Intramural Research Program of the NHLBI; Wellcome Trust/Royal Society grant [105663/Z/14/Z]; UK Biotechnology and Biological Sciences Research Council [BB/N007794/1] FX We thank S.A. Rosenberg, K. Hanada, K. Hirahara, K. Mousavi, H. Zare, V. Sartorelli, N. Van Panhuys, S. Kerkar and A. Restifo for ideas and discussion, A. Mixon and S. Farid for expertise with cell sorting, members of the NHLBI sequencing core facility for help with sequencing, L. Samsel for help with ImageStream imaging flow cytometry and G. McMullen for expertise with mouse handling. Supported by the Intramural Research Programs of the NCI and NHLBI, Wellcome Trust/Royal Society grant 105663/Z/14/Z (R.R.) and UK Biotechnology and Biological Sciences Research Council grant BB/N007794/1 (R.R. and K.O.). NR 57 TC 12 Z9 12 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD JUL PY 2016 VL 17 IS 7 BP 851 EP + DI 10.1038/ni.3441 PG 12 WC Immunology SC Immunology GA DP1XR UT WOS:000378283200018 PM 27158840 ER PT J AU Chatterjee, N Shi, JX Garcia-Closas, M AF Chatterjee, Nilanjan Shi, Jianxin Garcia-Closas, Montserrat TI Developing and evaluating polygenic risk prediction models for stratified disease prevention SO NATURE REVIEWS GENETICS LA English DT Review ID GENOME-WIDE ASSOCIATION; BREAST-CANCER RISK; SINGLE-NUCLEOTIDE POLYMORPHISMS; GENE-ENVIRONMENT INTERACTIONS; FAMILY-HISTORY; COMMON SNPS; SUSCEPTIBILITY LOCI; MYOCARDIAL-INFARCTION; LEVERAGING PLEIOTROPY; MULTIPLE-SCLEROSIS AB Knowledge of genetics and its implications for human health is rapidly evolving in accordance with recent events, such as discoveries of large numbers of disease susceptibility loci from genome-wide association studies, the US Supreme Court ruling of the non-patentability of human genes, and the development of a regulatory framework for commercial genetic tests. In anticipation of the increasing relevance of genetic testing for the assessment of disease risks, this Review provides a summary of the methodologies used for building, evaluating and applying risk prediction models that include information from genetic testing and environmental risk factors. Potential applications of models for primary and secondary disease prevention are illustrated through several case studies, and future challenges and opportunities are discussed. C1 [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. [Chatterjee, Nilanjan; Shi, Jianxin; Garcia-Closas, Montserrat] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 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.; Chatterjee, N (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM nilanjan@jhu.edu FU National Cancer Institute, part of the US National Institutes of Health; Bloomberg Distinguished Professorship endowment from Johns Hopkins University FX The research was supported by intramural funding from the National Cancer Institute, which is part of the US National Institutes of Health, and a Bloomberg Distinguished Professorship endowment from Johns Hopkins University. NR 113 TC 8 Z9 9 U1 13 U2 29 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 EI 1471-0064 J9 NAT REV GENET JI Nat. Rev. Genet. PD JUL PY 2016 VL 17 IS 7 BP 392 EP 406 DI 10.1038/nrg.2016.27 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA DO9EZ UT WOS:000378088700011 PM 27140283 ER PT J AU McDonald, SM Nelson, MI Turner, PE Patton, JT AF McDonald, Sarah M. Nelson, Martha I. Turner, Paul E. Patton, John T. TI Reassortment in segmented RNA viruses: mechanisms and outcomes SO NATURE REVIEWS MICROBIOLOGY LA English DT Review ID INFLUENZA-A VIRUS; GROUP C ROTAVIRUS; GENOMIC SEGMENTS; PHYLOGENETIC ANALYSIS; BACTERIOPHAGE PHI-6; REVERSE GENETICS; RIBONUCLEOPROTEIN COMPLEXES; POLYMERASE SUBUNITS; PACKAGING SIGNALS; BLUETONGUE VIRUS AB Segmented RNA viruses are widespread in nature and include important human, animal and plant pathogens, such as influenza viruses and rotaviruses. Although the origin of RNA virus genome segmentation remains elusive, a major consequence of this genome structure is the capacity for reassortment to occur during co-infection, whereby segments are exchanged among different viral strains. Therefore, reassortment can create viral progeny that contain genes that are derived from more than one parent, potentially conferring important fitness advantages or disadvantages to the progeny virus. However, for segmented RNA viruses that package their multiple genome segments into a single virion particle, reassortment also requires genetic compatibility between parental strains, which occurs in the form of conserved packaging signals, and the maintenance of RNA and protein interactions. In this Review, we discuss recent studies that examined the mechanisms and outcomes of reassortment for three well-studied viral families - Cystoviridae, Orthomyxoviridae and Reoviridae - and discuss how these findings provide new perspectives on the replication and evolution of segmented RNA viruses. C1 [McDonald, Sarah M.] Virginia Tech, Carilion Sch Med & Res Inst, 2 Riverside Circle, Roanoke, VA 24016 USA. [McDonald, Sarah M.] Virginia Maryland Coll Vet Med, Dept Biomed Sci & Pathobiol, 205 Duck Pond Dr, Blacksburg, VA 24061 USA. [Nelson, Martha I.] NIH, Fogarty Int Ctr, 31 Ctr Dr,MSC 2220, Bethesda, MD 20892 USA. [Turner, Paul E.] Yale Univ, Osborn Mem Labs, Dept Ecol & Evolutionary Biol, 165 Prospect St,POB 208106, New Haven, CT 06520 USA. [Patton, John T.] Univ Maryland, Virginia Maryland Coll Vet Med, 8075 Greenmead Dr, College Pk, MD 20742 USA. RP McDonald, SM (reprint author), Virginia Tech, Carilion Sch Med & Res Inst, 2 Riverside Circle, Roanoke, VA 24016 USA.; McDonald, SM (reprint author), Virginia Maryland Coll Vet Med, Dept Biomed Sci & Pathobiol, 205 Duck Pond Dr, Blacksburg, VA 24061 USA. EM mcdonaldsa@vtc.vt.edu FU Virginia Tech Carilion School of Medicine and Research Institute; US National Institutes of Health (NIH) [R01AI116815, R21AI113402, R21AI119588]; US National Science Foundation BEACON Center for Study of Evolution in Action; NIH [R01AI09164601]; University of Maryland, College Park, USA FX S.M.M. receives financial support from the Virginia Tech Carilion School of Medicine and Research Institute and the US National Institutes of Health (NIH; grants R01AI116815, R21AI113402 and R21AI119588). P.E.T. receives financial support from the US National Science Foundation BEACON Center for Study of Evolution in Action and the NIH (grant R01AI09164601). J.T.P. is supported by funding from the University of Maryland, College Park, USA. NR 135 TC 5 Z9 5 U1 10 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1740-1526 EI 1740-1534 J9 NAT REV MICROBIOL JI Nat. Rev. Microbiol. PD JUL PY 2016 VL 14 IS 7 BP 448 EP 460 DI 10.1038/nrmicro.2016.46 PG 13 WC Microbiology SC Microbiology GA DO8ZD UT WOS:000378073200010 PM 27211789 ER PT J AU Maynard, KR Hill, JL Calcaterra, NE Palko, ME Kardian, A Paredes, D Sukumar, M Adler, BD Jimenez, DV Schloesser, RJ Tessarollo, L Lu, B Martinowich, K AF Maynard, Kristen R. Hill, Julia L. Calcaterra, Nicholas E. Palko, Mary E. Kardian, Alisha Paredes, Daniel Sukumar, Mahima Adler, Benjamin D. Jimenez, Dennisse V. Schloesser, Robert J. Tessarollo, Lino Lu, Bai Martinowich, Keri TI Functional Role of BDNF Production from Unique Promoters in Aggression and Serotonin Signaling SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID NEUROTROPHIC FACTOR TRANSCRIPTS; DEPRESSION-RELATED BEHAVIORS; ADULT-RAT HIPPOCAMPUS; MESSENGER-RNA; DIFFERENTIAL REGULATION; SYNAPTIC PLASTICITY; MULTIPLE PROMOTERS; SPLICE VARIANTS; VISUAL-CORTEX; BRAIN AB Brain-derived neurotrophic factor (BDNF) regulates diverse biological functions ranging from neuronal survival and differentiation during development to synaptic plasticity and cognitive behavior in the adult. BDNF disruption in both rodents and humans is associated with neurobehavioral alterations and psychiatric disorders. A unique feature of Bdnf transcription is regulation by nine individual promoters, which drive expression of variants that encode an identical protein. It is hypothesized that this unique genomic structure may provide flexibility that allows different factors to regulate BDNF signaling in distinct cell types and circuits:This has led to the suggestion that isoforms may regulate specific BDNF-dependent functions; however, little scientific support for this idea exists. We generated four novel mutant mouse lines in which BDNF production from one of the four major promoters (I, II, IV, or VI) is selectively disrupted (Bdnf-e I, -e2,-e4, and -e6 mice) and used a comprehensive comparator approach to determine whether different Bdnf transcnpts are associated with specific BDNF-dependent molecular, cellular, and behavioral phenotypes. Bdnf-e I and -e2 mutant males displayed heightened aggression accompanied by convergent expression changes in specific genes associated with serotonin signaling. In contrast, BDNF-e4 and -e6 mutants were not aggressive but displayed impairments associated with GABAergic gene expression. Moreover, quantifications of BDNF protein in the hypothalamus, prefrontal cortex, and hippocampus revealed that individual Bdnf transcripts make differential, region specific contributions to total BDNF levels. The results highlight the biological significance of alternative Bdnf transcripts and provide evidence that individual isoforms serve distinct molecular and behavioral functions. C1 [Maynard, Kristen R.; Hill, Julia L.; Calcaterra, Nicholas E.; Kardian, Alisha; Paredes, Daniel; Sukumar, Mahima; Adler, Benjamin D.; Jimenez, Dennisse V.; Schloesser, Robert J.; Martinowich, Keri] Lieber Inst Brain Dev, Johns Hopkins Med Campus,855 North Wolfe St, Baltimore, MD 21205 USA. [Palko, Mary E.; Tessarollo, Lino] NCI, Frederick, MD 21701 USA. [Schloesser, Robert J.] Sheppard Pratt Lieber Res Inst, Baltimore, MD USA. [Lu, Bai] Tsinghua Univ, Sch Med, Beijing 100084, Peoples R China. [Martinowich, Keri] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Martinowich, Keri] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Martinowich, K (reprint author), Lieber Inst Brain Dev, Johns Hopkins Med Campus,855 North Wolfe St, Baltimore, MD 21205 USA. EM kerimartinowich@libd.org RI Martinowich, Keri/F-9841-2012; OI Hill, Julia/0000-0003-4744-0532 FU Lieber Institute for Brain Development; Intramural Program of the National Institute of Mental Health; Intramural Program for the National Cancer Institute; National Institute of Mental Health [MH105592]; Brain and Behavior Research Foundation FX We thank Ragini Ganjoo and Nicholas Hardy for technical assistance, and Dr Daniel Weinberger for critical reading of the manuscript. Funding for these studies was provided by the Lieber Institute for Brain Development, the Intramural Program of the National Institute of Mental Health, and the Intramural Program for the National Cancer Institute. Additional funding awards from the National Institute of Mental Health (PI: KM, MH105592) and the Brain and Behavior Research Foundation (PI: KM, Young Investigator Award) partially supported these studies. NR 59 TC 3 Z9 3 U1 9 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUL PY 2016 VL 41 IS 8 BP 1943 EP 1955 DI 10.1038/npp.2015.349 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DO5SJ UT WOS:000377842800002 PM 26585288 ER PT J AU McLaughlin, KA Sheridan, MA Gold, AL Duys, A Lambert, HK Peverill, M Heleniak, C Shechner, T Wojcieszak, Z Pine, DS AF McLaughlin, Katie A. Sheridan, Margaret A. Gold, Andrea L. Duys, Andrea Lambert, Hilary K. Peverill, Matthew Heleniak, Charlotte Shechner, Tomer Wojcieszak, Zuzanna Pine, Daniel S. TI Maltreatment Exposure, Brain Structure, and Fear Conditioning in Children and Adolescents SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; NEURAL DEVELOPMENT DEPRIVATION; ANXIETY DISORDERS; STRESS REACTIVITY; CONDUCT DISORDER; EARLY EXPERIENCE; THREAT; CORTEX; PTSD; AMYGDALA AB Alterations in leaming processes and the neural circuitry that supports fear conditioning and extinction represent mechanisms through which trauma exposure might influence risk for psychopathology. Few studies examine how trauma or neural structure relates to fear conditioning in children. Children (n = 94) aged 6-18 years, 40.4% (n = 38) with exposure to maltreatment (physical abuse, sexual abuse, or domestic violence), completed a fear conditioning paradigm utilizing blue and yellow bells-as conditioned stimuli (CS+/CS -) and an aversive alarm noise as the unconditioned stimulus. Skin conductance responses (SCR) and self-reported fear were acquired. Magnetic resonance imaging data were acquired from 60 children. children without maltreatment exposure exhibited strong differential conditioning to the CS+ vs CS -, based on SCR and self-reported fear. In contrast, maltreated children exhibited blunted SCR to the CS+ and failed to exhibit differential SCR to the CS+ vs CS - during early conditioning. Amygdala and hippocampal volume were reduced among children with maltreatment exposure and were negatively associated with SCR to the CS+ during early conditioning in the total sample, although thdse associations were negative only among non-maltreated children and were positive among maltreated children. The association of maltreatment with externalizing psychopathology was mediated by this perturbed pattern of fear conditioning. Child maltreatment is associated with failure to discriminate between threat and safety cues during fear conditioning in children. Poor threat safety discrimination might reflect either enhanced fear generalization or a deficit in associative leaming, which may in turn represent a central mechanism underlying the development of maltreatment-related externalizing psychopathology in children. C1 [McLaughlin, Katie A.; Duys, Andrea; Lambert, Hilary K.; Peverill, Matthew; Heleniak, Charlotte] Univ Washington, Dept Psychol, Box 351525, Seattle, WA 98195 USA. [Sheridan, Margaret A.] Univ N Carolina, Dept Psychol, Chapel Hill, NC USA. [Gold, Andrea L.; Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. [Shechner, Tomer] Univ Haifa, Dept Psychol, IL-31999 Haifa, Israel. [Wojcieszak, Zuzanna] Temple Univ, Dept Psychol, Philadelphia, PA 19122 USA. RP McLaughlin, KA (reprint author), Univ Washington, Dept Psychol, Box 351525, Seattle, WA 98195 USA. EM mclaughk@uw.edu OI Gold, Andrea/0000-0003-4447-776X; McLaughlin, Katie/0000-0002-1362-2410 FU NARSAD Young Investigator Award from the Brain and Behavior Foundation; National Institute of Mental Health [K01-MH092526, R01-MH103291, K01-MH092555]; National Institute of Child Health and Human Development [U54 HD083091]; Bezos Family Foundation; Intramural Research Program of the National Institutes of Health FX This research was supported by a NARSAD Young Investigator Award from the Brain and Behavior Foundation to McLaughlin and grants from the National Institute of Mental Health (K01-MH092526 and R01-MH103291 to KA McLaughlin and K01-MH092555 to MA Sheridan), the National Institute of Child Health and Human Development (U54 HD083091 to the University of Washington's Center on Human Development and Disability), and the Bezos Family Foundation to KA McLaughlin and MA Sheridan. These funders provided support for data collection and analysis. In addition, this research was supported in part by the Intramural Research Program of the National Institutes of Health. Drs. McLaughlin, Sheridan, and Pine have received compensation for activities related to teaching, editing, and clinical care that pose no conflicts of interest. The authors declare no conflict of interest. NR 51 TC 4 Z9 4 U1 10 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUL PY 2016 VL 41 IS 8 BP 1956 EP 1964 DI 10.1038/npp.2015.365 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DO5SJ UT WOS:000377842800003 PM 26677946 ER PT J AU Haney, M Malcolm, RJ Babalonis, S Nuzzo, PA Cooper, ZD Bedi, G Gray, KM McRae-Clarke, A Lofwall, MR Sparenborg, S Walsh, SL AF Haney, Margaret Malcolm, Robert J. Babalonis, Sharma Nuzzo, Paul A. Cooper, Ziva D. Bedi, Gillinder Gray, Kevin M. McRae-Clarke, Aimee Lofwall, Michelle R. Sparenborg, Steven Walsh, Sharon L. TI Oral Cannabidiol does not Alter the Subjective, Reinforcing or Cardiovascular Effects of Smoked Cannabis SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID NEURAL-BASIS; OROMUCOSAL SPRAY; DOUBLE-BLIND; DELTA-9-TETRAHYDROCANNABINOL; MARIJUANA; THC; ANXIETY; PHARMACOKINETICS; DELTA(9)-TETRAHYDROCANNABINOL; TETRAHYDROCANNABINOL AB Cannabidiol (CBD), a constituent of cannabis with few psychoactive effects, has been reported in some studies to attenuate certain aspects of Delta(9)-tetrahydrocannabinol (THC) intoxication. However, most studies have tested only one dose of CBD in combination with one dose of oral THC, making it difficult to assess the nature of this interaction. Further, the effect of oral CBD on smoked cannabis administration is unknown. The objective of this multi-site, randomized, double-blind, within-subject laboratory study was to assess the influence of CBD (0, 200, 400, 800 mg, p.o.) pretreatment on the reinforcing, subjective, cognitive, and physiological effects of smoked cannabis (0.01 (inactive), 5.30-5.80% THC). Nbn-treatment-seeking, healthy cannabis smokers (n = 3I; 17M, 14 F) completed eight outpatient sessions. CBD was administered 90 min prior to cannabis administration. The behavioral and cardiovascular effects of cannabis were measured at baseline and repeatedly throughout the session. A subset of participants (n = 8) completed an additional session to measure' plasma CBD concentrations after administration of the highest CBD dose (800 mg). Under placebo CBD conditions, active cannabis (I) was self-administered by significantly more participants than placebo cannabis and (2) produced significant, time-dependent increases in ratings of 'High', 'Good Effect', ratings of the cannabis cigarette (eg, strength, liking), and heart rate relative to inactive cannabis. CBD, which alone produced no significant psychoactive or cardiovascular effects, did not significantly alter any of these outcomes. Cannabis self-administration, subjective effects, and cannabis ratings did not vary as a function of CBD dose relative to placebo capsules. These findings suggest that oral CBD does not reduce the reinforcing, physiological, or positive subjective effects of smoked cannabis. C1 [Haney, Margaret; Cooper, Ziva D.; Bedi, Gillinder] New York State Psychiat Inst & Hosp, Div Subst Abuse, 1051 Riverside Dr,Unit 120, New York, NY 10032 USA. [Haney, Margaret; Cooper, Ziva D.; Bedi, Gillinder] Columbia Univ, Med Ctr, Dept Psychiat, 1051 Riverside Dr,Unit 120, New York, NY 10032 USA. [Malcolm, Robert J.; Gray, Kevin M.; McRae-Clarke, Aimee] Med Univ S Carolina, Charleston, SC 29425 USA. [Babalonis, Sharma; Nuzzo, Paul A.; Lofwall, Michelle R.; Walsh, Sharon L.] Univ Kentucky, Lexington, KY USA. [Sparenborg, Steven] NIDA, Bethesda, MD 20892 USA. RP Haney, M (reprint author), New York State Psychiat Inst & Hosp, Div Subst Abuse, 1051 Riverside Dr,Unit 120, New York, NY 10032 USA.; Haney, M (reprint author), Columbia Univ, Med Ctr, Dept Psychiat, 1051 Riverside Dr,Unit 120, New York, NY 10032 USA. EM mh235@columbia.edu FU US National Institute on Drug Abuse [DA009236, U10DA013727, U10DA13732]; Insys Therapeutics; Aelis Farma; Lifeloc Technologies; Forest Pharmaceuticals; Supernus Pharmaceuticals and Merck FX This research was supported by the US National Institute on Drug Abuse (DA009236, U10DA013727, U10DA13732). We also thank NIDA for supplying the cannabis to conduct this study, and Dr Hari Singh, PhD at NIDA for facilitating the analysis of plasma CBD concentrations by Dr David Moody, PhD at University of Utah (NIDA contract #NO1DA-14-7788). Many thanks to Dr Richard W Foltin (CUMC) and Dr Thomas H Kelly (UK) for their support in conducting this study, and to the expert contributions of Dr Adam Bisaga, Olivia Derella (CUMC), Dr Samy Claude Elayi, Tori Votaw, and Cleeve Emurian (UK). This research was funded by NIDA. Dr Haney has received research support from Aelis Farma and Lifeloc Technologies, and along with Dr Cooper, has received research support from investigator-initiated studies from Insys Therapeutics. Dr Cooper serves as a consultant to KannaLife Sciences and PharmaCann, LLC. Dr McRae-Clark has received research support from Forest Pharmaceuticals (medication only). Dr Gray has received research funding from Supernus Pharmaceuticals and Merck, for unrelated research. NR 52 TC 1 Z9 1 U1 8 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUL PY 2016 VL 41 IS 8 BP 1974 EP 1982 DI 10.1038/npp.2015.367 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DO5SJ UT WOS:000377842800005 PM 26708108 ER PT J AU Davis, RJ Van Waes, C Allen, CT AF Davis, Ruth J. Van Waes, Carter Allen, Clint T. TI Overcoming barriers to effective immunotherapy: MDSCs, TAMs, and Tregs as mediators of the immunosuppressive microenvironment in head and neck cancer SO ORAL ONCOLOGY LA English DT Article DE Immunity; Antigenicity; Immunogenicity; Immunotherapy ID REGULATORY T-CELLS; TUMOR-ASSOCIATED MACROPHAGES; MYELOID SUPPRESSOR-CELLS; ANTITUMOR IMMUNE-RESPONSES; HOST ENVIRONMENT PROMOTES; ORAL SQUAMOUS CARCINOMA; HEPATOCELLULAR-CARCINOMA; CYTOKINES IL-1-ALPHA; DEPENDENT MECHANISM; INTERFERON-GAMMA AB A significant subset of head and neck cancers display a T-cell inflamed phenotype, suggesting that patients with these tumors should respond to therapeutic approaches aimed at strengthening antitumor immune responses. A major barrier to the development of an effective anti-tumor immune response, at baseline or in response to immunotherapy, is the development of an immunosuppressive tumor microenvironment. Several well described mechanisms of effector immune cell suppression in the head and neck cancer microenvironment are discussed here, along with updates on current trials designed to translate what we have learned from pre-clinical and correlative clinical studies into improved responses in patients with head and neck cancer following immune activating therapies. Published by Elsevier Ltd. C1 [Davis, Ruth J.; Van Waes, Carter; Allen, Clint T.] Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD USA. [Allen, Clint T.] Johns Hopkins Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD USA. RP Allen, CT (reprint author), 10 Ctr Dr,CRC 4-2740, Bethesda, MD 20892 USA. EM clint.allen@nih.gov OI Davis, Ruth/0000-0001-9592-932X FU Intramural NIH HHS [ZIA DC000087-01]; NIDCD NIH HHS [R01 DC000087] NR 130 TC 0 Z9 0 U1 4 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 EI 1879-0593 J9 ORAL ONCOL JI Oral Oncol. PD JUL PY 2016 VL 58 BP 59 EP 70 DI 10.1016/j.oraloncology.2016.05.002 PG 12 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA DO7AV UT WOS:000377935500015 PM 27215705 ER PT J AU El-Maouche, D Dumitrescu, CE Andreopoulou, P Gafni, RI Brillante, BA Bhattacharyya, N Fedarko, NS Collins, MT AF El-Maouche, D. Dumitrescu, C. E. Andreopoulou, P. Gafni, R. I. Brillante, B. A. Bhattacharyya, N. Fedarko, N. S. Collins, M. T. TI Stability and degradation of fibroblast growth factor 23 (FGF23): the effect of time and temperature and assay type SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Assay; FGF23; Immutopics; Kainos; Stability ID FAMILIAL TUMORAL CALCINOSIS; O-GLYCOSYLATION; FIBROBLAST-GROWTH-FACTOR-23; HYPERPHOSPHATEMIA; HYPOPHOSPHATEMIA; OSTEOMALACIA; MUTATIONS; INTACT; SERUM AB There is growing need for a reliable assay for measuring fibroblast growth factor 23 (FGF23), a regulator of phosphorus and vitamin D. In this work, we analyze and compare the performance of three available assays, including the effect of temperature and time. This knowledge will allow for better understanding of FGF23 in the future. Intact and C-terminal FGF23 (iFGF23 and cFGF23) concentrations are important in the diagnosis of hypo- and hyperphosphatemic diseases. The effects of temperature, storage, and specimen handling on FGF23 levels are not well known. We investigated the effects of various factors on plasma and serum measurement of FGF23 using three different assays. Serum and plasma FGF23 were measured using three commercially available ELISA assays-two measuring iFGF23 and one measuring cFGF23. Samples from subjects with known FGF23 disorders were stored at 4, 22, and 37 A degrees C and analyzed at different intervals up to 48 hours (h). A subset of samples underwent repeated freeze-thaw cycles, and samples frozen at -80 A degrees C for up to 60 months were reanalyzed. The effect of adding a furin convertase inhibitor on FGF23 degradation was investigated using samples stored at 37 A degrees C for 48 h. Intact FGF23 levels were measured from plasma samples of four different groups to test the correlation of the two assays. Plasma FGF23 levels were stable when stored at 4 and 22 A degrees C for 48 h. Both plasma and serum FGF23 levels demonstrated relative stability after five freeze-thaw cycles. Long-term storage at -80 A degrees C for 40 months induced some variability in FGF23 levels. The addition of a furin inhibitor did not affect FGF23 degradation. Intact FGF23 levels showed good correlation only at the upper limit of the assay range when comparing the two assays. Sample type, handling, and choice of assay are factors that affect FGF23 levels and should be considered when measuring this hormone. C1 [El-Maouche, D.] Univ Miami, Miller Sch Med, Dept Med, Div Endocrinol Diabet & Metab, Miami, FL 33136 USA. [El-Maouche, D.; Gafni, R. I.; Brillante, B. A.; Collins, M. T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [Dumitrescu, C. E.] Alice Hyde Med Ctr, Div Endocrinol, Malone, NY USA. [Andreopoulou, P.] Hosp Special Surg, Endocrine Serv, Dept Med, 535 E 70th St, New York, NY 10021 USA. [Bhattacharyya, N.] NCI, Thorac & GI Oncol Branch, NIH, Bethesda, MD 20892 USA. [Fedarko, N. S.] Johns Hopkins Univ, Dept Med, Div Geriatr Med & Gerontol, Baltimore, MD USA. RP Collins, MT (reprint author), Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. EM mcollins@dir.nidcr.nih.gov OI Fedarko, Neal/0000-0001-6055-6279 FU Division of Intramural Research, National Institute of Dental and Craniofacial Research; National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD FX This study was supported by the Division of Intramural Research, National Institute of Dental and Craniofacial Research, and the National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD. NR 23 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD JUL PY 2016 VL 27 IS 7 BP 2345 EP 2353 DI 10.1007/s00198-016-3543-5 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DO8AQ UT WOS:000378004800021 PM 26928188 ER PT J AU Filipski, KK Pacanowski, MA Ramamoorthy, A Feero, WG Freedman, AN AF Filipski, Kelly K. Pacanowski, Michael A. Ramamoorthy, Anuradha Feero, William Gregory Freedman, Andrew N. TI Dosing recommendations for pharmacogenetic interactions related to drug metabolism SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE biomarkers; drug labeling; drug-metabolizing enzymes; pharmacogenomics ID EGAPP-WORKING-GROUP; IMPLEMENTATION CONSORTIUM; GUIDELINE AB Objective Pharmacogenomic studies have established the important contribution of drug-metabolizing enzyme genotype toward drug toxicity and treatment failure; however, clinical implementation of pharmacogenomics has been slow. The aim of this study was to systematically review the information on drug-metabolizing enzyme pharmacogenomics available in the US drug labeling, practice guidelines, and recommendations. Methods Drug-metabolizing enzyme genotype and phenotype information was assessed in US FDA drug labeling, clinical practice guidelines, and independent technology assessors to evaluate the consistency in information sources for healthcare providers. Results Eighty four gene-drug pairs were identified as having drug-metabolizing enzyme genotype or phenotype information within the label. The manner in which pharmacogenomic information was presented was heterogeneous both within the label and between clinical practice recommendations. Conclusion For proper implementation of pharmacogenomics in clinical practice, information sources for healthcare providers should relay consistent and clear information for the appropriate use of biomarkers. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Filipski, Kelly K.; Freedman, Andrew N.] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. [Pacanowski, Michael A.; Ramamoorthy, Anuradha] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Feero, William Gregory] Maine Dartmouth Family Med Residency Program, Augusta, ME USA. RP Filipski, KK (reprint author), 9609 Med Ctr Dr Room 4E228, Rockville, MD 20850 USA. EM kelly.filipski@nih.gov FU US Department of Energy; CDER FX A.R. was supported by an appointment to the Oak Ridge Institute for Science and Education (ORISE) Research Participation Program at the Center for Drug Evaluation and Research administered by the ORISE through an agreement between the US Department of Energy and CDER. NR 22 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1744-6872 EI 1744-6880 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD JUL PY 2016 VL 26 IS 7 BP 334 EP 339 DI 10.1097/FPC.0000000000000220 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA DO3MA UT WOS:000377684500003 PM 27058883 ER PT J AU Gebreab, SY Riestra, P Gaye, A Khan, RJ Xu, RH Davis, AR Quarells, RC Davis, SK Gibbons, GH AF Gebreab, Samson Y. Riestra, Pia Gaye, Amadou Khan, Rumana J. Xu, Ruihua Davis, Adam R. Quarells, Rakale C. Davis, Sharon K. Gibbons, Gary H. TI Perceived neighborhood problems are associated with shorter telomere length in African American women SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE African Americans; Cellular aging; Telomere length; Psychosocial stress; Perceived neighborhood environments ID SOCIOECONOMIC-STATUS; OXIDATIVE STRESS; HEALTH BEHAVIORS; MENTAL-HEALTH; LIFE STRESS; ATHEROSCLEROSIS; DISORDER; DISEASE; DISADVANTAGE; DISPARITIES AB Objectives: African Americans (AA) experience higher levels of stress related to living in racially segregated and poor neighborhoods. However, little is known about the associations between perceived neighborhood environments and cellular aging among adult AA. This study examined whether perceived neighborhood environments were associated with telomere length (TL) in AA after adjustment for individual-level risk factors. Methods: The analysis included 158 women and 75 men AA aged 30-55 years from the Morehouse School of Medicine Study. Relative TL (T/S ratio) was measured from peripheral blood leukocytes using quantitative real-time polymerase chain reaction. Multivariable linear regression models were used to examine the associations of perceived neighborhood social cohesion, problems, and overall unfavorable perceptions with log-TL. Results: Women had significantly longer TL than men (0.59 vs. 0.54, p = 0.012). After controlling for sociodemographic, and biomedical and psychosocial factors, a 1-SD increase in perceived neighborhood problems was associated with 7.3% shorter TL in women (Mean Difference [MD] = -0.073 (Standard Error = 0.03), p = 0.012). Overall unfavorable perception of neighborhood was also associated with 5.9% shorter TL among women (MD = 0.059(0.03),p = 0.023). Better perceived social cohesion were associated with 2.4% longer TL, but did not reach statistical significance (MD = 0.024(0.02), p = 0.218). No association was observed between perceived neighborhood environments and TL in men. Conclusions: Our findings suggest that perceived neighborhood environments may be predictive of cellular aging in AA women even after accounting for individual-level risk factors. Additional research with a larger sample is needed to determine whether perceived neighborhood environments are causally related to TL. Published by Elsevier Ltd. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.orgilicensesiby-nc-nd/4.0/). C1 [Gebreab, Samson Y.; Riestra, Pia; Gaye, Amadou; Khan, Rumana J.; Xu, Ruihua; Davis, Adam R.; Davis, Sharon K.; Gibbons, Gary H.] NHGRI, Metab Cardiovasc & Inflammatory Dis Genom Branch, Cardiovasc Sect, NIH, Bethesda, MD 20892 USA. [Quarells, Rakale C.] Morehouse Sch Med, Community Hlth & Prevent Med, Cardiovasc Res Inst, Atlanta, GA 30310 USA. RP Gebreab, SY (reprint author), NHGRI, NIH, Metab Cardiovasc & Inflammatory Dis Genom Branch, Cardiovasc Dis Sect,Social Epidemiol Res Unit, 10 Ctr Dr,Room 7N316,MSC 1644, Bethesda, MD 20892 USA. EM samson.gebreab@nih.gov OI Gaye, Amadou/0000-0002-1180-2792 FU Intramural Program of National Human Genomics Institute, National Institutes of Health; National Institute on Minority Health and Health Disparities [1RC4MD005964-01] FX This research is supported by Intramural Program of National Human Genomics Institute, National Institutes of Health. The MH-GRID study was supported by the National Institute on Minority Health and Health Disparities (1RC4MD005964-01). We also thank Cancer Genomics Research laboratory (CGR) for performing telomere assay for our study and we also wish to thank Casey Dagnall for her helpful comments on telomere length measurements. NR 54 TC 1 Z9 1 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD JUL PY 2016 VL 69 BP 90 EP 97 DI 10.1016/j.psyneuen.2016.03.018 PG 8 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA DO4CH UT WOS:000377728900011 PM 27070760 ER PT J AU Kim, EJ Yin, XY Fontes, JD Magnani, JW Lubitz, SA McManus, DD Seshadri, S Vasan, RS Ellinor, PT Larson, MG Benjamin, EJ Rienstra, M AF Kim, Eun-Jeong Yin, Xiaoyan Fontes, Joao D. Magnani, Jared W. Lubitz, Steve A. McManus, David D. Seshadri, Sudha Vasan, Ramachandran S. Ellinor, Patrick T. Larson, Martin G. Benjamin, Emelia J. Rienstra, Michiel TI Atrial fibrillation without comorbidities: Prevalence, incidence and prognosis (from the Framingham Heart Study) SO AMERICAN HEART JOURNAL LA English DT Article ID 30-YEAR FOLLOW-UP; RISK-FACTOR; PROGRESSION; SURVIVAL; DISEASE; CURVES AB Background The epidemiology of atrial fibrillation (AF) without comorbidities, known as 'lone AF', is uncertain. Although it has been considered a benign condition, we hypothesized that it confers a worse prognosis compared with a matched sample without AF. Methods We described the proportion of AF without comorbidities (clinical, subclinical cardiovascular disease and triggers) among the entire AF sample in Framingham Heart Study (FHS). We compared AF without comorbidities with typical AF, and age-, sex-and cohort-matched individuals without AF, using Cox proportional hazards analysis in relation to combined cardiovascular events (stroke, heart failure, myocardial infarction), and mortality. Results Of 10,311 FHS participants, 1,961 were diagnosed with incident AF, among which 173 individuals had AF without comorbidities (47% women, mean age 71 +/- 12 years). AF without comorbidities had a prevalence of 1.7% of the entire cohort, and an annual incidence of 0.5 per 1000 person-years. During a median follow-up of 9.7 years after initial AF, 137 individuals with AF without comorbidities (79.2%) died and 141 individuals developed cardiovascular events (81.5%). AF without comorbidities had significantly lower mortality (HR 0.67, 95% CI 0.55-0.81, P < .001) and total cardiovascular events (HR 0.66, 95% CI 0.55-0.80, P < .001) compared with typical AF. However, mortality (HR1.43, 95% CI 1.18-1.75, P < .001) and risk of total cardiovascular events (HR 1.73, 95% CI 1.39-2.16, P < .001) were higher than age-, sex-, and cohort-matched individuals without AF. Conclusions The risk of cardiovascular outcomes and mortality among individuals with AF without comorbidities is lower than typical AF, but is significantly elevated compared with matched individuals without AF. C1 [Kim, Eun-Jeong] Massachusetts Gen Hosp, Dept Med, Gen Internal Med Sect, Boston, MA 02114 USA. [Yin, Xiaoyan; Fontes, Joao D.; Magnani, Jared W.; Seshadri, Sudha; Vasan, Ramachandran S.; Larson, Martin G.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Yin, Xiaoyan; Fontes, Joao D.; Magnani, Jared W.; Seshadri, Sudha; Vasan, Ramachandran S.; Larson, Martin G.; Benjamin, Emelia J.] Boston Univ Framingham Heart Study, Framingham, MA USA. [Magnani, Jared W.; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc Med, Boston, MA 02215 USA. [Lubitz, Steve A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Lubitz, Steve A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Lubitz, Steve A.; Ellinor, Patrick T.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [McManus, David D.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [McManus, David D.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. [Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med, Boston, MA 02118 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Rienstra, Michiel] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands. RP Rienstra, M (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands. EM m.rienstra@umcg.nl OI Ramachandran, Vasan/0000-0001-7357-5970; Rienstra, Michiel/0000-0002-2581-070X FU Doris Duke Charitable Foundation [2014105]; NCATS NIH HHS [UL1 TR001453]; NCRR NIH HHS [KL2 RR031981]; NHLBI NIH HHS [N01 HC025195, HHSN268201500001C, HHSN268201500001I, K23 HL114724, N01HC25195, R01 HL092577, R01 HL102214, R15 HL121761, RC1 HL101056]; NINDS NIH HHS [R01 NS017950] NR 24 TC 1 Z9 1 U1 5 U2 10 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 JUL PY 2016 VL 177 BP 138 EP 144 DI 10.1016/j.ahj.2016.03.023 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO0MN UT WOS:000377473100018 PM 27297859 ER PT J AU Stolzenberg, S Michino, M LeVine, MV Weinstein, H Shi, L AF Stolzenberg, Sebastian Michino, Mayako LeVine, Michael V. Weinstein, Harel Shi, Lei TI Computational approaches to detect allosteric pathways in transmembrane molecular machines SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Article DE Molecular dynamics; Allosteric interaction network; Transmembrane protein ID PROTEIN-COUPLED RECEPTOR; GLUTAMATE TRANSPORTER HOMOLOG; NEUROTRANSMITTER SODIUM SYMPORTERS; AMINO-ACID TRANSPORTERS; CRYSTAL-STRUCTURE; NETWORK ANALYSIS; ION-BINDING; BIOMOLECULAR SIMULATIONS; CONFORMATIONAL DYNAMICS; FUNCTIONAL SELECTIVITY AB Many of the functions of transmembrane proteins involved in signal processing and transduction across the cell membrane are determined by allosteric couplings that propagate the functional effects well beyond the original site of activation. Data gathered from breakthroughs in biochemistry, crystallography, and single molecule fluorescence have established a rich basis of information for the study of molecular mechanisms in the allosteric couplings of such transmembrane proteins. The mechanistic details of these couplings, many of which have therapeutic implications, however, have only become accessible in synergy with molecular modeling and simulations. Here, we review some recent computational approaches that analyze allosteric coupling networks (ACNs) in transmembrane proteins, and in particular the recently developed Protein Interaction Analyzer (PIA) designed to study ACNs in the structural ensembles sampled by molecular dynamics simulations. The power of these computational approaches in interrogating the functional mechanisms of transmembrane proteins is illustrated with selected examples of recent experimental and computational studies pursued synergistically in the investigation of secondary active transporters and GPCRs. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov. Published by Elsevier B.V. C1 [Stolzenberg, Sebastian] Computat Mol Biol Grp, Inst Math, Arnimallee 6, D-14195 Berlin, Germany. [Stolzenberg, Sebastian; LeVine, Michael V.; Weinstein, Harel; Shi, Lei] Cornell Univ, Dept Physiol & Biophys, Weill Med Coll, New York, NY 10065 USA. [Stolzenberg, Sebastian] Cornell Univ, Dept Phys, Ithaca, NY 14850 USA. [Michino, Mayako; Shi, Lei] NIDA, Computat Chem & Mol Biophys Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Weinstein, Harel] Cornell Univ, Inst Computat Biomed, Weill Med Coll, New York, NY 10065 USA. RP Shi, L (reprint author), 333 Cassell Dr,Room 1121, Baltimore, MD 21224 USA. EM lei.shi2@nih.gov FU Intramural Research Program of the NIH, NIDA [ZIA DA000606-01]; DRS/Marie Curie Post-Doctoral POINT Fellowship [608829]; Ruth L. Kirschstein National Research Service Award [F31DA035533]; NIH [P01 DA012408, U54 GM087519, R01 MH054137, R01 DA035263]; XSEDE (Stampede supercomputer) [TG-MCB090132, TG-MCB120008]; Office of Science of the U.S. Department of Energy [DE-AC05-00OR22725, DE-AC02-05CH11231]; [PSCA14026P] FX This research was supported in part by Intramural Research Program of the NIH, NIDA (LS and MM) (ZIA DA000606-01). SS is supported by a DRS/Marie Curie Post-Doctoral POINT Fellowship (608829). MVL is supported by Ruth L. Kirschstein National Research Service Award F31DA035533. HW gratefully acknowledges support of research described herein from NIH grants P01 DA012408, U54 GM087519, R01 MH054137, and R01 DA035263, and the computational resources used at XSEDE (Stampede supercomputer, projects TG-MCB090132, TG-MCB120008); at the Oak Ridge Leadership Computing Facility (ALCC allocation BIP109) supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC05-00OR22725; an allocation at the National Energy Research Scientific Computing Center (NERSC, repository m1710) supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231; an allocation on the Anton supercomputer (grant number PSCA14026P); and the computational resources of the David A. Cofrin Center for Biomedical Information in the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine at Weill Cornell Medical College. NR 110 TC 7 Z9 7 U1 2 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 EI 0006-3002 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD JUL PY 2016 VL 1858 IS 7 SI SI BP 1652 EP 1662 DI 10.1016/j.bbamem.2016.01.010 PN B PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DN7CP UT WOS:000377233200010 PM 26806157 ER PT J AU Noskov, SY Rostovtseva, TK Chamberlin, AC Teijido, O Jiang, W Bezrukov, SM AF Noskov, Sergei Yu. Rostovtseva, Tatiana K. Chamberlin, Adam C. Teijido, Oscar Jiang, Wei Bezrukov, Sergey M. TI Current state of theoretical and experimental studies of the voltage-dependent anion channel (VDAC) SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Article DE VDAC; Molecular Dynamics simulations; Brownian Dynamics simulations; Mitochondrial transport; Beta-barrel channel reconstitution; pH regulation ID FACILITATED MEMBRANE-TRANSPORT; MITOCHONDRIAL OUTER-MEMBRANE; MOLECULAR-DYNAMICS METHOD; FREE-ENERGY CALCULATIONS; REPLICA EXCHANGE METHOD; ISCHEMIA-REPERFUSION INJURY; PROTEIN-FOLDING SIMULATION; HISTOGRAM ANALYSIS METHOD; BROWNIAN DYNAMICS; ION PERMEATION AB Voltage-dependent anion channel (VDAC), the major channel of the mitochondrial outer membrane provides a controlled pathway for respiratory metabolites in and out of the mitochondria. In spite of the wealth of experimental data from structural, biochemical, and biophysical investigations, the exact mechanisms governing selective ion and metabolite transport, especially the role of titratable charged residues and interactions with soluble cytosolic proteins, remain hotly debated in the field. The computational advances hold a promise to provide a much sought-after solution to many of the scientific disputes around solute and ion transport through VDAC and hence, across the mitochondrial outer membrane. In this review, we examine how Molecular Dynamics, Free Energy, and Brownian Dynamics simulations of the large beta-barrel channel, VDAC, advanced our understanding. We will provide a short overview of non-conventional techniques and also discuss examples of how the modeling excursions into VDAC biophysics prospectively aid experimental efforts. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov. (C) 2016 Elsevier B.V. All rights reserved. C1 [Noskov, Sergei Yu.] Univ Calgary, Dept Biol Sci, 2500 Univ Dr N-W, Calgary, AB T2N 1N4, Canada. [Noskov, Sergei Yu.] Univ Calgary, Ctr Mol Simulat, 2500 Univ Dr N-W, Calgary, AB T2N 1N4, Canada. [Rostovtseva, Tatiana K.; Teijido, Oscar; Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Transport, NIH, Bethesda, MD 20892 USA. [Chamberlin, Adam C.] Ambry Genet, 15 Argonaut, Aliso Viejo, CA 92656 USA. [Teijido, Oscar] Inst Med Sci & Genom Med, Dept Med Epigenet, EuroEspes Sta Marta de Babio S-N, Bergondo 15165, A Coruna, Spain. [Jiang, Wei] Argonne Natl Lab, Leadership Comp Facil, 9700S Cass Ave, Lemont, IL 60439 USA. RP Noskov, SY (reprint author), Univ Calgary, Dept Biol Sci, 2500 Univ Dr N-W, Calgary, AB T2N 1N4, Canada.; Noskov, SY (reprint author), Univ Calgary, Ctr Mol Simulat, 2500 Univ Dr N-W, Calgary, AB T2N 1N4, Canada.; Rostovtseva, TK; Bezrukov, SM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Transport, NIH, Bethesda, MD 20892 USA. EM snoskov@ucalgary.ca; rostovtt@mail.nih.gov; bezrukos@mail.nih.gov FU NICHD/NIH; National Sciences and Engineering Research Council [RGPIN-315019]; Alberta Innovates Technical Futures Strategic Chair in BioMolecular Simulations; Canadian Foundation for Innovation; Intramural Research Program of the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We would like to thank cordially Drs. Michael Grabe, Joshua Adelman and Om Choudray for sharing their structural data on the VDAC-ATP simulations. Drs. Wonpil Im, Benoit Roux and Pablo De Biase were instrumental in implementing, developing and extending GCMC-BD algorithms to a variety of systems providing excellent tools and advice for modeling data shown in this submission. The work in S.Y.N. lab was supported with intramural funding from NICHD/NIH and the National Sciences and Engineering Research Council (discovery grant RGPIN-315019 to S.Y.N.). S.Y.N. was supported by the Alberta Innovates Technical Futures Strategic Chair in BioMolecular Simulations. Computations were performed on the West-Grid/Compute Canada facilities and the University of Calgary TNK cluster supported by the Canadian Foundation for Innovation. The simulations of ATP transport in VDAC channel with 2D H-REMD were performed on MIRA Blue-Gene Cluster located in the Argonne National Laboratory under Discretional Director's award. T.K.R. and S.M.B. were supported by the Intramural Research Program of the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 141 TC 4 Z9 4 U1 5 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 EI 0006-3002 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD JUL PY 2016 VL 1858 IS 7 SI SI BP 1778 EP 1790 DI 10.1016/j.bbamem.2016.02.026 PN B PG 13 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DN7CP UT WOS:000377233200021 PM 26940625 ER PT J AU Mukhija, K Singhal, K Angmo, S Yadav, K Yadav, H Sandhir, R Singhal, NK AF Mukhija, Kimmi Singhal, Kirti Angmo, Stanzin Yadav, Kamalendra Yadav, Hariom Sandhir, Rajat Singhal, Nitin Kumar TI Potential of Alginate Encapsulated Ferric Saccharate Microemulsions to Ameliorate Iron Deficiency in Mice SO BIOLOGICAL TRACE ELEMENT RESEARCH LA English DT Article DE Microemulsions; Iron saccharate complex; Bioavailability; Emulsification; Sodium alginate; Anemia ID LIPID-PEROXIDATION; FERROUS SULFATE; ANTIOXIDANT STATUS; BINDING-CAPACITY; OXIDATIVE STRESS; FREE-RADICALS; IN-VITRO; MICROENCAPSULATION; SALTS; ANEMIA AB Iron deficiency is one of the most prominent mineral deficiencies around the world, which especially affects large population of women and children. Development of new technologies to combat iron deficiency is on high demand. Therefore, we developed alginate microcapsule with encapsulated iron that had better oral iron bioavailability. Microcapsules containing iron with varying ratios of sodium alginate ferric(III)-saccharide were prepared using emulsification method. In vitro studies with Caco-2 cells suggested that newly synthesized microemulsions had better iron bioavailability as compared to commercially available iron dextran formulations. Ferrozine in vitro assay showed that alginate-encapsulated ferric galactose microemulsion (AFGM) had highest iron bioavailability in comparison to other four ferric saccharate microemulsions, namely AFGlM, AFMM, AFSM, and AFFM synthesized in our laboratory. Mice studies also suggested that AFGM showed higher iron absorption as indicated by increased serum iron, hemoglobin, and other hematopoietic measures with almost no toxicity at tested doses. Development of iron-loaded microemulsions leads to higher bioavailability of iron and can provide alternative strategies to treat iron deficiency. C1 [Angmo, Stanzin; Yadav, Kamalendra; Yadav, Hariom; Singhal, Nitin Kumar] Natl Agri Food Biotechnol Inst, Mohali, Punjab, India. [Mukhija, Kimmi; Singhal, Kirti; Sandhir, Rajat] Panjab Univ, Dept Biochem, Chandigarh 160014, Punjab, India. [Yadav, Hariom] NIDDK, NIH, Bethesda, MD 20892 USA. RP Singhal, NK (reprint author), Natl Agri Food Biotechnol Inst, Mohali, Punjab, India. EM nitin@nabi.res.in OI Yadav, Hariom/0000-0003-4504-1597 FU Department of Biotechnology; National Agri-Food Biotechnology Institute FX Research was supported by the Department of Biotechnology and National Agri-Food Biotechnology Institute grants. NR 51 TC 0 Z9 0 U1 5 U2 9 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0163-4984 EI 1559-0720 J9 BIOL TRACE ELEM RES JI Biol. Trace Elem. Res. PD JUL PY 2016 VL 172 IS 1 BP 179 EP 192 DI 10.1007/s12011-015-0564-4 PG 14 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DO0JT UT WOS:000377465900020 PM 26637994 ER PT J AU Collins, PY Kondos, L Pillai, A Joestl, SS Frohlich, J AF Collins, Pamela Y. Kondos, Leeza Pillai, Aravind Joestl, Sarah S. Frohlich, Janet TI Passive Suicidal Ideation and Community Mental Health Resources in South Africa SO COMMUNITY MENTAL HEALTH JOURNAL LA English DT Article DE Passive suicidal ideation; Community resources; Community mental health; Africa; HIV/AIDS ID AIDS-RELATED MORTALITY; SYSTEMATIC ANALYSIS; COPING STRATEGIES; GLOBAL BURDEN; HIV; DEPRESSION; VALIDITY; QUESTIONNAIRE-9; BEHAVIOR; DISEASE AB South African communities continue to experience elevated incidence and prevalence of HIV infection. Passive suicidal ideation (PSI) may be one expression of distress in high prevalence communities. We report the prevalence of PSI and examine the relationship between PSI and participation in community organizations in a semi-rural sample of South African adults (N = 594). The prevalence of PSI in the 2 weeks prior to the interview was 9.1 %. Members of burial societies (I (2) = 7.34; p = 0.01) and stokvels (I (2) = 4.1; p = 0.04) (community-based savings groups) reported significantly less PSI compared to other respondents. Using a multivariate model adjusted for demographic characteristics, psychological distress, and socioeconomic status, we found lower odds of reporting PSI for members of burial societies (OR 0.48, CI 0.25 -0.91). Participation in community organizations that provide contextually salient resources in settings with high levels of distress may be a resource for mental health. C1 [Collins, Pamela Y.] NIMH, NIH, Bethesda, MD 20892 USA. [Kondos, Leeza] US Agcy Int Dev, Inst Publ Hlth, Global Hlth Bur, Washington, DC 20523 USA. [Pillai, Aravind] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Joestl, Sarah S.] CDC, Natl Ctr Hlth Stat, Hyattsville, MD USA. [Frohlich, Janet] Univ KwaZulu Natal, Ctr AIDS Programme Res South Africa, Durban, South Africa. RP Collins, PY (reprint author), NIMH, NIH, Bethesda, MD 20892 USA. EM pamela.collins@nih.gov; lmkondos@gmail.com; ap2664@cumc.columbia.edu; sjoestl@cdc.gov; Janet.Frohlich@caprisa.org FU NIAID Center for AIDS Research [NIAID P30AI42848] FX The majority of this work was conducted while Dr. Collins was at Columbia University and supported by a pilot award through the NIAID Center for AIDS Research grant (PI: Scott Hammer, NIAID P30AI42848). Dr. Sarah Joestl contributed to this work while she was a doctoral candidate at the Mailman School of Public Health at Columbia University. Ms. Leeza Kondos contributed to this work while employed at the National Institute of Mental Health. We gratefully acknowledge the contributions of Lise Werner, Henri Carrara, Robert Sember, Beverly Haddad, Ezra Susser, Dana March, Quarraisha Abdool-Karim and the CAPRISA research team. The views expressed in this manuscript do not necessarily reflect those of the National Institute of Mental Health or the US government. NR 44 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0010-3853 EI 1573-2789 J9 COMMUNITY MENT HLT J JI Community Ment. Health J. PD JUL PY 2016 VL 52 IS 5 BP 541 EP 550 DI 10.1007/s10597-016-0003-9 PG 10 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA DN8ZJ UT WOS:000377368300006 PM 27100867 ER PT J AU Schwartz, LH Litiere, S de Vries, E Ford, R Gwyther, S Mandrekar, S Shankar, L Bogaerts, J Chen, A Dancey, J Hayes, W Hodi, FS Hoekstra, OS Huang, EP Lin, N Liu, Y Therasse, P Wolchok, JD Seymour, L AF Schwartz, Lawrence H. Litiere, Saskia de Vries, Elisabeth Ford, Robert Gwyther, Stephen Mandrekar, Sumithra Shankar, Lalitha Bogaerts, Jan Chen, Alice Dancey, Janet Hayes, Wendy Hodi, F. Stephen Hoekstra, Otto S. Huang, Erich P. Lin, Nancy Liu, Yan Therasse, Patrick Wolchok, Jedd D. Seymour, Lesley TI RECIST 1.1-Update and clarification: From the RECIST committee SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE RECIST; Clarifications; Tumour response ID SOLID TUMORS AB The Response Evaluation Criteria in Solid Tumours (RECIST) were developed and published in 2000, based on the original World Health Organisation guidelines first published in 1981. In 2009, revisions were made (RECIST 1.1) incorporating major changes, including a reduction in the number of lesions to be assessed, a new measurement method to classify lymph nodes as pathologic or normal, the clarification of the requirement to confirm a complete response or partial response and new methodologies for more appropriate measurement of disease progression. The purpose of this paper was to summarise the questions posed and the clarifications provided as an update to the 2009 publication. (C) 2016 Published by Elsevier Ltd. C1 [Schwartz, Lawrence H.] Columbia Univ, Med Ctr, Dept Radiol, New York, NY USA. [Schwartz, Lawrence H.] New York Presbyterian Hosp, New York, NY USA. [Litiere, Saskia; Bogaerts, Jan; Liu, Yan] EORTC HQ, Brussels, Belgium. [de Vries, Elisabeth] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, NL-9713 AV Groningen, Netherlands. [Ford, Robert] Clin Trials Imaging Consulting, Belle Mead, NJ USA. [Gwyther, Stephen] East Surrey Hosp, Dept Med Imaging, Redhill, Surrey, England. [Mandrekar, Sumithra] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Shankar, Lalitha] NCI, Clin Trials Branch, Canc Imaging Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Chen, Alice] NCI, Early Clin Trials Dev Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Hayes, Wendy] Bristol Myers Squibb Co, Exploratory Clin & Translat Res, Princeton, NJ USA. [Hodi, F. Stephen; Lin, Nancy] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Hoekstra, Otto S.] Vrije Univ Amsterdam, Med Ctr, Dept Radiol & Nucl Med, Amsterdam, Netherlands. [Huang, Erich P.] NCI, NIH, Rockville, MD USA. [Therasse, Patrick] Labs Servier, Paris, France. [Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Wolchok, Jedd D.] Weill Cornell Med Coll, New York, NY USA. [Wolchok, Jedd D.] Grad Coll, New York, NY USA. [Wolchok, Jedd D.] Ludwig Inst Canc Res, New York, NY USA. [Dancey, Janet; Seymour, Lesley] Queens Univ, Canadian Canc Trials Grp, Kingston, ON, Canada. RP Schwartz, LH (reprint author), CUMC, 180 Ft Washington Ave, New York, NY 10032 USA. EM LSchwartz@columbia.edu FU Canadian Cancer Society Research Institute [021039]; EORTC Cancer Research Fund; National Cancer Institute (NCI) [5U10-CA11488-45] FX Canadian Cancer Trials Group participation was supported by the Canadian Cancer Society Research Institute (grant #021039). This publication was supported by the EORTC Cancer Research Fund and by the National Cancer Institute (NCI) grant number 5U10-CA11488-45. NR 6 TC 2 Z9 2 U1 2 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2016 VL 62 BP 132 EP 137 DI 10.1016/j.ejca.2016.03.081 PG 6 WC Oncology SC Oncology GA DN9FO UT WOS:000377385100015 PM 27189322 ER PT J AU Schwartz, LH Seymour, L Litiere, S Ford, R Gwyther, S Mandrekar, S Shankar, L Bogaerts, J Chen, A Dancey, J Hayes, W Hodi, FS Hoekstra, OS Huang, EP Lin, N Liu, Y Therasse, P Wolchok, JD de Vries, E AF Schwartz, Lawrence H. Seymour, Lesley Litiere, Saskia Ford, Robert Gwyther, Stephen Mandrekar, Sumithra Shankar, Lalitha Bogaerts, Jan Chen, Alice Dancey, Janet Hayes, Wendy Hodi, F. Stephen Hoekstra, Otto S. Huang, Erich P. Lin, Nancy Liu, Yan Therasse, Patrick Wolchok, Jedd D. de Vries, Elisabeth TI RECIST 1.1-Standardisation and disease-specific adaptations: Perspectives from the RECIST Working Group SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE RECIST; Modifications; Tumour response ID METASTATIC PROSTATE-CANCER; RESPONSE ASSESSMENT CRITERIA; INTERNATIONAL WORKSHOP; END-POINTS; LYMPHOMA; CHEMOTHERAPY; MANAGEMENT; CARCINOMA; SURVIVAL; TRIALS AB Radiologic imaging of disease sites plays a pivotal role in the management of patients with cancer. Response Evaluation Criteria in Solid Tumours (RECIST), introduced in 2000, and modified in 2009, has become the de facto standard for assessment of response in solid tumours in patients on clinical trials. The RECIST Working Group considers the ability of the global oncology community to implement and adopt updates to RECIST in a timely manner to be critical. Updates to RECIST must be tested, validated and implemented in a standardised, methodical manner in response to therapeutic and imaging technology advances as well as experience gained by users. This was the case with the development of RECIST 1.1, where an expanded data warehouse was developed to test and validate modifications. Similar initiatives are ongoing, testing RECIST in the evaluation of response to non-cytotoxic agents, immunotherapies, as well as in specific diseases. The RECIST Working Group has previously outlined the level of evidence considered necessary to formally and fully validate new imaging markers as an appropriate end-point for clinical trials. Achieving the optimal level of evidence desired is a difficult feat for phase III trials; this involves a meta -analysis of multiple prospective, randomised multicentre clinical trials. The rationale for modifications should also be considered; the modifications may be proposed to improve surrogacy, to provide a more mechanistic imaging technique, or be designed to improve reproducibility of the imaging biomarker. Here, we present the commonly described modifications of RECIST, each of which is associated with different levels of evidence and validation. (C) 2016 Published by Elsevier Ltd. C1 [Schwartz, Lawrence H.] Columbia Univ, Med Ctr, Dept Radiol, New York, NY USA. [Schwartz, Lawrence H.] New York Presbyterian Hosp, New York, NY USA. [Seymour, Lesley; Dancey, Janet] Queens Univ, Canadian Canc Trials Grp, Kingston, ON, Canada. [Litiere, Saskia; Bogaerts, Jan; Liu, Yan] EORTC HQ, Brussels, Belgium. [Ford, Robert] Clin Trials Imaging Consulting, Belle Mead, NJ USA. [Gwyther, Stephen] East Surrey Hosp, Dept Med Imaging, Redhill, Surrey, England. [Mandrekar, Sumithra] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Shankar, Lalitha] NCI, Clin Trials Branch, Canc Imaging Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Chen, Alice] NCI, Early Clin Trials Dev Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Hayes, Wendy] Bristol Myers Squibb Co, Exploratory Clin & Translat Res, Princeton, NJ USA. [Hodi, F. Stephen; Lin, Nancy] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Hoekstra, Otto S.] Vrije Univ Amsterdam, Med Ctr, Dept Radiol & Nucl Med, Amsterdam, Netherlands. [Huang, Erich P.] NCI, NIH, Rockville, MD USA. [Therasse, Patrick] Labs Servier, Paris, France. [Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Wolchok, Jedd D.] Weill Cornell Med Coll, New York, NY USA. [Wolchok, Jedd D.] Grad Coll, New York, NY USA. [Wolchok, Jedd D.] Ludwig Inst Canc Res, New York, NY USA. [de Vries, Elisabeth] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, NL-9713 AV Groningen, Netherlands. RP Schwartz, LH (reprint author), Columbia Univ, Coll Phys & Surg, New York Presbyterian Hosp, Dept Radiol, 180 Ft Washington Ave, New York, NY 10032 USA. EM LSchwartz@columbia.edu FU Canadian Cancer Society Research Institute [021039]; EORTC Cancer Research Fund; National Cancer Institute [5U10-CA11488-45] FX Canadian Cancer Trials Group participation was supported by the Canadian Cancer Society Research Institute (grant #021039). This publication was supported by the EORTC Cancer Research Fund and by the National Cancer Institute grant number 5U10-CA11488-45. NR 22 TC 3 Z9 4 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2016 VL 62 BP 138 EP 145 DI 10.1016/j.ejca.2016.03.082 PG 8 WC Oncology SC Oncology GA DN9FO UT WOS:000377385100016 PM 27237360 ER PT J AU Cuellar-Partida, G Lu, Y Dixon, SC Fasching, PA Hein, A Burghaus, S Beckmann, MW Lambrechts, D Van Nieuwenhuysen, E Vergote, I Vanderstichele, A Doherty, JA Rossing, MA Chang-Claude, J Rudolph, A Wang-Gohrke, S Goodman, MT Bogdanova, N Dork, T Durst, M Hillemanns, P Runnebaum, IB Antonenkova, N Butzow, R Leminen, A Nevanlinna, H Pelttari, LM Edwards, RP Kelley, JL Modugno, F Moysich, KB Ness, RB Cannioto, R Hogdall, E Hogdall, C Jensen, A Giles, GG Bruinsma, F Kjaer, SK Hildebrandt, MAT Liang, D Lu, KH Wu, XF Bisogna, M Dao, F Levine, DA Cramer, DW Terry, KL Tworoger, SS Stampfer, M Missmer, S Bjorge, L Salvesen, HB Kopperud, RK Bischof, K Aben, KKH Kiemeney, LA Massuger, LFAG Brooks-Wilson, A Olson, SH McGuire, V Rothstein, JH Sieh, W Whittemore, AS Cook, LS Le, ND Gilks, CB Gronwald, J Jakubowska, A Lubinski, J Kluz, T Song, HL Tyrer, JP Wentzensen, N Brinton, L Trabert, B Lissowska, J McLaughlin, JR Narod, SA Phelan, C Anton-Culver, H Ziogas, A Eccles, D Campbell, I Gayther, SA Gentry-Maharaj, A Menon, U Ramus, SJ Wu, AH Dansonka-Mieszkowska, A Kupryjanczyk, J Timorek, A Szafron, L Cunningham, JM Fridley, BL Winham, SJ Bandera, EV Poole, EM Morgan, TK Goode, EL Schildkraut, JM Pearce, CL Berchuck, A Pharoah, PDP Webb, PM Chenevix-Trench, G Risch, HA MacGregor, S AF Cuellar-Partida, Gabriel Lu, Yi Dixon, Suzanne C. Fasching, Peter A. Hein, Alexander Burghaus, Stefanie Beckmann, Matthias W. Lambrechts, Diether Van Nieuwenhuysen, Els Vergote, Ignace Vanderstichele, Adriaan Doherty, Jennifer Anne Rossing, Mary Anne Chang-Claude, Jenny Rudolph, Anja Wang-Gohrke, Shan Goodman, Marc T. Bogdanova, Natalia Doerk, Thilo Duerst, Matthias Hillemanns, Peter Runnebaum, Ingo B. Antonenkova, Natalia Butzow, Ralf Leminen, Arto Nevanlinna, Heli Pelttari, Liisa M. Edwards, Robert P. Kelley, Joseph L. Modugno, Francesmary Moysich, Kirsten B. Ness, Roberta B. Cannioto, Rikki Hogdall, Estrid Hogdall, Claus Jensen, Allan Giles, Graham G. Bruinsma, Fiona Kjaer, Susanne K. Hildebrandt, Michelle A. T. Liang, Dong Lu, Karen H. Wu, Xifeng Bisogna, Maria Dao, Fanny Levine, Douglas A. Cramer, Daniel W. Terry, Kathryn L. Tworoger, Shelley S. Stampfer, Meir Missmer, Stacey Bjorge, Line Salvesen, Helga B. Kopperud, Reidun K. Bischof, Katharina Aben, Katja K. H. Kiemeney, Lambertus A. Massuger, Leon F. A. G. Brooks-Wilson, Angela Olson, Sara H. McGuire, Valerie Rothstein, Joseph H. Sieh, Weiva Whittemore, Alice S. Cook, Linda S. Le, Nhu D. Gilks, C. Blake Gronwald, Jacek Jakubowska, Anna Lubinski, Jan Kluz, Tomasz Song, Honglin Tyrer, Jonathan P. Wentzensen, Nicolas Brinton, Louise Trabert, Britton Lissowska, Jolanta McLaughlin, John R. Narod, Steven A. Phelan, Catherine Anton-Culver, Hoda Ziogas, Argyrios Eccles, Diana Campbell, Ian Gayther, Simon A. Gentry-Maharaj, Aleksandra Menon, Usha Ramus, Susan J. Wu, Anna H. Dansonka-Mieszkowska, Agnieszka Kupryjanczyk, Jolanta Timorek, Agnieszka Szafron, Lukasz Cunningham, Julie M. Fridley, Brooke L. Winham, Stacey J. Bandera, Elisa V. Poole, Elizabeth M. Morgan, Terry K. Goode, Ellen L. Schildkraut, Joellen M. Pearce, Celeste L. Berchuck, Andrew Pharoah, Paul D. P. Webb, Penelope M. Chenevix-Trench, Georgia Risch, Harvey A. MacGregor, Stuart CA Australian Ovarian Canc Study TI Assessing the genetic architecture of epithelial ovarian cancer histological subtypes SO HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; MOLECULAR CHARACTERIZATION; SUSCEPTIBILITY LOCUS; DIABETES-MELLITUS; PROVIDES INSIGHTS; HUMAN HEIGHT; COMMON SNPS; RISK; METAANALYSIS; MUTATIONS AB Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ( = 8.8 +/- 1.1 %), endometrioid ( = 3.2 +/- 1.6 %), clear cell ( = 6.7 +/- 3.3 %) and all EOC ( = 5.6 +/- 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach. C1 [Cuellar-Partida, Gabriel; Lu, Yi; MacGregor, Stuart] Queensland Inst Med Res, Berghofer Med Res Inst, Stat Genet, 300 Herston Rd, Herston, Qld 4006, Australia. [Cuellar-Partida, Gabriel] Univ Queensland, Sch Med, St Lucia, Qld 4072, Australia. [Dixon, Suzanne C.; Webb, Penelope M.] Queensland Inst Med Res, Berghofer Med Res Inst, Gynaecol Canc Grp, 300 Herston Rd, Herston, Qld 4006, Australia. [Chenevix-Trench, Georgia] Queensland Inst Med Res, Berghofer Med Res Inst, Canc Genet, 300 Herston Rd, Herston, Qld 4006, Australia. [Campbell, Ian; Australian Ovarian Canc Study] Peter MacCallum Canc Ctr, Div Res, St Andrews Pl, East Melbourne, Vic, Australia. [Pharoah, Paul D. P.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Fasching, Peter A.; Hein, Alexander; Burghaus, Stefanie; Beckmann, Matthias W.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Comprehens Canc Ctr Erlangen EMN, Univ Str 21-23, D-91054 Erlangen, Germany. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Lambrechts, Diether] VIB, Vesalius Res Ctr, Louvain, Belgium. [Van Nieuwenhuysen, Els; Vanderstichele, Adriaan] Univ Hosp Leuven, Dept Obstet & Gynaecol, Div Gynecol Oncol, Louvain, Belgium. [Van Nieuwenhuysen, Els; Vergote, Ignace; Vanderstichele, Adriaan] Univ Hosp Leuven, Leuven Canc Inst, Louvain, Belgium. [Doherty, Jennifer Anne] Dartmouth Coll, Geisel Sch Med, Dept Community & Family Med, Epidemiol & Biostat Sect, Hanover, NH 03755 USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Rossing, Mary Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, 1124 Columbia St, Seattle, WA 98104 USA. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, D-89069 Ulm, Germany. [Goodman, Marc T.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Canc Prevent & Control, Los Angeles, CA 90048 USA. [Goodman, Marc T.] Cedars Sinai Med Ctr, Community & Populat Hlth Res Inst, Dept Biomed Sci, Los Angeles, CA 90048 USA. [Bogdanova, Natalia] Hannover Med Sch, Radiat Oncol Res Unit, Hannover, Germany. [Doerk, Thilo] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Duerst, Matthias; Runnebaum, Ingo B.] Univ Jena, Hospital Friedrich Schiller Univ, Dept Gynecol, Jena, Germany. [Hillemanns, Peter] Hannover Med Sch, Clin Obstet, Hannover, Germany. [Hillemanns, Peter] Hannover Med Sch, Clin Gynaecol, Hannover, Germany. [Antonenkova, Natalia] NN Alexandrov Natl Canc Ctr Belarus, Minsk, Byelarus. [Butzow, Ralf] Univ Helsinki, Dept Pathol, Helsinki, Finland. [Butzow, Ralf; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M.] Helsinki Univ Hosp, Helsinki, Finland. [Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M.] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Edwards, Robert P.; Kelley, Joseph L.; Modugno, Francesmary] Univ Pittsburgh, Sch Med, Div Gynecol Oncol, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Edwards, Robert P.; Modugno, Francesmary] Magee Womens Res Inst, Womens Canc Res Program, Pittsburgh, PA USA. [Edwards, Robert P.; Modugno, Francesmary] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Moysich, Kirsten B.; Cannioto, Rikki] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Ness, Roberta B.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Hogdall, Estrid; Jensen, Allan; Kjaer, Susanne K.] Danish Canc Soc Res Ctr, Dept Virus Lifestyle & Genes, Copenhagen, Denmark. [Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark. [Giles, Graham G.] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. [Giles, Graham G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia. [Giles, Graham G.; Bruinsma, Fiona] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Hogdall, Claus; Kjaer, Susanne K.] Univ Copenhagen, Rigshosp, Dept Gynaecol, DK-2100 Copenhagen, Denmark. [Hildebrandt, Michelle A. T.; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Liang, Dong] Texas So Univ, Coll Pharm & Hlth Sci, Houston, TX 77004 USA. [Lu, Karen H.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Bisogna, Maria; Dao, Fanny; Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10021 USA. [Cramer, Daniel W.; Terry, Kathryn L.; Missmer, Stacey] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA. [Terry, Kathryn L.; Tworoger, Shelley S.; Stampfer, Meir; Missmer, Stacey] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Tworoger, Shelley S.; Stampfer, Meir; Missmer, Stacey; Poole, Elizabeth M.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Tworoger, Shelley S.; Stampfer, Meir; Missmer, Stacey; Poole, Elizabeth M.] Harvard Univ, Sch Med, Boston, MA USA. [Dixon, Suzanne C.; Webb, Penelope M.] Univ Queensland, Sch Publ Hlth, Herston, Qld 4006, Australia. [Bjorge, Line; Salvesen, Helga B.; Kopperud, Reidun K.; Bischof, Katharina] Haukeland Hosp, Dept Gynecol & Obstet, N-5021 Bergen, Norway. [Bjorge, Line; Salvesen, Helga B.; Kopperud, Reidun K.; Bischof, Katharina] Univ Bergen, Ctr Canc Biomarkers, Dept Clin Sci, Bergen, Norway. [Aben, Katja K. H.; Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, RADBOUD Inst Hlth Sci, NL-6525 ED Nijmegen, Netherlands. [Aben, Katja K. H.] Netherlands Comprehens Canc Org, Utrecht, Netherlands. [Massuger, Leon F. A. G.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Dept Obstet & Gynaecol, NL-6525 ED Nijmegen, Netherlands. [Brooks-Wilson, Angela] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada. [Brooks-Wilson, Angela] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada. [Olson, Sara H.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [McGuire, Valerie; Rothstein, Joseph H.; Sieh, Weiva; Whittemore, Alice S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA. [Cook, Linda S.] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA. [Le, Nhu D.] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada. [Gilks, C. Blake] Univ British Columbia, Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada. [Gronwald, Jacek; Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland. [Kluz, Tomasz] Univ Rzeszow, Frederick Chopin Clin Prov Hosp 1, Clin Obstet & Gynecol, Fac Med,Inst Midwifery & Emergency Med, Rzeszow, Poland. [Song, Honglin; Tyrer, Jonathan P.; Pharoah, Paul D. P.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England. [Wentzensen, Nicolas; Brinton, Louise; Trabert, Britton] Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Lissowska, Jolanta] Maria Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [McLaughlin, John R.] Publ Hlth Ontario, Toronto, ON, Canada. [Narod, Steven A.] Univ Toronto, Womens Coll Res Inst, Toronto, ON, Canada. [Phelan, Catherine] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Anton-Culver, Hoda] Univ Calif Irvine, Sch Med, Ctr Canc Genet Res & Prevent, Irvine, CA USA. [Eccles, Diana] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England. [Gayther, Simon A.; Ramus, Susan J.; Wu, Anna H.; Pearce, Celeste L.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Gentry-Maharaj, Aleksandra] UCL, Inst Womens Hlth, Womens Canc, London, England. [Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Szafron, Lukasz] Maria Sklodowska Curie Mem Canc Ctr, Dept Pathol & Lab Diagnost, Warsaw, Poland. [Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Szafron, Lukasz] Inst Oncol, Warsaw, Poland. [Timorek, Agnieszka] Med Univ Warsaw, Fac Med 2, Dept Obstet Gynaecol & Oncol, Warsaw, Poland. [Timorek, Agnieszka] Brodnowski Hosp, Warsaw, Poland. [Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Div Expt Pathol, Rochester, MN USA. [Fridley, Brooke L.] Univ Kansas, Dept Biostat, Kansas City, KS USA. [Winham, Stacey J.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA. [Bandera, Elisa V.] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. [Morgan, Terry K.] OHSU, Dept Pathol & Obstet, Portland, OR USA. [Morgan, Terry K.] OHSU, Dept Gynaecol, Portland, OR USA. [Goode, Ellen L.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Schildkraut, Joellen M.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA 22903 USA. [Pearce, Celeste L.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC USA. RP Cuellar-Partida, G; MacGregor, S (reprint author), Queensland Inst Med Res, Berghofer Med Res Inst, Stat Genet, 300 Herston Rd, Herston, Qld 4006, Australia.; Cuellar-Partida, G (reprint author), Univ Queensland, Sch Med, St Lucia, Qld 4072, Australia. EM gabriel.cuellar@qimrberghofer.edu.au; Stuart.MacGregor@qimrberghofer.edu.au RI Trabert, Britton/F-8051-2015; Hein, Alexander/F-6999-2010; Dork, Thilo/J-8620-2012; Gronwald, Jacek/A-4576-2017; Bjorge, Line/C-1307-2017; salvesen, Helga/C-1187-2017; Cuellar Partida, Gabriel/C-6686-2017; Brooks-Wilson, Angela/E-9399-2012; OI Hein, Alexander/0000-0003-2601-3398; Gronwald, Jacek/0000-0002-3643-2871; Bjorge, Line/0000-0002-0240-2770; salvesen, Helga/0000-0002-4438-8831; Cuellar Partida, Gabriel/0000-0001-7648-4097; Brooks-Wilson, Angela/0000-0003-1009-6408; Ramus, Susan/0000-0003-0005-7798; Winham, Stacey/0000-0002-8492-9102 FU Ovarian Cancer Research Fund; California Cancer Research Program [00-01389V-20170, N01-CN25403, 2II0200]; Canadian Institutes of Health Research [MOP-86727]; Cancer Australia; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; Cancer Institute of New Jersey; Cancer Research UK [C490/A6187, C490/A10119, C490/A10124]; Danish Cancer Society [94-222-52]; ELAN Program of the University of Erlangen-Nuremberg; Eve Appeal; Helsinki University Central Hospital Research Fund; Helse Vest; Norwegian Cancer Society; Norwegian Research Council; National Kankerplan of Belgium; L & S Milken Foundation; Polish Ministry of Science and Higher Education [4 PO5C 028 14, 2 PO5A 068 27]; Roswell Park Cancer Institute Alliance Foundation; US National Cancer Institute [K07-CA095666, K07-CA80668, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC67001, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA072720, P30-CA15083, P30-CA008748, P50-CA159981, P50-CA105009, P50-CA136393, U01-CA069417, U01-CA071966]; NIH/National Center for Research Resources/General Clinical Research Center [MO1-RR000056]; US Army Medical Research and Material Command [DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-07-0449, W81XWH-10-1-02802]; US Public Health Service [PSA-042205]; National Health and Medical Research Council of Australia [199600, 400281]; German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research [01 GB 9401]; State of Baden-Wurttemberg through Medical Faculty of the University of Ulm [P.685]; German Cancer Research Center; Minnesota Ovarian Cancer Alliance; Mayo Foundation; Fred C. and Katherine B. Andersen Foundation; Lon V. Smith Foundation [LVS-39420]; Oak Foundation; OHSU Foundation; Mermaid I project; Rudolf-Bartling Foundation; UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; Imperial College London; University College Hospital 'Womens Health Theme'; Royal Marsden Hospital; WorkSafeBC [14]; University of Queensland; QIMR Berghofer; NHMRC Early Career Fellowship; National Health and Medical Research Council; ARC Future Fellowship; The US National Cancer Institute [R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063678, R01-CA063682, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-CA095023, R01-CA122443, R01-CA112523, R01-CA149429, R01-CA014089, R01-CA016056]; A US National Cancer Institute [UM1-CA186107, UM1-CA176726, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA114343, R01-CA126841, R01-CA136924, R03-CA113148, R03-CA115195, R01-CA017054, R01-CA049449] FX The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund, thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The Nurses' Health Studies would like to thank the participants and staff of the Nurses' Health Study and Nurses' Health Study II for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. Funding of the constituent studies was provided by the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); the Canadian Institutes of Health Research (MOP-86727); Cancer Australia; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A6187, C490/A10119, C490/A10124); the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Central Hospital Research Fund; Helse Vest; the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; National Kankerplan of Belgium; the L & S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); the Roswell Park Cancer Institute Alliance Foundation; the US National Cancer Institute (K07-CA095666, K07-CA80668, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC67001, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA072720, P30-CA15083, P30-CA008748, P50-CA159981, P50-CA105009, P50-CA136393, R01-CA149429, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063678, R01-CA063682, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-CA095023, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R03-CA113148, R03-CA115195, U01-CA069417, U01-CA071966, UM1-CA186107, UM1-CA176726 and Intramural research funds); the NIH/National Center for Research Resources/General Clinical Research Center (MO1-RR000056); the US Army Medical Research and Material Command (DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-07-0449, W81XWH-10-1-02802); the US Public Health Service (PSA-042205); the National Health and Medical Research Council of Australia (199600 and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401); the State of Baden-Wurttemberg through Medical Faculty of the University of Ulm (P.685); the German Cancer Research Center; the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V. Smith Foundation (LVS-39420); the Oak Foundation; Eve Appeal; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital 'Womens Health Theme' and the Royal Marsden Hospital; and WorkSafeBC 14. Investigator-specific funding: G.C.P receives scholarship support from the University of Queensland and QIMR Berghofer. Y. L.; was supported by the NHMRC Early Career Fellowship. G. C. T. is supported by the National Health and Medical Research Council. S. M. was supported by an ARC Future Fellowship. NR 60 TC 0 Z9 0 U1 4 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD JUL PY 2016 VL 135 IS 7 BP 741 EP 756 DI 10.1007/s00439-016-1663-9 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA DN8XX UT WOS:000377364300007 PM 27075448 ER PT J AU Benedict, SH Hoffman, K Martel, MK Abernethy, AP Asher, AL Capala, J Chen, RC Chera, B Couch, J Deye, J Efstathiou, JA Ford, E Fraass, BA Gabriel, PE Huser, V Kavanagh, BD Khuntia, D Marks, LB Mayo, C McNutt, T Miller, RS Moore, KL Prior, F Roelofs, E Rosenstein, BS Sloan, J Theriault, A Vikram, B AF Benedict, Stanley H. Hoffman, Karen Martel, Mary K. Abernethy, Amy P. Asher, Anthony L. Capala, Jacek Chen, Ronald C. Chera, Bhisham Couch, Jennifer Deye, James Efstathiou, Jason A. Ford, Eric Fraass, Benedick A. Gabriel, Peter E. Huser, Vojtech Kavanagh, Brian D. Khuntia, Deepak Marks, Lawrence B. Mayo, Charles McNutt, Todd Miller, Robert S. Moore, Kevin L. Prior, Fred Roelofs, Erik Rosenstein, Barry S. Sloan, Jeff Theriault, Anna Vikram, Bhadrasain TI Overview of the American Society for Radiation Oncology-National Institutes of Health-American Association of Physicists in Medicine Workshop 2015: Exploring Opportunities for Radiation Oncology in the Era of Big Data SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material ID SECONDARY USE; RADIOTHERAPY; FRAMEWORK; CARE C1 [Benedict, Stanley H.] Univ Calif Davis, Sacramento, CA 95817 USA. [Hoffman, Karen; Martel, Mary K.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Benedict, Stanley H.] Univ Calif Davis, Sacramento, CA 95817 USA. [Hoffman, Karen; Martel, Mary K.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Abernethy, Amy P.] Duke Univ, Durham, NC USA. [Asher, Anthony L.] Amer Assoc Neurol Surg, Rolling Meadows, IL USA. [Capala, Jacek] NCI, Clin Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Chen, Ronald C.; Chera, Bhisham; Marks, Lawrence B.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Couch, Jennifer; Deye, James; Vikram, Bhadrasain] NCI, NIH, Bethesda, MD 20892 USA. [Efstathiou, Jason A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Ford, Eric] Univ Washington, Seattle, WA 98195 USA. [Fraass, Benedick A.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Gabriel, Peter E.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Huser, Vojtech] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, Bethesda, MD USA. [Kavanagh, Brian D.] Univ Colorado, Denver, CO 80202 USA. [Khuntia, Deepak] Varian Med Syst, Palo Alto, CA USA. [Mayo, Charles] Univ Michigan, Ann Arbor, MI 48109 USA. [McNutt, Todd] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Miller, Robert S.] Amer Soc Clin Oncol, Alexandria, VA USA. [Moore, Kevin L.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Prior, Fred] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Roelofs, Erik] Maastricht Univ, Med Ctr, Dept Radiat Oncol MAASTRO, GROW Sch Oncol & Dev Biol, NL-6200 MD Maastricht, Netherlands. [Rosenstein, Barry S.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Sloan, Jeff] Mayo Clin, Rochester, MN USA. [Theriault, Anna] Elekta, Sunnyvale, CA USA. RP Benedict, SH (reprint author), Univ Calif Davis, Sacramento, CA 95817 USA. EM shbenedict@ucdavis.edu FU NCI NIH HHS [U01 CA187013] NR 18 TC 1 Z9 1 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2016 VL 95 IS 3 BP 873 EP 879 DI 10.1016/j.ijrobp.2016.03.006 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DN9AE UT WOS:000377370600003 PM 27302503 ER PT J AU Huser, V Cimino, JJ AF Huser, Vojtech Cimino, James J. TI Impending Challenges for the Use of Big Data SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material ID ONCOLOGY; RISK C1 [Huser, Vojtech] NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, 8600 Rockville Pike,Bld 38a,Rm 9N919, Bethesda, MD 20894 USA. [Cimino, James J.] Univ Alabama Birmingham, Inst Informat, Birmingham, AL USA. RP Huser, V (reprint author), NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, 8600 Rockville Pike,Bld 38a,Rm 9N919, Bethesda, MD 20894 USA. EM vojtech.huser@nih.gov FU Intramural NIH HHS [ZIH CL000907-02, Z99 LM999999] NR 16 TC 1 Z9 1 U1 3 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2016 VL 95 IS 3 BP 890 EP 894 DI 10.1016/j.ijrobp.2015.10.060 PG 5 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DN9AE UT WOS:000377370600006 PM 26797535 ER PT J AU Rosenstein, BS Capala, J Efstathiou, JA Hammerbacher, J Kerns, SL Kong, FM Ostrer, H Prior, FW Vikram, B Wong, J Xiao, Y AF Rosenstein, Barry S. Capala, Jacek Efstathiou, Jason A. Hammerbacher, Jeff Kerns, Sarah L. Kong, Feng-Ming (Spring) Ostrer, Harry Prior, Fred W. Vikram, Bhadrasain Wong, John Xiao, Ying TI How Will Big Data Improve Clinical and Basic Research in Radiation Therapy? SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material ID GENOME-WIDE ASSOCIATION; CANCER IMAGING ARCHIVE; SINGLE-NUCLEOTIDE POLYMORPHISMS; RADIOTHERAPY TOXICITY; PROSTATE-CANCER; RADIOGENOMICS; MEDICINE; NETWORK; HEALTH; ONCOLOGY C1 [Rosenstein, Barry S.] Icahn Sch Med Mt Sinai, Dept Radiat Oncol, One Gustave L Levy Pl,Box 1236, New York, NY 10029 USA. [Rosenstein, Barry S.; Hammerbacher, Jeff] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Rosenstein, Barry S.] Icahn Sch Med Mt Sinai, Dept Dermatol, New York, NY 10029 USA. [Rosenstein, Barry S.] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA. [Rosenstein, Barry S.] NYU, Sch Med, Dept Radiat Oncol, New York, NY USA. [Capala, Jacek; Vikram, Bhadrasain] NCI, Clin Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Efstathiou, Jason A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. [Kerns, Sarah L.] Univ Rochester, Med Ctr, Dept Radiat Oncol, Rochester, NY 14642 USA. [Kong, Feng-Ming (Spring)] Georgia Regents Univ, GRU Canc Ctr, Dept Radiat Oncol, Augusta, GA USA. [Kong, Feng-Ming (Spring)] Georgia Regents Univ, Med Coll Georgia, Augusta, GA USA. [Ostrer, Harry] Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10467 USA. [Ostrer, Harry] Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. [Prior, Fred W.] Univ Arkansas Med Sci, Dept Biomed Informat, Little Rock, AR 72205 USA. [Wong, John] Johns Hopkins Univ, Sch Med, Dept Radiat Oncol, Baltimore, MD USA. [Xiao, Ying] Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. RP Rosenstein, BS (reprint author), Icahn Sch Med Mt Sinai, Dept Radiat Oncol, One Gustave L Levy Pl,Box 1236, New York, NY 10029 USA. EM barry.rosenstein@mssm.edu OI Hammerbacher, Jeffrey/0000-0001-6596-8563 FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [HHSN261200800001E, K07 CA187546, R01 CA134444, R01 CA142840, U01 CA187013, U10 CA180822, U10 CA180868, U24 CA180803, UG1 CA189867] NR 34 TC 3 Z9 3 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2016 VL 95 IS 3 BP 895 EP 904 DI 10.1016/j.ijrobp.2015.11.009 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DN9AE UT WOS:000377370600007 PM 26797542 ER PT J AU Mayo, CS Deasy, JO Chera, BS Freymann, J Kirby, JS Hardenberg, PH AF Mayo, Charles S. Deasy, Joseph O. Chera, Bhishamjit S. Freymann, John Kirby, Justin S. Hardenberg, Patricia H. TI How Can We Effect Culture Change Toward Data-Driven Medicine? SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material ID CLINICIAN; TRIALS; PATTERNS; PATIENT; DRUG; CARE C1 [Mayo, Charles S.] Univ Michigan, Dept Radiat Oncol, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. [Deasy, Joseph O.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Chera, Bhishamjit S.] Univ North Carolina Hosp, Dept Radiat Oncol, Chapel Hill, NC USA. [Freymann, John; Kirby, Justin S.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [Hardenberg, Patricia H.] Shaw Reg Canc Ctr, Edwards, CO USA. RP Mayo, CS (reprint author), Univ Michigan, Dept Radiat Oncol, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM cmayo@med.umich.edu NR 26 TC 1 Z9 1 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2016 VL 95 IS 3 BP 916 EP 921 DI 10.1016/j.ijrobp.2015.12.355 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DN9AE UT WOS:000377370600010 PM 27302507 ER PT J AU Zhang, Q Jing, H Su, HC AF Zhang, Qian Jing, Huie Su, Helen C. TI Recent Advances in DOCK8 Immunodeficiency Syndrome SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Review DE DOCK8; combined immunodeficiency; hyperimmunoglobulinemia E syndrome; tissue residen memory T cells (T-RM); cytothripsis; cutaneous virus infection; somatic reversion; genetics; eczema; food allergy; hematopoietic stem cell transplantation ID STEM-CELL TRANSPLANTATION; CYTOKINESIS 8 DEFICIENCY; HYPER-IGE SYNDROME; BONE-MARROW-TRANSPLANTATION; WISKOTT-ALDRICH SYNDROME; T-CELLS; DOCK8-DEFICIENT PATIENTS; PROTECTIVE IMMUNITY; DEDICATOR; PHENOTYPE AB Since the discovery of the genetic basis of DOCK8 immunodeficiency syndrome (DIDS) in 2009, several hundred patients worldwide have been reported, validating and extending the initial clinical descriptions. Importantly, the beneficial role of hematopoietic stem cell transplantation for this disease has emerged, providing impetus for improved diagnosis. Additionally, several groups have further elucidated the biological functions of DOCK8 in the immune system that help explain disease pathogenesis. Here, we summarize these recent developments. C1 [Zhang, Qian; Jing, Huie; Su, Helen C.] NIAID, Host Def Lab, NIH, Bldg 10CRC,Room 5-3940,10 Ctr Dr,MSC 1456, Bethesda, MD 20892 USA. [Zhang, Qian] Sidra Med & Res Ctr, Div Translat Med, Doha, Qatar. RP Su, HC (reprint author), NIAID, Host Def Lab, NIH, Bldg 10CRC,Room 5-3940,10 Ctr Dr,MSC 1456, Bethesda, MD 20892 USA. EM hsu@niaid.nih.gov RI Su, Helen/H-9541-2015 OI Su, Helen/0000-0002-5582-9110 FU Intramural Research Program, NIH, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program, NIH, National Institute of Allergy and Infectious Diseases. Data in Fig. 2 were generated after obtaining written informed consent from the patient on an NIAID IRB-approved research protocol. NR 58 TC 1 Z9 1 U1 3 U2 6 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD JUL PY 2016 VL 36 IS 5 BP 441 EP 449 DI 10.1007/s10875-016-0296-z PG 9 WC Immunology SC Immunology GA DN8ZZ UT WOS:000377370100008 PM 27207373 ER PT J AU Patel, EU Laeyendecker, O Hsieh, YH Rothman, RE Kelen, GD Quinn, TC AF Patel, Eshan U. Laeyendecker, Oliver Hsieh, Yu-Hsiang Rothman, Richard E. Kelen, Gabor D. Quinn, Thomas C. TI Parallel declines in HIV and hepatitis C virus prevalence, but not in herpes simplex virus type 2 infection: A 10-year, serial cross-sectional study in an inner-city emergency department SO JOURNAL OF CLINICAL VIROLOGY LA English DT Article DE HIV; Hepatitis C; HCV; Herpes; HSV-2; Emergency department ID HUMAN-IMMUNODEFICIENCY-VIRUS; INJECTION-DRUG USERS; NUTRITION EXAMINATION SURVEY; STATES-NATIONAL-HEALTH; UNITED-STATES; VIRAL-HEPATITIS; TESTING PROGRAM; RISK; CARE; SEROPREVALENCE AB Background: The Johns Hopkins Hospital Emergency Department (JHHED) has served as an observational window on the HIV epidemic in a socioeconomically depressed, urban population. We previously reported that HIV incidence among JHHED patients is decreasing and that prevalence has declined from 11.4% in 2003-5.6% in 2013. Objectives: This study sought to observe temporal trends in hepatitis C virus (HCV) and herpes simplex virus type 2 (HSV-2) seroprevalence, which are surrogate markers for parenteral and sexual risk behavior, respectively. Study design: Identity unlinked-serosurveys were conducted over 6-8 weeks in the adult JHHED in 2003, 2007, and 2013. Excess sera from 10,274 patients, previously tested for HIV, were assayed for HSV-2 and HCV antibodies. Results: Overall HCV seroprevalence declined steadily from 22.0% in 2003-13.8% in 2013 (Ptrend < 0.01), and was significant by all gender and race strata. Overall HSV-2 prevalence declined from 55.3% in 2003-50.0% in 2013 (P-trend < 0.01), but was non-significant after adjustment for demographics. Among HIV+ individuals <45 years of age, there was a significant decrease in the proportion of individuals with HCV co-infection [without HSV-2] (P-trend = 0.02) from 2003 to 2013, however, there was an increase in individuals with HSV-2 co-infection [without HCV] (P-trend < 0.01). Discussion: Little change in age-specific HSV-2 prevalence suggests the decrease in HIV prevalence was likely not associated with changes in sexual risk behavior. In addition to clinical interventions, strategies to address sexual health disparities and continued parenteral harm-reduction efforts are needed to further drive the decline in HIV. Published by Elsevier B.V. C1 [Patel, Eshan U.; Laeyendecker, Oliver; Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, 855 North Wolfe St, Baltimore, MD 21205 USA. [Hsieh, Yu-Hsiang; Rothman, Richard E.; Kelen, Gabor D.] Johns Hopkins Sch Med, Dept Emergency Med, Baltimore, MD USA. RP Quinn, TC (reprint author), NIAID, Div Intramural Res, NIH, 855 North Wolfe St, Baltimore, MD 21205 USA. EM tquinn2@jhmi.edu OI Rothman, Richard/0000-0002-1017-9505; Kelen, Gabor/0000-0002-3236-8286; Patel, Eshan/0000-0003-2174-5004 FU Division of Intramural Research; National Institute of Allergy and Infectious Diseases [K01AI100681] FX This work was supported by the Division of Intramural Research and extramural support [K01AI100681] from the National Institute of Allergy and Infectious Diseases. NR 38 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1386-6532 EI 1873-5967 J9 J CLIN VIROL JI J. Clin. Virol. PD JUL PY 2016 VL 80 BP 93 EP 97 DI 10.1016/j.jcv.2016.05.003 PG 5 WC Virology SC Virology GA DN9HW UT WOS:000377391100019 PM 27232485 ER PT J AU Wu, J Armstrong, TS Gilbert, MR AF Wu, Jing Armstrong, Terri S. Gilbert, Mark R. TI Biology and management of ependymomas SO NEURO-ONCOLOGY LA English DT Article DE Collaborative Ependymoma Research Network; ependymoma; management; molecular classification; rare disease ID CENTRAL-NERVOUS-SYSTEM; SPINAL MYXOPAPILLARY EPENDYMOMAS; MALIGNANT BRAIN-TUMORS; INTRACRANIAL EPENDYMOMA; ADULT PATIENTS; IMMUNOHISTOCHEMICAL MARKERS; POSTOPERATIVE CHEMOTHERAPY; INFRATENTORIAL EPENDYMOMA; REFRACTORY EPENDYMOMA; PROGNOSTIC-FACTORS AB Ependymomas are rare primary tumors of the central nervous system in children and adults that comprise histologically similar but genetically distinct subgroups. The tumor biology is typically more associated with the site of origin rather than being age-specific. Genetically distinct subgroups have been identified by genomic studies based on locations in classic grade II and III ependymomas. They are supratentorial ependymomas with C11orf95-RELA fusion or YAP1 fusion, infratentorial ependymomas with or without a hypermethylated phenotype (CIMP), and spinal cord ependymomas. Myxopapillary ependymomas and subependymomas have different biology than ependymomas with typical WHO grade II or III histology. Surgery and radiotherapy are the mainstays of treatment, while the role of chemotherapy has not yet been established. An in-depth understanding of tumor biology, developing reliable animal models that accurately reflect tumor molecule features, and high throughput drug screening are essential for developing new therapies. Collaborative efforts between scientists, physicians, and advocacy groups will enhance the translation of laboratory findings into clinical trials. Improvements in disease control underscore the need to incorporate assessment and management of patients' symptoms to ensure that treatment advances translate into improvement in quality of life. C1 [Wu, Jing; Gilbert, Mark R.] NCI, Neurooncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Armstrong, Terri S.] Univ Texas Hlth Sci Ctr Houston, Dept Family Hlth, Houston, TX 77030 USA. RP Gilbert, MR (reprint author), NCI, Neurooncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM mark.gilbert@nih.gov RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 NR 79 TC 4 Z9 4 U1 3 U2 6 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 JUL PY 2016 VL 18 IS 7 BP 902 EP 913 DI 10.1093/neuonc/now016 PG 12 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DN7QZ UT WOS:000377273700003 PM 27022130 ER PT J AU Gonzalez, CE Venkatraman, VK An, Y Landman, BA Davatzikos, C Bandaru, VVR Haughey, NJ Ferrucci, L Mielke, MM Resnick, SM AF Gonzalez, Christopher E. Venkatraman, Vijay K. An, Yang Landman, Bennett A. Davatzikos, Christos Bandaru, Veera Venkata Ratnam Haughey, Norman J. Ferrucci, Luigi Mielke, Michelle M. Resnick, Susan M. TI Peripheral sphingolipids are associated with variation in white matter microstructure in older adults SO NEUROBIOLOGY OF AGING LA English DT Article DE DTI; Ceramides; Sphingomyelin; White matter; Fractional anisotropy; Sphingolipids ID MILD COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; PLASMA SPHINGOMYELINS; CERAMIDE PRODUCTION; HUMAN BRAIN; CHOLESTEROL; INTEGRITY; DEMENTIA; DECLINE; METABOLISM AB Sphingolipids serve important structural and functional roles in cellular membranes and myelin sheaths. Plasma sphingolipids have been shown to predict cognitive decline and Alzheimer's disease. However, the association between plasma sphingolipid levels and brain white matter (WM) microstructure has not been examined. We investigated whether plasma sphingolipids (ceramides and sphingomyelins) were associated with magnetic resonance imaging-based diffusion measures, fractional anisotropy (FA), and mean diffusivity, 10.5 years later in 17 WM regions of 150 cognitively normal adults (mean age 67.2). Elevated ceramide species (C20:0, C22:0, C22:1, and C24:1) were associated with lower FA in multiple WM regions, including total cerebral WM, anterior corona radiata, and the cingulum of the cingulate gyrus. Higher sphingomyelins (C18:1 and C20:1) were associated with lower FA in regions such as the anterior corona radiata and body of the corpus callosum. Furthermore, lower sphingomyelin to ceramide ratios (C22:0, C24:0, and C24:1) were associated with lower FA or higher mean diffusivity in regions including the superior and posterior corona radiata. However, although these associations were significant at the a priori p < 0.05, only associations with some regional diffusion measures for ceramide C22:0 and sphingomyelin C18:1 survived correction for multiple comparisons. These findings suggest plasma sphingolipids are associated with variation in WM microstructure in cognitively normal aging. (C) 2016 Elsevier Inc. All rights reserved. C1 [Gonzalez, Christopher E.; Venkatraman, Vijay K.; An, Yang; Ferrucci, Luigi; Resnick, Susan M.] NIA, Lab Behav Neurosci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Landman, Bennett A.] Vanderbilt Univ, Inst Imaging Sci, 221 Kirkland Hall, Nashville, TN 37235 USA. [Landman, Bennett A.] Vanderbilt Univ, Dept Elect Engn, Nashville, TN 37235 USA. [Davatzikos, Christos] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Bandaru, Veera Venkata Ratnam; Haughey, Norman J.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Mielke, Michelle M.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Mielke, Michelle M.] Mayo Clin, Dept Neurol, Rochester, MN USA. RP Mielke, MM (reprint author), Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, 200 First St South West, Rochester, MN 55905 USA. EM mielke.michelle@mayo.edu FU National Institutes of Health/National Institute on Aging [U01 AG37526]; Intramural Research Program of the National Institute on Aging, NIH FX This research was supported by a grant from the National Institutes of Health/National Institute on Aging (U01 AG37526) and by the Intramural Research Program of the National Institute on Aging, NIH. NR 47 TC 0 Z9 0 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2016 VL 43 BP 156 EP 163 DI 10.1016/j.neurobiolaging.2016.04.008 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA DN7XI UT WOS:000377293100016 PM 27255825 ER PT J AU Ramos, VFML Esquenazi, A Villegas, MAF Wu, TX Hallett, M AF Ramos, Vesper Fe Marie Llaneza Esquenazi, Alina Villegas, Monica Anne Faye Wu, Tianxia Hallett, Mark TI Temporal discrimination threshold with healthy aging SO NEUROBIOLOGY OF AGING LA English DT Article DE Temporal discrimination threshold; Aging; Age effects; Timing; Time perception ID PAIRED ASSOCIATIVE STIMULATION; PRIMARY TORSION DYSTONIA; FOCAL HAND DYSTONIA; HUMAN MOTOR CORTEX; PARKINSONS-DISEASE; INTRACORTICAL INHIBITION; CORTICAL EXCITABILITY; SOMATOSENSORY CORTEX; PSYCHOGENIC DYSTONIA; ABNORMAL PLASTICITY AB The temporal discrimination threshold (TDT) is the shortest interstimulus interval at which a subject can perceive successive stimuli as separate. To investigate the effects of aging on TDT, we studied tactile TDT using the method of limits with 120% of sensory threshold in each hand for each of 100 healthy volunteers, equally divided among men and women, across 10 age groups, from 18 to 79 years. Linear regression analysis showed that age was significantly related to left-hand mean, right-hand mean, and mean of 2 hands with R-square equal to 0.08, 0.164, and 0.132, respectively. Reliability analysis indicated that the 3 measures had fair-to-good reliability (intraclass correlation coefficient: 0.4-0.8). We conclude that TDT is affected by age and has fair-to-good reproducibility using our technique. Published by Elsevier Inc. C1 [Ramos, Vesper Fe Marie Llaneza; Esquenazi, Alina; Villegas, Monica Anne Faye; Wu, Tianxia; Hallett, Mark] NIH, Human Motor Control Sect, Bldg 10,Room 7D42,10 Ctr Dr, Bethesda, MD 20892 USA. RP Ramos, VFML (reprint author), NIH, Human Motor Control Sect, Bldg 10,Room 7D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM vesper.ramos@yahoo.com OI Ramos, Vesper Fe Marie/0000-0001-8513-7476 FU BCN Peptides; Dystonia Medical Research Foundation FX Dr. Ramos received research support from BCN Peptides and was supported by a fellowship grant from the Dystonia Medical Research Foundation. NR 56 TC 2 Z9 2 U1 3 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2016 VL 43 BP 174 EP 179 DI 10.1016/j.neurobiolaging.2016.04.009 PG 6 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA DN7XI UT WOS:000377293100018 PM 27255827 ER PT J AU Borghero, G Pugliatti, M Marrosu, F Marrosu, MG Murru, MR Floris, G Cannas, A Occhineri, P Cau, TB Loi, D Ticca, A Traccis, S Manera, U Canosa, A Moglia, C Calvo, A Barberis, M Brunetti, M Gibbs, JR Renton, AE Errichiello, E Zoledziewska, M Mulas, A Qian, Y Din, J Pliner, HA Traynor, BJ Chio, A Logullo, FO Simone, I Logroscino, G Salvi, F Bartolomei, I Capasso, M Caponnetto, C Mandich, P Mancardi, G Origone, P Conforti, FL Vita, G Messina, S Russo, M Mora, G Marinou, K Sideri, R Lunetta, C Penco, S Mosca, L Pinter, GL Corbo, M Riva, N Carrera, P Volanti, P Tremolizzo, L Ferrarese, C Fini, N Fasano, A Monsurro, MR Tedeschi, G Trojsi, F Piccirillo, G Cristillo, V Mazzini, L D'Alfonso, S Bersano, A Corrado, L Bagarotti, A La Bella, V Spataro, R Colletti, T Sabatelli, M Zollino, M Conte, A Luigetti, M Lattante, S Marangi, G Santarelli, M Petrucci, A Giannini, F Battistini, S Ricci, C Benigni, M Restagno, G Casale, F Marrali, G Fuda, G Ossola, I Cammarosano, S Ilardi, A Bertuzzo, D Tanel, R Pisano, F Costantino, E Pani, C Puddu, R Caredda, C Piras, V Tranquilli, S Cuccu, S Corongiu, D Melis, M Milia, A Pirisi, A Parish, LD Ortu, E AF Borghero, Giuseppe Pugliatti, Maura Marrosu, Francesco Marrosu, Maria Giovanna Murru, Maria Rita Floris, Gianluca Cannas, Antonino Occhineri, Patrizia Cau, Tea B. Loi, Daniela Ticca, Anna Traccis, Sebastiano Manera, Umberto Canosa, Antonio Moglia, Cristina Calvo, Andrea Barberis, Marco Brunetti, Maura Gibbs, J. Raphael Renton, Alan E. Errichiello, Edoardo Zoledziewska, Magdalena Mulas, Antonella Qian, Yong Din, Jun Pliner, Hannah A. Traynor, Bryan J. Chio, Adriano Logullo, Francesco O. Simone, Isabella Logroscino, Giancarlo Salvi, Fabrizio Bartolomei, Ilaria Capasso, Margherita Caponnetto, Claudia Mandich, Paolo Mancardi, Gianluigi Origone, Paola Conforti, Francesca L. Vita, Giuseppe Messina, Sonia Russo, Massimo Mora, Gabriele Marinou, Kalliopi Sideri, Riccardo Lunetta, Christian Penco, Silvana Mosca, Lorena Pinter, Giuseppe Lauria Corbo, Massimo Riva, Nilo Carrera, Paola Volanti, Paolo Tremolizzo, Lucio Ferrarese, Carlo Fini, Nicola Fasano, Antonio Monsurro, Maria Rosaria Tedeschi, Gioacchino Trojsi, Francesca Piccirillo, Giovanni Cristillo, Viviana Mazzini, Letizia D'Alfonso, Sandra Bersano, Anna Corrado, Lucia Bagarotti, Alessandra La Bella, Vincenzo Spataro, Rossella Colletti, Tiziana Sabatelli, Mario Zollino, Marcella Conte, Amelia Luigetti, Marco Lattante, Serena Marangi, Giuseppe Santarelli, Marialuisa Petrucci, Antonio Giannini, Fabio Battistini, Stefania Ricci, Claudia Benigni, Michele Restagno, Gabriella Casale, Federico Marrali, Giuseppe Fuda, Giuseppe Ossola, Irene Cammarosano, Stefania Ilardi, Antonio Bertuzzo, Davide Tanel, Raffaella Pisano, Fabrizio Costantino, Emanuela Pani, Carla Puddu, Roberta Caredda, Carla Piras, Valeria Tranquilli, Stefania Cuccu, Stefania Corongiu, Daniela Melis, Maurizio Milia, Antonio Pirisi, Angelo Parish, Leslie D. Ortu, Enzo CA ITALSGEN SARDINALS Consortia TI TBK1 is associated with ALS and ALS-FTD in Sardinian patients SO NEUROBIOLOGY OF AGING LA English DT Article DE Amyotrophic lateral sclerosis; Genetics; Sporadic; TBK1 ID AMYOTROPHIC-LATERAL-SCLEROSIS; SEQUENCING DATA AB Recently, mutations in the TANK-binding kinase 1 (TBK1) gene were identified as a cause for amyotrophic lateral sclerosis (ALS) with or without comorbid frontotemporal dementia. We have assessed the frequency and clinical characteristics of TBK1 mutations in a cohort of ALS patients of Sardinian ancestry. Whole-exome sequencing was performed on Hiseq2000 platform (Illumina). Genome analysis Toolkit was used to align and to code variants according to Human Genome (UCSC hg19). Mutation was confirmed with Sanger sequence. In our screening of 186 Sardinian ALS cases, we found 3 (1.6%) patients carrying 3 distinct novel genetic variants: a nonsynonymous SNV c.1150C>T leading to a p.Arg384Thr change in exon 9; a nonsynonymous SNV c.1331G>A causes a p.Arg444Gln change in exon 11; and a frameshift deletion c.2070delG (p.Met690fs) at the exon 20 of the gene leading to a stop at 693 codon. The latter patients also carried missense mutation c.98C>T of the SQSTM1 gene causing a substitution of an arginine with a valine at the position 33 (p.Arg33Val). All variants were found to be deleterious according to in silico predictions. All cases were apparently sporadic and one of them showed frontotemporal dementia associated to ALS. These mutations were not found in 2 cohorts of 6780 ethnic-matched controls. We have found that TBK1 mutations account for 1.6% of Sardinian ALS cases. Our data support the notion that TBK1 is a novel ALS gene, providing important evidence complementary to the first descriptions. (C) 2016 Elsevier Inc. All rights reserved. C1 [Borghero, Giuseppe; Marrosu, Francesco; Floris, Gianluca; Cannas, Antonino] Azienda Univ Osped Cagliari, Dept Neurol, Cagliari, Italy. [Borghero, Giuseppe; Marrosu, Francesco; Floris, Gianluca; Cannas, Antonino] Univ Cagliari, Cagliari, Italy. [Pugliatti, Maura; Occhineri, Patrizia] Univ Ferrara, Dept Biomed & Surg Sci, Sect Neurol Psychiat & Psychol Sci, I-44100 Ferrara, Italy. [Marrosu, Maria Giovanna; Murru, Maria Rita] Univ Cagliari, Dept Med Sci, Multiple Sclerosis Ctr, Cagliari, Italy. [Cau, Tea B.; Loi, Daniela] Azienda Sanit Locale 2, Olbia Tempio, Olbia, Italy. [Ticca, Anna] Azienda Osped San Francesco, Dept Neurol, Nuoro, Italy. [Traccis, Sebastiano] Osped Antonio Segni, Dept Neurol, Ozieri, Italy. [Manera, Umberto; Canosa, Antonio; Moglia, Cristina; Calvo, Andrea; Barberis, Marco; Brunetti, Maura; Errichiello, Edoardo; Chio, Adriano] Univ Turin, Amyotroph Lateral Sclerosis Ctr, Rita Levi Montalcini Dept Neurosci, Turin, Italy. [Canosa, Antonio] Univ Genoa, Dept Neurosci Ophthalmol Genet Rehabil & Child Hl, Genoa, Italy. [Calvo, Andrea; Gibbs, J. Raphael; Chio, Adriano] Azienda Osped Univ Citta Salute & Sci, Turin, Italy. [Renton, Alan E.; Errichiello, Edoardo; Pliner, Hannah A.; Traynor, Bryan J.] NIA, Neuromuscular Dis Res Sect, Neurogenet Lab, Bethesda, MD 20892 USA. [Zoledziewska, Magdalena] NIA, Mol Genet Sect, Neurogenet Lab, Bethesda, MD 20892 USA. [Zoledziewska, Magdalena] NIA, Computat Biol Core, Neurogenet Lab, Bethesda, MD 20892 USA. [Zoledziewska, Magdalena; Mulas, Antonella] CNR, Ist Ric Genet & Biomed, Cagliari, Italy. [Qian, Yong; Din, Jun] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Traynor, Bryan J.] Johns Hopkins Univ, Dept Neurol, Brain Sci Inst, Baltimore, MD 21218 USA. [Chio, Adriano] Neurosci Inst Torino NIT, Turin, Italy. [Chio, Adriano] CNR, Inst Cognit Sci & Technol, Rome, Italy. RP Chio, A (reprint author), Univ Turin, Rita Levi Montalcini Dept Neurosci, Turin, Italy. EM achio@usa.net RI Mosca, Lorena/K-4015-2016; Lunetta, Christian/K-9214-2016; La Bella, Vincenzo/H-4532-2012; Battistini, Stefania/N-2596-2015; MANDRIOLI, JESSICA/K-7235-2016; Moglia, Cristina/K-4142-2016; OI Marrosu, Maria Giovanna/0000-0003-2334-2081; Mosca, Lorena/0000-0002-6767-2368; Lunetta, Christian/0000-0002-4788-1875; Battistini, Stefania/0000-0003-2887-7624; MANDRIOLI, JESSICA/0000-0002-9244-9782; Moglia, Cristina/0000-0001-7377-7222; Riva, Nilo/0000-0002-0513-9517; Pliner, Hannah/0000-0003-1484-6501 FU Intramural Research Programs of the US National Institutes of Health (NIH), National Institute on Aging [Z01-AG000949-02]; Agenzia Italiana per la Ricerca sulla SLA (ARISLA) (SARDINIALS); Packard Centre for ALS Research at Johns Hopkins; Fondazione Vialli e Mauro Onlus; European Community [259867]; Joint Programme-Neurodegenerative Disease Research (Sophia Project) - Italian Health Ministry; Strength Project - Italian Ministry of University and Research); Fondazione Mario e Anna Magnetto; Associazione Piemontese per l'Assistenza alla Sclerosi Laterale Amiotrfica (APASLA) FX This work was supported in part by the Intramural Research Programs of the US National Institutes of Health (NIH), National Institute on Aging (Z01-AG000949-02). The work was also supported by the Agenzia Italiana per la Ricerca sulla SLA (ARISLA) (SARDINIALS grant), Packard Centre for ALS Research at Johns Hopkins, Fondazione Vialli e Mauro Onlus, European Community's Health Seventh Framework Programme (FP7/2007-2013) under grant agreement #259867, the Joint Programme-Neurodegenerative Disease Research (Sophia Project, granted by the Italian Health Ministry, and Strength Project, granted by the Italian Ministry of University and Research), the Fondazione Mario e Anna Magnetto, and the Associazione Piemontese per l'Assistenza alla Sclerosi Laterale Amiotrfica (APASLA). NR 13 TC 4 Z9 4 U1 12 U2 22 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2016 VL 43 DI 10.1016/j.neurobiolaging.2016.03.028 PG 5 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA DN7XI UT WOS:000377293100019 ER PT J AU Nie, XJ Lowe, DW Rollins, LG Bentzley, J Fraser, JL Martin, R Singh, I Jenkins, D AF Nie, Xingju Lowe, Danielle W. Rollins, Laura Grace Bentzley, Jessica Fraser, Jamie L. Martin, Renee Singh, Inderjit Jenkins, Dorothea TI Sex-specific effects of N-acetylcysteine in neonatal rats treated with hypothermia after severe hypoxia-ischemia SO NEUROSCIENCE RESEARCH LA English DT Article DE Neonatal hypoxia ischemia; N-acetylcysteine; Sex; Neuroprotection; Redox regulation ID FOCAL CEREBRAL-ISCHEMIA; UNFOLDED PROTEIN RESPONSE; EXPERIMENTAL STROKE; NITRIC-OXIDE; BRAIN-INJURY; OXIDATIVE STRESS; MODERATE HYPOTHERMIA; CELL-DEATH; INTRACELLULAR GLUTATHIONE; MATRIX METALLOPROTEINASES AB Approximately half of moderate to severely hypoxic-ischemic (HI) newborns do not respond to hypothermia, the only proven neuroprotective treatment. N-acetylcysteine (NAC), an antioxidant and glutathione precursor, shows promise for neuroprotection in combination with hypothermia, mitigating post-HI neuroinflammation due to oxidative stress. As mechanisms of HI injury and cell death differ in males and females, sex differences must be considered in translational research of neuroprotection. We assessed the potential toxicity and efficacy of NAC in combination with hypothermia, in male and female neonatal rats after severe HI injury. NAC 50 mg/kg/d administered 1 h after initiation of hypothermia significantly decreased iNOS expression and caspase 3 activation in the injured hemisphere versus hypothermia alone. However, only females treated with hypothermia +NAC 50 mg/kg showed improvement in short-term infarct volumes compared with saline treated animals. Hypothermia alone had no effect in this severe model. When NAC was continued for 6 weeks, significant improvement in long-term neuromotor outcomes over hypothermia treatment alone was observed, controlling for sex. Antioxidants may provide insufficient neuroprotection after HI for neonatal males in the short term, while long-term therapy may benefit both sexes. (C) 2016 The Authors. Published by Elsevier Ireland Ltd. C1 [Nie, Xingju] Med Univ S Carolina, Ctr Biomed Imaging, 165 Ashley Ave, Charleston, SC 29425 USA. [Lowe, Danielle W.; Bentzley, Jessica; Singh, Inderjit; Jenkins, Dorothea] Med Univ S Carolina, Dept Pediat, MSC 917,165 Ashley Ave, Charleston, SC 29425 USA. [Rollins, Laura Grace] Univ Massachusetts, Dept Psychol, 100 Morrissey Blvd, Boston, MA 02125 USA. [Fraser, Jamie L.] NIH, Med Genet Training Program, Natl Human Genome Res Inst, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Martin, Renee] Med Univ S Carolina, Dept Biostat & Epidemiol, 165 Ashley Ave, Charleston, SC 29425 USA. RP Jenkins, D (reprint author), Med Univ S Carolina, Dept Pediat, MSC 917,165 Ashley Ave, Charleston, SC 29425 USA. EM niexi@musc.edu; clarkdw@musc.edu; lgrollins@gmail.com; perkel@musc.edu; jamie.fraser@nih.gov; hebertrl@musc.edu; singhi@musc.edu; jenkd@musc.edu FU NIH [NS 054428, NS 022576, NS 037766] FX This work was supported by NIH grants NS 054428, NS 022576 and NS 037766. NR 77 TC 1 Z9 1 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0168-0102 EI 1872-8111 J9 NEUROSCI RES JI Neurosci. Res. PD JUL PY 2016 VL 108 BP 24 EP 33 DI 10.1016/j.neures.2016.01.008 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DN7ZK UT WOS:000377298500004 PM 26851769 ER PT J AU Julnes, PS Auh, S Krakora, R Withers, K Nora, D Matthews, L Steinbach, S Snow, J Smith, B Nath, A Morse, C Kapetanovic, S AF Julnes, Peter Siyahhan Auh, Sungyoung Krakora, Rebecca Withers, Keenan Nora, Diana Matthews, Lindsay Steinbach, Sally Snow, Joseph Smith, Bryan Nath, Avindra Morse, Caryn Kapetanovic, Suad TI The Association Between Post-traumatic Stress Disorder and Markers of Inflammation and Immune Activation in HIV-Infected Individuals With Controlled Viremia SO PSYCHOSOMATICS LA English DT Article DE client diagnostic questionnaire; PLWH; immunophenotyping; antiretroviral therapy; post-traumatic stress; mental health ID COMORBIDITY SURVEY REPLICATION; DSM-IV DISORDERS; CHILDHOOD MALTREATMENT; HEALTH OUTCOMES; SUBSTANCE USE; TRAUMA; PREVALENCE; LEUKOCYTE; SEVERITY; CARE AB Background: Post-traumatic stress disorder (PTSD) may be associated with chronic immune dysregulation and a proinflammatory state. Among HIV-infected individuals, PTSD is associated with greater morbidity and mortality, but the association with immune dysfunction has not been evaluated. This study explores the association between PTSD and selected markers of inflammation and immune activation in a cohort of HIV-infected, virally-suppressed individuals. Methods: HIV-infected adults who were virologically controlled on antiretroviral medications were recruited through a screening protocol for studies of HIV-related neurocognitive disorders. Each participant underwent blood draws, urine toxicology screen, and completed the Client Diagnostic Questionnaire, a semistructured psychiatric interview. Results: Of 114 eligible volunteers, 72 (63%) were male, 77 (68%) African American, and 34 (30%) participants met criteria for PTSD. Participants with PTSD were more likely to be current smokers (79%) than those without (60%) (p = 0.05). The PTSD cohort had significantly higher total white blood cell counts (5318 and 6404 cellsluL, p = 0.03), absolute neutrophil count (2767 and 3577 cellsluL, p = 0.02), CD8% (43 and 48, p = 0.05), and memory CD8% (70 and 78%, p = 0.04); lower naive CD8% (30 and22%, p = 0.04) and higher rate of high-sensitivity C-reactive protein > 3 mgIL (29 and 20, p = 0.03). Discussion: A high prevalence of PTSD was identified in this cohort of HIV-infected adults who were virally suppressed These results suggest that PTSD may be associated with immune dysregulation even among antiretroviral therapy-adherent HIV-infected individuals. C1 [Julnes, Peter Siyahhan; Steinbach, Sally; Smith, Bryan; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bldg 10,Rm 7C103,MSC 1430, Bethesda, MD 20892 USA. [Auh, Sungyoung] NIDDK, NIH, Bethesda, MD 20892 USA. [Krakora, Rebecca; Matthews, Lindsay; Morse, Caryn] NIH, Dept Crit Care Med, Bldg 10, Bethesda, MD 20892 USA. [Withers, Keenan; Nora, Diana; Snow, Joseph; Kapetanovic, Suad] NIMH, NIH, Bethesda, MD 20892 USA. [Steinbach, Sally] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [Kapetanovic, Suad] Univ So Calif, Keck Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA. RP Julnes, PS (reprint author), NINDS, Sect Infect Nervous Syst, NIH, Bldg 10,Rm 7C103,MSC 1430, Bethesda, MD 20892 USA. EM peterselim.siyahhanjulnes@nih.gov OI Morse, Caryn/0000-0002-1177-4365 NR 18 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD JUL-AUG PY 2016 VL 57 IS 4 BP 423 EP 430 PG 8 WC Psychiatry; Psychology SC Psychiatry; Psychology GA DN7XX UT WOS:000377294600010 ER PT J AU Chesnokova, LS Valencia, SM Hutt-Fletcher, LM AF Chesnokova, Liudmila S. Valencia, Sarah M. Hutt-Fletcher, Lindsey M. TI The BDLF3 gene product of Epstein-Barr virus, gp150, mediates non-productive binding to heparan sulfate on epithelial cells and only the binding domain of CD21 is required for infection SO VIROLOGY LA English DT Article DE Epstein-Barr virus; Glycoprotein 150; Heparan-binding; CD21; Epithelial cell infection ID B-CELLS; CONFORMATIONAL-CHANGE; GLYCOPROTEINS GHGL; RECEPTOR CR-2; LYMPHOCYTE-B; ENTRY; REPLICATION; ATTACHMENT; ALPHA-V-BETA-8; HERPESVIRUS AB The cell surface molecules used by Epstein-Barr virus (EBV) to attach to epithelial cells are not well-defined, although when CD21, the B cell receptor for EBV is expressed epithelial cell infection increases disproportionately to the increase in virus bound. Many herpesviruses use low affinity charge interactions with molecules such as heparan sulfate to attach to cells. We report here that the EBV glycoprotein gp150 binds to heparan sulfate proteoglycans, but that attachment via this glycoprotein is not productive of infection. We also report that only the aminoterminal two short consensus repeats of CD21 are required for efficient infection, This supports the hypothesis that, when expressed on an epithelial cell CD21 serves primarily to cluster the major attachment protein gp350 in the virus membrane and enhance access of other important glycoproteins to the epithelial cell surface. (C) 2016 Elsevier Inc. All rights reserved. C1 Louisiana State Univ, Hlth Sci Ctr, Dept Microbiol & Immunol, Ctr Mol & Tumor Virol, 1501 Kings Highway, Shreveport, LA 71130 USA. Louisiana State Univ, Hlth Sci Ctr, Feist Weiller Canc Ctr, 1501 Kings Highway, Shreveport, LA 71130 USA. [Valencia, Sarah M.] NIH, Infect Dis Lab, Bldg 50,Room 6134,50 South Dr,MSC8007, Bethesda, MD 20892 USA. RP Hutt-Fletcher, LM (reprint author), Louisiana State Univ, Hlth Sci Ctr, Dept Microbiol & Immunol, 1501 Kings Highway, Shreveport, LA 71130 USA. EM lchesn@lsuhsc.edu; sarah.valencia@nih.gov; lhuttf@lsuhsc.edu FU Public Health Service grants from the National Institute of Dental and Craniofacial Research [DE016669, DE019599] FX This work was supported by Public Health Service grants DE016669 (to LMH-F) and DE019599 (to SMV) from the National Institute of Dental and Craniofacial Research. We thank Karl Munger for the gift of the NOK cells. NR 54 TC 0 Z9 0 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 0042-6822 J9 VIROLOGY JI Virology PD JUL PY 2016 VL 494 BP 23 EP 28 DI 10.1016/j.virol.2016.04.002 PG 6 WC Virology SC Virology GA DN8IA UT WOS:000377321200003 PM 27061054 ER PT J AU Raran-Kurussi, S Waugh, DS AF Raran-Kurussi, Sreejith Waugh, David S. TI A dual protease approach for expression and affinity purification of recombinant proteins SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Maltose-binding protein; Tobacco etch virus protease; Rhinovirus 3C protease; His-tag; Affinity chromatography ID MALTOSE-BINDING PROTEIN; TOBACCO ETCH VIRUS; ESCHERICHIA-COLI; FUSION PROTEINS; SOLUBILITY; TAGS; SPECIFICITY; INSIGHTS AB We describe a new method for affinity purification of recombinant proteins using a dual protease protocol. Escherichia coli maltose binding protein (MBP) is employed as an N-terminal tag to increase the yield and solubility of its fusion partners. The MBP moiety is then removed by rhinovirus 3C protease, prior to purification, to yield an N-terminally His(6)-tagged protein. Proteins that are only temporarily rendered soluble by fusing them to MBP are readily identified at this stage because they will precipitate after the MBP tag is removed by 3C protease. The remaining soluble His(6)-tagged protein, if any, is subsequently purified by immobilized metal affinity chromatography (IMAC). Finally, the N-terminal His(6) tag is removed by His(6)-tagged tobacco etch virus (TEV) protease to yield the native recombinant protein, and the His(6)-tagged contaminants are removed by adsorption during a second round of IMAC, leaving only the untagged recombinant protein in the column effluent. The generic strategy described here saves time and effort by removing insoluble aggregates at an early stage in the process while also reducing the tendency of MBP to "stick" to its fusion partners during affinity purification. Published by Elsevier Inc. C1 [Raran-Kurussi, Sreejith; Waugh, David S.] NCI, Prot Engn Sect, Macromol Crystallog Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. RP Waugh, DS (reprint author), NCI, Prot Engn Sect, Macromol Crystallog Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. EM waughd@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research FX We thank Karina Keefe and Danielle Needle for constructing the ChikV protease and the Ubc9 entry clones, respectively. This project was funded by the Intramural Research Program of the National Institutes of Health (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 the mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. We thank the Biophysics Resource in the Structural Biophysics Laboratory, Frederick National Laboratory, for assistance with electrospray ionization mass spectroscopy. The authors declare that they have no conflicts of interest. NR 28 TC 0 Z9 0 U1 7 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 EI 1096-0309 J9 ANAL BIOCHEM JI Anal. Biochem. PD JUL 1 PY 2016 VL 504 BP 30 EP 37 DI 10.1016/j.ab.2016.04.006 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DN4RN UT WOS:000377055000007 PM 27105777 ER PT J AU Marcum, ZA Perera, S Thorpe, JM Switzer, GE Castle, NG Strotmeyer, ES Simonsick, EM Ayonayon, HN Phillips, CL Rubin, S Zucker-Levin, AR Bauer, DC Shorr, RI Kang, YH Gray, SL Hanlon, JT AF Marcum, Zachary A. Perera, Subashan Thorpe, Joshua M. Switzer, Galen E. Castle, Nicholas G. Strotmeyer, Elsa S. Simonsick, Eleanor M. Ayonayon, Hilsa N. Phillips, Caroline L. Rubin, Susan Zucker-Levin, Audrey R. Bauer, Douglas C. Shorr, Ronald I. Kang, Yihuang Gray, Shelly L. Hanlon, Joseph T. CA Hlth ABC Study TI Antidepressant Use and Recurrent Falls in Community-Dwelling Older Adults: Findings From the Health ABC Study SO ANNALS OF PHARMACOTHERAPY LA English DT Article DE antidepressants; aging; drug-related problems; epidemiology; geriatrics; outcomes research/analysis; pharmacoepidemiology ID BODY-COMPOSITION; RISK-FACTOR; PEOPLE; MEDICATION; ASSOCIATIONS; PERFORMANCE; DEPRESSION; ELDERS; WOMEN AB Background: Few studies have compared the risk of recurrent falls across various antidepressant agents-using detailed dosage and duration data-among community-dwelling older adults, including those who have a history of a fall/fracture. Objective: To examine the association of antidepressant use with recurrent falls, including among those with a history of falls/fractures, in community-dwelling elders. Methods: This was a longitudinal analysis of 2948 participants with data collected via interview at year 1 from the Health, Aging and Body Composition study and followed through year 7 (19972004). Any antidepressant medication use was self-reported at years 1, 2, 3, 5, and 6 and further categorized as (1) selective serotonin reuptake inhibitors (SSRIs), (2) tricyclic antidepressants, and (3) others. Dosage and duration were examined. The outcome was recurrent falls (>= 2) in the ensuing 12-month period following each medication data collection. Results: Using multivariable generalized estimating equations models, we observed a 48% greater likelihood of recurrent falls in antidepressant users compared with nonusers (adjusted odds ratio [AOR] = 1.48; 95% CI = 1.12-1.96). Increased likelihood was also found among those taking SSRIs (AOR = 1.62; 95% CI = 1.15-2.28), with short duration of use (AOR = 1.47; 95% CI = 1.04-2.00), and taking moderate dosages (AOR = 1.59; 95% CI = 1.15-2.18), all compared with no antidepressant use. Stratified analysis revealed an increased likelihood among users with a baseline history of falls/fractures compared with nonusers (AOR = 1.83; 95% CI = 1.28-2.63). Conclusion: Antidepressant use overall, SSRI use, short duration of use, and moderate dosage were associated with recurrent falls. Those with a history of falls/fractures also had an increased likelihood of recurrent falls. C1 [Marcum, Zachary A.; Gray, Shelly L.] Univ Washington, Seattle, WA 98102 USA. [Perera, Subashan; Thorpe, Joshua M.; Switzer, Galen E.; Castle, Nicholas G.; Strotmeyer, Elsa S.; Kang, Yihuang; Hanlon, Joseph T.] Univ Pittsburgh, Pittsburgh, PA USA. [Thorpe, Joshua M.; Switzer, Galen E.; Hanlon, Joseph T.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Simonsick, Eleanor M.; Phillips, Caroline L.] NIA, Baltimore, MD 21224 USA. [Ayonayon, Hilsa N.; Rubin, Susan; Bauer, Douglas C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Zucker-Levin, Audrey R.] Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. [Shorr, Ronald I.] Vet Affairs Med Ctr, Gainesville, FL 32608 USA. RP Marcum, ZA (reprint author), Univ Washington, Sch Pharm, Dept Pharm, 1959 NE Pacific St,H375G,Box 357630, Seattle, WA 98102 USA. EM zmarcum@uw.edu FU National Institute on Aging (NIA) [P30AG024827, T32 AG021885, K07AG033174, R01AG028050]; National Institutes of Health; NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; National Institute of Nursing Research [R01NR012459] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was primarily supported by National Institute on Aging (NIA) grants and contracts (P30AG024827, T32 AG021885, K07AG033174, R01AG028050). This research was also supported in part by the Intramural Research program of the National Institutes of Health and NIA (N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106) and a National Institute of Nursing Research grant (R01NR012459). NR 27 TC 2 Z9 2 U1 5 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1060-0280 EI 1542-6270 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD JUL PY 2016 VL 50 IS 7 BP 525 EP 533 DI 10.1177/1060028016644466 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DN5JO UT WOS:000377102900001 PM 27066988 ER PT J AU Rezgui, R Blumer, K Yeoh-Tan, G Trexler, AJ Magzoub, M AF Rezgui, Rachid Blumer, Katy Yeoh-Tan, Gilbert Trexler, Adam J. Magzoub, Mazin TI Precise quantification of cellular uptake of cell-penetrating peptides using fluorescence-activated cell sorting and fluorescence correlation spectroscopy SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Article DE Drug delivery; Cellular uptake; Internalization pathways; Intracellular distribution; Intracellular degradation; Toxicity threshold ID HUMAN-IMMUNODEFICIENCY-VIRUS; ARGININE-RICH PEPTIDES; INTRACELLULAR DELIVERY; CARGO MOLECULES; MEMBRANE; INTERNALIZATION; PROTEINS; PLASMA; MACROPINOCYTOSIS; TRANSLOCATION AB Cell-penetrating peptides (CPPs) have emerged as a potentially powerful tool for drug delivery due to their ability to efficiently transport a whole host of biologically active cargoes into cells. Although concerted efforts have shed some light on the cellular internalization pathways of CPPs, quantification of CPP uptake has proved problematic. Here we describe an experimental approach that combines two powerful biophysical techniques, fluorescence activated cell sorting (FACS) and fluorescence correlation spectroscopy (FCS), to directly, accurately and precisely measure the cellular uptake of fluorescently-labeled molecules. This rapid and technically simple approach is highly versatile and can readily be applied to characterize all major CPP properties that normally require multiple assays, including amount taken up by cells (in moles/cell), uptake efficiency, internalization pathways, intracellular distribution, intracellular degradation and toxicity threshold. The FACS-FCS approach provides a means for quantifying any intracellular biochemical entity, whether expressed in the cell or introduced exogenously and transported across the plasma membrane. (C) 2016 The Authors. Published by Elsevier B.V. C1 [Rezgui, Rachid; Magzoub, Mazin] New York Univ, Biol Program, POB 129188,Saadiyat Isl Campus, Abu Dhabi, U Arab Emirates. [Blumer, Katy] New York Univ, Phys Program, Abu Dhabi, U Arab Emirates. [Yeoh-Tan, Gilbert] New York Univ, CGSB, Abu Dhabi, U Arab Emirates. [Trexler, Adam J.] NHLBI, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Magzoub, M (reprint author), New York Univ, Biol Program, POB 129188,Saadiyat Isl Campus, Abu Dhabi, U Arab Emirates. EM mazin.magzoub@nyu.edu FU NYU Abu Dhabi; NYU Abu Dhabi Institute [G1205]; National Institutes of Health [F31 AG038110] FX The authors thank Justin Blau (NYU), Andrew Miranker (Yale University) and Elizabeth Rhoades (Yale University) for comments on the manuscript. Confocal imaging experiments were carried out using the Core Technology Platform resources at NYU Abu Dhabi. This work was supported by a start-up fund for M.M. from NYU Abu Dhabi. Additional support was provided by NYU Abu Dhabi Institute Grant G1205. A.J.T. received support from the National Institutes of Health (F31 AG038110). NR 47 TC 3 Z9 3 U1 9 U2 37 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 EI 0006-3002 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD JUL PY 2016 VL 1858 IS 7 BP 1499 EP 1506 DI 10.1016/j.bbamem.2016.03.023 PN A PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DN7CN UT WOS:000377233000011 PM 27033412 ER PT J AU Koshiol, J Castro, F Kemp, TJ Gao, YT Roa, JC Wang, BS Nogueira, L Araya, JC Shen, MC Rashid, A Hsing, AW Hildesheim, A Ferreccio, C Pfeiffer, RM Pinto, LA AF Koshiol, Jill Castro, Felipe Kemp, Troy J. Gao, Yu-Tang Carlos Roa, Juan Wang, Bingsheng Nogueira, Leticia Carlos Araya, Juan Shen, Ming-Chang Rashid, Asif Hsing, Ann W. Hildesheim, Allan Ferreccio, Catterina Pfeiffer, Ruth M. Pinto, Ligia A. TI Association of inflammatory and other immune markers with gallbladder cancer: Results from two independent case-control studies SO CYTOKINE LA English DT Article DE Local inflammation; Systemic inflammation; Gallbladder cancer ID BILIARY-TRACT CANCER; CLINICAL-SIGNIFICANCE; METABOLIC SYNDROME; SERUM-LEVELS; RISK; CHINA; SHANGHAI; STONES; INFILTRATION; METAANALYSIS AB Most gallbladder cancer (GBC) cases arise in the context of gallstones, which cause inflammation, but few gallstone patients develop GBC. We explored inflammation/immune-related markers measured in bile and serum in GBC cases compared to gallstone patients to better understand how inflammatory patterns in these two conditions differ. We measured 65 immune-related markers in serum and bile from 41 GBC cases and 127 gallstone patients from Shanghai, China, and calculated age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for GBC versus gallstones. We then focused on the markers that were significantly elevated in bile and serum to replicate the findings in serum from 35 GBC cases and 31 gallstone controls from Chile. Comparing the highest versus lowest quantile, 15 markers (23%) were elevated in both serum and bile from GBC versus gallstone patients in the Shanghai study (p <0.05). The strongest OR was for CXCL8 (interleukin-8) in serum (96.8, 95% CI: 11.9-790.2). Of these 15 markers, 6 were also significantly elevated in serum from Chile (CCL20, C -reactive protein, CXCL8, CXCL10, resistin, serum amyloid A). Pooled ORs from Shanghai and Chile for these 6 markers ranged from 7.2 (95% CI: 2.8-18.4) for CXCL10 to 58.2 (95% CI: 12.4-273.0) for CXCL8. GBC is associated with inflammation above and beyond that generated by gallstones alone. This local inflammatory process is reflected systemically. Future longitudinal studies are needed to identify the key players in cancer development, which may guide translational efforts to identify individuals at high risk of developing GBC. Published by Elsevier Ltd. C1 [Koshiol, Jill; Castro, Felipe; Nogueira, Leticia; Hildesheim, Allan] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Castro, Felipe] Roche, Real World Data Sci RWD S Oncol, Basel, Switzerland. [Kemp, Troy J.; Pinto, Ligia A.] Biomed Res Inc, Leidos, Frederick Natl Lab Canc Res, HPV Immunol Lab, Frederick, MD USA. [Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Carlos Roa, Juan; Ferreccio, Catterina] Pontificia Univ Catolica Chile, Sch Med, Alameda 340, Santiago, Chile. [Carlos Roa, Juan; Ferreccio, Catterina] FONDAP, Adv Ctr Chron Dis ACCDiS, Santiago, Chile. [Wang, Bingsheng] Fudan Univ, Sch Med, Zhongshan Hosp, Dept Gen Surg, Shanghai 200433, Peoples R China. [Nogueira, Leticia] Texas Dept State Hlth Serv, Austin, TX USA. [Carlos Araya, Juan] Hosp Dr Hernan Henriquez Aravena, Temuco, Chile. [Carlos Araya, Juan] Univ La Frontera, Fac Med, Dept Anat Pathol, Temuco, Chile. [Shen, Ming-Chang] Fudan Univ, Shanghai Canc Ctr, Dept Pathol, Shanghai 200433, Peoples R China. [Rashid, Asif] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Hsing, Ann W.] Stanford Canc Inst, Palo Alto, CA USA. [Hsing, Ann W.] Stanford Sch Med, Dept Hlth Res & Policy, Palo Alto, CA USA. [Pfeiffer, Ruth M.] NCI, Div Canc Epidemiol & Genet, Biostat Branch, Bethesda, MD 20892 USA. RP Koshiol, J (reprint author), 9609 Med Ctr Dr,Rm 6-E212,MSC 9767, Bethesda, MD 20892 USA. EM koshiolj@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics (DCEG); Office of Research on Women's Health (ORWH) [CONICYT/FONDAP/15130011]; Fondo Nacional de Investigacion y Desarrollo en Salud (FONIS) [SA11I2205] FX We thank the collaborating surgeons and pathologists in Shanghai and the Gallbladder Cancer Chile Working Group (GBCChWG) in Chile for assistance with field work, including patient recruitment and pathology review; Chia-Rong Cheng, Lu Sun, and Kai Wu of the Shanghai Cancer Institute and Johanna Acevedo and Paz Cook of the Pontificia Universidad Catolica the for coordinating data and specimen collection; and Shelley Niwa of Westat and Michael Curry of IMS for support with study and data management. This work was supported by general funds from the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics (DCEG) and the Office of Research on Women's Health (ORWH), CONICYT/FONDAP/15130011, and Fondo Nacional de Investigacion y Desarrollo en Salud (FONIS) #SA11I2205. These funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation of the manuscript; and decision to submit the manuscript for publication. DCEG did participate in the review and approval of the manuscript; however, the study authors functioned as investigators without direction or interference by DCEG. NR 35 TC 3 Z9 3 U1 3 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD JUL PY 2016 VL 83 BP 217 EP 225 DI 10.1016/j.cyto.2016.05.003 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA DN7AS UT WOS:000377228300029 PM 27173614 ER PT J AU Stroncek, DF Ren, JQ Lee, DW Tran, M Frodigh, SE Sabatino, M Khuu, H Merchant, MS Mackall, CL AF Stroncek, David F. Ren, Jiaqiang Lee, Daniel W. Minh Tran Frodigh, Sue Ellen Sabatino, Marianna Khuu, Hanh Merchant, Melinda S. Mackall, Crystal L. TI Myeloid cells in peripheral blood mononuclear cell concentrates inhibit the expansion of chimeric antigen receptor T cells SO CYTOTHERAPY LA English DT Article DE acute lymphocytic leukemia; adoptive cellular therapy; chimeric antigen receptor T cells; CD19; GD2; osteosarcoma ID SUPPRESSOR-CELLS; MALIGNANCY; LEUKEMIA; CANCER AB Background aims. Autologous chimeric antigen receptor (CAR) T-cell therapies have shown promising clinical outcomes, but T-cell yields have been variable. CD19- and GD2-CART-cell manufacturing records were reviewed to identify sources of variability. Methods. CD19-CAR T cells were used to treat 43 patients with acute lymphocytic leukemia or lymphoma and GD2-CAR T cells to treat eight patients with osteosarcoma and three with neuroblastoma. Both types of CART cells were manufactured using autologous peripheral blood mononuclear cells (PBMC) concentrates and anti-CD3/CD28 beads for T-cell enrichment and simulation. Results. A comparison of the first 6 GD2- and the first 22 CD19-CAR T-cell products manufactured revealed that GD2-CART-cell products contained fewer transduced cells than CD19-CART-cell products (147 +/- 102 x 10(6) vs 1502 +/- 1066 x 10(6); P = 0.0059), and their PBMC concentrates contained more monocytes (31.4 +/- 12.4% vs 18.5 +/- 13.7%; P = 0.019). Among the first 28 CD19-CART-cell products manufactured, four had poor expansion yielding less than 1 x 10(6) transduced T cells per kilogram. When PBMC concentrates from these four patients were compared with the 24 others, PBMC concentrates of poorly expanding products contained greater quantities of monocytes (39.8 +/- 12.9% vs. 15.3 +/- 10.8%, P = 0.0014). Among the patients whose CD19-CART cells expanded poorly, manufacturing for two patients was repeated using cryopreserved PBMC concentrates but incorporating a monocyte depleting plastic adherence step, and an adequate dose of CAR T cells was produced for both patients. Conclusions. Variability in CAR T-cell expansion is due, at least in part, to the contamination of the starting PBMC concentrates with monocytes. C1 [Stroncek, David F.; Ren, Jiaqiang; Minh Tran; Frodigh, Sue Ellen; Sabatino, Marianna; Khuu, Hanh] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, 10 Ctr Dr MSC 1184,Bldg 10,Room 3C720, Bethesda, MD 20892 USA. [Lee, Daniel W.; Merchant, Melinda S.; Mackall, Crystal L.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Stroncek, DF (reprint author), NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, 10 Ctr Dr MSC 1184,Bldg 10,Room 3C720, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov FU NIH, Clinical Center; St. Baldrick's Foundation; Hope from Harper Fund; NIH, National Cancer Institute FX We thank the staff of the Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health (NIH) for manufacturing the CART cells. This research was supported by the Intramural Research Program of the NIH, Clinical Center and National Cancer Institute. DWL is supported by the St. Baldrick's Foundation with generous support from the Hope from Harper Fund. NR 21 TC 3 Z9 3 U1 3 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD JUL PY 2016 VL 18 IS 7 BP 893 EP 901 DI 10.1016/j.jcyt.2016.04.003 PG 9 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA DN2II UT WOS:000376886900009 PM 27210719 ER PT J AU Mendola, P Wallace, M Liu, DP Robledo, C Mannisto, T Grantz, KL AF Mendola, Pauline Wallace, Maeve Liu, Danping Robledo, Candace Mannisto, Tuija Grantz, Katherine L. TI Air pollution exposure and preeclampsia among US women with and without asthma SO ENVIRONMENTAL RESEARCH LA English DT Article DE Preeclampsia; Pregnancy; Hypertension; Asthma; Air pollution ID HYPERTENSIVE DISORDERS; PREGNANCY; OUTCOMES; TOLUENE; METAANALYSIS; ASSOCIATION; COHORT AB Maternal asthma and air pollutants have been independently associated with preeclampsia but rarely studied together. Our objective was to comprehensively evaluate preeclampsia risk based on the interaction of maternal asthma and air pollutants. Preeclampsia and asthma diagnoses, demographic and clinical data came from electronic medical records for 210,508 singleton deliveries. Modified Community Multiscale Air Quality models estimated preconception, first and second trimester and whole pregnancy exposure to: particulate matter (PM) < 2.5 and < 10 mu m, ozone, nitrogen oxides (NOx), sulfur dioxide (SO2) and carbon monoxide (CO); PM2.5 constituents; volatile organic compounds (VOCs) and polycyclic aromatic hydrocarbons (PAHs). Asthma-pollutant interaction adjusted relative risks (RR) and 95% confidence intervals (CI) for preeclampsia were calculated by interquartile range for criteria pollutants and high exposure (>= 75th percentile) for PAHs and VOCs. Asthmatics had higher risk associated with first trimester NO and SO2 and whole pregnancy elemental carbon (EC) exposure than non-asthmatics, but only EC significantly increased risk (RR=1.11, CI:1.03-1.21). Asthmatics also had a 10% increased risk associated with second trimester CO. Significant interactions were observed for nearly all V005 and asthmatics had higher risk during all time windows for benzene, ethylbenzene, m-xylene, o-xylene, p-xylene and toluene while most PAHs did not increase risk. Published by Elsevier Inc. C1 [Mendola, Pauline; Wallace, Maeve; Robledo, Candace; Mannisto, Tuija; Grantz, Katherine L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Epidemiol Branch, Rockville, MD 20852 USA. [Liu, Danping] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Biostat & Bioinformat Branch, Rockville, MD 20852 USA. [Mannisto, Tuija] Northern Finland Lab Ctr NordLab, Oulu, Finland. [Mannisto, Tuija] Univ Oulu, Dept Clin Chem, Oulu, Finland. [Mannisto, Tuija] Oulu Univ Hosp, Med Res Ctr Oulu, POB 500, Oys 90029, Finland. [Mannisto, Tuija] Univ Oulu, POB 500, Oys 90029, Finland. [Mannisto, Tuija] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, POB 310, Oulu 90101, Finland. RP Mendola, P (reprint author), NICHD, NIH, 6100 Executive Blvd,Room 7B03F, Rockville, MD 20852 USA. EM pauline.mendola@nih.gov OI Mendola, Pauline/0000-0001-5330-2844; Grantz, Katherine/0000-0003-0276-8534 FU Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HHSN267200603425C, HHSN275200800002I, HHSN27500008] FX This research was supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), including funding for the Consortium on Safe Labor (Contract No. HHSN267200603425C) and the Air Quality and Reproductive Health Study (Contract No. HHSN275200800002I, Task Order No. HHSN27500008). This paper has been cleared for publication by the NICHD but the funding source had no role in the design, analysis, interpretation or writing of the manuscript. NR 29 TC 0 Z9 0 U1 5 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD JUL PY 2016 VL 148 BP 248 EP 255 DI 10.1016/j.envres.2016.04.004 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA DM9VC UT WOS:000376712800025 PM 27085496 ER PT J AU Linares, GR Chiu, CT Scheuing, L Leng, Y Liao, HM Maric, D Chuang, DM AF Linares, Gabriel R. Chiu, Chi-Tso Scheuing, Lisa Leng, Yan Liao, Hsiao-Mei Maric, Dragan Chuang, De-Maw TI Preconditioning mesenchymal stem cells with the mood stabilizers lithium and valproic acid enhances therapeutic efficacy in a mouse model of Huntington's disease SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Huntington's disease; Intranasal delivery; Lithium; Mesenchymal stem cells; Mood stabilizers; Preconditioning; Stem cell therapy; Valproic acid ID CENTRAL-NERVOUS-SYSTEM; TRAUMATIC BRAIN-INJURY; INTRANASAL DELIVERY; TRANSGENIC MICE; EXTENDS SURVIVAL; ISCHEMIC-STROKE; MUTANT; NEUROGENESIS; ANGIOGENESIS; MECHANISMS AB Huntington's disease (HD) is a fatal neurodegenerative disorder caused by CAG repeat expansions in the huntingtin gene. Although, stem cell-based therapy has emerged as a potential treatment for neurodegenerative diseases, limitations remain, including optimizing delivery to the brain and donor cell loss after transplantation. One strategy to boost cell survival and efficacy is to precondition cells before transplantation. Because the neuroprotective actions of the mood stabilizers lithium and valproic acid (VPA) induce multiple pro-survival signaling pathways, we hypothesized that preconditioning bone marrow-derived mesenchymal stem cells (MSCs) with lithium and VPA prior to intranasal delivery to the brain would enhance their therapeutic efficacy, and thereby facilitate functional recovery in N171-82Q HD transgenic mice. MSCs were treated in the presence or absence of combined lithium and VPA, and were then delivered by brain-targeted single intranasal administration to eight-week old HD mice. Histological analysis confirmed the presence of MSCs in the brain. Open-field test revealed that ambulatory distance and mean velocity were significantly improved in HD mice that received preconditioned MSCs, compared to HD vehicle-control and HD mice transplanted with non-preconditioned MSCs. Greater benefits on motor function were observed in HD mice given preconditioned MSCs, while HD mice treated with non-preconditioned MSCs showed no functional benefits. Moreover, preconditioned MSCs reduced striatal neuronal loss and huntingtin aggregates in HD mice. Gene expression profiling of preconditioned MSCs revealed a robust increase in expression of genes involved in trophic effects, antioxidant, anti-apoptosis, cytokine/chemokine receptor, migration, mitochondrial energy metabolism, and stress response signaling pathways. Consistent with this finding, preconditioned MSCs demonstrated increased survival after transplantation into the brain compared to non-preconditioned cells. Our results suggest that preconditioning stem cells with the mood stabilizers lithium and VPA before transplantation may serve as an effective strategy for enhancing the therapeutic efficacy of stem cell-based therapies. (C) 2016 Published by Elsevier Inc. C1 [Linares, Gabriel R.; Chiu, Chi-Tso; Scheuing, Lisa; Leng, Yan; Liao, Hsiao-Mei; Chuang, De-Maw] NIMH, Mol Neurobiol Sect, NIH, Bldg 10,Room 3D41,10 Ctr Dr MSC 1363, Bethesda, MD 20892 USA. [Maric, Dragan] NINDS, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. RP Linares, GR; Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, NIH, Bldg 10,Room 3D41,10 Ctr Dr MSC 1363, Bethesda, MD 20892 USA. EM gabriel.linares@med.usc.edu; chiuc@csr.nih.gov; lscheui@udel.edu; lengy@mail.nih.gov; hsiao-mei.liao@fda.hhs.gov; maricD@ninds.nih.gov; chuang@mail.nih.gov FU National Institute of Mental Health [ZIAMH002468-25] FX The authors thank Dr. Li-Kai Tsai of National Taiwan University Hospital for assistance with the preconditioning strategy and Drs. Francis McMahon and Carolyn Smith of the NIMH for their input in the course of the study. The authors also thank Peter Leeds of the Molecular Neurobiology Section/NIMH for editorial assistance. Microscopy imaging was performed at the Microscopy and Imaging Core (National Institute of Child Health and Human Development, NIH) with the assistance of Lynne Holtzclaw and Dr. Vincent Schram. Fluorescence-activated cell sorting was performed at the Flow Cytometry core facility (National Institute of Neurological Disorders and Stroke). All other work was performed at the facilities provided by the National Institutes of Health. We are grateful for the support of the intramural research program of the National Institute of Mental Health (ZIAMH002468-25). This work was written as part of the authors' official duties as Government employees (affiliated with Annual Report ZIAMH002468). The views expressed in this article do not necessarily represent the views of the NIMH, NIH, HHS, or the United States Government. NR 55 TC 1 Z9 2 U1 5 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 EI 1090-2430 J9 EXP NEUROL JI Exp. Neurol. PD JUL PY 2016 VL 281 BP 81 EP 92 DI 10.1016/j.expneurol.2016.04.003 PG 12 WC Neurosciences SC Neurosciences & Neurology GA DN4RO UT WOS:000377055100007 PM 27085395 ER PT J AU Yang, YC Lin, XM Lu, XY Luo, GJ Zeng, T Tang, J Jiang, F Li, L Cui, XL Huang, WT Hou, GJ Chen, X Ouyang, Q Tang, SH Sun, HL Chen, LN Gonzalez, FJ Wu, MC Cong, WM Chen, L Wang, HY AF Yang, Yingcheng Lin, Ximeng Lu, Xinyuan Luo, Guijuan Zeng, Tao Tang, Jing Jiang, Feng Li, Liang Cui, Xiuliang Huang, Wentao Hou, Guojun Chen, Xin Ouyang, Qing Tang, Shanhua Sun, Huanlin Chen, Luonan Gonzalez, Frank J. Wu, Mengchao Cong, Wenming Chen, Lei Wang, Hongyang TI Interferon-microRNA signalling drives liver precancerous lesion formation and hepatocarcinogenesis SO GUT LA English DT Article ID PERSISTENT LCMV INFECTION; HEPATOCELLULAR-CARCINOMA; DYSPLASTIC NODULES; I INTERFERON; MALIGNANT PROGRESSION; CANCER DEVELOPMENT; KAPPA-B; INFLAMMATION; ACTIVATION; INTERNALIZATION AB Objective Precancerous lesion, a well-established histopathologically premalignant tissue with the highest risk for tumourigenesis, develops preferentially from activation of DNA damage checkpoint and persistent inflammation. However, little is known about the mechanisms by which precancerous lesions are initiated and their physiological significance. Design Laser capture microdissection was used to acquire matched normal liver, precancerous lesion and tumour tissues. miR-484(-/-), Ifnar1(-/-) and Tgfbr2(Delta hep) mice were employed to determine the critical role of the interferon (IFN)-microRNA pathway in precancerous lesion formation and tumourigenesis. RNA immunoprecipitation (RIP), pull-down and chromatin immunoprecipitation (ChIP) assays were applied to explore the underlying mechanisms. Results miR-484 is highly expressed in over 88% liver samples clinically. DEN-induced precancerous lesions and hepatocellular carcinoma were dramatically impaired in miR-484(-/-) mice. Mechanistically, ectopic expression of miR-484 initiates tumourigenesis and cell malignant transformation through synergistic activation of the transforming growth factor-beta/Gli and nuclear factor-kappa B/type I IFN pathways. Specific acetylation of H3K27 is indispensable for basal IFN-induced continuous transcription of miR-484 and cell transformation. Convincingly, formation of precancerous lesions were significantly attenuated in both Tgfbr2(Delta hep) and Ifnar1(-/-) mice. Conclusions These findings demonstrate a new protumourigenic axis involving type I IFN-microRNA signalling, providing a potential therapeutic strategy to manipulate or reverse liver precancerous lesions and tumourigenesis. C1 [Yang, Yingcheng; Lin, Ximeng; Luo, Guijuan; Tang, Jing; Jiang, Feng; Li, Liang; Cui, Xiuliang; Huang, Wentao; Hou, Guojun; Chen, Xin; Ouyang, Qing; Tang, Shanhua; Sun, Huanlin; Chen, Lei; Wang, Hongyang] Second Mil Med Univ, Eastern Hepatobiliary Surg Inst, Int Cooperat Lab Signal Transduct, 225 Changhai Rd, Shanghai 200438, Peoples R China. [Yang, Yingcheng; Lin, Ximeng; Wu, Mengchao] Eastern Hepatobiliary Surg Hosp, Dept Hepat Surg, Shanghai, Peoples R China. [Lu, Xinyuan; Cong, Wenming] Second Mil Med Univ, Eastern Hepatobiliary Surg Hosp, Dept Pathol, Shanghai, Peoples R China. [Luo, Guijuan; Tang, Jing; Li, Liang; Cui, Xiuliang; Chen, Lei; Wang, Hongyang] Natl Ctr Liver Canc, Shanghai, Peoples R China. [Zeng, Tao; Chen, Luonan] Chinese Acad Sci, Shanghai Inst Biol Sci, Key Lab Syst Biol, Shanghai, Peoples R China. [Gonzalez, Frank J.; Chen, Lei] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wang, Hongyang] Shanghai Jiao Tong Univ, RenJi Hosp, Inst Canc, State Key Lab Oncogenes & Related Genes, Shanghai, Peoples R China. RP Chen, L; Wang, HY (reprint author), Second Mil Med Univ, Eastern Hepatobiliary Surg Inst, Int Cooperat Lab Signal Transduct, 225 Changhai Rd, Shanghai 200438, Peoples R China. EM Chenlei@smmu.edu.cn; hywangk@vip.sina.com FU state Key project for liver cancer [2012ZX10002-009]; National Research Program of China [2012CB316503, 2012AA02A201]; National Natural Science Foundation of China [81221061, 81422032, 81272212, 81300306, 81372674, 91529303]; Science Foundation of Shanghai [134119a3700] FX This work was supported by the state Key project for liver cancer (2012ZX10002-009), the National Research Program of China (2012CB316503, 2012AA02A201), National Natural Science Foundation of China (81221061, 81422032, 81272212, 81300306, 81372674 and 91529303) and Science Foundation of Shanghai (134119a3700). NR 49 TC 2 Z9 2 U1 1 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD JUL PY 2016 VL 65 IS 7 BP 1186 EP 1201 DI 10.1136/gutjnl-2015-310318 PG 16 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DN6GE UT WOS:000377170200017 PM 26860770 ER PT J AU Rutter, CM Knudsen, AB Marsh, TL Doria-Rose, VP Johnson, E Pabiniak, C Kuntz, KM van Ballegooijen, M Zauber, AG Lansdorp-Vogelaar, I AF Rutter, Carolyn M. Knudsen, Amy B. Marsh, Tracey L. Doria-Rose, V. Paul Johnson, Eric Pabiniak, Chester Kuntz, Karen M. van Ballegooijen, Marjolein Zauber, Ann G. Lansdorp-Vogelaar, Iris TI Validation of Models Used to Inform Colorectal Cancer Screening Guidelines: Accuracy and Implications SO MEDICAL DECISION MAKING LA English DT Article DE colorectal cancer; preventive medicine; gastroenterology; discrete event simulation; simulation methods ID SERVICES TASK-FORCE; COST-EFFECTIVENESS; FLEXIBLE SIGMOIDOSCOPY; MEDICARE POPULATION; BOWEL PREPARATION; COLONOSCOPY; COLON; PREVALENCE; CALIBRATION; STRATEGIES AB Background. Microsimulation models synthesize evidence about disease processes and interventions, providing a method for predicting long-term benefits and harms of prevention, screening, and treatment strategies. Because models often require assumptions about unobservable processes, assessing a model's predictive accuracy is important. Methods. We validated 3 colorectal cancer (CRC) microsimulation models against outcomes from the United Kingdom Flexible Sigmoidoscopy Screening (UKFSS) Trial, a randomized controlled trial that examined the effectiveness of one-time flexible sigmoidoscopy screening to reduce CRC mortality. The models incorporate different assumptions about the time from adenoma initiation to development of preclinical and symptomatic CRC. Analyses compare model predictions to study estimates across a range of outcomes to provide insight into the accuracy of model assumptions. Results. All 3 models accurately predicted the relative reduction in CRC mortality 10 years after screening (predicted hazard ratios, with 95% percentile intervals: 0.56 [0.44, 0.71], 0.63 [0.51, 0.75], 0.68 [0.53, 0.83]; estimated with 95% confidence interval: 0.56 [0.45, 0.69]). Two models with longer average preclinical duration accurately predicted the relative reduction in 10-year CRC incidence. Two models with longer mean sojourn time accurately predicted the number of screen-detected cancers. All 3 models predicted too many proximal adenomas among patients referred to colonoscopy. Conclusion. Model accuracy can only be established through external validation. Analyses such as these are therefore essential for any decision model. Results supported the assumptions that the average time from adenoma initiation to development of preclinical cancer is long (up to 25 years), and mean sojourn time is close to 4 years, suggesting the window for early detection and intervention by screening is relatively long. Variation in dwell time remains uncertain and could have important clinical and policy implications. C1 [Rutter, Carolyn M.] RAND Corp, 1776 Main St, Santa Monica, CA 90401 USA. [Knudsen, Amy B.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Marsh, Tracey L.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Doria-Rose, V. Paul] NCI, Hlth Syst & Intervent Res Branch, Bethesda, MD 20892 USA. [Johnson, Eric; Pabiniak, Chester] Grp Hlth Res Inst, Seattle, WA USA. [Kuntz, Karen M.] Univ Minnesota, Sch Publ Hlth, Dept Hlth Policy & Management, Minneapolis, MN USA. [van Ballegooijen, Marjolein; Lansdorp-Vogelaar, Iris] Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Zauber, Ann G.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. RP Rutter, CM (reprint author), RAND Corp, 1776 Main St, Santa Monica, CA 90401 USA. EM crutter@rand.org OI Doria-Rose, Vincent/0000-0002-8802-5143 FU National Cancer Institute as part of the Cancer Intervention and Surveillance Modeling Network (CISNET) [U01-CA-52959]; Center Core Grant [P30-CA-008748] FX This publication was made possible by financial support for this study by a grant from the National Cancer Institute (U01-CA-52959) as part of the Cancer Intervention and Surveillance Modeling Network (CISNET). The funding agreement ensured the authors' independence in designing the study, interpreting the data, writing, and publishing the report. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. For all authors other than Zauber, the entirety of this work was supported by U01-CA-52959. Zauber was also supported by a Center Core Grant (P30-CA-008748). Revision accepted for publication 20 October 2015. NR 46 TC 1 Z9 1 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X EI 1552-681X J9 MED DECIS MAKING JI Med. Decis. Mak. PD JUL PY 2016 VL 36 IS 5 BP 604 EP 614 DI 10.1177/0272989X15622642 PG 11 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA DN5XL UT WOS:000377144900005 PM 26746432 ER PT J AU Ayestaran, FW Schneider, MF Kaskel, FJ Srivaths, PR Seo-Mayer, PW Moxey-Mims, M Furth, SL Warady, BA Greenbaum, LA AF Ayestaran, Frank W. Schneider, Michael F. Kaskel, Frederick J. Srivaths, Poyyapakkam R. Seo-Mayer, Patricia W. Moxey-Mims, Marva Furth, Susan L. Warady, Bradley A. Greenbaum, Larry A. TI Perceived appetite and clinical outcomes in children with chronic kidney disease SO PEDIATRIC NEPHROLOGY LA English DT Article DE Nutrition; Pediatric; ER visits; Quality of life; Hospitalization; Renal function ID STAGE RENAL-DISEASE; QUALITY-OF-LIFE; HEMODIALYSIS-PATIENTS; PEDIATRIC-PATIENTS; RISK-FACTORS; GROWTH; NUTRITION; DEATH; DIALYSIS; INFANTS AB Children with chronic kidney disease (CKD) may have impaired caloric intake through a variety of mechanisms, with decreased appetite as a putative contributor. In adult CKD, decreased appetite has been associated with poor clinical outcomes. There is limited information about this relationship in pediatric CKD. A total of 879 participants of the Chronic Kidney Disease in Children (CKiD) study were studied. Self-reported appetite was assessed annually and categorized as very good, good, fair, or poor/very poor. The relationship between appetite and iohexol or estimated glomerular filtration rate (ieGFR), annual changes in anthropometrics z-scores, hospitalizations, emergency room visits, and quality of life were assessed. An ieGFR < 30 ml/min per 1.73 m(2) was associated with a 4.46 greater odds (95 % confidence interval: 2.80, 7.09) of having a worse appetite than those with ieGFR > 90. Appetite did not predict changes in height, weight, or BMI z-scores. Patients not reporting a very good appetite had more hospitalizations over the next year than those with a very good appetite. Worse appetite was significantly associated with lower parental and patient reported quality of life. Self-reported appetite in children with CKD worsens with lower ieGFR and is correlated with clinical outcomes, including hospitalizations and quality of life. C1 [Ayestaran, Frank W.] Emory Univ, Div Pediat Nephrol, 2015 Uppergate Dr NE, Atlanta, GA 30322 USA. [Ayestaran, Frank W.; Greenbaum, Larry A.] Emory Univ, Atlanta, GA 30322 USA. [Ayestaran, Frank W.; Greenbaum, Larry A.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Schneider, Michael F.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Kaskel, Frederick J.] Albert Einstein Coll Med, New York, NY USA. [Srivaths, Poyyapakkam R.] Baylor Coll Med, Houston, TX 77030 USA. [Srivaths, Poyyapakkam R.] Texas Childrens Hosp, Houston, TX 77030 USA. [Seo-Mayer, Patricia W.] Pediat Specialists Virginia, Fairfax, VA USA. [Seo-Mayer, Patricia W.] Georgetown Univ Hosp, Fairfax, VA USA. [Moxey-Mims, Marva] NIDDK, NIH, Bethesda, MD 20892 USA. [Furth, Susan L.] Childrens Hosp Penn, Philadelphia, PA USA. [Furth, Susan L.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Warady, Bradley A.] Childrens Mercy Hosp, Kansas City, MO 64108 USA. RP Ayestaran, FW (reprint author), Emory Univ, Div Pediat Nephrol, 2015 Uppergate Dr NE, Atlanta, GA 30322 USA.; Ayestaran, FW (reprint author), Emory Univ, Atlanta, GA 30322 USA.; Ayestaran, FW (reprint author), Childrens Healthcare Atlanta, Atlanta, GA USA. EM frankayestar@health.usf.edu FU National Institute of Diabetes and Digestive and Kidney Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Heart, Lung, and Blood Institute [U01-DK-66143, U01-DK-66174, U01DK-082194, U01-DK-66116]; National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR000454] FX Data in this manuscript were collected by the Chronic Kidney Disease in Children prospective cohort study (CKiD) with clinical coordinating centers (Principal Investigators) at Children's Mercy Hospital and the University of Missouri - Kansas City (Bradley Warady, MD) and Children's Hospital of Philadelphia (Susan Furth, MD, PhD), Central Biochemistry Laboratory (George Schwartz, MD) at the University of Rochester Medical Center, and data coordinating center (Alvaro Munoz, PhD) at the Johns Hopkins Bloomberg School of Public Health. The CKiD Study is supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases, with additional funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Heart, Lung, and Blood Institute (U01-DK-66143, U01-DK-66174, U01DK-082194, U01-DK-66116). The CKiD website is located at http://www.statepi.jhsph.edu/ckid. Research at Emory University supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 25 TC 1 Z9 1 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X EI 1432-198X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD JUL PY 2016 VL 31 IS 7 BP 1121 EP 1127 DI 10.1007/s00467-016-3321-9 PG 7 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA DN2XI UT WOS:000376925900012 PM 26857711 ER PT J AU Arnold, B Mitchell, SA Lent, L Mendoza, TR Rogak, LJ Barragan, NM Willis, G Medina, M Lechner, S Penedo, FJ Harness, JK Basch, EM AF Arnold, Benjamin Mitchell, Sandra A. Lent, Lauren Mendoza, Tito R. Rogak, Lauren J. Barragan, Natalie M. Willis, Gordon Medina, Mauricio Lechner, Suzanne Penedo, Frank J. Harness, Jay K. Basch, Ethan M. CA PRO-CTCAE Spanish Translation Ling TI Linguistic validation of the Spanish version of the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Translation; Spanish; PRO-CTCAE; Cancer; Adverse events; Toxicity; Patient-Reported outcomes ID TASK-FORCE; TRANSLATION; INSTRUMENTS AB Purpose The U.S. NCI's PRO-CTCAE is a library of self-report items for assessing symptomatic adverse events in cancer clinical trials from the patient perspective. The aim of this study was to translate and linguistically validate a Spanish version. Methods PRO-CTCAE's 124 items were translated from English into Spanish using multiple forward and back translations. Native Spanish speakers undergoing cancer treatment were enrolled at six cancer treatment sites. Participants each completed approximately 50 items and were then interviewed using cognitive probes. The interviews were analyzed at the item level by linguistic themes, and responses were examined for evidence of equivalence to English. Items for which >= 20 % of participants experienced difficulties were reviewed, and phrasing was revised and then retested in subsequent interviews. Items where <20 % of respondents experienced difficulties were also reviewed and were considered for rephrasing and retesting. Results One hundred nine participants from diverse Spanish-speaking countries were enrolled ( 77 in Round 1 and 32 in Round 2). A majority of items were well comprehended in Round 1. Two items presented difficulties in >= 20 % of participants and were revised/retested without further difficulties. Two items presented difficulties in <20 %, and when retested exhibited no further difficulties. Two items presented difficulties in < 20 %, but were not revised due to lack of alternatives. Sixteen items presented difficulties in <= 12 % and were not revised because difficulties were minor. Conclusions The Spanish PRO-CTCAE has been developed and refined for use in Spanish-speaking populations, with high levels of comprehension and equivalence to the English PRO-CTCAE. C1 [Arnold, Benjamin; Lent, Lauren] FACITtrans LLC, 381 S Cottage Hill Ave, Elmhurst, IL 60126 USA. [Mitchell, Sandra A.] NCI, Div Canc Control & Populat Sci, Outcomes Res Branch, 9609 Med Ctr Dr,East Tower,Room 3-448, Rockville, MD 20850 USA. [Mendoza, Tito R.] Univ Texas MD Anderson Canc Ctr, Dept Symptom Res, 1400 Pressler St,Unit 1450, Houston, TX 77030 USA. [Rogak, Lauren J.; Barragan, Natalie M.; Basch, Ethan M.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 48 Lexington Ave,2nd Floor, New York, NY 10017 USA. [Willis, Gordon] NCI, Div Canc Control & Populat Sci, Behav Res Program, 9609 Med Ctr Dr, Rockville, MD 20850 USA. [Medina, Mauricio] NHLBI, Hlth Educ & Digital Informat Disseminat Branch, OSPEEC, NIH, Bldg 10, Bethesda, MD 20892 USA. [Lechner, Suzanne] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, 1120 NW 14 St,C202, Miami, FL 33136 USA. [Penedo, Frank J.] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, 633 N, St Clair, MO USA. [Harness, Jay K.] St Joseph Hosp, Ctr Canc Prevent & Treatment, 1010 West La Veta Ave,Suite 470, Orange, CA 92868 USA. [Basch, Ethan M.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Med, Campus Box 7305, Chapel Hill, NC 27599 USA. RP Mitchell, SA (reprint author), NCI, Div Canc Control & Populat Sci, Outcomes Res Branch, 9609 Med Ctr Dr,East Tower,Room 3-448, Rockville, MD 20850 USA. EM barnold@facit.org; mitchlls@mail.nih.gov; llent@facit.org; tmendoza@mdanderson.org; rogakl@mskcc.org; barragan@mskcc.org; Willisg@mail.nih.gov; mauricio.medina@nih.gov; SLechner@med.miami.edu; fpenedo@northwestern.edu; jkharness@gmail.com; ebasch@med.unc.edu FU U.S. National Cancer Institute [HHSN261201000063C] FX This work was supported by the U.S. National Cancer Institute contract HHSN261201000063C. NR 19 TC 1 Z9 1 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 EI 1433-7339 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD JUL PY 2016 VL 24 IS 7 BP 2843 EP 2851 DI 10.1007/s00520-015-3062-5 PG 9 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA DM9II UT WOS:000376678400005 PM 26838022 ER PT J AU Slater, ME Castle, IJP Logan, BK Hingson, RW AF Slater, Megan E. Castle, I-Jen P. Logan, Barry K. Hingson, Ralph W. TI Differences in state drug testing and reporting by driver type in US fatal traffic crashes SO ACCIDENT ANALYSIS AND PREVENTION LA English DT Article DE Drugged driving; FARS data; Drug testing rates; Marijuana; State variation ID INJURED DRIVERS; UNITED-STATES; ALCOHOL; IMPACT; RECOMMENDATIONS; RESPONSIBILITY; PREVALENCE; CANNABIS; TRENDS; BLOOD AB Introduction: Driving under the influence of drugs, including marijuana, has become more prevalent in recent years despite local, state, and federal efforts to prevent such increases. The Fatality Analysis Reporting System (FARS) is the primary source of drugged driving data for fatal crashes in the United States but lacks the completeness required to calculate unbiased estimates of drug use among drivers involved in fatal crashes. Methods: This article uses the 2013 FARS dataset to present differences in state drug testing rates by driver type, driver fault type, and state-level factors; discusses limitations related to analysis and interpretation of drugged driving data; and offers suggestions for improvements that may enable appropriate use of FARS drug testing data in the future. Results: Results showed that state drug testing rates were highest among drivers who died at the scene of the crash (median = 70.8%) and drivers who died and were at fault in the crash (median = 64.4%). The lowest testing rates were seen among surviving drivers who were not transported to a hospital (median = 14.0%) and surviving drivers who were not at fault in the crash (median = 10.0%). Drug testing rates differed by state blood alcohol content (BAC) testing rate across all driver types and driver fault types, and in general, states that tested a higher percentage of drivers for BAC had higher drug testing rates. Discussion: Testing rates might be increased through standardization and mandatory testing policies. FARS data users should continue to be cautious about the limitations of using currently available data to quantify drugged driving. More efforts are needed to improve drug testing and reporting practices, and more research is warranted to establish drug concentration levels at which driving skills become impaired. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Slater, Megan E.; Castle, I-Jen P.] CSR Inc, 4250 Fairfax Dr,Suite 500, Arlington, VA 22203 USA. [Logan, Barry K.] NMS Labs, 3701 Welsh Rd, Willow Grove, PA 19090 USA. [Hingson, Ralph W.] NIAAA, 5635 Fishers LN, Rockville, MD 20852 USA. RP Slater, ME (reprint author), CSR Inc, 4250 Fairfax Dr,Suite 500, Arlington, VA 22203 USA. EM mslater@csrincorporated.com FU National Institute on Alcohol Abuse and Alcoholism [HHSN275201300016C] FX This article is based on a study conducted for the Alcohol Epidemiologic Data System project funded by the National Institute on Alcohol Abuse and Alcoholism through contract No. HHSN275201300016C to CSR, Incorporated. The authors wish to thank Chiung M. Chen (CSR, Incorporated) for, providing insights and Hunter Barrat (CSR, Incorporated) for editorial assistance in the preparation of the manuscript. NR 33 TC 0 Z9 0 U1 3 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0001-4575 EI 1879-2057 J9 ACCIDENT ANAL PREV JI Accid. Anal. Prev. PD JUL PY 2016 VL 92 BP 122 EP 129 DI 10.1016/j.aap.2016.03.015 PG 8 WC Ergonomics; Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary; Transportation SC Engineering; Public, Environmental & Occupational Health; Social Sciences - Other Topics; Transportation GA DM9NW UT WOS:000376694000014 PM 27060753 ER PT J AU Hartman, RL Richman, JE Hayes, CE Huestis, MA AF Hartman, Rebecca L. Richman, Jack E. Hayes, Charles E. Huestis, Marilyn A. TI Drug Recognition Expert (DRE) examination characteristics of cannabis impairment SO ACCIDENT ANALYSIS AND PREVENTION LA English DT Article DE Drug Recognition Expert; Drug Evaluation and Classification Program; Cannabis; Driving; Impairment; THC ID FIELD SOBRIETY TESTS; MOTOR-VEHICLE CRASHES; CLASSIFICATION PROGRAM; DRIVING PERFORMANCE; THC INTOXICATION; FREQUENT SMOKERS; MARIJUANA; ALCOHOL; BLOOD; DRIVERS AB Background: The Drug Evaluation and Classification Program (DECP) is commonly utilized in driving under the influence (DUI) cases to help determine category(ies) of impairing drug(s) present in drivers. Cannabis, one of the categories, is associated with approximately doubled crash risk. Our objective was to determine the most reliable DECP metrics for identifying cannabis-driving impairment. Methods: We evaluated 302 toxicologically-confirmed (blood Delta(9)-tetrahydrocannabinol [THC] >= 1 mu g/L) cannabis-only DECP cases, wherein examiners successfully identified cannabis, compared to normative data (302 non-impaired individuals). Physiological measures, pupil size/light reaction, and performance on psychophysical tests (one leg stand [OLS], walk and turn [WAT], finger to nose [FIN], Modified Romberg Balance [MRB]) were included. Results: Cases significantly differed from controls (p < 0.05) in pulse (increased), systolic blood pressure (elevated), and pupil size (dilated). Blood collection time after arrest significantly decreased THC concentrations; no significant differences were detected between cases with blood THC <5 mu g/Lversus >= 5 mu g/L. The FTN best predicted cannabis impairment (sensitivity, specificity, positive/negative predictive value, and efficiency >= 87.1%) utilizing >= 3 misses as the deciding criterion; MRB eyelid tremors produced >= 86.1% for all diagnostic characteristics. Other strong indicators included OLS sway, >= 2 WAT clues, and pupil rebound dilation. Requiring >= 2/4 of: >= 3 FTN misses, MRB eyelid tremors, >= 2 OLS clues, and/or >= 2 WAT clues produced the best results (all characteristics >= 96.7%). Conclusions: Blood specimens should be collected as early as possible. The frequently-debated 5 mu g/L blood THC per se cutoff showed limited relevance. Combined observations on psychophysical and eye exams produced the best cannabis-impairment indicators. Published by Elsevier Ltd. C1 [Hartman, Rebecca L.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, Intramural Res Program, NIH, 251 Bayview Blvd Ste 200 Rm 05A721, Baltimore, MD 21224 USA. [Richman, Jack E.] Hingham Police Dept, 212 Cent St, Hingham, MA 02043 USA. [Hayes, Charles E.] Int Assoc Chiefs Police, 44 Canal Ctr Plaza,Suite 200, Alexandria, VA 22314 USA. RP Huestis, MA (reprint author), Huestis & Smith Toxicol LLC, 683 Shore Rd, Severna Pk, MD 21146 USA. EM rebecca.hartman@umaryland.edu; jack.richman@comcast.net; hayes@theiacp.org; marilyn.huestis@gmail.com FU Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health FX Research was funded [in part] by the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health. The authors would like to recognize the Drug Recognition Expert (DRE) state coordinators and DREs who provided the cases and controls for this research, and the International Association of Chiefs of Police for assisting with the collection and reporting of the data for this research. NR 60 TC 2 Z9 2 U1 10 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0001-4575 EI 1879-2057 J9 ACCIDENT ANAL PREV JI Accid. Anal. Prev. PD JUL PY 2016 VL 92 BP 219 EP 229 DI 10.1016/j.aap.2016.04.012 PG 11 WC Ergonomics; Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary; Transportation SC Engineering; Public, Environmental & Occupational Health; Social Sciences - Other Topics; Transportation GA DM9NW UT WOS:000376694000024 PM 27107471 ER PT J AU Briassoulis, G Keil, MF Naved, B Liu, S Starost, MF Nesterova, M Gokarn, N Batistatos, A Wu, TJ Stratakis, CA AF Briassoulis, George Keil, Margaret F. Naved, Bilal Liu, Sophie Starost, Matthew F. Nesterova, Maria Gokarn, Nirmal Batistatos, Anna Wu, T. John Stratakis, Constantine A. TI Studies of mice with cyclic AMP-dependent protein kinase (PKA) defects reveal the critical role of PKA's catalytic subunits in anxiety SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Anxiety; Amygdala; Protein kinase a; Knockout mice ID ELEVATED PLUS-MAZE; G-ALPHA-S; CARNEY COMPLEX; REGULATORY SUBUNIT; BURYING BEHAVIOR; MOUSE-BRAIN; THREAT BIAS; STRESS; EXPRESSION; RATS AB Cyclic adenosine mono-phosphate-dependent protein kinase (PICA) is critically involved in the regulation of behavioral responses. Previous studies showed that PKA's main regulatory subunit, R1 alpha, is involved in anxiety-like behaviors. The purpose of this study was to determine how the catalytic subunit, C alpha, might affect R1 alpha's function and determine its effects on anxiety-related behaviors. The marble bury (MB) and elevated plus maze (EPM) tests were used to assess anxiety-like behavior and the hotplate test to assess nociception in wild type (WT) mouse, a Prkar1a heterozygote (Prkar1a(+/-)) mouse with haploinsufficiency for the regulatory subunit (R1 alpha), a Prkaca heterozygote (Prkar1a(+/-)) mouse with haploinsufficiency for the catalytic subunit (C alpha), and a double heterozygote mouse (Prkar1a(+/-)/Prkaca(+/-)) with haploinsufficiency for both R1 alpha and C alpha. We then examined specific brain nuclei involved in anxiety. Results of MB test showed a genotype effect, with increased anxiety-like behavior in Prkar1a(+/-) and Prkar1a(+/-)/Prkaca(+/-) compared to WT mice. In the EPM, Prkar1a(+/-) spent significantly less time in the open arms, while Prkaca(+/-) and Prkar1a(+/-)/Prkaca(+/-) mice displayed less exploratory behavior compared to WT mice. The loss of one Prkar1a allele was associated with a significant increase in PKA activity in the basolateral (BLA) and central (CeA) amygdala and ventromedial hypothalamus (VMH) in both Prkar1a(+/-) and Prkar1a(+/-)/Prkaca(+/-) mice. Alterations of PICA activity induced by haploinsufficiency of its main regulatory or most important catalytic subunits result in anxiety-like behaviors. The BLA, CeA, and VMH are implicated in mediating these PICA effects in brain. Published by Elsevier B.V. C1 [Briassoulis, George; Keil, Margaret F.; Naved, Bilal; Liu, Sophie; Nesterova, Maria; Gokarn, Nirmal; Batistatos, Anna; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Briassoulis, George] Univ Crete, Dept Pediat Intens Care, Iraklion, Greece. [Starost, Matthew F.] ORS, Div Vet Resources, OD, NIH, Bethesda, MD 20892 USA. [Wu, T. John] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. [Wu, T. John] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. RP Keil, MF (reprint author), NICHD, NIH, PDEGEN, 10 Ctr Dr,Bldg 10 CRC,Room 1 E3330, Bethesda, MD 20892 USA. EM keilm@mail.nih.gov RI Briassoulis, George/F-6035-2013 FU NICHD, NIH [Z01-HD008920-01]; Uniformed Services University of the Health Sciences; Office of Naval Research; Department of Pediatrics, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece FX We thank Dr. Kitman Tsang, Ms. Florencia Vasta, Ms. Emily Sun, and Ms. Melissa Tang for their assistance with this project. This work was supported by NICHD, NIH intramural project Z01-HD008920-01 to Dr. C.A. Stratakis. This study was supported in part by intramural graduate student grant from the Uniformed Services University of the Health Sciences (MFK) and Office of Naval Research (TJW) and, in part, by the Department of Pediatrics, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece (GB). NR 79 TC 1 Z9 1 U1 7 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 EI 1872-7549 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JUL 1 PY 2016 VL 307 BP 1 EP 10 DI 10.1016/j.bbr.2016.03.001 PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DM7OD UT WOS:000376549000001 PM 26992826 ER PT J AU Renner, M Feng, R Springer, D Chen, MK Ntamack, A Espina, A Saligan, LN AF Renner, Michael Feng, Rebekah Springer, Danielle Chen, Mei-Kuang Ntamack, Andre Espina, Alexandra Saligan, Leorey N. TI A murine model of peripheral irradiation-induced fatigue SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Cancer; Fatigue; Radiation therapy; Murine model; Radiation-induced fatigue ID CANCER-RELATED FATIGUE; DEPRESSIVE-LIKE BEHAVIOR; TUMOR-BEARING MICE; RUNNING-WHEEL; RADIATION-THERAPY; BREAST-CANCER; C57BL/6J MICE; MOUSE MODEL; CHEMOTHERAPY; LIPOPOLYSACCHARIDE AB Purpose: Fatigue is the most ubiquitous side effect of cancer treatment, but its etiology remains elusive. Further investigations into cancer-related fatigue pathobiology necessitate the expanded use of animal models. This study describes the development of a murine model of radiation-induced fatigue. Methods: Voluntary wheel running activity measured fatigue in 5-8 week-old, male C57BL/6 mice before and after gamma irradiation totaling 2400 cGy (3 consecutive days x 800 cGy daily fractionated doses) to the lower abdominal areas. Three trials confirmed fatigue behavior at this dose. Anhedonia, body weight, and hemoglobin were also measured. Gastrointestinal, skeletal muscle, and bone marrow tissue samples were evaluated for signs of damage. Results: In two validation trials, irradiated mice (trial 1, n = 8; trial 2, n = 8) covered less cumulative distance in kilometers post-irradiation (trial 1, mean = 115.3 +/- 12.3; trial 2, mean = 113.6 +/- 21.8) than sham controls (trial 1, n = 5, mean = 126.3 +/- 5.7, p = 0.05; trial 2, n = 8, mean = 140.9 +/- 25.4, p = 0.02). Decreased mean daily running distance and speed were observed during the last four hours of the dark cycle in irradiated mice compared to controls for two weeks post-irradiation. There were no differences in saccharin preference or hemoglobin levels between groups, no effect of changes in body weight or hemoglobin on wheel running distance, additionally, histology showed no damage to muscle, bone marrow, or gastrointestinal integrity, with the latter confirmed by ELISA. Conclusion: We characterized a novel mouse model of fatigue caused by peripheral radiation and not associated with anemia, weight changes, or anhedonia. This model provides opportunities for detailed study of the mechanisms of radiation-induced fatigue. Published by Elsevier B.V. C1 [Renner, Michael; Feng, Rebekah; Ntamack, Andre; Espina, Alexandra; Saligan, Leorey N.] NIH, Natl Inst Nursing Res, Bethesda, MD 20892 USA. [Springer, Danielle] NHLBI, Murine Phenotyping Core, NIH, Bldg 10, Bethesda, MD 20892 USA. [Chen, Mei-Kuang] Univ Arizona, Dept Psychol, Tucson, AZ 85721 USA. RP Saligan, LN (reprint author), NIH, Div Intramural Res, Natl Inst Nursing Res, Bldg 3,Room 5E14, Bethesda, MD 20892 USA. EM saliganl@mail.nih.gov OI Chen, Mei-kuang/0000-0002-0407-6788 FU Division of Intramural Research, National Institute of Nursing Research, National Institutes of Health FX This research was supported by the Division of Intramural Research, National Institute of Nursing Research, National Institutes of Health. NR 46 TC 1 Z9 1 U1 2 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 EI 1872-7549 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JUL 1 PY 2016 VL 307 BP 218 EP 226 DI 10.1016/j.bbr.2016.03.035 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DM7OD UT WOS:000376549000026 PM 27012391 ER PT J AU Archier, A Varoquaux, A Garrigue, P Montava, M Guerin, C Gabriel, S Beschmout, E Morange, I Fakhry, N Castinetti, F Sebag, F Barlier, A Loundou, A Guillet, B Pacak, K Taieb, D AF Archier, Aurelien Varoquaux, Arthur Garrigue, Philippe Montava, Marion Guerin, Carole Gabriel, Sophie Beschmout, Eva Morange, Isabelle Fakhry, Nicolas Castinetti, Frederic Sebag, Frederic Barlier, Anne Loundou, Anderson Guillet, Benjamin Pacak, Karel Taieb, David TI Prospective comparison of Ga-68-DOTATATE and F-18-FDOPA PET/CT in patients with various pheochromocytomas and paragangliomas with emphasis on sporadic cases SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE Positron emission tomography; Gallium radioisotopes; Somatostatin; Paragangliomas; Neuroendocrine ID GA-68 DOTATATE PET/CT; NECK PARAGANGLIOMAS; EXTRAADRENAL PARAGANGLIOMA; IMAGING MODALITIES; MR-ANGIOGRAPHY; HEAD; LOCALIZATION; SCINTIGRAPHY; OSTEOMALACIA; SPECT/CT AB Purpose Pheochromocytomas/paragangliomas (PHEOs/PGLs) overexpress somatostatin receptors and recent studies have already shown excellent results in the localization of these tumors using Ga-68-labeled somatostatin analogs (Ga-68-DOTA-SSA), especially in patients with germline succinate dehydrogenase subunit B gene (SDHB) mutations and head and neck PGLs (HNPGLs). The value of Ga-68-DOTA-SSA has to be established in sporadic cases, including PHEOs. Thus, the aim of this study was to compare Ga-68-DOTATATE PET/CT, F-18-FDOPA PET/CT, and conventional imaging in patients with various PHEOs/PGLs with a special emphasis on sporadic cases, including those located in the adrenal gland. Design Ga-68-DOTATATE, F-18-FDOPA PET/CT, and conventional imaging (contrast-enhanced CT and MRI with MR angiography sequences) were prospectively performed in 30 patients (8 with SDHD mutations, 1 with a MAX mutation and 21 sporadic cases) with PHEO/PGL at initial diagnosis or relapse. Results The patient-based sensitivities were 93 % (28/30), 97 % (29/30), and 93 % (28/30) for Ga-68-DOTATATE PET/CT, F-18-FDOPA PET/CT, and conventional imaging, respectively. The lesion-based sensitivities were 93 % (43/46), 89 % (41/46), and 76 % (35/46) for Ga-68-DOTATATE PET/CT, F-18-FDOPA PET/CT, and conventional imaging respectively (p = 0.042). Ga-68-DOTATATE PET/CT detected a higher number of HNPGLs (30/30) than F-18-FDOPA PET/CT (26/30; p = 0.112) and conventional imaging (24/30; p = 0.024). Ga-68-DOTATATE PET/CT missed two PHEOs of a few millimeters in size and a large recurrent PHEO. One lesion was considered false-positive on Ga-68-DOTATATE PET/CT and corresponded to a typical focal lesion of fibrous dysplasia on MRI. Among the 11 lesions missed by conventional imaging, 7 were detected by conventional imaging with knowledge of the PET results (4 HNPGLs, 2 LNs, and 1 recurrent PHEO). Conclusion Ga-68-DOTATATE PET/CT is the most sensitive tool in the detection of HNPGLs, especially SDHD-related tumors, which may be very small and fail to concentrate sufficient F-18-FDOPA. The present study further expands the use of Ga-68-DOTATATE for all patients with HNPGLs, regardless of their genotype. Ga-68-DOTATATE PET/CT may be inferior to F-18-FDOPA PET/CT in the detection PHEOs. C1 [Archier, Aurelien; Garrigue, Philippe; Gabriel, Sophie; Guillet, Benjamin; Taieb, David] Aix Marseille Univ, La Timone & North Univ Hosp, Dept Nucl Med, Marseille, France. [Archier, Aurelien; Gabriel, Sophie; Taieb, David] Aix Marseille Univ, European Ctr Res Med Imaging, Marseille, France. [Archier, Aurelien; Taieb, David] INSERM, Inst J Paoli I Calmettes, UMR1068, Marseille Cancerol Res Ctr, Marseille, France. [Varoquaux, Arthur; Beschmout, Eva] Aix Marseille Univ, Concept Hosp, Dept Med Imaging, Marseille, France. [Garrigue, Philippe; Guillet, Benjamin] Aix Marseille Univ, La Timone & North Univ Hosp, Dept Radiopharm, Marseille, France. [Montava, Marion; Fakhry, Nicolas] Aix Marseille Univ, Concept Hosp, Dept Otorhinolaryngol Head & Neck Surg, Marseille, France. [Guerin, Carole; Sebag, Frederic] Aix Marseille Univ, Concept Hosp, Dept Endocrine Surg, Marseille, France. [Morange, Isabelle; Castinetti, Frederic] Aix Marseille Univ, Concept Hosp, Dept Endocrinol, Marseille, France. [Barlier, Anne] Aix Marseille Univ, Concept Hosp, Lab Biochem & Mol Biol, Marseille, France. [Loundou, Anderson] Aix Marseille Univ, Dept Publ Hlth, Marseille, France. [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth Human, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Taieb, D (reprint author), Aix Marseille Univ, La Timone & North Univ Hosp, Dept Nucl Med, Marseille, France.; Taieb, D (reprint author), Aix Marseille Univ, European Ctr Res Med Imaging, Marseille, France.; Taieb, D (reprint author), INSERM, Inst J Paoli I Calmettes, UMR1068, Marseille Cancerol Res Ctr, Marseille, France. EM david.taieb@ap-hm.fr OI Barlier, Anne/0000-0002-3740-6173; Castinetti, Frederic/0000-0002-1808-8800 FU Intramural Research Program of the Assistance Publique-Hopitaux de Marseille (AP-HM, France) FX This research was supported by the Intramural Research Program of the Assistance Publique-Hopitaux de Marseille (AP-HM, France). NR 30 TC 6 Z9 6 U1 4 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 EI 1619-7089 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD JUL PY 2016 VL 43 IS 7 BP 1248 EP 1257 DI 10.1007/s00259-015-3268-2 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DM3KV UT WOS:000376246200007 PM 26637204 ER PT J AU Smith, S Rossignol, P Willis, S Zannad, F Mentz, R Pocock, S Bisognano, J Nadim, Y Geller, N Ruble, S Linde, C AF Smith, S. Rossignol, P. Willis, S. Zannad, F. Mentz, R. Pocock, S. Bisognano, J. Nadim, Y. Geller, N. Ruble, S. Linde, C. TI Neural modulation for hypertension and heart failure SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Review DE Hypertension; Heart failure; Neural modulation; Renal denervation; Baroreceptor ID BAROREFLEX ACTIVATION THERAPY; CARDIAC RESYNCHRONIZATION THERAPY; RENAL SYMPATHETIC DENERVATION; VAGUS NERVE-STIMULATION; CAROTID BARORECEPTOR STIMULATION; AUTONOMIC REGULATION THERAPY; DRUG-RESISTANT HYPERTENSION; LEFT-VENTRICULAR FUNCTION; LOWERS BLOOD-PRESSURE; RHEOS PIVOTAL TRIAL AB Hypertension (HTN) and heart failure (HF) have a significant global impact on health, and lead to increased morbidity and mortality. Despite recent advances in pharmacologic and device therapy for these conditions, there is a need for additional treatment modalities. Patients with sub-optimally treated HTN have increased risk for stroke, renal failure and heart failure. The outcome of HF patients remains poor despite modern pharmacological therapy and with established device therapies such as CRT and ICDs. Therefore, the potential role of neuromodulation via renal denervation, baro-reflex modulation and vagal stimulation for the treatment of resistant HTN and HF is being explored. In this manuscript, we review current evidence for neuromodulation in relation to established drug and device therapies and how these therapies may be synergistic in achieving therapy goals in patients with treatment resistant HTN and heart failure. We describe lessons learned from recent neuromodulation trials and outline strategies to improve the potential for success in future trials. This review is based on discussions between scientists, clinical trialists, and regulatory representatives at the 11th annual CardioVascular Clinical Trialist Forum in Washington, DC on December 5-7, 2014. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Smith, S.; Willis, S.] Ohio State Univ, Wexner Med Ctr, Dept Internal Med, Columbus, OH 43210 USA. [Smith, S.; Willis, S.] Ohio State Univ, Div Cardiol, Columbus, OH 43210 USA. [Rossignol, P.; Zannad, F.] Univ Lorraine, CHU, F CRIN INI CRCT, Inserm,CIC 1433, Nancy, France. [Mentz, R.] Duke Univ, Med Ctr, Dept Med, Div Cardiol, Durham, NC 27710 USA. [Pocock, S.] Med Stat Unit LSHTM, London, England. [Bisognano, J.] Univ Rochester, Med Ctr, Dept Med, Cardiol, 601 Elmwood Ave, Rochester, NY 14642 USA. [Nadim, Y.] CVRx Inc, Minneapolis, MN USA. [Geller, N.] NHLBI, Off Biostat Res, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Ruble, S.] Boston Sci CRV, St Paul, MN USA. [Linde, C.] Karolinska Inst, Inst Internal Med, Stockholm, Sweden. [Linde, C.] Karolinska Univ Hosp, Dept Cardiol, N205, S-11776 Stockholm, Sweden. RP Linde, C (reprint author), Karolinska Univ Hosp, Dept Cardiol, N205, S-11776 Stockholm, Sweden.; Smith, S (reprint author), Ohio State Univ, Div Cardiol, 473 West 12th Ave Suite 200, Columbus, OH 43210 USA. EM sakima.smith@osumc.edu; cecilia.linde@ki.se FU Robert Wood Johnson Harold Amos Faculty Development Grant; National Center for Advancing Translational Sciences [TL1TR001069]; Medtonic; Swedish Heart Lung Foundation [20080498, 20110406]; Stockholm County Council [20090376, 20110610]; National Institutes of Health [U10HL110312]; Amgen; AstraZeneca; Bristol-Myers Squibb; GlaxoSmithKline; Gilead; Novartis; Otsuka; ResMed; Relypsa; Boston Scientific; Takeda; Boehringer Ingelheim; GE Healthcare; Servier; Bayer; Johnson and Johnson; Pfizer; CVRx FX Dr. Smith receives research support from the Robert Wood Johnson Harold Amos Faculty Development Grant and the National Center for Advancing Translational Sciences [TL1TR001069] and serves as a consultant to CareDx. Dr. Linde has received research grants from Medtonic, Consultant to Vifor, Novartis. Cardio3, St Jude and Biotronik, and Financial support CL Swedish Heart Lung Foundation [grants 20080498 and 20110406] and the Stockholm County Council [grants 20090376 and 20110610]. Dr. Mentz receives research support from the National Institutes of Health (U10HL110312), Amgen, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Novartis, Otsuka, and ResMed; honoraria from HeartWare, Janssen, Luitpold Pharmaceuticals, Novartis, ResMed, and Thoratec; and has served on an advisory board for Luitpold Pharmaceuticals, Inc. Dr. Rossignol received fees from Relypsa. Dr. Zannad has received fees for serving on the board of Boston Scientific; consulting fees from Novartis, Takeda, AstraZeneca, Boehringer Ingelheim, GE Healthcare, Relypsa, Servier, Boston Scientific, Bayer, Johnson and Johnson, and Resmed; and speakers' fees from Pfizer and AstraZeneca. Dr. Bisognano has received research support and consulting fees from CVRx. Nadim Yared is an employee of CVRx. Stephen Ruble is an employee of Boston Scientific. The other authors report no conflicts. NR 110 TC 2 Z9 2 U1 5 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD JUL 1 PY 2016 VL 214 BP 321 EP 331 DI 10.1016/j.ijcard.2016.03.078 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DL9BG UT WOS:000375935700091 PM 27085120 ER PT J AU Kannan, G Crawford, JA Yang, CX Gressitt, KL Ihenatu, C Krasnova, IN Cadet, JL Yolken, RH Severance, EG Pletnikov, MV AF Kannan, Geetha Crawford, Joshua A. Yang, ChunXia Gressitt, Kristin L. Ihenatu, Chinezimuzo Krasnova, Irina N. Cadet, Jean Lud Yolken, Robert H. Severance, Emily G. Pletnikov, Mikhail V. TI Anti-NMDA receptor autoantibodies and associated neurobehavioral pathology in mice are dependent on age of first exposure to Toxoplasma gondii SO NEUROBIOLOGY OF DISEASE LA English DT Article DE NMDAR; Toxoplasma; C1q; Schizophrenia; Autoantibody; Neurodevelopment ID PREPULSE INHIBITION; COMPLEMENT CASCADE; IMMUNE ACTIVATION; ADOLESCENT BRAIN; HUMAN-BEHAVIOR; SCHIZOPHRENIA; ENCEPHALITIS; ANTIBODIES; AMPHETAMINE; MOUSE AB Background: Toxoplasma gondii is a pathogen implicated in psychiatric disorders. As elevated antibodies to T. gondii are also present in non-symptomatic individuals, we hypothesized that the age during first exposure to the pathogen may affect symptom manifestation. We tested this hypothesis by evaluating neurobehavioral abnormalities and the immune response in mice following adolescent or adult T. gondii infection. Methods: Mice were infected with T. gondii at postnatal day 33 (adolescent/juvenile) or 61 (adult). At 8 weeks post-infection (wpi), pre-pulse inhibition of the acoustic startle (PPI) in mice administered MK-801 (0.1 and 0.3 mg/kg) and amphetamine (5 and 10 mg/kg) was assessed. Peripheral (anti-T. gondii, C1q-associated IgG and anti-GLUN2 antibodies) and central (C1q and Iba1) markers of the immune response were also evaluated. In addition, regional brain expression of N-methyl-D-aspartate receptor (NMDAR) subunits (GLUN1 and GLUN2A), glutamatergic (vGLUT1, PSD95) and GABAergic (GAD67) markers, and monoamines (DA, NE, 5-HT) and their metabolites were measured. Results: Juvenile and adult infected mice exhibited opposite effects of MK-801 on PPI, with decreased PPI in juveniles and increased PPI in adults. There was a significantly greater elevation of GLUN2 autoantibodies in juvenile compared to adult-infected mice. In addition, age-dependent differences were found in regional expression of NMDAR subunits and markers of glutamatergic, GABAergic, and monoaminergic systems. Activated microglia and C1q elevations were found in both juvenile- and adult-T. gondii infected mice. Conclusions: Our study demonstrates that the age at first exposure to T. gondii is an important factor in shaping distinct behavioral and neurobiological abnormalities. Elevation in GLUN2 autoantibodies or complement protein C1q may be a potential underlying mechanism. A better understanding of these age-related differences may lead to more efficient treatments of behavioral disorders associated with T. gondii infection. (C) 2016 Published by Elsevier Inc. C1 [Kannan, Geetha; Crawford, Joshua A.; Yang, ChunXia; Pletnikov, Mikhail V.] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Sch Med, 600 North Wolfe St, Baltimore, MD 21287 USA. [Gressitt, Kristin L.; Ihenatu, Chinezimuzo; Yolken, Robert H.; Severance, Emily G.] Johns Hopkins Univ, Dept Pediat, Sch Med, Stanley Div Dev Neurovirol, Baltimore, MD 21287 USA. [Krasnova, Irina N.; Cadet, Jean Lud] NIDA, Mol Neuropsychiat Res Branch, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Pletnikov, Mikhail V.] Johns Hopkins Univ, Sch Med, Mol & Comparat Pathobiol, Baltimore, MD 21287 USA. [Pletnikov, Mikhail V.] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21287 USA. [Pletnikov, Mikhail V.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Kannan, Geetha] Univ Michigan, Sch Med, Dept Microbiol & Immunol, Med Sci 2 5641, 1150 West Med Ctr Dr, Ann Arbor, MI 48109 USA. RP Kannan, G (reprint author), Johns Hopkins Univ, Dept Psychiat & Behav Sci, Sch Med, 600 North Wolfe St, Baltimore, MD 21287 USA.; Kannan, G (reprint author), Univ Michigan, Sch Med, Dept Microbiol & Immunol, Med Sci 2 5641, 1150 West Med Ctr Dr, Ann Arbor, MI 48109 USA. EM KannanG17@gmail.com OI Ihenatu, Chinezimuzo/0000-0001-9865-646X FU Stanley Medical Research Institute (SMRI), Chevy Chase, MD, USA; Silvio O. Conte Grant [MH-094268] FX The authors would like to thank Dr. Lorraine Jones-Brando for critical reading of the manuscript. Funding for this work was provided by the Stanley Medical Research Institute (SMRI), Chevy Chase, MD, USA and the Silvio O. Conte Grant MH-094268. NR 50 TC 2 Z9 2 U1 5 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD JUL PY 2016 VL 91 BP 307 EP 314 DI 10.1016/j.nbd.2016.03.005 PG 8 WC Neurosciences SC Neurosciences & Neurology GA DL8IL UT WOS:000375885600026 PM 26969530 ER PT J AU Stapleton, LRT Schetter, CD Dooley, LN Guardino, CM Huynh, J Paek, C Clark-Kauffman, E Schafer, P Woolard, R Lanzi, RG AF Stapleton, Lynlee R. Tanner Schetter, Christine Dunkel Dooley, Larissa N. Guardino, Christine M. Huynh, Jan Paek, Cynthia Clark-Kauffman, Elizabeth Schafer, Peter Woolard, Richard Lanzi, Robin Gaines CA Community Child Hlth Network TI The Community Child Health Network Life Stress Interview: a brief chronic stress measure for community health research SO ANXIETY STRESS AND COPING LA English DT Article DE Chronic stress; stress measures; Life Stress Interview; community research; CBPR; parenting stress ID DEPRESSION; WOMEN; ADVERSITY; VULNERABILITY; RELIABILITY; DISPARITIES; DISORDERS; MEDIATORS; SYMPTOMS; EVENTS AB Background and Objectives: Chronic stress is implicated in many theories as a contributor to a wide range of physical and mental health problems. The current study describes the development of a chronic stress measure that was based on the UCLA Life Stress Interview (LSI) and adapted in collaboration with community partners for use in a large community health study of low-income, ethnically diverse parents of infants in the USA (Community Child Health Network [CCHN]). We describe the instrument, its purpose and adaptations, implementation, and results of a reliability study in a subsample of the larger study cohort. Design and Methods: Interviews with 272 mothers were included in the present study. Chronic stress was assessed using the CCHN LSI, an instrument designed for administration by trained community interviewers to assess four domains of chronic stress, each rated by interviewers. Results: Significant correlations ranging from small to moderate in size between chronic stress scores on this measure, other measures of stress, biomarkers of allostatic load, and mental health provide initial evidence of construct and concurrent validity. Reliability data for interviewer ratings are also provided. Conclusions: This relatively brief interview (15 minutes) is available for use and may be a valuable tool for researchers seeking to measure chronic stress reliably and validly in future studies with time constraints. C1 [Stapleton, Lynlee R. Tanner; Schetter, Christine Dunkel; Dooley, Larissa N.; Guardino, Christine M.; Huynh, Jan; Paek, Cynthia] Univ Calif Los Angeles, Dept Psychol, 1285A Franz Hall, Los Angeles, CA 90095 USA. [Clark-Kauffman, Elizabeth] NorthShore Univ HealthSyst, 2650 Ridge Ave, Evanston, IL 60201 USA. [Schafer, Peter] New York Acad Sci, 1216 5th Ave, New York, NY 10029 USA. [Woolard, Richard] Baby Love Plus Consortium, Mail Serv Ctr Raleigh 1929, Raleigh, NC 27699 USA. [Lanzi, Robin Gaines] Univ Alabama Birmingham, Sch Publ Hlth, 1665 Univ Blvd,227 RPHB, Birmingham, AL 35294 USA. [Community Child Hlth Network] Eunice Kennedy Shriver Natl Inst Child Hlth & Hu, NIH, 6100 Execut Blvd, Bethesda, MD 20892 USA. RP Schetter, CD (reprint author), Univ Calif Los Angeles, Dept Psychol, 1285A Franz Hall, Los Angeles, CA 90095 USA. EM dunkel@psych.ucla.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U HD44207, U HD44219, U HD44226, U HD44245, U HD44253, U HD54791, U HD54019, U HD44226-05S1, U HD44245-06S1, R03 HD59584]; National Institute for Nursing Research [U NR008929] FX The Community Child Health Network (CCHN) is a community-based participatory research network 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, U HD44253, U HD54791, U HD54019, U HD44226-05S1, U HD44245-06S1, R03 HD59584] and the National Institute for Nursing Research [U NR008929]. NR 44 TC 0 Z9 0 U1 4 U2 5 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1061-5806 EI 1477-2205 J9 ANXIETY STRESS COPIN JI Anxiety Stress Coping PD JUL PY 2016 VL 29 IS 4 BP 352 EP 366 DI 10.1080/10615806.2015.1058368 PG 15 WC Neurosciences; Psychiatry; Psychology, Multidisciplinary SC Neurosciences & Neurology; Psychiatry; Psychology GA DK5KW UT WOS:000374959800002 ER PT J AU Sampson, JN Matthews, CE Freedman, LS Carroll, RJ Kipnis, V AF Sampson, Joshua N. Matthews, Charles E. Freedman, Laurence S. Carroll, Raymond J. Kipnis, Victor TI Methods to assess measurement error in questionnaires of sedentary behavior SO JOURNAL OF APPLIED STATISTICS LA English DT Article DE Measurement error; PDR; questionnaire; sedentary ID COVARIATE MEASUREMENT ERROR; DIETARY MEASUREMENT ERROR; PHYSICAL-ACTIVITY; SELF-REPORT; NUTRITIONAL EPIDEMIOLOGY; STRUCTURE MODELS; VALIDATION; VALIDITY; TIME; RELIABILITY AB Sedentary behavior has already been associated with mortality, cardiovascular disease, and cancer. Questionnaires are an affordable tool for measuring sedentary behavior in large epidemiological studies. Here, we introduce and evaluate two statistical methods for quantifying measurement error in questionnaires. Accurate estimates are needed for assessing questionnaire quality. The two methods would be applied to validation studies that measure a sedentary behavior by both questionnaire and accelerometer on multiple days. The first method fits a reduced model by assuming the accelerometer is without error, while the second method fits a more complete model that allows both measures to have error. Because accelerometers tend to be highly accurate, we show that ignoring the accelerometer's measurement error, can result in more accurate estimates of measurement error in some scenarios. In this article, we derive asymptotic approximations for the mean-squared error of the estimated parameters from both methods, evaluate their dependence on study design and behavior characteristics, and offer an R package so investigators can make an informed choice between the two methods. We demonstrate the difference between the two methods in a recent validation study comparing previous day recalls to an accelerometer-based ActivPal. C1 [Sampson, Joshua N.] NCI, DCEG, Biostat Branch, Rockville, MD USA. [Matthews, Charles E.] NCI, Nutr Epidemiol Branch, DCEG, Rockville, MD USA. [Freedman, Laurence S.] Gertner Inst, Biostat Unit, Tel Hashomer, Israel. [Carroll, Raymond J.] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. [Kipnis, Victor] NCI, Biometry Res Grp, DCP, Rockville, MD USA. RP Sampson, JN (reprint author), NCI, DCEG, Biostat Branch, Rockville, MD USA. EM joshua.sampson@nih.gov FU intramural research program at the NIH; National Cancer Institute [R37-CA057030] FX This research was supported by the intramural research program at the NIH (JNS, CEM) and by a grant from the National Cancer Institute, R37-CA057030 (RJC). NR 39 TC 0 Z9 0 U1 4 U2 7 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0266-4763 EI 1360-0532 J9 J APPL STAT JI J. Appl. Stat. PD JUL PY 2016 VL 43 IS 9 BP 1706 EP 1721 DI 10.1080/02664763.2015.1117593 PG 16 WC Statistics & Probability SC Mathematics GA DK6AJ UT WOS:000375002600009 PM 27340315 ER PT J AU Nagore, E Heidenreich, B Rachakonda, S Garcia-Casado, Z Requena, C Soriano, V Frank, C Traves, V Quecedo, E Sanjuan-Gimenez, J Hemminki, K Landi, MT Kumar, R AF Nagore, Eduardo Heidenreich, Barbara Rachakonda, Sivaramakrishna Garcia-Casado, Zaida Requena, Celia Soriano, Virtudes Frank, Christoph Traves, Victor Quecedo, Esther Sanjuan-Gimenez, Josefa Hemminki, Kari Landi, Maria Teresa Kumar, Rajiv TI TERT promoter mutations in melanoma survival SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE melanoma; TERT promoter mutations; BRAF mutations; disease-free survival; melanoma-specific survival ID CUTANEOUS MELANOMA; PROSTATE-CANCER; TELOMERE LENGTH; BLADDER-CANCER; LUNG-CANCER; POLYMORPHISM; EXPRESSION; RS2853669; RISK; REACTIVATION AB Despite advances in targeted therapies, the treatment of advanced melanoma remains an exercise in disease management, hence a need for biomarkers for identification of at-risk primary melanoma patients. In this study, we aimed to assess the prognostic value of TERT promoter mutations in primary melanomas. Tumors from 300 patients with stage I/II melanoma were sequenced for TERT promoter and BRAF/NRAS mutations. Cumulative curves were drawn for patients with and without mutations with progression-free and melanoma-specific survival as outcomes. Cox proportional hazard regression models were used to determine the effect of the mutations on survivals. Individually, presence of TERT promoter and BRAF/NRAS mutations associated with poor disease-free and melanoma-specific survival with modification of the effect by the rs2853669 polymorphism within the TERT promoter. Hazard ratio (HR) for simultaneous occurrence of TERT promoter and BRAF/NRAS mutations for disease-free survival was 2.3 (95% CI 1.2-4.4) and for melanoma-specific survival 5.8 (95% CI 1.9-18.3). The effect of the mutations on melanoma-specific survival in noncarriers of variant allele of the polymorphism was significant (HR 4.5, 95% CI 1.4-15.2) but could not be calculated for the carriers due to low number of events. The variant allele per se showed association with increased survival (HR 0.3, 95% CI 0.1-0.9). The data in this study provide preliminary evidence that TERT promoter mutations in combination with BRAF/NRAS mutations can be used to identify patients at risk of aggressive disease and the possibility of refinement of the classification with inclusion of the rs2853669 polymorphism within TERT promoter. What's new? Mutations in the promoter of the TERT gene lead to increases in telomerase activity, prolonged telomere maintenance, and cell immortality. Such mutations are associated with parameters of adverse outcome in different cancer types, including melanoma. Data from this study shows that in primary melanoma, mutations in the TERT promoter together with mutations in BRAF/NRAS are associated with very poor survival and can be used to identify patients at risk of disease relapse and death. The prognostic value of the mutations is potentially improved through inclusion of a common polymorphism harbored within the TERT promoter. C1 [Nagore, Eduardo; Requena, Celia] Inst Valenciano Oncol, Dept Dermatol, C Prof Beltran Baguena 8, Valencia 46009, Spain. [Heidenreich, Barbara; Rachakonda, Sivaramakrishna; Frank, Christoph; Hemminki, Kari; Kumar, Rajiv] German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany. [Garcia-Casado, Zaida] Inst Valenciano Oncol, Mol Biol Lab, C Prof Beltran Baguena 8, Valencia 46009, Spain. [Soriano, Virtudes] Inst Valenciano Oncol, Dept Med Oncol, C Prof Beltran Baguena 8, Valencia 46009, Spain. [Traves, Victor] Inst Valenciano Oncol, Dept Pathol, C Prof Beltran Baguena 8, Valencia 46009, Spain. [Quecedo, Esther] Hosp Arnau Vilanova Valencia, Dept Dermatol, Valencia, Spain. [Sanjuan-Gimenez, Josefa] Hosp Arnau Vilanova Valencia, Dept Pathol, Valencia, Spain. [Hemminki, Kari] Lund Univ, Ctr Primary Hlth Care Res, Malmo, Sweden. [Landi, Maria Teresa] NCI, US Natl Inst Hlth, Div Epidemiol & Genet, Bethesda, MD 20892 USA. RP Nagore, E (reprint author), Inst Valenciano Oncol, Dept Dermatol, C Prof Beltran Baguena 8, Valencia 46009, Spain. EM eduardo_nagore@ono.com FU TRANSCAN (German Ministry of Education and Science) [01KT1511] FX Grant sponsor: TRANSCAN (German Ministry of Education and Science); Grant number: 01KT1511 NR 44 TC 10 Z9 10 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JUL 1 PY 2016 VL 139 IS 1 BP 75 EP 84 DI 10.1002/ijc.30042 PG 10 WC Oncology SC Oncology GA DJ7HB UT WOS:000374381400011 PM 26875008 ER PT J AU Halec, G Schmitt, M Egger, S Abnet, CC Babb, C Dawsey, SM Flechtenmacher, C Gheit, T Hale, M Holzinger, D Malekzadeh, R Taylor, PR Tommasino, M Urban, MI Waterboer, T Pawlita, M Sitas, F AF Halec, Gordana Schmitt, Markus Egger, Sam Abnet, Christian C. Babb, Chantal Dawsey, Sanford M. Flechtenmacher, Christa Gheit, Tarik Hale, Martin Holzinger, Dana Malekzadeh, Reza Taylor, Philip R. Tommasino, Massimo Urban, Margaret I. Waterboer, Tim Pawlita, Michael Sitas, Freddy CA InterSCOPE Collaboration TI Mucosal alpha-papillomaviruses are not associated with esophageal squamous cell carcinomas: Lack of mechanistic evidence from South Africa, China and Iran and from a world-wide meta-analysis SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE esophageal cancer; human papillomavirus; HPV RNA; serology; HPV-transformed phenotype; p16(INK4); meta-analysis ID RISK HUMAN-PAPILLOMAVIRUS; ACTIVE HPV16 INVOLVEMENT; CERVICAL-CANCER; VIRAL LOAD; P16(INK4A) EXPRESSION; OROPHARYNGEAL CANCER; P16 EXPRESSION; DNA MICROARRAY; MULTIPLEX PCR; TRACT TUMORS AB Epidemiological and mechanistic evidence on the causative role of human papillomaviruses (HPV) in esophageal squamous cell carcinoma (ESCC) is unclear. We retrieved alcohol- and formalin-fixed paraffin-embedded ESCC tissues from 133 patients seropositive for antibodies against HPV early proteins, from high-incidence ESCC regions: South Africa, China and Iran. With rigorous care to prevent nucleic acid contamination, we analyzed these tissues for the presence of 51 mucosotropic human alpha-papillomaviruses by two sensitive, broad-spectrum genotyping methods, and for the markers of HPV-transformed phenotype: (i) HPV16/18 viral loads by quantitative real-time PCR, (ii) type-specific viral mRNA by E6*I/E6 full-length RT-PCR assays and (iii) expression of cellular protein p16(INK4a). Of 118 analyzable ESCC tissues, 10 (8%) were positive for DNA of HPV types: 16 (4 tumors); 33, 35, 45 (1 tumor each); 11 (2 tumors) and 16, 70 double infection (1 tumor). Inconsistent HPV DNA+ findings by two genotyping methods and negativity in qPCR indicated very low viral loads. A single HPV16 DNA+ tumor additionally harbored HPV16 E6*I mRNA but was p16(INK4a) negative (HPV16 E1 seropositive patient). Another HPV16 DNA+ tumor from an HPV16 E6 seropositive patient showed p16(INK4a) upregulation but no HPV16 mRNA. In the tumor tissues of these serologically preselected ESCC patients, we did not find consistent presence of HPV DNA, HPV mRNA or p16(INK4a) upregulation. These results were supported by a meta-analysis of 14 other similar studies regarding HPV-transformation of ESCC. Our study does not support the etiological role of the 51 analyzed mucosotropic HPV types in the ESCC carcinogenesis. What's new? South Africa, China and Iran are countries with the highest incidences and mortalities of esophageal squamous cell carcinoma (ESCC). Epidemiological studies suggested a causative role for mucosal high-risk human papillomavirus (HPV) types in ESCC, but consistent evidence of viral transformation is missing. Here the authors examined ESCC samples from high-incidence regions and could not detect biological activity of 51 mucosotropic HPV types. This result is surprising as patients were preselected as being seropositive for papillomavirus infection and points to alternative causes of ESCC carcinogenesis. C1 [Halec, Gordana; Schmitt, Markus; Holzinger, Dana; Waterboer, Tim; Pawlita, Michael] German Canc Res Ctr, Div Mol Diagnost Oncogen Infect, Res Program Infect Inflammat & Canc, Heidelberg, Germany. [Halec, Gordana] Univ Calif Los Angeles, David Geffen Sch Med, Obstet & Gynecol, Los Angeles, CA 90095 USA. [Egger, Sam; Sitas, Freddy] NSW Canc Council, Canc Res Div, Sydney, NSW, Australia. [Abnet, Christian C.; Dawsey, Sanford M.; Taylor, Philip R.] US Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Babb, Chantal; Urban, Margaret I.] NHLS MRC Canc Epidemiol Res Grp, Natl Hlth Lab Serv, Johannesburg, South Africa. [Flechtenmacher, Christa] Heidelberg Univ, Inst Pathol, Neuenheimer Feld 220, Heidelberg, Germany. [Gheit, Tarik; Tommasino, Massimo] Int Agcy Res Canc, Infect & Canc Biol Grp, 150 Cours Albert Thomas, F-69372 Lyon, France. [Hale, Martin] Natl Hlth Lab Serv, Dept Anat Pathol, Johannesburg, South Africa. [Hale, Martin; Urban, Margaret I.] Univ Witwatersrand, Fac Hlth Sci, Johannesburg, South Africa. [Malekzadeh, Reza] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran, Iran. [Sitas, Freddy] Univ Sydney, Sch Publ Hlth, Sydney, NSW 2006, Australia. [Sitas, Freddy] Univ New S Wales, Sch Publ Hlth & Community Med, Sydney, NSW, Australia. RP Pawlita, M (reprint author), German Canc Res Ctr, Div Mol Diagnost Oncogen Infect, Res Program Infect Inflammat & Canc, Heidelberg, Germany. EM m.pawlita@dkfz-heidelberg.de RI Abnet, Christian/C-4111-2015; Waterboer, Tim/G-1252-2010; OI Abnet, Christian/0000-0002-3008-7843; Babb de Villiers, Chantal/0000-0003-1334-1819; Pawlita, Michael/0000-0002-4720-8306 FU DKFZ; Roche; Qiagen FX MP and MS have received research support through co-operation contracts of DKFZ with Roche and Qiagen in the field of development of HPV diagnostics. They are inventors on patents owned by DKFZ in the field of HPV diagnostics. Authors GH, SE, CCA, CB, SMD, CF, TG, MH, DH, RM, PRT, MT, MIU, TW and FS have no conflict. NR 98 TC 3 Z9 3 U1 1 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JUL 1 PY 2016 VL 139 IS 1 BP 85 EP 98 DI 10.1002/ijc.29911 PG 14 WC Oncology SC Oncology GA DJ7HB UT WOS:000374381400012 PM 26529033 ER PT J AU Chen, W Park, K Volkow, ND Pan, YT Du, CW AF Chen, Wei Park, Kicheon Volkow, Nora D. Pan, Yingtian Du, Congwu TI Cocaine-Induced Abnormal Cerebral Hemodynamic Responses to Forepaw Stimulation Assessed by Integrated Multi-Wavelength Spectroimaging and Laser Speckle Contrast Imaging SO IEEE JOURNAL OF SELECTED TOPICS IN QUANTUM ELECTRONICS LA English DT Article DE Biomedical optical imaging; blood flow measurement; brain stimulation; drug delivery ID RAT SOMATOSENSORY CORTEX; BLOOD-FLOW; FUNCTIONAL ACTIVATION; QUANTIFICATION; TOMOGRAPHY AB Simultaneous imaging of cerebral hemodynamic changes in response to functional activation during drug intoxication provides a valuable strategy to assess cocaine-induced neurovascular dysfunction. However, this requires tools with sufficient spatiotemporal resolution and an adequate signal to noise ratio (SNR). Though several technologies have been developed to address this demand during functional brain activation, their spatiotemporal resolution has been compromised to preserve SNR. In this study, we combine spatiotemporal-domain laser speckle contrast analysis and image correlation techniques to integrate the multi-wavelength spectroimaging and laser speckle contrast imaging (MW-LSCI). Experimental results show that optimized spatiotemporal resolution with enhanced SNR were achieved that enabled simultaneous measurement of multiple hemodynamic responses (i.e., Delta HbO(2), Delta HbR, Delta HbT, and Delta CBF) during cocaine administration. Specifically, cocaine-induced functional cerebral hemodynamic changes were accessed by measuring the activation responses to forepaw electrical stimulation at different times after cocaine administration. With an improved spatiotemporal resolution and SNR, the system was able to differentiate the heterogeneity of cocaine's effects on the cerebral vasculature and on tissue metabolism, demonstrating the unique capability of MW-LSCI for various brain functional and pharmacological studies. C1 [Chen, Wei; Park, Kicheon; Pan, Yingtian; Du, Congwu] SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. [Volkow, Nora D.] Natl Inst Drug Abuse, NIH, Bethesda, MD 20892 USA. RP Pan, YT; Du, CW (reprint author), SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. EM yingtian.pan@stonybrook.edu; congwu.du@stonybrook.edu FU National Institutes of Health [R21DA032228, 1R01DA029718, R01NS084817]; NIH's Intramural Program FX This work was supported in part by the National Institutes of Health under Grants R21DA032228 (YP/CD), 1R01DA029718 (CD/YP), R01NS084817 (CD/XH), and NIH's Intramural Program (NDV). (Corresponding authors: Yingtian Pan and Congwu Du.) NR 22 TC 0 Z9 0 U1 4 U2 21 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1077-260X EI 1558-4542 J9 IEEE J SEL TOP QUANT JI IEEE J. Sel. Top. Quantum Electron. PD JUL-AUG PY 2016 VL 22 IS 4 AR 6802608 DI 10.1109/JSTQE.2015.2503319 PG 8 WC Engineering, Electrical & Electronic; Optics; Physics, Applied SC Engineering; Optics; Physics GA DH8SG UT WOS:000373066000001 ER PT J AU Lee, MS Lee, B Park, KE Utsuki, T Shin, T Oh, CW Kim, HR AF Lee, Min-Sup Lee, Bonggi Park, Kyoung-Eun Utsuki, Tadanobu Shin, Taisun Oh, Chul Woong Kim, Hyeung-Rak TI Dieckol enhances the expression of antioxidant and detoxifying enzymes by the activation of Nrf2-MAPK signaling pathway in HepG2 cells (vol 174, pg 538, 2015) SO FOOD CHEMISTRY LA English DT Correction C1 [Lee, Min-Sup; Lee, Bonggi; Park, Kyoung-Eun; Kim, Hyeung-Rak] Pukyong Natl Univ, Dept Food Sci & Nutr, Busan 608737, South Korea. [Lee, Bonggi] NICHHD, NIH, Bethesda, MD 20892 USA. [Utsuki, Tadanobu] Louisiana State Univ, Sch Vet Med, Dept Pathobiol Sci, Skip Bertman Dr, Baton Rouge, LA 70803 USA. [Shin, Taisun] Chonnam Natl Univ, Dept Food Sci & Nutr, Yeosu 550749, South Korea. [Oh, Chul Woong] Pukyong Natl Univ, Dept Marine Biol, Busan 608737, South Korea. [Lee, Bonggi] Pusan Natl Univ, Coll Pharm, Busan, South Korea. RP Kim, HR (reprint author), Pukyong Natl Univ, Dept Food Sci & Nutr, Busan 608737, South Korea. EM hrkim@pknu.ac.kr NR 1 TC 0 Z9 0 U1 16 U2 26 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0308-8146 EI 1873-7072 J9 FOOD CHEM JI Food Chem. PD JUL 1 PY 2016 VL 202 BP 521 EP 521 DI 10.1016/j.foodchem.2016.02.084 PG 1 WC Chemistry, Applied; Food Science & Technology; Nutrition & Dietetics SC Chemistry; Food Science & Technology; Nutrition & Dietetics GA DE7IS UT WOS:000370810000070 ER PT J AU Revell, A Khabo, P Ledwaba, L Emery, S Wang, D Wood, R Morrow, C Tempelman, H Hamers, RL Reiss, P van Sighem, A Pozniak, A Montaner, J Lane, HC Larder, B AF Revell, Andrew Khabo, Paul Ledwaba, Lotty Emery, Sean Wang, Dechao Wood, Robin Morrow, Carl Tempelman, Hugo Hamers, Raph L. Reiss, Peter van Sighem, Ard Pozniak, Anton Montaner, Julio Lane, H. Clifford Larder, Brendan TI Computational models as predictors of HIV treatment outcomes for the Phidisa cohort in South Africa SO SOUTHERN AFRICAN JOURNAL OF HIV MEDICINE LA English DT Article ID RESOURCE-LIMITED SETTINGS; THERAPY; GENOTYPE AB Background: Selecting the optimal combination of HIV drugs for an individual in resourcelimited settings is challenging because of the limited availability of drugs and genotyping. Objective: The evaluation as a potential treatment support tool of computational models that predict response to therapy without a genotype, using cases from the Phidisa cohort in South Africa. Methods: Cases from Phidisa of treatment change following failure were identified that had the following data available: baseline CD4 count and viral load, details of failing and previous antiretroviral drugs, drugs in new regimen and time to follow-up. The HIV Resistance Response Database Initiative's (RDI's) models used these data to predict the probability of a viral load < 50 copies/mL at follow-up. The models were also used to identify effective alternative combinations of three locally available drugs. Results: The models achieved accuracy (area under the receiver-operator characteristic curve) of 0.72 when predicting response to therapy, which is less accurate than for an independent global test set (0.80) but at least comparable to that of genotyping with rules-based interpretation. The models were able to identify alternative locally available three-drug regimens that were predicted to be effective in 69% of all cases and 62% of those whose new treatment failed in the clinic. Conclusion: The predictive accuracy of the models for these South African patients together with the results of previous studies suggest that the RDI's models have the potential to optimise treatment selection and reduce virological failure in different patient populations, without the use of a genotype. C1 [Revell, Andrew; Wang, Dechao] HIV Resistance Response Database Initiat RDI, London, England. [Khabo, Paul] SAMHS, Project PHIDISA, Lyttelton, South Africa. [Ledwaba, Lotty; Reiss, Peter] SANDF, Project PHIDISA, Lyttelton, South Africa. [Emery, Sean] Univ New South Wales, Kirby Inst, Sydney, NSW, Australia. [Wood, Robin; Reiss, Peter] Univ Cape Town, Desmond Tutu HIV Ctr, Cape Town, South Africa. [Tempelman, Hugo] Ndlovu Care Grp, Elandsdoorn, South Africa. [Hamers, Raph L.] Univ Amsterdam, Acad Med Ctr, Amsterdam, Netherlands. [Reiss, Peter] Stichting HIV Monitoring, Amsterdam, Netherlands. [Pozniak, Anton] Chelsea & Westminster Hosp, London, England. [Montaner, Julio] BC Ctr Excellence HIV AIDS, Vancouver, WA USA. [Lane, H. Clifford] Nat Inst Allergy & Infect Dis, Bethesda, MD USA. RP Revell, A (reprint author), HIV Resistance Response Database Initiat RDI, London, England. EM andrewrevell@hivrdi.org RI Emery, Sean/H-4920-2013 OI Emery, Sean/0000-0001-6072-8309 FU federal funds from the National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. This research was supported by the National Institute of Allergy and Infectious Diseases. 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 organisations imply endorsement by the U.S. Government. NR 16 TC 0 Z9 0 U1 0 U2 0 PU AOSIS PI CAPE TOWN PA POSTNET SUITE 55, PRIVATE BAG X22, TYGERVALLEY, CAPE TOWN, 00000, SOUTH AFRICA SN 1608-9693 EI 2078-6751 J9 S AFR J HIV MED JI South. Afr. J. HIV Med. PD JUN 30 PY 2016 VL 17 IS 1 AR UNSP 450 DI 10.4102/sajhivmed.v17i1.450 PG 7 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA EK0IW UT WOS:000393611100001 ER PT J AU Sannerud, R Esselens, C Ejsmont, P Mattera, R Rochin, L Tharkeshwar, AK De Baets, G De Wever, V Habets, R Baert, V Vermeire, W Michiels, C Groot, AJ Wouters, R Dillen, K Vints, K Baatsen, P Munck, S Derua, R Waelkens, E Basi, GS Mercken, M Vooijs, M Bollen, M Schymkowitz, J Rousseau, F Bonifacino, JS Van Niel, G De Strooper, B Annaert, W AF Sannerud, Ragna Esselens, Cary Ejsmont, Paulina Mattera, Rafael Rochin, Leila Tharkeshwar, Arun Kumar De Baets, Greet De Wever, Veerle Habets, Roger Baert, Veerle Vermeire, Wendy Michiels, Christine Groot, Arjan J. Wouters, Rosanne Dillen, Katleen Vints, Katlijn Baatsen, Pieter Munck, Sebastian Derua, Rita Waelkens, Etienne Basi, Guriqbal S. Mercken, Mark Vooijs, Marc Bollen, Mathieu Schymkowitz, Joost Rousseau, Frederic Bonifacino, Juan S. Van Niel, Guillaume De Strooper, Bart Annaert, Wim TI Restricted Location of PSEN2/gamma-Secretase Determines Substrate Specificity and Generates an Intracellular A beta Pool SO CELL LA English DT Article ID GAMMA-SECRETASE ACTIVITY; LYSOSOMAL MEMBRANE-PROTEINS; ALZHEIMERS-DISEASE; ENDOSOMAL DYSFUNCTION; AMYLOID ACCUMULATION; FORCE-FIELD; LOCALIZATION; PRESENILINS; MUTATIONS; MECHANISM AB gamma-Secretases are a family of intramembrane-cleaving proteases involved in various signaling pathways and diseases, including Alzheimer's disease (AD). Cells co-express differing gamma-secretase complexes, including two homologous presenilins (PSENs). We examined the significance of this heterogeneity and identified a unique motif in PSEN2 that directs this gamma-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex. Accordingly, PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular A beta that contains longer A beta; familial AD (FAD)-associated mutations in PSEN2 increased the levels of longer A beta further. Moreover, a subset of FAD mutants in PSEN1, normally more broadly distributed in the cell, phenocopies PSEN2 and shifts its localization to late endosomes/lysosomes. Thus, localization of gamma-secretases determines substrate specificity, while FAD-causing mutations strongly enhance accumulation of aggregation-prone A beta 42 in intracellular acidic compartments. The findings reveal potentially important roles for specific intracellular, localized reactions contributing to AD pathogenesis. C1 [Sannerud, Ragna; Esselens, Cary; Ejsmont, Paulina; Tharkeshwar, Arun Kumar; Baert, Veerle; Vermeire, Wendy; Michiels, Christine; Wouters, Rosanne; Dillen, Katleen; De Strooper, Bart; Annaert, Wim] Katholieke Univ Leuven, VIB Ctr Biol Dis, B-3000 Leuven, Belgium. [Sannerud, Ragna; Esselens, Cary; Ejsmont, Paulina; Tharkeshwar, Arun Kumar; Baert, Veerle; Vermeire, Wendy; Michiels, Christine; Wouters, Rosanne; Dillen, Katleen; De Strooper, Bart; Annaert, Wim] Katholieke Univ Leuven, Dept Human Genet, B-3000 Leuven, Belgium. [Mattera, Rafael; Bonifacino, Juan S.] NICHD, Cell Biol & Neurobiol Branch, NIH, Bethesda, MD 20892 USA. [Rochin, Leila; Van Niel, Guillaume] PSL Res Univ, CNRS, Inst Curie, UMR 144, F-75005 Paris, France. [Rochin, Leila; Van Niel, Guillaume] CNRS, UMR 144, F-75005 Paris, France. [De Baets, Greet; Schymkowitz, Joost; Rousseau, Frederic] Katholieke Univ Leuven, VIB Switch Lab, B-3000 Louvain, Belgium. [De Baets, Greet; De Wever, Veerle; Derua, Rita; Waelkens, Etienne; Bollen, Mathieu; Schymkowitz, Joost; Rousseau, Frederic] Katholieke Univ Leuven, Dept Cellular & Mol Med, B-3000 Louvain, Belgium. [Groot, Arjan J.; Vooijs, Marc] Maastricht Univ, Dept Radiotherapy MAASTRO GROW, NL-6211 Maastricht, Netherlands. [Vints, Katlijn; Baatsen, Pieter; Munck, Sebastian] VIB BioImaging Core, B-3000 Louvain, Belgium. [Basi, Guriqbal S.] Avalanche Biotechnol, Menlo Pk, CA 94025 USA. [Mercken, Mark] Janssen Pharmaceut, B-2340 Beerse, Belgium. [De Strooper, Bart] UCL Inst Neurol, Dept Mol Neurosci, London WC1E 6BT, England. RP Annaert, W (reprint author), Katholieke Univ Leuven, VIB Ctr Biol Dis, B-3000 Leuven, Belgium.; Annaert, W (reprint author), Katholieke Univ Leuven, Dept Human Genet, B-3000 Leuven, Belgium. EM wim.annaert@cme.vib-kuleuven.be RI Rousseau, Frederic/J-9044-2016; OI Rousseau, Frederic/0000-0002-9189-7399; Esselens, Cary/0000-0001-8876-634X FU VIB; KU Leuven [C16/15/073, IDO/12/020]; federal government [IAP P7/16]; Hercules [AKUL/09/037, 11/30, 13/39]; SAO [14017]; Alzheimer's Association [IIRG-08-91535]; NICHD Intramural Program [ZIA HD001607]; IWT; EU-ERC [208259]; "Fondation ARC" [DOC20130606986, PJA20131200286] FX Financial support was from VIB (W.A., B.D.S., F.R., and J.S.), KU Leuven (C16/15/073 and IDO/12/020 to W.A.), the federal government (IAP P7/16: W.A., B.D.S., F.R., and J.S.), Hercules (AKUL/09/037, 11/30, 13/39 to W.A.), SAO (S#14017 to W.A.), the Alzheimer's Association (IIRG-08-91535 to W.A.), and the NICHD Intramural Program (ZIA HD001607 to J.S.B.). A.K.T. and G.D.B. held PhD fellowships from VIB and IWT. We thank K. Ivanova for initial FP-PSEN rescue. P.E. was a Marie-Curie postdoc, and R.W. is an FWO fellow. A.G., R.H., and M.V. are supported by EU-ERC (208259); L.R. and G.V.N. are supported by "Fondation ARC" (no. DOC20130606986 and # PJA20131200286). We thank PICT-IBiSA (Institut Curie) and France-Bio-Imaging (ANR-10-INSB-04). NR 51 TC 10 Z9 10 U1 11 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUN 30 PY 2016 VL 166 IS 1 BP 193 EP 208 DI 10.1016/j.cell.2016.05.020 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DR9ZH UT WOS:000380254400021 PM 27293189 ER PT J AU Khundakar, AA Hanson, PS Erskine, D Lax, NZ Roscamp, J Karyka, E Tsefou, E Singh, P Cockell, SJ Gribben, A Ramsay, L Blain, PG Mosimann, UP Lett, DJ Elstner, M Turnbull, DM Xiang, CC Brownstein, MJ O'Brien, JT Taylor, JP Attems, J Thomas, AJ McKeith, IG Morris, CM AF Khundakar, Ahmad A. Hanson, Peter S. Erskine, Daniel Lax, Nichola Z. Roscamp, Joseph Karyka, Evangelia Tsefou, Eliona Singh, Preeti Cockell, Simon J. Gribben, Andrew Ramsay, Lynne Blain, Peter G. Mosimann, Urs P. Lett, Deborah J. Elstner, Matthias Turnbull, Douglass M. Xiang, Charles C. Brownstein, Michael J. O'Brien, John T. Taylor, John-Paul Attems, Johannes Thomas, Alan J. McKeith, Ian G. Morris, Christopher M. TI Analysis of primary visual cortex in dementia with Lewy bodies indicates GABAergic involvement associated with recurrent complex visual hallucinations SO ACTA NEUROPATHOLOGICA COMMUNICATIONS LA English DT Article DE Dementia with Lewy bodies; alpha-synuclein; Primary visual cortex; Hallucinations; Alzheimer's disease ID TEMPORAL AREAS TE; PARKINSON-DISEASE DEMENTIA; ALZHEIMERS-DISEASE; MACAQUE MONKEYS; SUBCORTICAL CONNECTIONS; DEPENDENT PLASTICITY; ILLUMINA MICROARRAY; BODY DEMENTIAS; BRAIN; PATHOLOGY AB Dementia with Lewy bodies (DLB) patients frequently experience well formed recurrent complex visual hallucinations (RCVH). This is associated with reduced blood flow or hypometabolism on imaging of the primary visual cortex. To understand these associations in DLB we used pathological and biochemical analysis of the primary visual cortex to identify changes that could underpin RCVH. Alpha-synuclein or neurofibrillary tangle pathology in primary visual cortex was essentially absent. Neurone density or volume within the primary visual cortex in DLB was also unchanged using unbiased stereology. Microarray analysis, however, demonstrated changes in neuropeptide gene expression and other markers, indicating altered GABAergic neuronal function. Calcium binding protein and GAD65/67 immunohistochemistry showed preserved interneurone populations indicating possible interneurone dysfunction. This was demonstrated by loss of post synaptic GABA receptor markers including gephyrin, GABARAP, and Kif5A, indicating reduced GABAergic synaptic activity. Glutamatergic neuronal signalling was also altered with vesicular glutamate transporter protein and PSD-95 expression being reduced. Changes to the primary visual cortex in DLB indicate that reduced GABAergic transmission may contribute to RCVH in DLB and treatment using targeted GABAergic modulation or similar approaches using glutamatergic modification may be beneficial. C1 [Khundakar, Ahmad A.; Erskine, Daniel; Lax, Nichola Z.; Ramsay, Lynne; Lett, Deborah J.; Turnbull, Douglass M.; Attems, Johannes; Morris, Christopher M.] Newcastle Univ, Inst Neurosci, Edwardson Bldg,Campus Ageing & Vital,Westgate Rd, Newcastle Upon Tyne NE4 5PL, Tyne & Wear, England. [Hanson, Peter S.; Erskine, Daniel; Roscamp, Joseph; Karyka, Evangelia; Tsefou, Eliona; Singh, Preeti; Gribben, Andrew; Blain, Peter G.; Morris, Christopher M.] Newcastle Univ, Med Toxicol Ctr, Wolfson Bldg,Claremont Pl, Newcastle Upon Tyne NE2 4AA, Tyne & Wear, England. [Lax, Nichola Z.; Turnbull, Douglass M.] Newcastle Univ, Sch Med, Inst Neurosci, Wellcome Trust Ctr Mitochondrial Res, Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Cockell, Simon J.] Newcastle Univ, Bioinformat Support Unit, Leech Bldg,Frarnlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Mosimann, Urs P.] Univ Bern, Univ Hosp Old Age Psychiat, CH-3010 Bern, Switzerland. [Elstner, Matthias] Tech Univ Munich, Acad Hosp Bogenhausen, Dept Neurol & Clin Neurophysiol, Munich, Germany. [Xiang, Charles C.; Brownstein, Michael J.; Morris, Christopher M.] NHGRI, Genet Lab, NIMH, NIH, Bethesda, MD 20892 USA. [O'Brien, John T.; Taylor, John-Paul; Thomas, Alan J.; McKeith, Ian G.] Newcastle Univ, Inst Neurosci, Biomed Res Bldg,Westgate Rd, Newcastle Upon Tyne NE4 5PL, Tyne & Wear, England. [O'Brien, John T.] Univ Cambridge, Sch Clin Med, Dept Psychiat, Box 189 Level E4 Cambridge Biomed Campus, Cambridge CB2 0SP, England. RP Morris, CM (reprint author), Newcastle Univ, Inst Neurosci, Edwardson Bldg,Campus Ageing & Vital,Westgate Rd, Newcastle Upon Tyne NE4 5PL, Tyne & Wear, England.; Morris, CM (reprint author), Newcastle Univ, Med Toxicol Ctr, Wolfson Bldg,Claremont Pl, Newcastle Upon Tyne NE2 4AA, Tyne & Wear, England.; Morris, CM (reprint author), NHGRI, Genet Lab, NIMH, NIH, Bethesda, MD 20892 USA. EM c.m.morris@ncl.ac.uk OI Cockell, Simon/0000-0002-6831-9806 FU Medical Research Council [G0400074, G0502157, G0900652, G1100540, MR/L016354/1]; Wellcome Trust [096919] NR 102 TC 2 Z9 2 U1 2 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 30 PY 2016 VL 4 AR UNSP 66 DI 10.1186/s40478-016-0334-3 PG 18 WC Neurosciences SC Neurosciences & Neurology GA DQ9IL UT WOS:000379523500001 PM 27357212 ER PT J AU Brudno, JN Kochenderfer, JN AF Brudno, Jennifer N. Kochenderfer, James N. TI Toxicities of chimeric antigen receptor T cells: recognition and management SO BLOOD LA English DT Review ID CYTOKINE RELEASE SYNDROME; ANTITUMOR-ACTIVITY; PHASE-I; RHEUMATOID-ARTHRITIS; ENGAGING THERAPIES; RETROVIRAL VECTOR; RANDOMIZED-TRIAL; CLINICAL-TRIAL; ADVERSE EVENT; TUMOR-GROWTH AB Chimeric antigen receptor (CAR) T cells can produce durable remissions in hematologic malignancies that are not responsive to standard therapies. Yet the use of CAR T cells is limited by potentially severe toxicities. Early case reports of unexpected organ damage and deaths following CAR T-cell therapy first highlighted the possible dangers of this new treatment. CAR T cells can potentially damage normal tissues by specifically targeting a tumor-associated antigen that is also expressed on those tissues. Cytokine release syndrome (CRS), a systemic inflammatory response caused by cytokines released by infused CAR T cells can lead to widespread reversible organ dysfunction. CRS is the most common type of toxicity caused by CAR T cells. Neurologic toxicity due to CAR T cells might in some cases have a different pathophysiology than CRS and requires different management. Aggressive supportive care is necessary for all patients experiencing CAR T-cell toxicities, with early intervention for hypotension and treatment of concurrent infections being essential. Interleukin-6 receptor blockade with tocilizumab remains the mainstay pharmacologic therapy for CRS, though indications for administration vary among centers. Corticosteroids should be reserved for neurologic toxicities and CRS not responsive to tocilizumab. Pharmacologic management is complicated by the risk of immunosuppressive therapy abrogating the antimalignancy activity of the CAR T cells. This review describes the toxicities caused by CAR T cells and reviews the published approaches used to manage toxicities. We present guidelines for treating patients experiencing CRS and other adverse events following CAR T-cell therapy. C1 [Brudno, Jennifer N.] NCI, Off Clin Director, Ctr Canc Res, Bethesda, MD 20892 USA. [Kochenderfer, James N.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. RP Kochenderfer, JN (reprint author), NIH Bldg 10,10 Ctr Dr,CRC Room 3-3888, Bethesda, MD 20892 USA. EM kochendj@mail.nih.gov FU NCI FX Funding for preparation of this review was provided by the NCI intramural funds. NR 71 TC 22 Z9 23 U1 5 U2 9 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUN 30 PY 2016 VL 127 IS 26 BP 3321 EP 3330 DI 10.1182/blood-2016-04-703751 PG 10 WC Hematology SC Hematology GA DQ5MC UT WOS:000379248500008 PM 27207799 ER PT J AU Gertz, EM Chowdhury, SA Lee, WJ Wangsa, D Heselmeyer-Haddad, K Ried, T Schwartz, R Schaffer, AA AF Gertz, E. Michael Chowdhury, Salim Akhter Lee, Woei-Jyh Wangsa, Darawalee Heselmeyer-Haddad, Kerstin Ried, Thomas Schwartz, Russell Schaffer, Alejandro A. TI FISHtrees 3.0: Tumor Phylogenetics Using a Ploidy Probe SO PLOS ONE LA English DT Article ID COPY NUMBER CHANGES; IN-SITU HYBRIDIZATION; CELL GENETIC-ANALYSIS; CROSS-SECTIONAL DATA; CLONAL EVOLUTION; BREAST-CANCER; SEQUENCING DATA; MAXIMUM-LIKELIHOOD; PROGRESSION MODELS; ONCOGENETIC TREE AB Advances in fluorescence in situ hybridization (FISH) make it feasible to detectmultiple copy-number changes in hundreds of cells of solid tumors. Studies using FISH, sequencing, and other technologies have revealed substantial intra-tumor heterogeneity. The evolution of subclones in tumors may bemodeled by phylogenies. Tumors often harbor aneuploid or polyploid cell populations. Using a FISH probe to estimate changes in ploidy can guide the creation of trees that model changes in ploidy and individual gene copy-number variations. We present FISHtrees 3.0, which implements a ploidy-based tree building method based on mixed integer linear programming (MILP). The ploidy-based modeling in FISHtrees includes a new formulation of the problem of merging trees for changes of a single gene into trees modeling changes in multiple genes and the ploidy. When multiple samples are collected from each patient, varying over time or tumor regions, it is useful to evaluate similarities in tumor progression among the samples. Therefore, we further implemented in FISHtrees 3.0 a new method to build consensus graphs for multiple samples. We validate FISHtrees 3.0 on a simulated data and on FISH data from paired cases of cervical primary and metastatic tumors and on paired breast ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC). Tests on simulated data show improved accuracy of the ploidy-based approach relative to prior ploidyless methods. Tests on real data further demonstrate novel insights these methods offer into tumor progression processes. Trees for DCIS samples are significantly less complex than trees for paired IDC samples. Consensus graphs show substantial divergence among most paired samples from both sets. Low consensus between DCIS and IDC trees may help explain the difficulty in finding biomarkers that predict which DCIS cases are at most risk to progress to IDC. The FISHtrees software is available at ftp://ftp.ncbi.nih.gov/pub/FISHtrees. C1 [Gertz, E. Michael] US Natl Inst Hlth, Natl Ctr Biotechnol Informat, Computat Biol Branch, 31 Ctr Dr, Bethesda, MD 20892 USA. [Chowdhury, Salim Akhter; Schwartz, Russell] Carnegie Mellon Univ, Computat Biol Dept, Pittsburgh, PA USA. [Chowdhury, Salim Akhter] Carnegie Mellon Univ Pittsburgh, Joint PhD Program Computat Biol, Pittsburgh, PA USA. [Wangsa, Darawalee; Heselmeyer-Haddad, Kerstin; Ried, Thomas] US Natl Inst Hlth, Sect Canc Genom, Genet Branch, Ctr Canc Res,Natl Canc Inst, Bethesda, MD USA. [Schwartz, Russell] Carnegie Mellon Univ, Dept Biol Sci, Pittsburgh, PA USA. [Chowdhury, Salim Akhter] Simons Fdn, Simons Ctr Data Anal, New York, NY USA. [Chowdhury, Salim Akhter] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ USA. [Lee, Woei-Jyh] Univ Maryland, Robert H Smith Sch Business, Dept Decis Operat & Informat Technol, College Pk, MD USA. RP Gertz, EM (reprint author), US Natl Inst Hlth, Natl Ctr Biotechnol Informat, Computat Biol Branch, 31 Ctr Dr, Bethesda, MD 20892 USA. EM gertz@ncbi.nlm.nih.gov RI Schwartz, Russell/A-1998-2016 OI Schwartz, Russell/0000-0002-4970-2252 FU Intramural Research Program of the National Institutes of Health, NLM and NCI; U.S. National Institutes of Health [1R01CA140214] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, NLM and NCI, and by U.S. National Institutes of Health award 1R01CA140214. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 74 TC 1 Z9 1 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 30 PY 2016 VL 11 IS 6 AR e0158569 DI 10.1371/journal.pone.0158569 PG 27 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ0CH UT WOS:000378865200093 PM 27362268 ER PT J AU Mitra, A Herren, CD Patel, IR Coleman, A Mukhopadhyay, S AF Mitra, Arindam Herren, Christopher D. Patel, Isha R. Coleman, Adam Mukhopadhyay, Suman TI Integration of AI-2 Based Cell-Cell Signaling with Metabolic Cues in Escherichia coli SO PLOS ONE LA English DT Article ID VIRULENCE GENE-EXPRESSION; SALMONELLA-TYPHIMURIUM; RESPONSE REGULATOR; BIOFILM FORMATION; VIBRIO-CHOLERAE; GLOBAL CONTROL; QUORUM; LUXS; PSEUDOMONAS; SYSTEM AB The quorum sensing molecule Autoinducer-2 (AI-2) is generated as a byproduct of activated methyl cycle by the action of LuxS in Escherichia coli. AI-2 is synthesized, released and later internalized in a cell-density dependent manner. Here, by mutational analysis of the genes, uvrY and csrA, we describe a regulatory circuit of accumulation and uptake of AI-2. We constructed a single-copy chromosomal luxS-lacZ fusion in a luxS (+) merodiploid strain and evaluated its relative expression in uvrY and csrA mutants. At the entry of stationary phase, the expression of the fusion and AI-2 accumulation was positively regulated by uvrY and negatively regulated by csrA respectively. A deletion of csrA altered message stability of the luxS transcript and CsrA protein exhibited weak binding to 5' luxS regulatory region. DNA protein interaction and chromatin immunoprecipitation analysis confirmed direct interaction of UvrY with the luxS promoter. Additionally, reduced expression of the fusion in hfq deletion mutant suggested involvement of small RNA interactions in luxS regulation. In contrast, the expression of lsrA operon involved in AI-2 uptake, is negatively regulated by uvrY and positively by csrA in a cell-density dependent manner. The dual role of csrA in AI-2 synthesis and uptake suggested a regulatory crosstalk of cell signaling with carbon regulation in Escherichia coli. We found that the cAMP-CRP mediated catabolite repression of luxS expression was uvrY dependent. This study suggests that luxS expression is complex and regulated at the level of transcription and translation. The multifactorial regulation supports the notion that cell-cell communication requires interaction and integration of multiple metabolic signals. C1 [Mitra, Arindam; Herren, Christopher D.; Patel, Isha R.; Coleman, Adam; Mukhopadhyay, Suman] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Mitra, Arindam] Adamas Univ, Dept Microbiol, Kolkata, W Bengal, India. [Herren, Christopher D.] Kansas State Univ, Div Biol, Manhattan, KS USA. [Patel, Isha R.] US FDA, Div Mol Biol, Off Appl Res & Safety Assessment HFS 025, Ctr Food Safety & Appl Nutr, Laurel, MD USA. [Coleman, Adam] Maryland Dept Hlth & Mental Hyg, Div Newborn & Childhood Screening, Baltimore, MD USA. [Mukhopadhyay, Suman] NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD USA. RP Mukhopadhyay, S (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA.; Mukhopadhyay, S (reprint author), NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD USA. EM mukhopadhyays@mail.nih.gov FU USDA-NRI-CSREES Competitive Grant [2004-35204-14749]; USDA-Animal Health [2002-1106-0195318]; Maryland Agriculture Experimental Station grant from the University of Maryland FX This work was in part supported by USDA-NRI-CSREES Competitive Grant 2004-35204-14749, USDA-Animal Health 2002-1106-0195318 and Maryland Agriculture Experimental Station grant from the University of Maryland. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 0 Z9 0 U1 7 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 30 PY 2016 VL 11 IS 6 AR e0157532 DI 10.1371/journal.pone.0157532 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ0CH UT WOS:000378865200019 PM 27362507 ER PT J AU Xu, ZZ Proschan, M Lee, S AF Xu, Zhenzhen Proschan, Michael Lee, Shiowjen TI Validity and power considerations on hypothesis testing under minimization SO STATISTICS IN MEDICINE LA English DT Article DE covariate adaptive randomization; minimization; dynamic allocation; randomization; analyze as you randomize; re-randomization test; permutation test; temporal trend; validity; power ID COVARIATE-ADAPTIVE RANDOMIZATION; TREATMENT ALLOCATION PROCEDURES; BIASED COIN DESIGN; CLINICAL-TRIALS; PROGNOSTIC-FACTORS; BALANCE AB Minimization, a dynamic allocation method, is gaining popularity especially in cancer clinical trials. Aiming to achieve balance on all important prognostic factors simultaneously, this procedure can lead to a substantial reduction in covariate imbalance compared with conventional randomization in small clinical trials. While minimization has generated enthusiasm, some controversy exists over the proper analysis of such a trial. Critics argue that standard testing methods that do not account for the dynamic allocation algorithm can lead to invalid statistical inference. Acknowledging this limitation, the International Conference on Harmonization E9 guideline suggests that 'the complexity of the logistics and potential impact on analyses be carefully evaluated when considering dynamic allocation'. In this article, we investigate the proper analysis approaches to inference in a minimization design for both continuous and time-to-event endpoints and evaluate the validity and power of these approaches under a variety of scenarios both theoretically and empirically. Published 2016. This article is a U.S. Government work and is in the public domain in the USA C1 [Xu, Zhenzhen; Lee, Shiowjen] US FDA, CBER, Silver Spring, MD 20993 USA. [Proschan, Michael] NIAID, Biostat Res Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Xu, ZZ (reprint author), US FDA, CBER, Silver Spring, MD 20993 USA. EM Zhenzhen.Xu@fda.hhs.gov NR 32 TC 2 Z9 2 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JUN 30 PY 2016 VL 35 IS 14 BP 2315 EP 2327 DI 10.1002/sim.6874 PG 13 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA DP5LB UT WOS:000378537100002 PM 26787557 ER PT J AU von der Ecken, J Heissler, SM Pathan-Chhatbar, S Manstein, DJ Raunser, S AF von der Ecken, Julian Heissler, Sarah M. Pathan-Chhatbar, Salma Manstein, Dietmar J. Raunser, Stefan TI Cryo-EM structure of a human cytoplasmic actomyosin complex at near-atomic resolution SO NATURE LA English DT Article ID HEAVY-CHAIN GENE; FAMILIAL HYPERTROPHIC CARDIOMYOPATHY; DICTYOSTELIUM MYOSIN-II; ACTIN-BINDING SITE; BETA-MYOSIN; FUNCTIONAL-CHARACTERIZATION; DILATED CARDIOMYOPATHY; MUSCLE-CONTRACTION; MISSENSE MUTATION; ATPASE ACTIVITY AB The interaction of myosin with actin filaments is the central feature of muscle contraction(1) and cargo movement along actin filaments of the cytoskeleton(2). The energy for these movements is generated during a complex mechanochemical reaction cycle(3,4). Crystal structures of myosin in different states have provided important structural insights into the myosin motor cycle when myosin is detached from F-actin(5-7). The difficulty of obtaining diffracting crystals, however, has prevented structure determination by crystallography of actomyosin complexes. Thus, although structural models exist of F-actin in complex with various myosins(8-11), a high-resolution structure of the F-actin-myosin complex is missing. Here, using electron cryomicroscopy, we present the structure of a human rigor actomyosin complex at an average resolution of 3.9 angstrom. The structure reveals details of the actomyosin interface, which is mainly stabilized by hydrophobic interactions. The negatively charged amino (N) terminus of actin interacts with a conserved basic motif in loop 2 of myosin, promoting cleft closure in myosin. Surprisingly, the overall structure of myosin is similar to rigor-like myosin structures in the absence of F-actin, indicating that F-actin binding induces only minimal conformational changes in myosin. A comparison with pre-powerstroke and intermediate (P-i-release)(7) states of myosin allows us to discuss the general mechanism of myosin binding to F-actin. Our results serve as a strong foundation for the molecular understanding of cytoskeletal diseases, such as autosomal dominant hearing loss and diseases affecting skeletal and cardiac muscles, in particular nemaline myopathy and hypertrophic cardiomyopathy. C1 [von der Ecken, Julian; Raunser, Stefan] Max Planck Inst Mol Physiol, Dept Struct Biochem, D-44227 Dortmund, Germany. [Heissler, Sarah M.; Pathan-Chhatbar, Salma; Manstein, Dietmar J.] Hannover Med Sch, Inst Biophys Chem, D-30625 Hannover, Germany. [Manstein, Dietmar J.] Hannover Med Sch, Div Struct Anal, D-30625 Hannover, Germany. [Heissler, Sarah M.] NHLBI, Lab Mol Physiol, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Raunser, S (reprint author), Max Planck Inst Mol Physiol, Dept Struct Biochem, D-44227 Dortmund, Germany. EM stefan.raunser@mpi-dortmund.mpg.de OI Raunser, Stefan/0000-0001-9373-3016 FU Max Planck Society; European Research Council under the European Union [615984]; Behrens-Weise foundation; German Research Foundation (DFG) [MA 1081/21-1] FX We thank O. Hofnagel for assistance in cryo sample preparation. We acknowledge R. Matadeen and S. de Carlo for image acquisition at the Netherlands Centre for Nanoscopy in Leiden. We thank R. S. Goody for reading the manuscript. This work was supported by the Max Planck Society, the European Research Council under the European Union's Seventh Framework Program (FP7/2007-2013) (grant number 615984) (to S.R.), the Behrens-Weise foundation (to S. R.) and German Research Foundation (DFG) grant MA 1081/21-1 (to D.J.M.). J.v.d.E. is a fellow of Studienstiftung des deutschen Volkes. NR 78 TC 8 Z9 8 U1 11 U2 24 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUN 30 PY 2016 VL 534 IS 7609 BP 724 EP + DI 10.1038/nature18295 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP7JV UT WOS:000378676000045 PM 27324845 ER PT J AU Nghiem, PT Bhatia, S Lipson, EJ Kudchadkar, RR Miller, NJ Annamalai, L Berry, S Chartash, EK Daud, A Fling, SP Friedlander, PA Kluger, HM Kohrt, HE Lundgren, L Margolin, K Mitchell, A Olencki, T Pardoll, DM Reddy, SA Shantha, EM Sharfman, WH Sharon, E Shemanski, LR Shinohara, MM Sunshine, JC Taube, JM Thompson, JA Townson, SM Yearley, JH Topalian, SL Cheever, MA AF Nghiem, Paul T. Bhatia, Shailender Lipson, Evan J. Kudchadkar, Ragini R. Miller, Natalie J. Annamalai, Lakshmanan Berry, Sneha Chartash, Elliot K. Daud, Adil Fling, Steven P. Friedlander, Philip A. Kluger, Harriet M. Kohrt, Holbrook E. Lundgren, Lisa Margolin, Kim Mitchell, Alan Olencki, Thomas Pardoll, Drew M. Reddy, Sunil A. Shantha, Erica M. Sharfman, William H. Sharon, Elad Shemanski, Lynn R. Shinohara, Michi M. Sunshine, Joel C. Taube, Janis M. Thompson, John A. Townson, Steven M. Yearley, Jennifer H. Topalian, Suzanne L. Cheever, Martin A. TI PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LUNG-CANCER; IMMUNE RESISTANCE; POLYOMAVIRUS; RESPONSES; NIVOLUMAB; EXPRESSION; SURVIVAL; TUMORS; CHEMOTHERAPY; ANTI-PD-1 AB BACKGROUND Merkel-cell carcinoma is an aggressive skin cancer that is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus (MCPyV). Advanced Merkel-cell carcinoma often responds to chemotherapy, but responses are transient. Blocking the programmed death 1 (PD-1) immune inhibitory pathway is of interest, because these tumors often express PD-L1, and MCPyV-specific T cells express PD-1. METHODS In this multicenter, phase 2, noncontrolled study, we assigned adults with advanced Merkel-cell carcinoma who had received no previous systemic therapy to receive pembrolizumab (anti-PD-1) at a dose of 2 mg per kilogram of body weight every 3 weeks. The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Efficacy was correlated with tumor viral status, as assessed by serologic and immunohistochemical testing. RESULTS A total of 26 patients received at least one dose of pembrolizumab. The objective response rate among the 25 patients with at least one evaluation during treatment was 56% (95% confidence interval [CI], 35 to 76); 4 patients had a complete response, and 10 had a partial response. With a median follow-up of 33 weeks (range, 7 to 53), relapses occurred in 2 of the 14 patients who had had a response (14%). The response duration ranged from at least 2.2 months to at least 9.7 months. The rate of progression-free survival at 6 months was 67% (95% CI, 49 to 86). A total of 17 of the 26 patients (65%) had virus-positive tumors. The response rate was 62% among patients with MCPyV-positive tumors (10 of 16 patients) and 44% among those with virus-negative tumors (4 of 9 patients). Drug-related grade 3 or 4 adverse events occurred in 15% of the patients. CONCLUSIONS In this study, first-line therapy with pembrolizumab in patients with advanced Merkel-cell carcinoma was associated with an objective response rate of 56%. Responses were observed in patients with virus-positive tumors and those with virus-negative tumors. C1 [Nghiem, Paul T.; Bhatia, Shailender; Miller, Natalie J.; Shantha, Erica M.; Shinohara, Michi M.; Thompson, John A.; Cheever, Martin A.] Univ Washington, Med Ctr, 850 Republican St,Brotman Rm 240, Seattle, WA 98109 USA. [Nghiem, Paul T.; Bhatia, Shailender; Fling, Steven P.; Lundgren, Lisa; Thompson, John A.; Cheever, Martin A.] Univ Washington, Fred Hutchinson Canc Res Ctr, 850 Republican St,Brotman Rm 240, Seattle, WA 98109 USA. [Fling, Steven P.; Lundgren, Lisa; Cheever, Martin A.] Univ Washington, Canc Immunotherapy Trials Network, 850 Republican St,Brotman Rm 240, Seattle, WA 98109 USA. [Mitchell, Alan; Shemanski, Lynn R.] Univ Washington, Canc Res & BioStat, 850 Republican St,Brotman Rm 240, Seattle, WA 98109 USA. [Lipson, Evan J.; Berry, Sneha; Pardoll, Drew M.; Sharfman, William H.; Sunshine, Joel C.; Taube, Janis M.; Topalian, Suzanne L.] Johns Hopkins Univ, Sch Med, 1550 Orleans St,CBR2,Rm 508, Baltimore, MD 21287 USA. [Lipson, Evan J.; Berry, Sneha; Pardoll, Drew M.; Sharfman, William H.; Sunshine, Joel C.; Taube, Janis M.; Topalian, Suzanne L.] Johns Hopkins Univ, Kimmel Canc Ctr, 1550 Orleans St,CBR2,Rm 508, Baltimore, MD 21287 USA. [Sharon, Elad] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Kudchadkar, Ragini R.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Annamalai, Lakshmanan; Chartash, Elliot K.; Townson, Steven M.; Yearley, Jennifer H.] Merck Res Labs, Kenilworth, NJ USA. [Daud, Adil] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Kohrt, Holbrook E.; Margolin, Kim; Reddy, Sunil A.] Stanford Univ, Stanford, CA 94305 USA. [Friedlander, Philip A.] Mt Sinai Med Ctr, New York, NY 10029 USA. [Kluger, Harriet M.] Yale Univ, New Haven, CT USA. [Olencki, Thomas] Ohio State Univ, Columbus, OH 43210 USA. RP Topalian, SL (reprint author), Johns Hopkins Univ, Sch Med, 1550 Orleans St,CBR2,Rm 508, Baltimore, MD 21287 USA.; Nghiem, PT (reprint author), Univ Washington, Dermatol Med, 850 Republican St,Brotman Rm 240, Seattle, WA 98109 USA. EM pnghiem@uw.edu; stopali1@jhmi.edu RI Nghiem, Paul/A-9210-2011 OI Nghiem, Paul/0000-0003-2784-963X FU National Cancer Institute; Merck FX Funded by the National Cancer Institute and Merck; ClinicalTrials.gov number, NCT02267603. NR 40 TC 50 Z9 50 U1 7 U2 16 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 30 PY 2016 VL 374 IS 26 BP 2542 EP 2552 DI 10.1056/NEJMoa1603702 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DP8DD UT WOS:000378727200006 PM 27093365 ER PT J AU Taurog, JD Chhabra, A Colbert, RA AF Taurog, Joel D. Chhabra, Avneesh Colbert, Robert A. TI Ankylosing Spondylitis and Axial Spondyloarthritis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID SOCIETY CLASSIFICATION CRITERIA; ENTHESITIS-RELATED ARTHRITIS; INFLAMMATORY BACK-PAIN; PERIPHERAL SPONDYLOARTHRITIS; JUVENILE SPONDYLOARTHRITIS; SACROILIAC JOINTS; AMERICAN-COLLEGE; T-CELLS; DISEASE; HLA-B27 C1 [Taurog, Joel D.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Rheumat Dis, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. [Chhabra, Avneesh] Univ Texas SW Med Ctr Dallas, Dept Radiol, Musculoskeletal Imaging Div, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. [Colbert, Robert A.] NIAMSD, Pediat Translat Res Branch, NIH, Bethesda, MD 20892 USA. RP Taurog, JD (reprint author), Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Rheumat Dis, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM joel.taurog@utsouthwestern.edu FU UT Southwestern; AbbVie Pharmaceuticals; Siemens; General Electric-Association of University Radiologists FX Dr. Taurog reports receiving laboratory funding and discretionary funding through a license agreement between UT Southwestern and AbbVie Pharmaceuticals, through which AbbVie has acquired access to HLA-B27 transgenic rats from Dr. Taurog's laboratory; Dr. Chhabra, receiving fees for the development of computer-aided detection technology from Siemens and grant support from the General Electric-Association of University Radiologists; and Dr. Colbert, being principal investigator in a cooperative research and development agreement between his institution and Eli Lilly. No other potential conflict of interest relevant to this article was reported. NR 76 TC 16 Z9 16 U1 7 U2 12 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 30 PY 2016 VL 374 IS 26 BP 2563 EP 2574 DI 10.1056/NEJMra1406182 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DP8DD UT WOS:000378727200008 PM 27355535 ER PT J AU Alam, MA Arora, K Gurrapu, S Jonnalagadda, SK Nelson, GL Kiprof, P Jonnalagadda, SC Mereddy, VR AF Alam, Mohammad A. Arora, Kriti Gurrapu, Shirisha Jonnalagadda, Sravan K. Nelson, Grady L. Kiprof, Paul Jonnalagadda, Subash C. Mereddy, Venkatram R. TI Synthesis and evaluation of functionalized benzoboroxoles as potential anti-tuberculosis agents SO TETRAHEDRON LA English DT Article DE Benzoboroxoles; Nitrobenzoboroxole; Aminobenzoboroxole; Bromoaminobenzoboroxole; anti-Tuberculosis agents ID ALPHA-AMINO-ACIDS; MYCOBACTERIUM-TUBERCULOSIS; BENZOXABOROLES; DISCOVERY; METHODOLOGIES; INHIBITORS; CHEMISTRY; SMEGMATIS; STRATEGY; ANALOGS AB Several derivatives of aminobenzoboroxole have been prepared starting from 2-boronobenzaldehyde. All of these derivatives have been evaluated for their anti-mycobacterial activity on Mycobacterium smegmatis and cytotoxicity on breast cancer cell line MCF7. Based on these studies, all the tested molecules have been found to be generally non-toxic and benzoboroxoles with unsubstituted (primary) amines have been found to exhibit good anti-mycobacterial activity. Some of the key compounds have been evaluated for their anti-tubercular activity on Mycobacterium tuberculosis H37Rv using 7H9 and GAST media. 7-Bromo-6-aminobenzoboroxole 4 has been identified as the lead candidate compound for further development. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Alam, Mohammad A.; Jonnalagadda, Subash C.] Rowan Univ, Dept Chem & Biochem, Glassboro, NJ 08028 USA. [Arora, Kriti] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Gurrapu, Shirisha; Jonnalagadda, Sravan K.; Nelson, Grady L.; Mereddy, Venkatram R.] Univ Minnesota, Integrated Biosci Grad Program, Duluth, MN 55812 USA. [Kiprof, Paul; Mereddy, Venkatram R.] Univ Minnesota, Dept Chem & Biochem, Duluth, MN 55812 USA. [Jonnalagadda, Subash C.] Rowan Univ, Dept Biomed & Translat Sci, Glassboro, NJ 08028 USA. [Mereddy, Venkatram R.] Univ Minnesota, Dept Pharm Practice & Pharmaceut Sci, Duluth, MN 55812 USA. RP Jonnalagadda, SC (reprint author), Rowan Univ, Dept Chem & Biochem, Glassboro, NJ 08028 USA.; Mereddy, VR (reprint author), Univ Minnesota, Integrated Biosci Grad Program, Duluth, MN 55812 USA.; Mereddy, VR (reprint author), Univ Minnesota, Dept Chem & Biochem, Duluth, MN 55812 USA.; Jonnalagadda, SC (reprint author), Rowan Univ, Dept Biomed & Translat Sci, Glassboro, NJ 08028 USA.; Mereddy, VR (reprint author), Univ Minnesota, Dept Pharm Practice & Pharmaceut Sci, Duluth, MN 55812 USA. EM jonnalagadda@rowan.edu; vmereddy@d.umn.edu OI Jonnalagadda, Subash/0000-0001-5234-1235 FU Intramural Research Program at NIAID, National Institutes of Health FX The work was funded, in part by the Intramural Research Program at NIAID, National Institutes of Health. We thank Dr. Clifton E. Barry and Dr. Helena Boshoff (NIAID, NIH) for their guidance with the study. We thank Dr. John Dahl, Department of Biology, University of Minnesota Duluth for kindly providing Mycobacterium smegmatis culture. We thank the Departments of Chemistry and Biochemistry at Rowan University and University of Minnesota Duluth as well as the Integrated Biosciences Program. NR 66 TC 1 Z9 1 U1 7 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4020 J9 TETRAHEDRON JI Tetrahedron PD JUN 30 PY 2016 VL 72 IS 26 BP 3795 EP 3801 DI 10.1016/j.tet.2016.03.038 PG 7 WC Chemistry, Organic SC Chemistry GA DO4BB UT WOS:000377725700024 PM 27642196 ER PT J AU Keil, MF Briassoulis, G Stratakis, CA Wu, TJ AF Keil, Margaret F. Briassoulis, George Stratakis, Constantine A. Wu, T. John TI Protein Kinase A and Anxiety-Related Behaviors: A Mini-Review SO FRONTIERS IN ENDOCRINOLOGY LA English DT Review DE protein kinase A; anxiety; knockout mice; regulatory subunit; catalytic subunit ID LONG-TERM POTENTIATION; OBSESSIVE-COMPULSIVE DISORDER; BASOLATERAL AMYGDALA; PREFRONTAL CORTEX; MEMORY CONSOLIDATION; ANATOMICAL LOCATION; KINDLING ELECTRODE; UNTREATED PATIENTS; MAJOR DEPRESSION; BIPOLAR DISORDER AB This review focuses on the anxiety related to cyclic AMP/protein kinase A (PKA) signaling pathway that regulates stress responses. PKA regulates an array of diverse signals that interact with various neurotransmitter systems associated with alertness, mood, and acute and social anxiety-like states. Recent mouse studies support the involvement of the PKA pathway in common neuropsychiatric disorders characterized by heightened activation of the amygdala. The amygdala is critical for adaptive responses leading to fear learning and aberrant fear memory and its heightened activation is widely thought to underpin various anxiety disorders. Stress-induced plasticity within the amygdala is involved in the transition from normal vigilance responses to emotional reactivity, fear over-generalization, and deficits in fear inhibition resulting in pathological anxiety and conditions, such as panic and depression. Human studies of PKA signaling defects also report an increased incidence of psychiatric disorders, including anxiety, depression, bipolar disorder, learning disorders, and attention deficit hyperactivity disorder. We speculate that the PKA system is uniquely suited for selective, molecularly targeted intervention that may be proven effective in anxiolytic therapy. C1 [Keil, Margaret F.; Briassoulis, George; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Briassoulis, George] Univ Crete, Dept Pediat Intens Care, Iraklion, Greece. [Wu, T. John] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. RP Keil, MF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, Bethesda, MD 20892 USA.; Wu, TJ (reprint author), Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. EM keilm@mail.nih.gov; twu@usuhs.edu FU NICHD, NIH [Z01-HD-000642-04]; Uniformed Services University of the Health Sciences; Office of Naval Research; Department of Pediatrics, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece FX The authors thank Dr. D. Omar Larco for critically reading this review. This work was supported by NICHD, NIH intramural project Z01-HD-000642-04 (CS). This study was supported in part by intramural graduate student grant from the Uniformed Services University of the Health Sciences (MK) and Office of Naval Research (TW) and, in part, by the Department of Pediatrics, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece (GB). NR 98 TC 2 Z9 2 U1 4 U2 4 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2392 J9 FRONT ENDOCRINOL JI Front. Endocrinol. PD JUN 29 PY 2016 VL 7 AR 83 DI 10.3389/fendo.2016.00083 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DY7DT UT WOS:000385290500003 PM 27445986 ER PT J AU Panasevich, S Haberg, SE Aamodt, G London, SJ Stigum, H Nystad, W Nafstad, P AF Panasevich, Sviatlana Haberg, Siri Eldevik Aamodt, Geir London, Stephanie J. Stigum, Hein Nystad, Wenche Nafstad, Per TI Association between pregnancy exposure to air pollution and birth weight in selected areas of Norway SO ARCHIVES OF PUBLIC HEALTH LA English DT Article DE Air pollution; Birth weight; MoBa; The Norwegian Mother and Child Cohort Study ID EPIDEMIOLOGIC EVIDENCE; PRETERM BIRTH; OUTCOMES; COHORT; HEALTH; RISK AB Background: Exposure to air pollution has adverse effects on cardiopulmonary health of adults. Exposure to air pollution in pregnancy may affect foetal development. However, the evidence of such effect remains inconsistent. We investigated the effects of exposure to air pollution during pregnancy on birth outcomes. Methods: This study, based within the Norwegian Mother and Child Cohort Study (MoBa), includes 17,533 participants living in the two largest cities in Norway: Oslo and Bergen, and their two surrounding counties: Akershus and Hordaland. Air pollution levels at residential addresses were estimated using land use regression models and back-extrapolated to the period of each pregnancy using continuous monitoring station data. Birth outcomes were birth weight, low birth weight, gestational age, and preterm delivery obtained from the Medical Birth Registry of Norway. Information on lifestyle factors was collected from MoBa questionnaires completed by mothers during pregnancy. Linear and logistic regression models were used to analyse the associations between pregnancy NO2 exposure and birth outcomes. Results: We found a statistically significant negative association between pregnancy exposure to NO2 and birth weight -43.6 (95% CI -55.8 to -31.5) g per 10 mu g/m(3) NO2. However, after adjusting for either area or the combination of parity and maternal weight, no substantive effects of air pollution exposure were evident. Conclusions: Exposure to air pollution during pregnancy was associated with decrease in birth weight, but area-related and lifestyle factors attenuated this association. We found no statistically significant associations of air pollution exposure with gestational age, low birth weight or preterm delivery. C1 [Panasevich, Sviatlana; Haberg, Siri Eldevik; Stigum, Hein; Nystad, Wenche; Nafstad, Per] Norwegian Inst Publ Hlth, Domain Mental & Phys Hlth, Oslo, Norway. [Aamodt, Geir] Norwegian Univ Life Sci, Dept Landscape Architecture & Spatial Plan, As, Norway. [London, Stephanie J.] NIEHS, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Stigum, Hein; Nafstad, Per] Univ Oslo, Fac Med, Dept Gen Practice & Community Med, Oslo, Norway. RP Panasevich, S (reprint author), Norwegian Inst Publ Hlth, Domain Mental & Phys Hlth, Oslo, Norway. EM Sviatlana.Panasevich@fhi.no OI London, Stephanie/0000-0003-4911-5290 FU NIEHS NIH HHS [N01ES75558, Z01 ES049019]; NINDS NIH HHS [U01 NS047537] NR 22 TC 1 Z9 2 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 0778-7367 EI 2049-3258 J9 ARCH PUBLIC HEALTH JI Arch. Public Health PD JUN 29 PY 2016 VL 74 AR 26 DI 10.1186/s13690-016-0138-8 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DS0ZC UT WOS:000380324400001 PM 27358731 ER PT J AU Opendak, M Offit, L Monari, P Schoenfeld, TJ Sonti, AN Cameron, HA Gould, E AF Opendak, Maya Offit, Lily Monari, Patrick Schoenfeld, Timothy J. Sonti, Anup N. Cameron, Heather A. Gould, Elizabeth TI Lasting Adaptations in Social Behavior Produced by Social Disruption and Inhibition of Adult Neurogenesis SO JOURNAL OF NEUROSCIENCE LA English DT Article DE dominance hierarchy; GFAP-TK transgenic rats; hippocampus; neurogenesis; oxytocin; social behavior ID ELEVATED PLUS-MAZE; POSTTRAUMATIC-STRESS-DISORDER; BORN HIPPOCAMPAL-NEURONS; NEURAL STEM-CELLS; DENTATE GYRUS; VICARIOUS TRIAL; MALE-RATS; INSTABILITY STRESS; DECISION-MAKING; ERROR BEHAVIOR AB Research on social instability has focused on its detrimental consequences, but most people are resilient and respond by invoking various coping strategies. To investigate cellular processes underlying such strategies, a dominance hierarchy of rats was formed and then destabilized. Regardless of social position, rats from disrupted hierarchies had fewer new neurons in the hippocampus compared with rats from control cages and those from stable hierarchies. Social disruption produced a preference for familiar over novel conspecifics, a change that did not involve global memory impairments or increased anxiety. Using the neuropeptide oxytocin as a tool to increase neurogenesis in the hippocampus of disrupted rats restored preference for novel conspecifics to predisruption levels. Conversely, reducing the number of new neurons by limited inhibition of adult neurogenesis in naive transgenic GFAP-thymidine kinase rats resulted in social behavior similar to disrupted rats. Together, these results provide novel mechanistic evidence that social disruption shapes behavior in a potentially adaptive way, possibly by reducing adult neurogenesis in the hippocampus. C1 [Opendak, Maya; Offit, Lily; Monari, Patrick; Gould, Elizabeth] Princeton Univ, Princeton Neurosci Inst, Princeton, NJ 08540 USA. [Offit, Lily; Monari, Patrick; Gould, Elizabeth] Princeton Univ, Dept Psychol, Princeton, NJ 08540 USA. [Schoenfeld, Timothy J.; Sonti, Anup N.; Cameron, Heather A.] NIMH, NIH, Bethesda, MD 20892 USA. [Opendak, Maya] Nathan S Kline Inst Psychiat Res, Emot Brain Inst, Orangeburg, NY USA. [Opendak, Maya] NYU, Sch Med, Ctr Child Study, Child & Adolescent Psychiat, New York, NY USA. RP Gould, E (reprint author), Princeton Univ, Princeton Neurosci Inst, Dept Psychol, Princeton, NJ 08540 USA. EM goulde@princeton.edu RI Cameron, Heather/E-6221-2011; OI Cameron, Heather/0000-0002-3245-5777; Opendak, Maya/0000-0003-4334-3188 FU Intramural Program of the National Institutes of Health/National Institute of Mental Health [ZIAMH002784] FX This work was supported in part by the Intramural Program of the National Institutes of Health/National Institute of Mental Health (Grant ZIAMH002784 to H.A.C.). NR 96 TC 2 Z9 2 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 29 PY 2016 VL 36 IS 26 BP 7027 EP 7038 DI 10.1523/JNEUROSCI.4435-15.2016 PG 12 WC Neurosciences SC Neurosciences & Neurology GA DQ2GJ UT WOS:000379020200017 PM 27358459 ER PT J AU Kunimatsu, J Suzuki, TW Tanaka, M AF Kunimatsu, Jun Suzuki, Tomoki W. Tanaka, Masaki TI Implications of Lateral Cerebellum in Proactive Control of Saccades SO JOURNAL OF NEUROSCIENCE LA English DT Article DE anti-saccade; cerebellum; dentate nucleus; inactivation; primate; single neurons ID SUPPLEMENTARY EYE FIELD; PRIMATE GLOBUS-PALLIDUS; NEURONAL-ACTIVITY; DENTATE NUCLEUS; BASAL GANGLIA; TRANSNEURONAL TRANSPORT; SUPERIOR COLLICULUS; COGNITIVE CONTROL; MOTOR; MOVEMENTS AB Although several lines of evidence establish the involvement of the medial and vestibular parts of the cerebellum in the adaptive control of eye movements, the role of the lateral hemisphere of the cerebellum in eye movements remains unclear. Ascending projections from the lateral cerebellum to the frontal and parietal association cortices via the thalamus are consistent with a role of these pathways in higher-order oculomotor control. In support of this, previous functional imaging studies and recent analyses in subjects with cerebellar lesions have indicated a role for the lateral cerebellum in volitional eye movements such as anti-saccades. To elucidate the underlying mechanisms, we recorded from single neurons in the dentate nucleus of the cerebellum in monkeys performing anti-saccade/pro-saccade tasks. We found that neurons in the posterior part of the dentate nucleus showed higher firing rates during the preparation of anti-saccades compared with pro-saccades. When the animals made erroneous saccades to the visual stimuli in the anti-saccade trials, the firing rate during the preparatory period decreased. Furthermore, local inactivation of the recording sites with muscimol moderately increased the proportion of error trials, while successful anti-saccades were more variable and often had shorter latency during inactivation. Thus, our results show that neuronal activity in the cerebellar dentate nucleus causally regulates anti-saccade performance. Neuronal signals from the lateral cerebellum to the frontal cortex might modulate the proactive control signals in the corticobasal ganglia circuitry that inhibit early reactive responses and possibly optimize the speed and accuracy of anti-saccades. C1 [Kunimatsu, Jun; Suzuki, Tomoki W.; Tanaka, Masaki] Hokkaido Univ, Sch Med, Dept Physiol, North 15,West 7, Sapporo, Hokkaido 0608638, Japan. [Kunimatsu, Jun] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Kunimatsu, J; Tanaka, M (reprint author), Hokkaido Univ, Sch Med, Dept Physiol, North 15,West 7, Sapporo, Hokkaido 0608638, Japan. EM kunimatsu.jun@gmail.com; masaki@med.hokudai.ac.jp RI Tanaka, Masaki/D-9199-2011 FU Ministry of Education, Culture, Sports, Science and Technology of Japan; Ministry of Health, Labour and Welfare of Japan; Takeda Science Foundation FX This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Ministry of Health, Labour and Welfare of Japan; and the Takeda Science Foundation. We thank R. Takeya for participating in some recording experiments; T. Mori and A. Hironaka for their assistance with animal care, surgery, and histological work; and M. Suzuki for her administrative help. We also thank M. Takei and Y. Hirata in the Equipment Developing Group, Research Institute for Electronic Science, for manufacturing equipment. NR 65 TC 0 Z9 0 U1 4 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 29 PY 2016 VL 36 IS 26 BP 7066 EP 7074 DI 10.1523/JNEUROSCI.0733-16.2016 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DQ2GJ UT WOS:000379020200020 PM 27358462 ER PT J AU Mikita, N Simonoff, E Pine, DS Goodman, R Artiges, E Banaschewski, T Bokde, AL Bromberg, U Buchel, C Cattrell, A Conrod, PJ Desrivieres, S Flor, H Frouin, V Gallinat, J Garavan, H Heinz, A Ittermann, B Jurk, S Martinot, JL Martinot, MLP Nees, F Orfanos, DP Paus, T Poustka, L Smolka, MN Walter, H Whelan, R Schumann, G Stringaris, A AF Mikita, N. Simonoff, E. Pine, D. S. Goodman, R. Artiges, E. Banaschewski, T. Bokde, A. L. Bromberg, U. Buechel, C. Cattrell, A. Conrod, P. J. Desrivieres, S. Flor, H. Frouin, V. Gallinat, J. Garavan, H. Heinz, A. Ittermann, B. Jurk, S. Martinot, J. L. Martinot, M. L. Paillere Nees, F. Orfanos, D. Papadopoulos Paus, T. Poustka, L. Smolka, M. N. Walter, H. Whelan, R. Schumann, G. Stringaris, A. TI Disentangling the autism - anxiety overlap: fMRI of reward processing in a community-based longitudinal study SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID EVENT-RELATED FMRI; WELL-BEING ASSESSMENT; SPECTRUM DISORDERS; PREFRONTAL CORTEX; PSYCHIATRIC-DISORDERS; RESPONSE-INHIBITION; NEURAL MECHANISMS; COGNITIVE CONTROL; DECISION-MAKING; TWIN SAMPLE AB Up to 40% of youth with autism spectrum disorder (ASD) also suffer from anxiety, and this comorbidity is linked with significant functional impairment. However, the mechanisms of this overlap are poorly understood. We investigated the interplay between ASD traits and anxiety during reward processing, known to be affected in ASD, in a community sample of 1472 adolescents (mean age = 14.4 years) who performed a modified monetary incentive delay task as part of the Imagen project. Blood-oxygen-level dependent (BOLD) responses to reward anticipation and feedback were compared using a 2x2 analysis of variance test (ASD traits: low/high; anxiety symptoms: low/high), controlling for plausible covariates. In addition, we used a longitudinal design to assess whether neural responses during reward processing predicted anxiety at 2-year follow-up. High ASD traits were associated with reduced BOLD responses in dorsal prefrontal regions during reward anticipation and negative feedback. Participants with high anxiety symptoms showed increased lateral prefrontal responses during anticipation, but decreased responses following feedback. Interaction effects revealed that youth with combined ASD traits and anxiety, relative to other youth, showed high right insula activation when anticipating reward, and low right-sided caudate, putamen, medial and lateral prefrontal activations during negative feedback (all clusters P-FWE < 0.05). BOLD activation patterns in the right dorsal cingulate and right medial frontal gyrus predicted new-onset anxiety in participants with high but not low ASD traits. Our results reveal both quantitatively enhanced and qualitatively distinct neural correlates underlying the comorbidity between ASD traits and anxiety. Specific neural responses during reward processing may represent a risk factor for developing anxiety in ASD youth. C1 [Mikita, N.; Simonoff, E.; Goodman, R.; Stringaris, A.] Kings Coll London, Dept Child & Adolescent Psychiat, Inst Psychiat Psychol & Neurosci, London, England. [Simonoff, E.] Kings Coll London, NIHR Biomed Res Ctr, London, England. [Simonoff, E.] Kings Coll London, Dementia Unit South London, London, England. [Simonoff, E.] Kings Coll London, Maudsley NHS Fdn Trust, London, England. [Simonoff, E.] Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England. [Pine, D. S.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. [Artiges, E.; Martinot, J. L.; Martinot, M. L. Paillere] Serv Hosp Freder Joliot, INSERM, Unit Neuroimaging & Psychiat 1000, Orsay, France. [Artiges, E.; Martinot, J. L.; Martinot, M. L. Paillere] Univ Paris 11, Orsay, France. [Artiges, E.; Martinot, J. L.; Martinot, M. L. Paillere] Univ Paris 05, Sorbonne Paris Cite, Paris, France. [Artiges, E.] Orsay Hosp, Dept Psychiat, Orsay, France. [Banaschewski, T.] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Child & Adolescent Psychiat & Psychot, Mannheim, Germany. [Bokde, A. L.] Trinity Coll Dublin, Discipline Psychiat, Sch Med, Dublin, Ireland. [Bokde, A. L.] Trinity Coll Dublin, Trinity Coll Inst Neurosci, Dublin, Ireland. [Bromberg, U.; Buechel, C.] Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany. [Cattrell, A.; Desrivieres, S.; Schumann, G.] Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC, Social Genet & Dev Psychiat Ctr, London, England. [Conrod, P. J.] Univ Montreal, CHU Ste Justine Hosp, Dept Psychiat, Montreal, PQ, Canada. [Conrod, P. J.] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Psychol Med & Psychiat, London, England. [Flor, H.; Nees, F.] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Cognit & Clin Neurosci, Mannheim, Germany. [Frouin, V.; Orfanos, D. Papadopoulos] CEA Saclay, Commissariat Energie Atom, Neurospin, Saclay Ctr, Paris, France. [Gallinat, J.] Univ Med Ctr Hamburg Eppendorf, Dept Psychiat & Psychotherapy, Hamburg, Germany. [Garavan, H.] Univ Vermont, Dept Psychiat, Burlington, VT USA. [Garavan, H.] Univ Vermont, Dept Psychol, Burlington, VT 05405 USA. [Heinz, A.; Walter, H.] Charite, Dept Psychiat & Psychotherapy, Campus Charite Mitte, Berlin, Germany. [Ittermann, B.] Phys Tech Bundesanstalt, Braunschweig, Germany. [Jurk, S.; Smolka, M. N.] Tech Univ Dresden, Dept Psychiat & Neuroimaging Ctr, Dresden, Germany. [Martinot, J. L.; Martinot, M. L. Paillere] Cochin Hosp, AP HP, Dept Adolescent Psychopathol & Med, Maison Solenn, Paris, France. [Paus, T.] Baycrest, Rotman Res Inst, Toronto, ON, Canada. [Paus, T.] Child Mind Inst, New York, NY USA. [Paus, T.] Univ Toronto, Dept Psychol, Toronto, ON, Canada. [Paus, T.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Poustka, L.] Med Univ Vienna, Dept Child & Adolescent Psychiat & Psychotherapy, Vienna, Austria. [Whelan, R.] Univ Coll Dublin, Dept Psychol, Dublin, Ireland. RP Mikita, N (reprint author), Kings Coll London, Dept Child & Adolescent Psychiat, Inst Psychiat Psychol & Neurosci, PO85, Crespigny Pk, London SE5 8AF, England. EM nina.mikita@kcl.ac.uk RI Poustka, Luise/D-9299-2017; OI Flor, Herta/0000-0003-4809-5398 FU European Union-funded FP6 Integrated Project IMAGEN (reinforcement-related behaviour in normal brain function and psychopathology) [LSHM-CT- 2007-037286]; FP7 project IMAGE-MEND (IMAging GEnetics for MENtal Disorders) [602450]; FP7 project AGGRESSOTYPE [602805]; FP7 project MATRICS [603016]; Innovative Medicine Initiative Project EU-AIMS [115300-2]; Medical Research Council Grants 'Developmental pathways into adolescent substance abuse' [93558]; Consortium on Vulnerability to Externalizing Disorders and Addictions (c-VEDA) [MR/N000390/1]; Swedish funding agency VR; Swedish funding agency FORTE; Swedish funding agency FORMAS; Medical Research Council; Wellcome Trust (Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK); National Institute for Health Research (NIHR) Biomedical Research Centre at South London; Maudsley NHS Foundation Trust and King's College London; Bundesministeriumfur Bildung und Forschung (BMBF Forschungsnetz AERIAL) [01GS08152, 01EV0711, eMED SysAlc01ZX1311A]; Deutsche Forschungsgemeinschaft (DFG) [SM 80/7-1, SM 80/7-2, SFB 940/1]; ANR [AF12-NEUR0008-01-WM2NA, ANR-12-SAMA-0004]; Fondation de France; Fondation pour la Recherche Medicale; Mission Interministerielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA); Assistance-Publique-Hopitaux-de-Paris; INSERM (interface grant); Paris Sud University IDEX; National Institutes of Health, USA (Axon, Testosterone and Mental Health during Adolescence) [RO1 MH085772-01A1]; NIH Consortium grant [U54 EB020403]; cross-NIH alliance; Wellcome Trust FX This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (reinforcement-related behaviour in normal brain function and psychopathology) (LSHM-CT- 2007-037286), the FP7 projects IMAGE-MEND (602450; IMAging GEnetics for MENtal Disorders), AGGRESSOTYPE (602805) and MATRICS (603016), the Innovative Medicine Initiative Project EU-AIMS (115300-2), the Medical Research Council Grants 'Developmental pathways into adolescent substance abuse' (93558) and Consortium on Vulnerability to Externalizing Disorders and Addictions (c-VEDA) (MR/N000390/1), the Swedish funding agencies VR, FORTE and FORMAS, the Medical Research Council and the Wellcome Trust (Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK), the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, the Bundesministeriumfur Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; eMED SysAlc01ZX1311A; Forschungsnetz AERIAL) and the Deutsche Forschungsgemeinschaft (DFG grants SM 80/7-1, SM 80/7-2, SFB 940/1). Further support was provided by grants from ANR (project AF12-NEUR0008-01-WM2NA, and ANR-12-SAMA-0004), the Fondation de France, the Fondation pour la Recherche Medicale, the Mission Interministerielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-Hopitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012, the National Institutes of Health, USA (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01A1), and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence. Dr Stringaris gratefully acknowledges funding from the Wellcome Trust. NR 88 TC 0 Z9 0 U1 20 U2 20 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD JUN 28 PY 2016 VL 6 AR e845 DI 10.1038/tp.2016.107 PG 10 WC Psychiatry SC Psychiatry GA DW1QW UT WOS:000383418700002 PM 27351599 ER PT J AU Mena, I Nelson, MI Quezada-Monroy, F Dutta, J Cortes-Fernandez, R Lara-Puente, JH Castro-Peralta, F Cunha, LF Trovao, NS Lozano-Dubernard, B Rambaut, A van Bakel, H Garcia-Sastre, A AF Mena, Ignacio Nelson, Martha I. Quezada-Monroy, Francisco Dutta, Jayeeta Cortes-Fernandez, Refugio Horacio Lara-Puente, J. Castro-Peralta, Felipa Cunha, Luis F. Trovao, Nidia S. Lozano-Dubernard, Bernardo Rambaut, Andrew van Bakel, Harm Garcia-Sastre, Adolfo TI Origins of the 2009 H1N1 influenza pandemic in swine in Mexico SO ELIFE LA English DT Article ID A VIRUSES; TRANSMISSION DYNAMICS; UNITED-STATES; EVOLUTION; ALIGNMENT; FERRETS; PIGS; HEMAGGLUTININ; ESTABLISHMENT; REASSORTMENT AB Asia is considered an important source of influenza A virus (IAV) pandemics, owing to large, diverse viral reservoirs in poultry and swine. However, the zoonotic origins of the 2009 A/H1N1 influenza pandemic virus (pdmH1N1) remain unclear, due to conflicting evidence from swine and humans. There is strong evidence that the first human outbreak of pdmH1N1 occurred in Mexico in early 2009. However, no related swine viruses have been detected in Mexico or any part of the Americas, and to date the most closely related ancestor viruses were identified in Asian swine. Here, we use 58 new whole-genome sequences from IAVs collected in Mexican swine to establish that the swine virus responsible for the 2009 pandemic evolved in central Mexico. This finding highlights how the 2009 pandemic arose from a region not considered a pandemic risk, owing to an expansion of IAV diversity in swine resulting from long-distance live swine trade. C1 [Mena, Ignacio; Cunha, Luis F.; Garcia-Sastre, Adolfo] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA. [Mena, Ignacio; Trovao, Nidia S.; Garcia-Sastre, Adolfo] Icahn Sch Med Mt Sinai, Global Hlth & Emerging Pathogens Inst, New York, NY 10029 USA. [Nelson, Martha I.; Trovao, Nidia S.; Rambaut, Andrew] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Quezada-Monroy, Francisco; Cortes-Fernandez, Refugio; Horacio Lara-Puente, J.; Castro-Peralta, Felipa; Lozano-Dubernard, Bernardo] Lab Avi Mex, Mexico City, DF, Mexico. [Dutta, Jayeeta; Cunha, Luis F.; van Bakel, Harm] Icahn Sch Med Mt Sinai, Genet & Genom Sci, New York, NY 10029 USA. [Trovao, Nidia S.] Univ Leuven, Rega Inst, Dept Microbiol & Immunol, Leuven, Belgium. [Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Rambaut, Andrew] Univ Edinburgh, Ctr Immunol Infect & Evolut, Edinburgh, Midlothian, Scotland. [Garcia-Sastre, Adolfo] Icahn Sch Med Mt Sinai, Div Infect Dis, Dept Med, New York, NY 10029 USA. RP Garcia-Sastre, A (reprint author), Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA.; Garcia-Sastre, A (reprint author), Icahn Sch Med Mt Sinai, Global Hlth & Emerging Pathogens Inst, New York, NY 10029 USA.; Garcia-Sastre, A (reprint author), Icahn Sch Med Mt Sinai, Div Infect Dis, Dept Med, New York, NY 10029 USA. EM adolfo.garcia-sastre@mssm.edu OI Mena, Ignacio/0000-0001-5464-7086; Garcia-Sastre, Adolfo/0000-0002-6551-1827; Sequeira Trovao, Nidia/0000-0002-2106-1166 FU National Institutes of Health Centers of Excellence for Influenza Research and Surveillance [HHSN272201400008C]; Fogarty International Center Multinational Influenza Seasonal Mortality Study FX National Institutes of Health Centers of Excellence for Influenza Research and Surveillance, Contract No. HHSN272201400008C Adolfo Garcia-Sastre; Fogarty International Center Multinational Influenza Seasonal Mortality Study Martha I Nelson; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 55 TC 0 Z9 0 U1 5 U2 10 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JUN 28 PY 2016 VL 5 AR e16777 DI 10.7554/eLife.16777 PG 21 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DS6VI UT WOS:000380920700001 ER PT J AU Kim, G Levine, RL AF Kim, Geumsoo Levine, Rodney L. TI A Methionine Residue Promotes Hyperoxidation of the Catalytic Cysteine of Mouse Methionine Sulfoxide Reductase A SO BIOCHEMISTRY LA English DT Article ID ESCHERICHIA-COLI; OXIDATIVE DAMAGE; ACTIVE-SITE; PROTEIN; MECHANISM; INTERMEDIATE; BIOCHEMISTRY; ENZYMES; SULFUR; ROLES AB Methionine sulfoxide reductase A (msrA) reduces methionine sulfoxide in proteins back to methionine. Its, catalytic cysteine (Cys72-SH) has a low pK(a) that facilitates oxidation by methionine sulfoxide to cysteine sulfenic acid. If the catalytic cycle proceeds efficiently, the sulfenic acid is reduced back to cysteine at the expense of thioredoxin. However, the sulfenic acid is vulnerable to "irreversible" oxidation to cysteine sulfinic acid that inactivates msrA (hyperoxidation). We observed that human msrA is resistant to hyperoxidation while mouse msrA is readily hyperoxidized by micromolar concentrations of hydrogen peroxide. We investigated the basis of this difference in susceptibility to hyperoxidation and established that it is controlled by the presence or absence of a Met residue in the carboxyl-terminal domain of the enzyme, Met229. This residue is Val in human msrA, and when it was mutated to Met, human msrA became sensitive to hyperoxidation. Conversely, mouse msrA was rendered insensitive to hyperoxidation when Met229 was mutated to Val or one of five other residues. Positioning of the methionine at residue 229 is not critical, as hyperoxidation occurred as long as the methionine was located within the group of 14 carboxyl-terminal residues. The carboxyl domain of msrA is known to be flexible and to have access to the active site, and Met residues are known to form stable, noncovalent bonds with aromatic residues through interaction of the sulfur atom with the aromatic ring. We propose that Met229 forms-such a bond with Trp74 at the active site, preventing formation of a protective sulfenylamide with Cys72 sulfenic acid. As a consequence, the sulfenic acid is available for facile, irreversible oxidation to cysteine sulfinic acid. C1 [Kim, Geumsoo; Levine, Rodney L.] NHLBI, Biochem Lab, Bldg 3, Bethesda, MD 20892 USA. RP Levine, RL (reprint author), NIH, Bldg 50,Room 2351, Bethesda, MD 20892 USA. EM rlevine@nih.gov RI Levine, Rodney/D-9885-2011 FU Intramural Research Division of the National Heart, Lung, and Blood Institute [ZIA HL000225] FX This research was supported by the Intramural Research Division of the National Heart, Lung, and Blood Institute (ZIA HL000225). NR 32 TC 0 Z9 0 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 28 PY 2016 VL 55 IS 25 BP 3586 EP 3593 DI 10.1021/acs.biochem.6b00180 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DQ1PS UT WOS:000378973500010 PM 27259041 ER PT J AU Wang, YB Hersheson, J Lopez, D Hammer, M Liu, Y Lee, KH Pinto, V Seinfeld, J Wiethoff, S Sun, JD Amouri, R Hentati, F Baudry, N Tran, J Singleton, AB Coutelier, M Brice, A Stevanin, G Durr, A Bi, XN Houlden, H Baudry, M AF Wang, Yubin Hersheson, Joshua Lopez, Dulce Hammer, Monia Liu, Yan Lee, Ka-Hung Pinto, Vanessa Seinfeld, Jeff Wiethoff, Sarah Sun, Jiandong Amouri, Rim Hentati, Faycal Baudry, Neema Tran, Jennifer Singleton, Andrew B. Coutelier, Marie Brice, Alexis Stevanin, Giovanni Durr, Alexandra Bi, Xiaoning Houlden, Henry Baudry, Michel TI Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans SO CELL REPORTS LA English DT Article ID D-ASPARTATE RECEPTORS; GRANULE CELLS; SYNAPTIC PLASTICITY; RAT-BRAIN; TUMOR-SUPPRESSOR; DEFICIENT MICE; MUTANT MOUSE; MU-CALPAIN; ACTIVATION; SURVIVAL AB A CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous or heterozygous CAPN1-null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knockout (KO) mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1-mediated cleavage of PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans. C1 [Wang, Yubin; Lopez, Dulce; Liu, Yan; Lee, Ka-Hung; Seinfeld, Jeff; Baudry, Neema; Tran, Jennifer; Baudry, Michel] Western Univ Hlth Sci, Grad Coll Biomed Sci, Pomona, CA 91766 USA. [Pinto, Vanessa; Sun, Jiandong; Bi, Xiaoning] Western Univ Hlth Sci, Coll Osteopath Med Pacific, Pomona, CA 91766 USA. [Hersheson, Joshua; Wiethoff, Sarah; Houlden, Henry] Natl Hosp Neurol & Neurosurg, Queen Sq, London WC1N 3BG, England. [Hersheson, Joshua; Wiethoff, Sarah; Houlden, Henry] UCL Inst Neurol, Queen Sq, London WC1N 3BG, England. [Wiethoff, Sarah] Univ Tubingen, Ctr Neurol, D-72076 Tubingen, Germany. [Wiethoff, Sarah] Univ Tubingen, Hertie Inst Clin Brain Res, D-72076 Tubingen, Germany. [Hammer, Monia; Amouri, Rim; Hentati, Faycal] Natl Inst Neurol, Dept Mol Neurobiol & Neuropathol, Tunis 1007, Tunisia. [Hammer, Monia; Singleton, Andrew B.] NIH, Neurogenet Lab, Bldg 10, Bethesda, MD 20892 USA. [Coutelier, Marie; Brice, Alexis; Stevanin, Giovanni; Durr, Alexandra] Univ Paris 06, INSERM U1127, CNRS UMR 7225, Sorbonne Univ,Inst Cerveau & Moelle Epiniere,UMRS, F-75013 Paris, France. [Coutelier, Marie] Catholic Univ Louvain, Lab Human Mol Genet, de Duve Inst, B-1200 Brussels, Belgium. [Coutelier, Marie; Stevanin, Giovanni] Paris Sci & Lettres PSL Res Univ, EPHE, F-75013 Paris, France. [Brice, Alexis; Stevanin, Giovanni; Durr, Alexandra] Hop La Pitie Salpetriere, AP HP, Ctr Reference Neurogenet, F-75013 Paris, France. RP Baudry, M (reprint author), Western Univ Hlth Sci, Grad Coll Biomed Sci, Pomona, CA 91766 USA.; Houlden, H (reprint author), Natl Hosp Neurol & Neurosurg, Queen Sq, London WC1N 3BG, England. EM h.houlden@ucl.ac.uk; mbaudry@westernu.edu RI Houlden, Henry/C-1532-2008; OI Houlden, Henry/0000-0002-2866-7777; Coutelier, Marie/0000-0002-0261-7210 FU NINDS [P01NS045260-01]; Medical Research Council UK; Brain Research Trust; Wellcome Trust; NIHR UCL/UCLH BRC; Agence Nationale de la Recherche (ANR); Verum Foundation; patient association Connaitre les Syndromes Cerebelleux; Roger de Spoelberg Foundation; European Union; program Investissements d'avenir [ANR-10-IAIHU-06]; Western University of Health Sciences; Daljit and Elaine Sarkaria Chair; Fond National de la Recherche Scientifique (aspirant FNRS) FX This work was supported by grant P01NS045260-01 from NINDS (PI: Dr. C.M. Gall), the Medical Research Council UK, Brain Research Trust, Wellcome Trust, NIHR UCL/UCLH BRC, the Agence Nationale de la Recherche (ANR; to G.S.), the Verum Foundation (to G.S. and A.B.), the patient association Connaitre les Syndromes Cerebelleux (CSC; to G.S.), the Roger de Spoelberg Foundation (to A.B.), and the European Union (Omics call: NEUROMICS, to A.B. and A.D.) and benefited from the program Investissements d'avenir ANR-10-IAIHU-06 (to the ICM Institute). The authors want to thank Western University of Health Sciences for the financial support to M.B. X.B. is also supported by funds from the Daljit and Elaine Sarkaria Chair. M.C. was the recipient of a fellowship from the Fond National de la Recherche Scientifique (aspirant FNRS). The authors are grateful to Claire Sophie Davoine and to the DNA and cell biobank of the ICM institute for their technical assistance. NR 45 TC 5 Z9 5 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUN 28 PY 2016 VL 16 IS 1 BP 79 EP 91 DI 10.1016/j.celrep.2016.05.044 PG 13 WC Cell Biology SC Cell Biology GA DQ1GY UT WOS:000378950700009 PM 27320912 ER PT J AU Zaaijer, S Shaikh, N Nageshan, RK Cooper, JP AF Zaaijer, Sophie Shaikh, Nadeem Nageshan, Rishi Kumar Cooper, Julia Promisel TI Rif1 Regulates the Fate of DNA Entanglements during Mitosis SO CELL REPORTS LA English DT Article ID ULTRAFINE ANAPHASE BRIDGES; PROTEIN PHOSPHATASE 1; FISSION YEAST; DYSFUNCTIONAL TELOMERES; CHROMOSOME SEGREGATION; REPLICATION STRESS; GLOBAL REGULATOR; TAZ1; CHECKPOINT; 53BP1 AB Clearance of entangled DNA from the anaphase mid-region must accurately proceed in order for chromosomes to segregate with high fidelity. Loss of Taz1 (fission yeast ortholog of human TRF1/TRF2) leads to stalled telomeric replication forks that trigger telomeric entanglements; the resolution of these entanglements fails at <= 20 degrees C. Here, we investigate these entanglements and their promotion by the conserved replication/repair protein Rif1. Rif1 plays no role in taz1 Delta fork stalling. Rather, Rif1 localizes to the anaphase mid-region and regulates the resolution of persisting DNA structures. This anaphase role for Rif1 is genetically separate from the role of Rif1 in S/G2, though both roles require binding to PP1 phosphatase, implying spatially and temporally distinct Rif1-regulated phosphatase substrates. Rif1 thus acts as a double-edged sword. Although it inhibits the resolution of taz1 Delta telomere entanglements, it promotes the resolution of non-telomeric ultrafine anaphase bridges at <= 20 degrees C We suggest a unifying model for Rif1's seemingly diverse roles in chromosome segregation in eukaryotes. C1 [Zaaijer, Sophie; Shaikh, Nadeem; Nageshan, Rishi Kumar; Cooper, Julia Promisel] NCI, Biochem & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Zaaijer, Sophie] New York Genome Ctr, 101 Ave Amer, New York, NY 10013 USA. RP Cooper, JP (reprint author), NCI, Biochem & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM julie.cooper@nih.gov FU Cancer Research UK; National Cancer Institute FX We thank all members of the J.P.C. lab for useful discussion and experimental help, and special thanks for advice go to our former lab members Jessica Greenwood and Ofer Rog. We thank Alexander Kelly for valuable discussion and Alessandro Bianchi and Miguel Godinho Ferreira for kind gifts of reagents and advice. This work was supported by Cancer Research UK and the National Cancer Institute. NR 45 TC 2 Z9 2 U1 3 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUN 28 PY 2016 VL 16 IS 1 BP 148 EP 160 DI 10.1016/j.celrep.2016.05.077 PG 13 WC Cell Biology SC Cell Biology GA DQ1GY UT WOS:000378950700014 PM 27320927 ER PT J AU Lu, HM Shamanna, RA Keijzers, G Anand, R Rasmussen, LJ Cejka, P Croteau, DL Bohr, VA AF Lu, Huiming Shamanna, Raghavendra A. Keijzers, Guido Anand, Roopesh Rasmussen, Lene Juel Cejka, Petr Croteau, Deborah L. Bohr, Vilhelm A. TI RECQL4 Promotes DNA End Resection in Repair of DNA Double-Strand Breaks SO CELL REPORTS LA English DT Article ID ROTHMUND-THOMSON-SYNDROME; HOMOLOGOUS RECOMBINATION; PATHWAY CHOICE; MRE11-RAD50-NBS1 COMPLEX; SYNDROME PROTEIN; MAMMALIAN-CELLS; MRE11 NUCLEASE; EXONUCLEASE 1; HELICASE; REPLICATION AB The RecQ helicase RECQL4, mutated in Rothmund-Thomson syndrome, regulates genome stability, aging, and cancer. Here, we identify a crucial role for RECQL4 in DNA end resection, which is the initial and an essential step of homologous recombination (HR)-dependent DNA double-strand break repair (DSBR). Depletion of RECQL4 severely reduces HR-mediated repair and 50 end resection in vivo. RECQL4 physically interacts with MRE11-RAD50-NBS1 (MRN), which senses DSBs and initiates DNA end resection with CtIP. The MRE11 exonuclease regulates the retention of RECQL4 at laser-induced DSBs. RECQL4 also directly interacts with CtIP via its N-terminal domain and promotes CtIP recruitment to the MRN complex at DSBs. Moreover, inactivation of RECQL4's helicase activity impairs DNA end processing and HR-dependent DSBR without affecting its interaction with MRE11 and CtIP, suggesting an important role for RECQL4's unwinding activity in the process. Thus, we report that RECQL4 is an important participant in HR-dependent DSBR. C1 [Lu, Huiming; Shamanna, Raghavendra A.; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Keijzers, Guido; Rasmussen, Lene Juel; Bohr, Vilhelm A.] Univ Copenhagen, Ctr Hlth Aging, DK-2200 Copenhagen, Denmark. [Keijzers, Guido; Rasmussen, Lene Juel; Bohr, Vilhelm A.] Univ Copenhagen, Dept Cellular & Mol Med, DK-2200 Copenhagen, Denmark. [Anand, Roopesh; Cejka, Petr] Univ Zurich, Inst Mol Canc Res, Winterthurerstr 190, CH-8057 Zurich, Switzerland. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA.; Bohr, VA (reprint author), Univ Copenhagen, Ctr Hlth Aging, DK-2200 Copenhagen, Denmark.; Bohr, VA (reprint author), Univ Copenhagen, Dept Cellular & Mol Med, DK-2200 Copenhagen, Denmark. EM vbohr@nih.gov FU Intramural Research Program of the NIH, National Institute on Aging FX AID-DIVA U2OS is under MTA between Dr. Gaelle Legube and NIA. We thank Dr. Xiaofan Wang for DR-GFP U2OS, Drs. Dik van Gent and Roland Kanaar for YFP-MRE11 plasmid, Dr. Marc Wold for the GFP-RPA plasmids, Dr. Binghui Shen for FLAG-DNA2 plasmid, Dr. Tomasz Kulikowicz and Christopher Dunn for RECQL4 protein, Tomasz Kulikowicz and Alfred May for IR operation, and Drs. Morten Scheibye-Knudsen and Jaya Sarkar for their critical comments. This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. NR 56 TC 3 Z9 3 U1 4 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUN 28 PY 2016 VL 16 IS 1 BP 161 EP 173 DI 10.1016/j.celrep.2016.05.079 PG 13 WC Cell Biology SC Cell Biology GA DQ1GY UT WOS:000378950700015 PM 27320928 ER PT J AU Savidis, G McDougall, WM Meraner, P Perreira, JM Portmann, JM Trincucci, G John, SP Aker, AM Renzette, N Robbins, DR Guo, ZR Green, S Kowalik, TF Brass, AL AF Savidis, George McDougall, William M. Meraner, Paul Perreira, Jill M. Portmann, Jocelyn M. Trincucci, Gaia John, Sinu P. Aker, Aaron M. Renzette, Nicholas Robbins, Douglas R. Guo, Zhiru Green, Sharone Kowalik, Timothy F. Brass, Abraham L. TI Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics SO CELL REPORTS LA English DT Article ID PHOSPHATIDYLSERINE RECEPTORS; ENDOPLASMIC-RETICULUM; GENES; CELLS; REPLICATION; INFECTION; CRISPR-CAS9; SCREEN; ENTRY; RNAI AB The flaviviruses dengue virus (DENV) and Zika virus (ZIKV) are severe health threats with rapidly expanding ranges. To identify the host cell dependencies of DENV and ZIKV, we completed orthologous functional genomic screens using RNAi and CRISPR/Cas9 approaches. The screens recovered the ZIKV entry factor AXL as well as multiple host factors involved in endocytosis (RAB5C and RABGEF), heparin sulfation (NDST1 and EXT1), and transmembrane protein processing and maturation, including the endoplasmic reticulum membrane complex (EMC). We find that both flaviviruses require the EMC for their early stages of infection. Together, these studies generate a high-confidence, systems-wide view of human-flavivirus interactions and provide insights into the role of the EMC in flavivirus replication. C1 [Savidis, George; McDougall, William M.; Meraner, Paul; Perreira, Jill M.; Portmann, Jocelyn M.; Trincucci, Gaia; Aker, Aaron M.; Renzette, Nicholas; Robbins, Douglas R.; Kowalik, Timothy F.; Brass, Abraham L.] Univ Massachusetts Med, Dept Microbiol & Physiol Syst MaPS, Worcester, MA 01655 USA. [John, Sinu P.] NIAID, Signaling Syst Unit, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Guo, Zhiru; Green, Sharone] Univ Massachusetts, Sch Med, Dept Med, Div Infect Dis & Immunol, Worcester, MA 01655 USA. [Brass, Abraham L.] Univ Massachusetts, Sch Med, Dept Med, Div Gastroenterol, Worcester, MA 01655 USA. RP Brass, AL (reprint author), Univ Massachusetts Med, Dept Microbiol & Physiol Syst MaPS, Worcester, MA 01655 USA.; Brass, AL (reprint author), Univ Massachusetts, Sch Med, Dept Med, Div Gastroenterol, Worcester, MA 01655 USA. EM abraham.brass@umassmed.edu FU Burroughs Wellcome Foundation; NIAID, NIH [HHSN272200900041C]; UMMS Center for Clinical and Translational Science; Bill and Melinda Gates Foundation FX We thank R.H. Scheuermann and B. Pickett (J. Craig Venter Institute), the University of Maryland Medical System (UMMS; R. Fish, L. Benson, and J. Barrett), ICCB-L (C. Shamu, J. Smith, S. Rudnicki, S. Johnston, K. Rudnicki, and D. Wrobel), and T. Soellner of Heidelberg University for help and inspiration. This work was supported by an Investigators in the Pathogenesis of Infectious Disease award from the Burroughs Wellcome Foundation to A. L. B. and a subcontract to A. L. B. from contract HHSN272200900041C to Northrup Grumman Corporation from NIAID, NIH. A.L.B. is grateful to the UMMS Center for Clinical and Translational Science and to the Bill and Melinda Gates Foundation for their support. NR 48 TC 23 Z9 23 U1 14 U2 26 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUN 28 PY 2016 VL 16 IS 1 BP 232 EP 246 DI 10.1016/j.celrep.2016.06.028 PG 15 WC Cell Biology SC Cell Biology GA DQ1GY UT WOS:000378950700021 PM 27342126 ER PT J AU Allott, EH Geradts, J Sun, XZ Cohen, SM Zirpoli, GR Khoury, T Bshara, W Chen, MJ Sherman, ME Palmer, JR Ambrosone, CB Olshan, AF Troester, MA AF Allott, Emma H. Geradts, Joseph Sun, Xuezheng Cohen, Stephanie M. Zirpoli, Gary R. Khoury, Thaer Bshara, Wiam Chen, Mengjie Sherman, Mark E. Palmer, Julie R. Ambrosone, Christine B. Olshan, Andrew F. Troester, Melissa A. TI Intratumoral heterogeneity as a source of discordance in breast cancer biomarker classification SO BREAST CANCER RESEARCH LA English DT Article DE Automated algorithm; Digital pathology; Discordance; Estrogen receptor; HER2; Immunohistochemistry; Intratumoral heterogeneity; Progesterone receptor; Tissue microarray ID IN-SITU HYBRIDIZATION; ESTROGEN-RECEPTOR; PROGESTERONE-RECEPTORS; FORMALIN FIXATION; AMBER CONSORTIUM; IMMUNOHISTOCHEMISTRY; HER2; CARCINOMAS; SPECIMENS; TUMOR AB Background: Spatial heterogeneity in biomarker expression may impact breast cancer classification. The aims of this study were to estimate the frequency of spatial heterogeneity in biomarker expression within tumors, to identify technical and biological factors contributing to spatial heterogeneity, and to examine the impact of discordant biomarker status within tumors on clinical record agreement. Methods: Tissue microarrays (TMAs) were constructed using two to four cores (1.0 mm) for each of 1085 invasive breast cancers from the Carolina Breast Cancer Study, which is part of the AMBER Consortium. Immunohistochemical staining for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) was quantified using automated digital imaging analysis. The biomarker status for each core and for each case was assigned using clinical thresholds. Cases with core-to-core biomarker discordance were manually reviewed to distinguish intratumoral biomarker heterogeneity from misclassification of biomarker status by the automated algorithm. The impact of core-to-core biomarker discordance on case-level agreement between TMAs and the clinical record was evaluated. Results: On the basis of automated analysis, discordant biomarker status between TMA cores occurred in 9 %, 16 %, and 18 % of cases for ER, PR, and HER2, respectively. Misclassification of benign epithelium and/or ductal carcinoma in situ as invasive carcinoma by the automated algorithm was implicated in discordance among cores. However, manual review of discordant cases confirmed spatial heterogeneity as a source of discordant biomarker status between cores in 2 %, 7 %, and 8 % of cases for ER, PR, and HER2, respectively. Overall, agreement between TMA and clinical record was high for ER (94 %), PR (89 %), and HER2 (88 %), but it was reduced in cases with core-to-core discordance (agreement 70 % for ER, 61 % for PR, and 57 % for HER2). Conclusions: Intratumoral biomarker heterogeneity may impact breast cancer classification accuracy, with implications for clinical management. Both manually confirmed biomarker heterogeneity and misclassification of biomarker status by automated image analysis contribute to discordant biomarker status between TMA cores. Given that manually confirmed heterogeneity is uncommon (<10 % of cases), large studies are needed to study the impact of heterogeneous biomarker expression on breast cancer classification and outcomes. C1 [Allott, Emma H.; Cohen, Stephanie M.; Olshan, Andrew F.; Troester, Melissa A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Allott, Emma H.; Sun, Xuezheng; Olshan, Andrew F.; Troester, Melissa A.] Univ N Carolina, Dept Epidemiol, 135 Dauer Dr,CB 7435, Chapel Hill, NC 27599 USA. [Geradts, Joseph] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Zirpoli, Gary R.; Ambrosone, Christine B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Khoury, Thaer; Bshara, Wiam] Roswell Pk Canc Inst, Dept Pathol, Buffalo, NY 14263 USA. [Chen, Mengjie] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Chen, Mengjie] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Sherman, Mark E.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Palmer, Julie R.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. RP Troester, MA (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA.; Troester, MA (reprint author), Univ N Carolina, Dept Epidemiol, 135 Dauer Dr,CB 7435, Chapel Hill, NC 27599 USA. EM troester@unc.edu FU National Cancer Institute [5P01CA151135-04, P50-CA058223, U01 CA179715, 3P30CA016086]; University Cancer Research Fund at the University of North Carolina at Chapel Hill; Breast Cancer Research Foundation; American Institute for Cancer Research; University of North Carolina at Chapel Hill University Cancer Research Fund FX This work was supported by the National Cancer Institute (grant 5P01CA151135-04 to the AMBER Consortium: JG, TK, WB, GRZ, JRP, CBA, AFO, and MAT; grant P50-CA058223 to SPORE in Breast Cancer: MAT and AFO; grant U01 CA179715 to MAT), by the University Cancer Research Fund at the University of North Carolina at Chapel Hill (EHA, AFO, and MAT), by the Breast Cancer Research Foundation (CBA), and by the American Institute for Cancer Research (EHA). The Translational Pathology Laboratory (SMC) is supported in part by grants from the National Cancer Institute (3P30CA016086) and the University of North Carolina at Chapel Hill University Cancer Research Fund. NR 33 TC 2 Z9 2 U1 2 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD JUN 28 PY 2016 VL 18 AR 68 DI 10.1186/s13058-016-0725-1 PG 11 WC Oncology SC Oncology GA DQ0OH UT WOS:000378898600002 PM 27349894 ER PT J AU Yang, BY Hagberg, KW Chen, J Sahasrabuddhe, VV Graubard, BI Jick, S McGlynn, KA AF Yang, Baiyu Hagberg, Katrina Wilcox Chen, Jie Sahasrabuddhe, Vikrant V. Graubard, Barry I. Jick, Susan McGlynn, Katherine A. TI Associations of antibiotic use with risk of primary liver cancer in the Clinical Practice Research Datalink SO BRITISH JOURNAL OF CANCER LA English DT Article DE antibiotics; liver cancer; medical records database; case-control study ID PRACTICE RESEARCH DATABASE; INFECTIONS; MICROBIOTA AB Background: Use of antibiotics could alter human microbiota composition and decrease bacterial diversity. Such microbial dysbiosis may have implications in hepatocarcinogenesis; however, the association between antibiotic use and liver cancer risk has been minimally examined in humans. Methods: We performed a nested case-control study (1195 primary liver cancer cases and 4640 matched controls) within the United Kingdom's Clinical Practice Research Datalink. Antibiotic use was obtained from prescription records. Multivariableadjusted odds ratio (OR) and 95% confidence interval (CI) were estimated using conditional logistic regression. Results: Ever-use of prescription antibiotics was associated with a slightly increased risk of liver cancer, compared to non-use (OR = 1.22, 95% CI = 1.03 = 1.45). However, there was no clear dose-response relationship by the number of prescriptions or cumulative dose of antibiotic use, suggesting a non-causal association. Conclusions: Our results do not support a role of antibiotic use in liver cancer development. C1 [Yang, Baiyu; Chen, Jie; Sahasrabuddhe, Vikrant V.; Graubard, Barry I.; McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hagberg, Katrina Wilcox; Jick, Susan] Boston Collaborat Drug Surveillance Program, Lexington, MA 02421 USA. [Hagberg, Katrina Wilcox; Jick, Susan] Boston Univ, Sch Publ Hlth, Lexington, MA 02421 USA. [Sahasrabuddhe, Vikrant V.] NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Yang, BY (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM baiyu.yang@nih.gov RI CPRD, CPRD/B-9594-2017 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. We thank Ms. Megan Braunlin for her help with the analyses. NR 9 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 28 PY 2016 VL 115 IS 1 BP 85 EP 89 DI 10.1038/bjc.2016.148 PG 5 WC Oncology SC Oncology GA DQ0HR UT WOS:000378880400013 PM 27219020 ER PT J AU Cannioto, RA LaMonte, MJ Kelemen, LE Risch, HA Eng, KH Minlikeeva, AN Hong, CC Szender, JB Sucheston-Campbell, L Joseph, JM Berchuck, A Chang-Claude, J Cramer, DW DeFazio, A Diergaarde, B Dork, T Doherty, JA Edwards, RP Fridley, BL Friel, G Goode, EL Goodman, MT Hillemanns, P Hogdall, E Hosono, S Kelley, JL Kjaer, SK Klapdor, R Matsuo, K Odunsi, K Nagle, CM Olsen, CM Paddock, LE Pearce, CL Pike, MC Rossing, MA Schmalfeldt, B Segal, BH Szamreta, EA Thompson, PJ Tseng, CC Vierkant, R Schildkraut, JM Wentzensen, N Wicklund, KG Winham, SJ Wu, AH Modugno, F Ness, RB Jensen, A Webb, PM Terry, K Bandera, EV Moysich, KB AF Cannioto, Rikki A. LaMonte, Michael J. Kelemen, Linda E. Risch, Harvey A. Eng, Kevin H. Minlikeeva, Albina N. Hong, Chi-Chen Szender, J. Brian Sucheston-Campbell, Lara Joseph, Janine M. Berchuck, Andrew Chang-Claude, Jenny Cramer, Daniel W. DeFazio, Anna Diergaarde, Brenda Doerk, Thilo Doherty, Jennifer A. Edwards, Robert P. Fridley, Brooke L. Friel, Grace Goode, Ellen L. Goodman, Marc T. Hillemanns, Peter Hogdall, Estrid Hosono, Satoyo Kelley, Joseph L. Kjaer, Susanne K. Klapdor, Ruediger Matsuo, Keitaro Odunsi, Kunle Nagle, Christina M. Olsen, Catherine M. Paddock, Lisa E. Pearce, Celeste L. Pike, Malcolm C. Rossing, Mary A. Schmalfeldt, Barbara Segal, Brahm H. Szamreta, Elizabeth A. Thompson, Pamela J. Tseng, Chiu-Chen Vierkant, Robert Schildkraut, Joellen M. Wentzensen, Nicolas Wicklund, Kristine G. Winham, Stacey J. Wu, Anna H. Modugno, Francesmary Ness, Roberta B. Jensen, Allan Webb, Penelope M. Terry, Kathryn Bandera, Elisa V. Moysich, Kirsten B. CA Australian Ovarian Canc Study Grp TI Recreational physical inactivity and mortality in women with invasive epithelial ovarian cancer: evidence from the Ovarian Cancer Association Consortium SO BRITISH JOURNAL OF CANCER LA English DT Article DE recreational physical activity; inactivity; epithelial ovarian cancer; mortality risk; survival ID PROGNOSTIC-FACTORS; HORMONE-THERAPY; RISK; SURVIVAL; COHORT; POLYMORPHISMS AB Background: Little is known about modifiable behaviours that may be associated with epithelial ovarian cancer (EOC) survival. We conducted a pooled analysis of 12 studies from the Ovarian Cancer Association Consortium to investigate the association between pre-diagnostic physical inactivity and mortality. Methods: Participants included 6806 women with a primary diagnosis of invasive EOC. In accordance with the Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. We utilised Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) representing the associations of inactivity with mortality censored at 5 years. Results: In multivariate analysis, inactive women had significantly higher mortality risks, with (HR = 1.34, 95% CI: 1.18-1.52) and without (HR = 1.22, 95% CI: 1.12-1.33) further adjustment for residual disease, respectively. Conclusion: In this large pooled analysis, lack of recreational physical activity was associated with increased mortality among women with invasive EOC. C1 [Cannioto, Rikki A.; Minlikeeva, Albina N.; Hong, Chi-Chen; Sucheston-Campbell, Lara; Joseph, Janine M.; Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [LaMonte, Michael J.; Minlikeeva, Albina N.] Univ Buffalo, Dept Epidemiol & Environm Hlth, Buffalo, NY USA. [Kelemen, Linda E.] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC USA. [Risch, Harvey A.] Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Eng, Kevin H.] Roswell Pk Canc Inst, Dept Biostat & Bioinformat, Buffalo, NY 14263 USA. [Szender, J. Brian; Odunsi, Kunle] Roswell Pk Canc Inst, Dept Gynecol Oncol, Buffalo, NY 14263 USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Unit Genet Epidemiol, Heidelberg, Germany. [Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, UCCH, Hamburg, Germany. [Cramer, Daniel W.; Terry, Kathryn] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA. [Cramer, Daniel W.; Terry, Kathryn] Harvard Med Sch, Boston, MA USA. [DeFazio, Anna] Univ Sydney, Westmead Hosp, Dept Gynecol Oncol, Sydney, NSW, Australia. [DeFazio, Anna] Univ Sydney, Westmead Inst Med Res, Sydney, NSW, Australia. [Diergaarde, Brenda; Modugno, Francesmary] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Doerk, Thilo] Hannover Med Sch, Gynecol Res Unit, Hannover, Germany. [Doherty, Jennifer A.] Dartmouth Med, Geisel Sch Med, Dept Epidemiol, Hanover, NH USA. [Edwards, Robert P.; Kelley, Joseph L.; Modugno, Francesmary] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Edwards, Robert P.; Modugno, Francesmary] Magee Womens Res Inst, Ovarian Canc Ctr Excellence, Womens Canc Res Program, Pittsburgh, PA USA. [Edwards, Robert P.; Modugno, Francesmary] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Fridley, Brooke L.] Univ Kansas, Med Ctr, Biostat & Informat Shared Resource, Kansas City, KS 66103 USA. [Friel, Grace] Independent Hlth, Buffalo, NY USA. [Goode, Ellen L.] Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN USA. [Goodman, Marc T.; Thompson, Pamela J.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Canc Prevent & Control, Los Angeles, CA 90048 USA. [Hillemanns, Peter; Klapdor, Ruediger] Hannover Med Sch, Clin Gynaecol, Hannover, Germany. [Hillemanns, Peter; Klapdor, Ruediger] Hannover Med Sch, Clin Obstet, Hannover, Germany. [Hogdall, Estrid; Kjaer, Susanne K.; Jensen, Allan] Danish Canc Soc Res Ctr, Dept Virus Lifestyle & Genes, Copenhagen, Denmark. [Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark. [Hosono, Satoyo] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan. [Kjaer, Susanne K.] Univ Copenhagen, Rigshosp, Dept Gynaecol, Copenhagen, Denmark. [Matsuo, Keitaro] Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan. [Nagle, Christina M.; Olsen, Catherine M.; Webb, Penelope M.] QIMR Berghofer Med Res Inst, Populat Hlth Dept, Brisbane, Qld, Australia. [Paddock, Lisa E.] Rutgers Canc Inst New Jersey, New Jersey State Canc Registry, New Brunswick, NJ USA. [Pearce, Celeste L.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Rossing, Mary A.; Wicklund, Kristine G.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, 1124 Columbia St, Seattle, WA 98104 USA. [Schmalfeldt, Barbara] Univ Med Ctr Hamburg Eppendorf UKE, Dept Gynecol, Hamburg, Germany. [Segal, Brahm H.] Roswell Pk Canc Inst, Dept Immunol, Buffalo, NY 14263 USA. [Segal, Brahm H.] Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. [Szamreta, Elizabeth A.; Bandera, Elisa V.] Rutgers Canc Inst New Jersey, Canc Prevent & Control, New Brunswick, NJ USA. [Tseng, Chiu-Chen; Wu, Anna H.] Univ Southern Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Vierkant, Robert; Winham, Stacey J.] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN USA. [Schildkraut, Joellen M.] Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Clin Genet Branch, Bethesda, MD 20892 USA. [Ness, Roberta B.] Univ Texas Sch Publ Hlth, Houston, TX USA. RP Moysich, KB (reprint author), Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. EM Kirsten.moysich@roswellpark.org RI Olsen, Catherine/C-8785-2009; Dork, Thilo/J-8620-2012; OI Olsen, Catherine/0000-0003-4483-1888; Matsuo, Keitaro/0000-0003-1761-6314; Winham, Stacey/0000-0002-8492-9102 FU NIH/NCI [R01CA095023, R01CA126841]; Roswell Park Alliance Foundation; Interdisciplinary Training Grant in Cancer Epidemiology [R25CA113951]; U.S. Army Medical Research and Materiel Command [DAMD17-01-1-0729]; National Health & Medical Research Council of Australia; Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania; Cancer Foundation of Western Australia; National Health and Medical Research Council of Australia [199600, 400281]; National Institutes of Health [R01-CA074850, R01-CA080742, R01-CA112523, R01-CA87538, R01-CA122443, P30-CA15083, P50-CA136393, R01-CA54419, P50-CA105009]; U.S. National Institutes of Health [R01-CA58598, N01-CN-55424, N01-PC-67001]; Ministry of Health, Labour and Welfare; National Cancer Institute, Bethesda, MD [R01-CA61107]; Danish Cancer Society, Copenhagen, Denmark [94 222 52]; Mermaid I project; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; Department of Defense [W81XWH-10-1-02802]; National Cancer Institute [NIH-K07 CA095666, R01-CA83918, NIH-K22-CA138563, P30-CA072720]; Cancer Institute of New Jersey; NCI CCSG award [P30-CA008748]; California Cancer Research Program [00-01389V-20170, 2II0200]; [5T32CA108456]; [R01 CA188900]; [DOD: DAMD17-02-1-0669]; [NCI: K07-CA080668]; [R01-CA95023]; [P50-CA159981]; [R01-CA126841]; [P01CA17054]; [P30CA14089]; [R01CA61132]; [N01PC67010]; [R03CA113148]; [R03CA115195]; [N01CN025403] FX KBM is supported by NIH/NCI R01CA095023 and NIH/NCI R01CA126841; KHE and KBM were supported by the Roswell Park Alliance Foundation; JBS was supported by 5T32CA108456; ANM was supported by Interdisciplinary Training Grant in Cancer Epidemiology R25CA113951; BHS was supported by R01 CA188900; AUS was supported by the U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729), National Health & Medical Research Council of Australia, Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania, Cancer Foundation of Western Australia; National Health and Medical Research Council of Australia (199600 and 400281); CON was supported by National Institutes of Health (R01-CA074850; R01-CA080742); DOV was supported by National Institutes of Health R01-CA112523 and R01-CA87538; HAW was supported by U.S. National Institutes of Health (R01-CA58598, N01-CN-55424 and N01-PC-67001); HOP was supported by DOD: DAMD17-02-1-0669 and NCI: K07-CA080668, R01-CA95023, P50-CA159981, R01-CA126841; JPN was supported by Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare; MAC was supported by National Institutes of Health (R01-CA122443, P30-CA15083, P50-CA136393); MAL was supported by research grant R01-CA61107 from the National Cancer Institute, Bethesda, MD; research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark; and the Mermaid I project; MAY was supported by National Institutes of Health (R01-CA122443, P30-CA15083, P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; NEC was supported by National Institutes of Health R01-CA54419 and P50-CA105009 and Department of Defense W81XWH-10-1-02802; NJO was supported by National Cancer Institute (NIH-K07 CA095666, R01-CA83918, NIH-K22-CA138563, and P30-CA072720) and the Cancer Institute of New Jersey and NCI CCSG award (P30-CA008748); USC was supported by P01CA17054, P30CA14089, R01CA61132, N01PC67010, R03CA113148, R03CA115195, N01CN025403, and California Cancer Research Program (00-01389V-20170, 2II0200). NR 34 TC 0 Z9 0 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 28 PY 2016 VL 115 IS 1 BP 95 EP 101 DI 10.1038/bjc.2016.153 PG 7 WC Oncology SC Oncology GA DQ0HR UT WOS:000378880400015 PM 27299959 ER PT J AU Malachowa, N Kobayashi, SD Quinn, MT DeLeo, FR AF Malachowa, Natalia Kobayashi, Scott D. Quinn, Mark T. DeLeo, Frank R. TI NET Confusion SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE host defense; extracellular trap; inflammation; inflammatory disorder; neutrophil ID NEUTROPHIL EXTRACELLULAR TRAPS; RECOMBINANT HUMAN DEOXYRIBONUCLEASE; MONOCYTE-DERIVED MACROPHAGES; PANTON-VALENTINE LEUKOCIDIN; PROGRAMMED CELL-DEATH; STAPHYLOCOCCUS-AUREUS; CYSTIC-FIBROSIS; DNA TRAPS; IN-VIVO; POLYMORPHONUCLEAR LEUKOCYTES AB Neutrophils are arguably the most important white blood cell for defense against bacterial and fungal infections. These leukocytes are produced in high numbers on a daily basis in humans and are recruited rapidly to injured/infected tissues. Phagocytosis and subsequent intraphagosomal killing and digestion of microbes have historically been the accepted means by which neutrophils carry out their role in innate host defense. Indeed, neutrophils contain and produce numerous cytotoxic molecules, including antimicrobial peptides, proteases, and reactive oxygen species, that are highly effective at killing the vast majority of ingested microbes. On the other hand, it is these characteristics - high numbers and toxicity - that endow neutrophils with the potential to injure and destroy host tissues. This potential is borne out by many inflammatory processes and diseases. Therefore, it is not surprising that host mechanisms exist to control virtually all steps in the neutrophil activation process and to prevent unintended neutrophil activation and/or lysis during the resolution of inflammatory responses or during steady-state turnover. The notion that neutrophil extracellular traps (NETs) form by cytolysis as a standard host defense mechanism seems inconsistent with these aforementioned neutrophil "containment" processes. It is with this caveat in mind that we provide perspective on the role of NETs in human host defense and disease. C1 [Malachowa, Natalia; Kobayashi, Scott D.; DeLeo, Frank R.] NIAID, Rocky Mt Lab, Bacteriol Lab, NIH, Hamilton, MT 59840 USA. [Quinn, Mark T.] Montana State Univ, Dept Microbiol & Immunol, Bozeman, MT 59717 USA. RP DeLeo, FR (reprint author), NIAID, Rocky Mt Lab, Bacteriol Lab, NIH, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Institutes of Health IDeA Program COBRE grant [GM110732]; USDA National Institute of Food and Agriculture Hatch project [1009546]; Montana State University Agricultural Experiment Station FX NM, SK, and FD are supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. MQ is supported by National Institutes of Health IDeA Program COBRE grant GM110732; USDA National Institute of Food and Agriculture Hatch project 1009546; and the Montana State University Agricultural Experiment Station. NR 132 TC 2 Z9 2 U1 3 U2 7 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD JUN 28 PY 2016 VL 7 AR 259 DI 10.3389/fimmu.2015.00259 PG 10 WC Immunology SC Immunology GA DP6DH UT WOS:000378586600001 PM 27446089 ER PT J AU Wang, JY Huang, YN Chiu, CC Tweedie, D Luo, WM Pick, CG Chou, SY Luo, Y Hoffer, BJ Greig, NH Wang, JY AF Wang, Jin-Ya Huang, Ya-Ni Chiu, Chong-Chi Tweedie, David Luo, Weiming Pick, Chaim G. Chou, Szu-Yi Luo, Yu Hoffer, Barry J. Greig, Nigel H. Wang, Jia-Yi TI Pomalidomide mitigates neuronal loss, neuroinflammation, and behavioral impairments induced by traumatic brain injury in rat SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Pomalidomide; Thalidomide; Traumatic brain injury; Controlled cortical impact; Tumor necrosis factor-alpha; Interleukin-1 beta; Interleukin-6; Glutamate excitotoxicity; Neuronal apoptosis; Neuroinflammation ID TUMOR-NECROSIS-FACTOR; CENTRAL-NERVOUS-SYSTEM; CLOSED-HEAD INJURY; CONTROLLED CORTICAL IMPACT; ALPHA SYNTHESIS INHIBITOR; TNF-ALPHA; IN-VITRO; INFLAMMATORY CYTOKINES; FUNCTIONAL OUTCOMES; COGNITIVE DEFICITS AB Background: Traumatic brain injury (TBI) is a global health concern that typically causes emotional disturbances and cognitive dysfunction. Secondary pathologies following TBI may be associated with chronic neurodegenerative disorders and an enhanced likelihood of developing dementia-like disease in later life. There are currently no approved drugs for mitigating the acute or chronic effects of TBI. Methods: The effects of the drug pomalidomide (Pom), an FDA-approved immunomodulatory agent, were evaluated in a rat model of moderate to severe TBI induced by controlled cortical impact. Post-TBI intravenous administration of Pom (0.5 mg/kg at 5 or 7 h and 0.1 mg/kg at 5 h) was evaluated on functional and histological measures that included motor function, fine more coordination, somatosensory function, lesion volume, cortical neurodegeneration, neuronal apoptosis, and the induction of pro-inflammatory cytokines (TNF-alpha, IL-1 beta, IL-6). Results: Pom 0.5 mg/kg administration at 5 h, but not at 7 h post-TBI, significantly mitigated the TBI-induced injury volume and functional impairments, neurodegeneration, neuronal apoptosis, and cytokine mRNA and protein induction. To evaluate underlying mechanisms, the actions of Pom on neuronal survival, microglial activation, and the induction of TNF-alpha were assessed in mixed cortical cultures following a glutamate challenge. Pom dose-dependently ameliorated glutamate-mediated cytotoxic effects on cell viability and reduced microglial cell activation, significantly attenuating the induction of TNF-alpha. Conclusions: Post-injury treatment with a single Pom dose within 5 h significantly reduced functional impairments in a well-characterized animal model of TBI. Pom decreased the injury lesion volume, augmented neuronal survival, and provided anti-inflammatory properties. These findings strongly support the further evaluation and optimization of Pom for potential use in clinical TBI. C1 [Tweedie, David; Luo, Weiming; Greig, Nigel H.] NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Wang, Jin-Ya; Huang, Ya-Ni; Wang, Jia-Yi] Taipei Med Univ, Coll Med, Grad Inst Med Sci, 250 Wu Hsing St, Taipei 110, Taiwan. [Huang, Ya-Ni] Hsin Sheng Jr Coll Med Care & Management, Dept Nursing, Taoyuan, Taiwan. [Chiu, Chong-Chi] Chi Mei Med Ctr, Dept Gen Surg, Tainan, Taiwan. [Chiu, Chong-Chi] Chi Mei Med Ctr, Dept Gen Surg, Liouying, Taiwan. [Pick, Chaim G.] Tel Aviv Univ, Dept Anat & Anthropol, Sackler Sch Med, Tel Aviv, Israel. [Pick, Chaim G.] Tel Aviv Univ, Sagol Sch Neurosci, Tel Aviv, Israel. [Chou, Szu-Yi] Taipei Med Univ, Coll Med Sci & Technol, Grad Program Neuroregenerat, Taipei, Taiwan. [Luo, Yu; Hoffer, Barry J.] Case Western Reserve Univ, Sch Med, Dept Neurosurg, Cleveland, OH 44106 USA. [Wang, Jia-Yi] Taipei Med Univ, Coll Med, Dept Physiol, 250 Wu Hsing St, Taipei 110, Taiwan. RP Greig, NH (reprint author), NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA.; Wang, JY (reprint author), Taipei Med Univ, Coll Med, Grad Inst Med Sci, 250 Wu Hsing St, Taipei 110, Taiwan.; Wang, JY (reprint author), Taipei Med Univ, Coll Med, Dept Physiol, 250 Wu Hsing St, Taipei 110, Taiwan. EM greign@mail.NIH.gov; jywang2010@tmu.edu.tw FU Ministry of Science and Technology, Taiwan [MOST104-2923-B-038-001-MY3]; Ari and Regine Aprijaskis Fund at Tel-Aviv University, Tel-Aviv, Israel; National Institute of Neurological Disorders and Stroke, NIH [RO1NS094152]; Intramural Research Program of the National Institute on Aging, NIH [AG 000311-16] FX This study was supported in part by (i) a grant from the Ministry of Science and Technology, Taiwan (MOST104-2923-B-038-001-MY3); (ii) the Ari and Regine Aprijaskis Fund at Tel-Aviv University, Tel-Aviv, Israel; (iii) the National Institute of Neurological Disorders and Stroke, NIH (grant RO1NS094152); and (iv) the Intramural Research Program of the National Institute on Aging, NIH (AG 000311-16). These funding organizations had no role in the design of the study or the collection, analysis, and interpretation of data and in writing the manuscript. NR 89 TC 1 Z9 1 U1 2 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD JUN 28 PY 2016 VL 13 AR 168 DI 10.1186/s12974-016-0631-6 PG 17 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DQ0BZ UT WOS:000378864100002 PM 27353053 ER PT J AU Lustig, A Shterev, I Geyer, S Shi, A Hu, YQ Morishita, Y Nagamura, H Sasaki, K Maki, M Hayashi, I Furukawa, K Yoshida, K Kajimura, J Kyoizumi, S Kusunoki, Y Ohishi, W Nakachi, K Weng, NP Hayashi, T AF Lustig, Ana Shterev, Ivo Geyer, Susan Shi, Alvin Hu, Yiqun Morishita, Yukari Nagamura, Hiroko Sasaki, Keiko Maki, Mayumi Hayashi, Ikue Furukawa, Kyoji Yoshida, Kengo Kajimura, Junko Kyoizumi, Seishi Kusunoki, Yoichiro Ohishi, Waka Nakachi, Kei Weng, Nan-ping Hayashi, Tomonori TI Long term effects of radiation exposure on telomere lengths of leukocytes and its associated biomarkers among atomic-bomb survivors SO ONCOTARGET LA English DT Article DE Ionizing radiation; telomeres; leukocytes; aging; Hiroshima; Gerotarget ID FALSE DISCOVERY RATE; IONIZING-RADIATION; BLOOD-LYMPHOCYTES; DNA-DAMAGE; IN-VIVO; AGE; SENESCENCE; CELL; SENSITIVITY; MARKERS AB Ionizing radiation (IR) is a major source of cellular damage and the immediate cellular response to IR has been well characterized. But the long-term impact of IR on cell function and its relationship with aging are not known. Here, we examined the IR effects on telomere length and other biomarkers 50 to 68 years post-exposure (two time points per person) in survivors of the atomic bombing at Hiroshima during WWII. We found that telomere length of leukocytes was inversely correlated with the dose of IR (p=0.008), and this effect was primarily found in survivors who were exposed at younger ages; specifically those <12 years old (p=0.0004). Although a dose-related retardation of telomere shortening with age was observed in the cross-sectional data, longitudinal follow-up after 11 years did not show IR exposure-related alteration of the rate of telomere shortening with age. In addition, IR diminished the associations between telomere length and selected aging biomarkers that were observed in survivors with no dose. These included uric acid metabolism, cytokines, and blood T cell counts. These findings showed long-lasting detrimental effects of IR on telomere length of leukocytes in both dose- and age-at-exposure dependent manner, and on alterations of biomarkers with aging. C1 [Lustig, Ana; Shi, Alvin; Weng, Nan-ping] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Shterev, Ivo] Duke Univ, Durham, NC USA. [Geyer, Susan] Univ S Florida, Hlth Informat Inst, Tampa, FL USA. [Hu, Yiqun; Morishita, Yukari; Nagamura, Hiroko; Sasaki, Keiko; Maki, Mayumi; Yoshida, Kengo; Kajimura, Junko; Kyoizumi, Seishi; Kusunoki, Yoichiro; Nakachi, Kei; Hayashi, Tomonori] Radiat Effects Res Fdn RERF, Dept Radiobiol Mol Epidemiol, Hiroshima, Japan. [Hayashi, Ikue] Hiroshima Univ, Fac Dent, Cent Res Lab, Hiroshima, Japan. [Furukawa, Kyoji] RERF, Dept Stat, Hiroshima, Japan. [Ohishi, Waka] RERF, Dept Clin Studies, Hiroshima, Japan. RP Weng, NP (reprint author), NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA.; Hayashi, T (reprint author), Radiat Effects Res Fdn RERF, Dept Radiobiol Mol Epidemiol, Hiroshima, Japan. EM wengn@mail.nih.gov; tomo@rerf.or.jp FU Radiation and Nuclear Countermeasures Program of the National Institute of Allergy and Infectious Diseases (NIAID); National Institute on Aging, National Institutes of Health (NIH) FX We thank Richard Hatchett for his comments and suggestions. This study is supported by the Radiation and Nuclear Countermeasures Program of the National Institute of Allergy and Infectious Diseases (NIAID), and the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH). NR 33 TC 1 Z9 1 U1 3 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUN 28 PY 2016 VL 7 IS 26 BP 38988 EP 38998 DI 10.18632/oncotarget.8801 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DP6NV UT WOS:000378614700002 PM 27102155 ER PT J AU Di Germanio, C Bernier, M Petr, M Mattioli, M Barboni, B de Cabo, R AF Di Germanio, Clara Bernier, Michel Petr, Michael Mattioli, Mauro Barboni, Barbara de Cabo, Rafael TI Conditioned medium derived from rat amniotic epithelial cells confers protection against inflammation, cancer, and senescence SO ONCOTARGET LA English DT Article DE amniotic epithelial cells; inflammation; tumorigenesis; senescence; SASP; Gerotarget ID STEM-CELLS; SECRETORY PHENOTYPE; CELLULAR SENESCENCE; HUMAN FIBROBLASTS; IN-VITRO; MEMBRANE; DIFFERENTIATION; POLARIZATION; PLACENTA; TRANSPLANTATION AB Amniotic epithelial cells (AECs) are a class of fetal stem cells that derives from the epiblast and resides in the amnion until birth. AECs are suitable candidates for regenerative medicine because of the ease of collection, their low immunogenicity and inability to form tumors after transplantation. Even though human AECs have been widely investigated, the fact remains that very little is known about AECs isolated from rat, one of the most common animal models in medical testing. In this study, we showed that rat AECs retained stemness properties and plasticity, expressed the pluripotency markers Sox2, Nanog, and Oct4 and were able to differentiate toward the osteogenic lineage. The addition of conditioned medium collected from rat AECs to lipopolysaccharide-activated macrophages elicited anti-inflammatory properties through a decrease of Tnfa expression and slowed tumor cell proliferation in vitro and in vivo. The senescence-associated secretory phenotype was also significantly lower upon incubation of senescent human IMR-90 fibroblast cells with conditioned medium from rat AECs. These results confirm the potential of AECs in the modulation of inflammatory mechanisms and open new therapeutic possibilities for regenerative medicine and anti-aging therapies as well. C1 [Di Germanio, Clara; Mattioli, Mauro; Barboni, Barbara] Univ Teramo, Fac Vet Med, Teramo, Italy. [Di Germanio, Clara; Bernier, Michel; Petr, Michael; de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Mattioli, Mauro] Ist Zooprofilatt Sperimentale Abruzzo & Molise G, Teramo, Italy. RP Barboni, B (reprint author), Univ Teramo, Fac Vet Med, Teramo, Italy.; de Cabo, R (reprint author), NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. EM bbarboni@unite.it; decabora@grc.nia.nih.gov FU National Institute on Aging, National Institutes of Health; Fatro S.p.A.; PRIN FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (MB and RdC) and funding from Fatro S.p.A. 2014 (MM). This work had also the financial support of PRIN 2010-11 "Cellule staminali e scaffold 3D: un biocomplesso innovativo nella rigenerazione ossea" (BB). NR 67 TC 0 Z9 0 U1 5 U2 6 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUN 28 PY 2016 VL 7 IS 26 BP 39051 EP 39064 DI 10.18632/oncotarget.9694 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DP6NV UT WOS:000378614700007 PM 27259996 ER PT J AU Wang, DR Narula, N Azzopardi, S Smith, RS Nasar, A Altorki, NK Mittal, V Somwar, R Stiles, BM Du, YCN AF Wang, Dunrui Narula, Navneet Azzopardi, Stephanie Smith, Roger S. Nasar, Abu Altorki, Nasser K. Mittal, Vivek Somwar, Romel Stiles, Brendon M. Du, Yi-Chieh Nancy TI Expression of the receptor for hyaluronic acid mediated motility (RHAMM) is associated with poor prognosis and metastasis in non-small cell lung carcinoma SO ONCOTARGET LA English DT Article DE lung cancer; receptor for hyaluronic acid-mediated motility; metastasis; prognosis ID BREAST-CANCER; TUMOR PROGRESSION; MUTATIONS; PROTEIN; GEFITINIB; PROLIFERATION; SURVIVAL; THERAPY; DISEASE; CD168 AB The receptor for hyaluronic acid-mediated motility (RHAMM) is upregulated in various cancers, but its role in primary and metastatic non-small cell lung carcinoma (NSCLC) remains to be determined. Here, we investigate the clinical relevance of RHAMM expression in NSCLC. RHAMM protein expression correlates with histological differentiation stages and extent of the primary tumor (T stages) in 156 patients with primary NSCLC. Importantly, while focal RHAMM staining pattern is present in 57% of primary NSCLC, intense RHAMM protein expression is present in 96% of metastatic NSCLC cases. In a publicly available database, The Cancer Genome Atlas (TCGA), RHAMM mRNA expression is 12- and 10-fold higher in lung adenocarcinoma and squamous lung carcinoma than in matched normal lung tissues, respectively. RHAMM mRNA expression correlates with stages of differentiation and inferior survival in more than 400 cases of lung adenocarcinoma in the Director's Challenge cohort. Of 4 RHAMM splice variants, RHAMMv3 (also known as RHAMM(B)) is the dominant variant in NSCLC. Moreover, shRNA-mediated knockdown of RHAMM reduced the migratory ability of two lung adenocarcinoma cell lines, H1975 and H3255. Taken together, RHAMM, most likely RHAMMv3 (RHAMM(B)), can serve as a prognostic factor for lung adenocarcinomas and a potential therapeutic target in NSCLC to inhibit tumor migration. C1 [Wang, Dunrui] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Narula, Navneet; Azzopardi, Stephanie; Du, Yi-Chieh Nancy] Weill Cornell Med, Dept Pathol & Lab Med, New York, NY 10065 USA. [Smith, Roger S.; Somwar, Romel] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Nasar, Abu; Altorki, Nasser K.; Mittal, Vivek; Stiles, Brendon M.] Weill Cornell Med, Dept Cardiothorac Surg, New York, NY 10065 USA. RP Du, YCN (reprint author), Weill Cornell Med, Dept Pathol & Lab Med, New York, NY 10065 USA. EM nad2012@med.cornell.edu FU DOD [W81XWH-13-1-0331]; NIH [1R21CA173348-01A1] FX This work is partially supported by DOD grant W81XWH-13-1-0331 and NIH grant 1R21CA173348-01A1 (to Y.-C.N.D.). NR 42 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUN 28 PY 2016 VL 7 IS 26 BP 39957 EP 39969 DI 10.18632/oncotarget.9554 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DP6NV UT WOS:000378614700078 PM 27220886 ER PT J AU Bullova, P Cougnoux, A Abunimer, L Kopacek, J Pastorekova, S Pacak, K AF Bullova, Petra Cougnoux, Antony Abunimer, Luma Kopacek, Juraj Pastorekova, Silvia Pacak, Karel TI Hypoxia potentiates the cytotoxic effect of piperlongumine in pheochromocytoma models SO ONCOTARGET LA English DT Article DE pheochromocytoma; piperlongumine; hypoxia; reactive-oxygen species; apoptosis ID PROTEASOME INHIBITOR BORTEZOMIB; CANCER-CELL-DEATH; HEPATOCELLULAR-CARCINOMA; MESENCHYMAL TRANSITION; DEPENDENT APOPTOSIS; AUTOPHAGY; ACTIVATION; ROS; PARAGANGLIOMAS; NECROPTOSIS AB Hypoxia is a common feature of solid tumors that activates a plethora of pathways, resulting in proliferation and resistance of cancer cells to radio-and chemotherapy. Pheochromocytomas/paragangliomas (PHEOs/PGLs) with mutations in the gene coding for the subunit B of succinate dehydrogenase (SDHB) are the most aggressive forms of the disease, which is partially due to their pseudohypoxic character, metabolic abnormalities, and elevated reactive oxygen species (ROS) levels. We investigated the effect of piperlongumine (PL), a natural product with cytotoxic properties restricted to cancer cells by significantly increasing intracellular ROS levels, on PHEO cells. Here we report for the first time that PL mediates PHEO cell death by activating both apoptosis and necroptosis in vitro and in vivo. This effect is magnified in hypoxic conditions, making PL a promising potential candidate for use as a therapeutic option for patients with PHEO/PGL, including those with SDHB mutations. C1 [Bullova, Petra; Abunimer, Luma; Pacak, Karel] Eunice Kennedy Shriver NICHD, Sect Med Neuroendocrinol, NIH, Bethesda, MD 20892 USA. [Bullova, Petra; Kopacek, Juraj; Pastorekova, Silvia] Slovak Acad Sci, Dept Mol Med, Inst Virol, Biomed Res Ctr, Bratislava 84505, Slovakia. [Cougnoux, Antony] Eunice Kennedy Shriver NICHD, Sect Mol Dysmorphol, NIH, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver NICHD, Sect Med Neuroendocrinol, NIH, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. NR 59 TC 0 Z9 0 U1 4 U2 6 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUN 28 PY 2016 VL 7 IS 26 BP 40531 EP 40545 DI 10.18632/oncotarget.9643 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DP6NV UT WOS:000378614700120 PM 27244895 ER PT J AU Williamson, JD Supiano, MA Applegate, WB Berlowitz, DR Campbell, RC Chertow, GM Fine, LJ Haley, WE Hawfield, AT Ix, JH Kitzman, D Kostis, JB Krousel-Wood, MA Launer, LJ Oparil, S Rodriguez, CJ Roumie, CL Shorr, RI Sink, KM Wadley, VG Whelton, PK Whittle, J Woolard, NF Wright, JT Pajewski, NM AF Williamson, Jeff D. Supiano, Mark A. Applegate, William B. Berlowitz, Dan R. Campbell, Ruth C. Chertow, Glenn M. Fine, Larry J. Haley, William E. Hawfield, Amret T. Ix, Joachim H. Kitzman, DalaneW. Kostis, John B. Krousel-Wood, Marie A. Launer, Lenore J. Oparil, Suzanne Rodriguez, Carlos J. Roumie, Christianne L. Shorr, Ronald I. Sink, Kaycee M. Wadley, Virginia G. Whelton, Paul K. Whittle, Jeffrey Woolard, Nancy F. Wright, Jackson T., Jr. Pajewski, Nicholas M. CA SPRINT Res Grp TI Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged >= 75 Years A Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ANTIHYPERTENSIVE TREATMENT; INTERVENTION TRIAL; ELDERLY POPULATION; OLDER-PEOPLE; HYPERTENSION; FRAILTY; STROKE; RISK; DISABILITY; GUIDELINES AB IMPORTANCE The appropriate treatment target for systolic blood pressure (SBP) in older patients with hypertension remains uncertain. OBJECTIVE To evaluate the effects of intensive (<120mmHg) compared with standard (<140mmHg) SBP targets in persons aged 75 years or older with hypertension but without diabetes. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized clinical trial of patients aged 75 years or older who participated in the Systolic Blood Pressure Intervention Trial (SPRINT). Recruitment began on October 20, 2010, and follow-up ended on August 20, 2015. INTERVENTIONS Participants were randomized to an SBP target of less than 120mmHg (intensive treatment group, n = 1317) or an SBP target of less than 140mmHg (standard treatment group, n = 1319). MAIN OUTCOMES AND MEASURES The primary cardiovascular disease outcomewas a composite of nonfatalmyocardial infarction, acute coronary syndrome not resulting in a myocardial infarction, nonfatal stroke, nonfatal acute decompensated heart failure, and death from cardiovascular causes. All-cause mortality was a secondary outcome. RESULTS Among 2636 participants (mean age, 79.9 years; 37.9% women), 2510 (95.2%) provided complete follow-up data. At a median follow-up of 3.14 years, there was a significantly lower rate of the primary composite outcome (102 events in the intensive treatment group vs 148 events in the standard treatment group; hazard ratio [HR], 0.66 [95% CI, 0.51-0.85]) and all-cause mortality (73 deaths vs 107 deaths, respectively; HR, 0.67 [95% CI, 0.49-0.91]). The overall rate of serious adverse events was not different between treatment groups (48.4% in the intensive treatment group vs 48.3% in the standard treatment group; HR, 0.99 [95% CI, 0.89-1.11]). Absolute rates of hypotension were 2.4% in the intensive treatment group vs 1.4% in the standard treatment group (HR, 1.71 [95% CI, 0.97-3.09]), 3.0% vs 2.4%, respectively, for syncope (HR, 1.23 [95% CI, 0.76-2.00]), 4.0% vs 2.7% for electrolyte abnormalities (HR, 1.51 [95% CI, 0.99-2.33]), 5.5% vs 4.0% for acute kidney injury (HR, 1.41 [95% CI, 0.98-2.04]), and 4.9% vs 5.5% for injurious falls (HR, 0.91 [95% CI, 0.65-1.29]). CONCLUSIONS AND RELEVANCE Among ambulatory adults aged 75 years or older, treating to an SBP target of less than 120mmHg compared with an SBP target of less than 140mmHg resulted in significantly lower rates of fatal and nonfatal major cardiovascular events and death from any cause. C1 [Williamson, Jeff D.; Applegate, William B.; Sink, Kaycee M.; Woolard, Nancy F.] Wake Forest Sch Med, Med Ctr Blvd, Sect Gerontol & Geriatr Med, Winston Salem, NC 27157 USA. [Supiano, Mark A.] Univ Utah, Sch Med, Div Geriatr, Salt Lake City, UT USA. [Supiano, Mark A.] Vet Affairs Salt Lake City, Geriatr Res Educ & Clin Ctr, Salt Lake City, UT USA. [Berlowitz, Dan R.] Bedford Vet Affairs Hosp, Bedford, MA USA. [Berlowitz, Dan R.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Campbell, Ruth C.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Chertow, Glenn M.] Stanford Univ, Sch Med, Dept Med, Palo Alto, CA 94304 USA. [Fine, Larry J.] NHLBI, Div Cardiovasc Sci, Clin Applicat & Prevent Branch, Bldg 10, Bethesda, MD 20892 USA. [Haley, William E.] Mayo Clin, Dept Hypertens & Nephrol, Jacksonville, FL 32224 USA. [Hawfield, Amret T.] Wake Forest Sch Med, Nephrol Sect, Winston Salem, NC USA. [Ix, Joachim H.] Univ Calif San Diego, Dept Med, Div Nephrol & Hypertens, San Diego, CA 92103 USA. [Ix, Joachim H.] Univ Calif San Diego, Dept Family Med & Publ Hlth, Div Prevent Med, San Diego, CA 92103 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Dept Med, Nephrol Sect, San Diego, CA USA. [Kitzman, DalaneW.] Wake Forest Sch Med, Sect Cardiovasc Med, Winston Salem, NC USA. [Kostis, John B.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Cardiovasc Inst Rutgers, New Brunswick, NJ USA. [Krousel-Wood, Marie A.] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. [Krousel-Wood, Marie A.] Tulane Univ, Dept Epidemiol, Sch Publ Hlth & Trop Med, New Orleans, LA 70118 USA. [Krousel-Wood, Marie A.] Ochsner Clin Fdn, Ctr Appl Hlth Res, New Orleans, LA USA. [Launer, Lenore J.] NIA, Intramural Res Program, Bethesda, MD 20892 USA. [Oparil, Suzanne] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Rodriguez, Carlos J.] Wake Forest Sch Med, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC USA. [Roumie, Christianne L.] HSR&D Ctr, Vet Hlth Adm Tennessee Valley Healthcare Syst Ger, Nashville, TN USA. [Roumie, Christianne L.] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Shorr, Ronald I.] Univ Florida, Dept Epidemiol, Gainesville, FL USA. [Shorr, Ronald I.] Malcom Randall Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Gainesville, FL USA. [Wadley, Virginia G.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Whelton, Paul K.] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA. [Whittle, Jeffrey] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. [Whittle, Jeffrey] Clement J Zablocki Vet Affairs Med Ctr, Primary Care Div, Milwaukee, WI USA. [Wright, Jackson T., Jr.] Case Western Reserve Univ, Dept Med, Div Nephrol & Hypertens, Cleveland, OH 44106 USA. Wake Forest Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC USA. RP Williamson, JD (reprint author), Wake Forest Sch Med, Med Ctr Blvd, Dept Internal Med, Sect Gerontol & Geriatr Med,Sticht Ctr Aging, Winston Salem, NC 27157 USA.; Williamson, JD (reprint author), Wake Forest Sch Med, Med Ctr Blvd, Sect Gerontol & Geriatr Med, Winston Salem, NC 27157 USA. EM jwilliam@wakehealth.edu FU National Institutes of Health (National Heart, Lung, and Blood Institute) [HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN268200900049C, A-HL-13-002-001]; National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases) [HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN268200900049C, A-HL-13-002-001]; National Institutes of Health (National Institute on Aging) [HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN268200900049C, A-HL-13-002-001]; National Institutes of Health (National Institute of Neurological Disorders and Stroke) [HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN268200900049C, A-HL-13-002-001]; Department of Veterans Affairs; Wake Forest Claude Pepper Older Americans Independence Center [P30-AG21332, R01-HL10741]; National Center for Advancing Translational Sciences [UL1TR000439, UL1RR025755, UL1RR024134, UL1TR000003, UL1RR025771, UL1TR000093, UL1RR025752, UL1TR000073, UL1TR001064, UL1TR000050, UL1TR000005, 9U54TR000017-06, UL1TR000105-05, UL1 TR000064, UL1TR000433]; National Institute of General Medical Sciences, Centers of Biomedical Research Excellence [NIGMS P30GM103337] FX The SPRINT study was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke) under contracts HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, and HHSN268200900049C and interagency agreement A-HL-13-002-001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. Azilsartan and chlorthalidone (combined with azilsartan) were provided by Takeda Pharmaceuticals International Inc. Additional support was provided by grants P30-AG21332 and R01-HL10741 from the Wake Forest Claude Pepper Older Americans Independence Center; through the following National Center for Advancing Translational Sciences clinical and translational science awards: UL1TR000439 (awarded to Case Western Reserve University); UL1RR025755 (Ohio State University); UL1RR024134 and UL1TR000003 (University of Pennsylvania); UL1RR025771 (Boston University); UL1TR000093 (Stanford University); UL1RR025752, UL1TR000073, and UL1TR001064 (Tufts University); UL1TR000050 (University of Illinois); UL1TR000005 (University of Pittsburgh); 9U54TR000017-06 (University of Texas Southwestern Medical Center); UL1TR000105-05 (University of Utah); UL1 TR000445 (Vanderbilt University); UL1TR000075 (George Washington University); UL1 TR000002 (University of California, Davis); UL1 TR000064 (University of Florida); and UL1TR000433 (University of Michigan); and by National Institute of General Medical Sciences, Centers of Biomedical Research Excellence award NIGMS P30GM103337 (awarded to Tulane University). NR 34 TC 52 Z9 52 U1 4 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 28 PY 2016 VL 315 IS 24 BP 2673 EP 2682 DI 10.1001/jama.2016.7050 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DP7WG UT WOS:000378709300018 PM 27195814 ER PT J AU Vermeulen, E Stronks, K Visser, M Brouwer, IA Schene, AH Mocking, RJT Colpo, M Bandinelli, S Ferrucci, L Nicolaou, M AF Vermeulen, Esther Stronks, Karien Visser, Marjolein Brouwer, Ingeborg A. Schene, Aart H. Mocking, Roel J. T. Colpo, Marco Bandinelli, Stefania Ferrucci, Luigi Nicolaou, Mary TI The association between dietary patterns derived by reduced rank regression and depressive symptoms over time: the Invecchiare in Chianti (InCHIANTI) study SO BRITISH JOURNAL OF NUTRITION LA English DT Article DE Depressive symptoms; Diet; Dietary patterns; Reduced rank regression; Invecchiare in Chianti study ID SCALE CES-D; MEDITERRANEAN DIET; FURUKAWA NUTRITION; CRITERION VALIDITY; JAPANESE EMPLOYEES; MAGNESIUM INTAKE; SUN COHORT; ADULTS; COMMUNITY; WOMEN AB This study aimed to identify dietary patterns using reduced rank regression (RRR) and to explore their associations with depressive symptoms over 9 years in the Invecchiare in Chianti study. At baseline, 1362 participants (55.4% women) aged 18-102 years (mean age 68 (SD 15.5) years) were included in the study. Baseline data collection started in 1998 and was repeated after 3, 6 and 9 years. Dietary intake information was obtained using a country-specific, validated FFQ with 188 food items. For baseline diet, dietary pattern scores in quartiles (Q) were derived using RRR with the nutrients EPA+DHA, folate, Mg and Zn as response variables. Continuous depression scores from the Centre for Epidemiologic Studies Depression (CES-D) scale were used for assessing depressive symptoms. The derived dietary pattern was rich in vegetables, olive oil, grains, fruit, fish and moderate in wine and red and processed meat, and was labelled as 'typical Tuscan dietary pattern'. After full adjustment, an inverse association was observed between this dietary pattern and depressive symptoms at baseline (Q1 v. Q4, B -2.77; 95% CI -4.55, -0.98). When examining the relationship between the above-mentioned dietary pattern at baseline and depressive symptoms over 9 years, a similar association was found after full adjustment for confounding factors (Q1 v. Q4, B -1.78; 95% CI -3.17, -0.38). A diet rich in vegetables, olive oil, grains, fruits, fish and moderate in wine and red and processed meat was consistently associated with lower CES-D scores over a 9-year period in the Tuscan population. C1 [Vermeulen, Esther; Stronks, Karien; Nicolaou, Mary] Univ Amsterdam, Acad Med Ctr, Dept Publ Hlth, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Visser, Marjolein; Brouwer, Ingeborg A.] Vrije Univ Amsterdam, EMGO Inst, Dept Hlth Sci, NL-1081 HV Amsterdam, Netherlands. [Visser, Marjolein] Vrije Univ Amsterdam, Med Ctr, Internal Med, Dept Nutr & Dietet, NL-1081 HV Amsterdam, Netherlands. [Schene, Aart H.; Mocking, Roel J. T.] Univ Amsterdam, Acad Med Ctr, Dept Psychiat, Program Mood Disorders, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Schene, Aart H.] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, NL-6525 GA Nijmegen, Netherlands. [Schene, Aart H.] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 HP Nijmegen, Netherlands. [Bandinelli, Stefania] Azienda Sanit Firenze, InCHIANTI Study Grp, I-50125 Florence, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Baltimore, MD 21224 USA. RP Vermeulen, E (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Publ Hlth, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM e.vermeulen@amc.uva.nl FU EU [613598]; Italian Ministry of Health [ICS110.1/RF97.71]; US National Institute on Aging, Bethesda, MD [236 MD 916413, 236 MD 821336]; US National Institute on Aging [N.1-AG-1-1, N.1-AG-1-2111]; US National Institute on Aging - National Institute on Aging, National Institutes of Health [N01-AG-5-0002] FX Funding for this research was provided by EU FP7 MooD-FOOD Project 'Multi-country cOllaborative project on the rOle of Diet, FOod-related behaviour, and Obesity in the prevention of Depression', grant agreement no. 613598. The InCHIANTI study baseline (1998-2000) was funded by the Italian Ministry of Health (ICS110.1/RF97.71) and in part by the US National Institute on Aging, Bethesda, MD (contracts: 236 MD 916413 and 236 MD 821336). The InCHIANTI follow-up 1 (2001-2003) was funded by the US National Institute on Aging (contracts: N.1-AG-1-1 and N.1-AG-1-2111); the InCHIANTI follow-ups two and three (2004-2010) were financed by the US National Institute on Aging (contract: N01-AG-5-0002), supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 46 TC 0 Z9 0 U1 5 U2 9 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 EI 1475-2662 J9 BRIT J NUTR JI Br. J. Nutr. PD JUN 28 PY 2016 VL 115 IS 12 BP 2145 EP 2153 DI 10.1017/S0007114516001318 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DO7PB UT WOS:000377973400008 PM 27080555 ER PT J AU Nagaya, T Nakamura, Y Sato, K Harada, T Choyke, PL Kobayashi, H AF Nagaya, Tadanobu Nakamura, Yuko Sato, Kazuhide Harada, Toshiko Choyke, Peter L. Kobayashi, Hisataka TI Improved micro-distribution of antibody-photon absorber conjugates after initial near infrared photoimmunotherapy (NIR-PIT) SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE Photoimmunotherapy; Enhanced permeability and retention effect; Drug delivery; Micro distribution; Near infrared light ID PHOTODYNAMIC THERAPY; CANCER-CELLS; IN-VIVO; ENHANCED PERMEABILITY; TUMOR; MOUSE; CHEMOSENSITIVITY; METASTASIS; DELIVERY; CYCLE AB Near infrared photoimmunotherapy (NIR-PIT), a targeted cancer therapy which uses an antibody-photo absorber conjugate (APC) and near infrared light exposure, dramatically improves nano-drug delivery into treated tumor beds due to enhanced vascular permeability. We investigated the micro-distribution of APCs in a variety of NIR-PIT treated tumors. Either cetuximab (cet) or trastuzumab (tra) conjugated with IR700 (cet-tra-IR700) was administered, as appropriate, to each mouse model of tumor. Tumor-bearing mice implanted with A431-GFP, MDAMB468-GFP, 3T3Her2-GFP or N87-GFP were separated into 5 groups: group 1 = no treatment; group 2 = cet-tra-IR700 i.v., no light exposure; group 3 = cet-tra-IR700 i.v., NIR light exposure; group 4 = cet-tra-IR700 i.v. and additional cet-tra-IR700 i.v. at 24 h but no light exposure; group 5 = cet-tra-IR700 i.v., NIR light exposure and additional cet-tra-IR700 i.v. immediately after NIR but no additional NIR light exposure. In vivo, ex vivo and microscopic fluorescence imaging was performed. Fluorescence from the surface of the tumor (s-tumor) was compared to fluorescence from deeper areas of the tumor (d-tumor). In general, therewas no significant difference in the fluorescence intensity of GFP in the tumors among all groups, however the highest IR700 fluorescence intensity was consistently shown in group 5 tumors due to added APC after NIR-PIT. Fluorescence microscopy in all tumor types demonstrated that GFP relative fluorescence intensity (RFI) in s-tumor was significantly lower in group 3 and 5 (NIR-PIT groups) than in group 1, 2, and 4 (no NIR-PIT) yet there was no significant difference in d-tumor RFI among all groups. IR700 fluorescent RFI in the d-tumor was highest in group 5 (NIR-PIT + additional APC) compared to the other groups. Cell killing after NIR-PIT was primarily on the surface, however, APCs administered immediately after NIR-PIT penetrated deeper into tissue resulting in improved cell killing after a 2nd NIR-PIT session. This phenomenon is explained by increased vascular permeability immediately after NIR-PIT. Published by Elsevier B.V. C1 [Nagaya, Tadanobu; Nakamura, Yuko; Sato, Kazuhide; Harada, Toshiko; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research [ZIA BC 011513]; JSPS FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (ZIA BC 011513). Kazuhide Sato is supported with JSPS Research Fellowship for Japanese Biomedical and Behavioral Researchers at NIH. NR 25 TC 3 Z9 3 U1 12 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 EI 1873-4995 J9 J CONTROL RELEASE JI J. Control. Release PD JUN 28 PY 2016 VL 232 BP 1 EP 8 DI 10.1016/j.jconrel.2016.04.003 PG 8 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DN9LL UT WOS:000377401000001 PM 27059723 ER PT J AU Liu, JJ Liu, JY Chen, J Wu, YX Yan, P Ji, CD Wang, YX Xiang, DF Zhang, X Zhang, P Cui, YH Wang, JM Bian, XW Qian, F AF Liu, Jia-jia Liu, Jun-yan Chen, Jun Wu, Yi-xi Yan, Peng Ji, Cheng-dong Wang, Yan-xia Xiang, Dong-fang Zhang, Xia Zhang, Peng Cui, You-hong Wang, Ji Ming Bian, Xiu-wu Qian, Feng TI Scinderin promotes the invasion and metastasis of gastric cancer cells and predicts the outcome of patients SO CANCER LETTERS LA English DT Article DE Scinderin; Gastric cancer; Invasion; Metastasis; Filopodia; Cdc42 ID EPITHELIAL-MESENCHYMAL TRANSITION; SEVERING PROTEIN ADSEVERIN; HUMAN BLADDER-CANCER; MOLECULAR ARCHITECTURE; INHIBITS PROLIFERATION; ACTIN CYTOSKELETON; DIFFERENTIATION; FILOPODIA; MOTILITY; MIGRATION AB Invasion and metastasis are major malignant characteristics of human gastric cancer (GC), but the underlying molecular mechanisms are poorly understood. Recent studies have shown that scinderin (SCIN), an actin severing and capping protein that regulates the actin cytoskeleton, is involved in the proliferation and migration of certain cancer cells. Accordingly, this study aimed to investigate the potential role of SCIN in the invasion and metastasis of human GC cells and to evaluate its prognostic value for GC patients. We found that high levels of SCIN expression in GC tumors were correlated with poor overall survival of patients. Silencing of SCIN effectively suppressed the migratory and invasive capabilities of human GC cells in vitro and tumorigenicity and metastasis in vivo. Furthermore, knockdown of SCIN markedly inhibited the formation of filopodia, decreasing GC cell migration and the expression of Cdc42, an important regulator of filopodia by GC cells. These findings suggest that SCIN may be a novel prognostic marker and a potential therapeutic target in human GC. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Liu, Jia-jia; Liu, Jun-yan; Chen, Jun; Wu, Yi-xi; Yan, Peng; Qian, Feng] Third Mil Med Univ, Southwest Hosp, Dept Gen Surg, Chongqing 400038, Peoples R China. [Liu, Jia-jia; Liu, Jun-yan; Chen, Jun; Wu, Yi-xi; Yan, Peng; Qian, Feng] Third Mil Med Univ, Southwest Hosp, Ctr Minimal Invas Gastrointestinal Surg, Chongqing 400038, Peoples R China. [Ji, Cheng-dong; Wang, Yan-xia; Xiang, Dong-fang; Zhang, Xia; Zhang, Peng; Cui, You-hong; Wang, Ji Ming; Bian, Xiu-wu] Third Mil Med Univ, Southwest Hosp, Inst Pathol, Key Lab Tumor Immunopathol,Minist Educ China, Chongqing 400038, Peoples R China. [Ji, Cheng-dong; Wang, Yan-xia; Xiang, Dong-fang; Zhang, Xia; Zhang, Peng; Cui, You-hong; Wang, Ji Ming; Bian, Xiu-wu] Third Mil Med Univ, Southwest Hosp, Southwest Canc Ctr, Key Lab Tumor Immunopathol,Minist Educ China, Chongqing 400038, Peoples R China. [Wang, Ji Ming] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Qian, F (reprint author), Third Mil Med Univ, Southwest Hosp, Dept Gen Surg, Chongqing 400038, Peoples R China.; Qian, F (reprint author), Third Mil Med Univ, Southwest Hosp, Ctr Minimal Invas Gastrointestinal Surg, Chongqing 400038, Peoples R China.; Bian, XW (reprint author), Third Mil Med Univ, Southwest Hosp, Inst Pathol, Key Lab Tumor Immunopathol,Minist Educ China, Chongqing 400038, Peoples R China.; Bian, XW (reprint author), Third Mil Med Univ, Southwest Hosp, Southwest Canc Ctr, Key Lab Tumor Immunopathol,Minist Educ China, Chongqing 400038, Peoples R China. EM bianxiuwu@263.net; qianfengpuwaia@163.com RI Bian, Xiu-wu/D-4736-2017; Zhang, Xia/B-8152-2008 OI Bian, Xiu-wu/0000-0003-4383-0197; Zhang, Xia/0000-0002-9040-1486 FU National Science Foundation of China [81272365, 81372555] FX This project was supported by grants from the National Science Foundation of China (Nos. 81272365 and 81372555). We thank Prof. Pei-wu Yu (Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China) for supporting this work. We thank Mrs. Ze-xuan Yan (Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China) for technical assistance in cell culture. NR 42 TC 0 Z9 0 U1 3 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD JUN 28 PY 2016 VL 376 IS 1 BP 110 EP 117 DI 10.1016/j.canlet.2016.03.035 PG 8 WC Oncology SC Oncology GA DL8IP UT WOS:000375886000012 PM 27033455 ER PT J AU Surewaard, BGJ Deniset, JF Zemp, FJ Amrein, M Otto, M Conly, J Omri, A Yates, RM Kubes, P AF Surewaard, Bas G. J. Deniset, Justin F. Zemp, Franz J. Amrein, Matthias Otto, Michael Conly, John Omri, Abdelwahab Yates, Robin M. Kubes, Paul TI Identification and treatment of the Staphylococcus aureus reservoir in vivo SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID S. AUREUS; INFECTIONS; BACTEREMIA; VANCOMYCIN; MANAGEMENT; EPIDEMIOLOGY; PHAGOCYTOSIS; MACROPHAGES; NEUTROPHILS; ACTIVATION AB Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is reaching epidemic proportions causing morbidity, mortality, and chronic disease due to relapses, suggesting an intracellular reservoir. Using spinning-disk confocal intravital microscopy to track MRSA-GFP in vivo, we identified that within minutes after intravenous infection MRSA is primarily sequestered and killed by intravascular Kupffer cells (KCs) in the liver. However, a minority of the Staphylococci overcome the KC's antimicrobial defenses. These bacteria survive and proliferate for many days within this intracellular niche, where they remain undetected by recruited neutrophils. Over time, the KCs lyse, releasing bacteria into the circulation, enabling dissemination to other organs such as the kidneys. Vancomycin, the antibiotic of choice to treat MRSA bacteremia, could not penetrate the KCs to eradicate intracellular MRSA. However, based on the intravascular location of these specific macrophages, we designed a liposomal formulation of vancomycin that is efficiently taken up by KCs and diminished the intracellular MRSA. Targeting the source of the reservoir dramatically protected the liver but also dissemination to other organs, and prevented mortality. This vancomycin formulation strategy could help treat patients with Staphylococcal bacteremia without a need for novel antibiotics by targeting the previously inaccessible intracellular reservoir in KCs. C1 [Surewaard, Bas G. J.; Deniset, Justin F.; Zemp, Franz J.; Conly, John; Yates, Robin M.; Kubes, Paul] Univ Calgary, Snyder Inst Chron Dis, Calgary, AB T2N 1N4, Canada. [Amrein, Matthias] Univ Calgary, Dept Cell Biol & Anat, Calgary, AB T2N 1N4, Canada. [Conly, John] Univ Calgary, Dept Med, Cumming Sch Med, Calgary, AB T2N 1N4, Canada. [Conly, John] Univ Calgary, Dept Pathol & Lab Med, Calgary, AB T2N 1N4, Canada. [Conly, John] Univ Calgary, Dept Microbiol Infect Dis & Immunol, Calgary, AB T2N 1N4, Canada. [Yates, Robin M.] Univ Calgary, Dept Comparat Biol & Expt Med, Fac Vet Med, Calgary, AB T2N 1N4, Canada. [Kubes, Paul] Univ Calgary, Dept Physiol & Pharmacol, Calgary, AB T2N 1N4, Canada. [Surewaard, Bas G. J.] Univ Med Ctr, Dept Med Microbiol, NL-3584 CX Utrecht, Netherlands. [Otto, Michael] NIAID, Pathogen Mol Genet Sect, Bacteriol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Omri, Abdelwahab] Laurentian Univ, Dept Chem & Biochem, Sudbury, ON P3E 2C6, Canada. RP Kubes, P (reprint author), Univ Calgary, Snyder Inst Chron Dis, Calgary, AB T2N 1N4, Canada.; Kubes, P (reprint author), Univ Calgary, Dept Physiol & Pharmacol, Calgary, AB T2N 1N4, Canada. EM pkubes@ucalgary.ca RI Yates, Robin/K-5032-2015 OI Yates, Robin/0000-0003-3122-1845 FU Alberta Innovates Health Solutions (AIHS); Canadian Institutes of Health Research; Canada Research Chairs Program; Marie Currie actions FP7-PEOPLE-IOF [627575]; AIHS FX P. Kubes is supported by Alberta Innovates Health Solutions (AIHS), the Canadian Institutes of Health Research, and the Canada Research Chairs Program. B.G.J. Surewaard is partially funded by Marie Currie actions FP7-PEOPLE-2013-IOF (grant no. 627575) and AIHS. J.F. Deniset and F.J. Zemp are financially supported by AIHS. NR 33 TC 2 Z9 2 U1 7 U2 10 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JUN 27 PY 2016 VL 213 IS 7 BP 1141 EP 1151 DI 10.1084/jem.20160334 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DS5VA UT WOS:000380849800005 PM 27325887 ER PT J AU Avery, CL Holliday, KM Chakladar, S Engeda, JC Hardy, ST Reis, JP Schreiner, PJ Shay, CM Daviglus, ML Heiss, G Lin, DY Zeng, DL AF Avery, Christy L. Holliday, Katelyn M. Chakladar, Sujatro Engeda, Joseph C. Hardy, Shakia T. Reis, Jared P. Schreiner, Pamela J. Shay, Christina M. Daviglus, Martha L. Heiss, Gerardo Lin, Dan Yu Zeng, Donglin TI Disparities in Early Transitions to Obesity in Contemporary Multi-Ethnic US Populations SO PLOS ONE LA English DT Article ID BODY-MASS INDEX; UNITED-STATES; CARDIOVASCULAR-DISEASE; AMERICAN-INDIANS; YOUNG ADULTHOOD; WEIGHT-GAIN; MIDDLE-AGE; OVERWEIGHT; RISK; METAANALYSIS AB Background Few studies have examined weight transitions in contemporary multi-ethnic populations spanning early childhood through adulthood despite the ability of such research to inform obesity prevention, control, and disparities reduction. Methods and Results We characterized the ages at which African American, Caucasian, and Mexican American populations transitioned to overweight and obesity using contemporary and nationally representative cross-sectional National Health and Nutrition Examination Survey data (n = 21,220; aged 2-80 years). Age-, sex-, and race/ethnic-specific one-year net transition probabilities between body mass index-classified normal weight, overweight, and obesity were estimated using calibrated and validated Markov-type models that accommodated complex sampling. At age two, the obesity prevalence ranged from 7.3% in Caucasian males to 16.1% in Mexican American males. For all populations, estimated one-year overweight to obesity net transition probabilities peaked at age two and were highest for Mexican American males and African American females, for whom a net 12.3%(95% CI: 7.6%-17.0%) and 11.9% (95% CI: 8.5%-15.3%) of the overweight populations transitioned to obesity by age three, respectively. However, extrapolation to the 2010 U.S. population demonstrated that Mexican American males were the only population for whom net increases in obesity peaked during early childhood; age-specific net increases in obesity were approximately constant through the second decade of life for African Americans and Mexican American females and peaked at age 20 for Caucasians. Conclusions African American and Mexican American populations shoulder elevated rates of many obesity-associated chronic diseases and disparities in early transitions to obesity could further increase these inequalities if left unaddressed. C1 [Avery, Christy L.; Holliday, Katelyn M.; Engeda, Joseph C.; Hardy, Shakia T.; Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Chakladar, Sujatro; Lin, Dan Yu; Zeng, Donglin] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Reis, Jared P.] NHLBI, Epidemiol Branch, Populat & Prevent Sci Program, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Schreiner, Pamela J.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Shay, Christina M.] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Daviglus, Martha L.] Univ Illinois, Dept Med, Inst Minor Hlth Res, Chicago, IL USA. RP Avery, CL (reprint author), Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. EM Christy_avery@unc.edu FU National Heart, Lung, and Blood Institute (NHLBI) [AG0005]; University of Alabama at Birmingham [HHSN268201300025C, HHSN268201300026C]; Northwestern University [HHSN268201300027C]; University of Minnesota [HHSN268201300028C]; Kaiser Foundation Research Institute [HHSN268201300029C]; Johns Hopkins University School of Medicine [HHSN268200900041C]; Intramural Research Program of the National Institute on Aging (NIA); NIA [AG0005] FX This publication was made possible in part by R21HL121580, R00HL098458, and T32HL007055. The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham HHSN268201300025C & HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005). This manuscript has been reviewed by CARDIA for scientific content. NR 38 TC 0 Z9 0 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 27 PY 2016 VL 11 IS 6 AR e0158025 DI 10.1371/journal.pone.0158025 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP9FD UT WOS:000378801200028 PM 27348868 ER PT J AU Pierce, JV Bernstein, HD AF Pierce, Jessica V. Bernstein, Harris D. TI Genomic Diversity of Enterotoxigenic Strains of Bacteroides fragilis SO PLOS ONE LA English DT Article ID SECRETION SYSTEM EFFECTORS; HUMAN GUT; ANTIMICROBIAL RESISTANCE; PATHOGENICITY ISLAND; COLON CARCINOGENESIS; BACTERIAL BIOFILMS; TOXIN GENE; MICROBIOTA; SYMBIONT; METALLOPROTEASE AB Enterotoxigenic (ETBF) strains of Bacteroides fragilis are the subset of strains that secrete a toxin called fragilysin (Bft). Although ETBF strains are known to cause diarrheal disease and have recently been associated with colorectal cancer, they have not been well characterized. By sequencing the complete genome of four ETBF strains, we found that these strains exhibit considerable variation at the genomic level. Only a small number of genes that are located primarily in the Bft pathogenicity island (BFT PAI) and the flanking CTn86 conjugative transposon are conserved in all four strains and a fifth strain whose genome was previously sequenced. Interestingly, phylogenetic analysis strongly suggests that the BFT PAI was acquired by non-toxigenic (NTBF) strains multiple times during the course of evolution. At the phenotypic level, we found that the ETBF strains were less fit than the NTBF strain NCTC 9343 and were susceptible to a growth-inhibitory protein that it produces. The ETBF strains also showed a greater tendency to form biofilms, which may promote tumor formation, than NTBF strains. Although the genomic diversity of ETBF strains raises the possibility that they vary in their pathogenicity, our experimental results also suggest that they share common properties that are conferred by different combinations of non-universal genetic elements. C1 [Pierce, Jessica V.; Bernstein, Harris D.] NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Bernstein, HD (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM harris_bernstein@nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We would like to thank Cynthia Sears and Andy Goodman for the gift of B. fragilis strains and Harold Smith (NIDDK Genomics Core) for sequencing the genome of ETBF strain 2-078382-3 and providing bioinformatics support. We would also like to thank Marlena Wilson for the anti-TssD antiserum and for helpful discussions. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 52 TC 0 Z9 0 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 27 PY 2016 VL 11 IS 6 AR e0158171 DI 10.1371/journal.pone.0158171 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP9FD UT WOS:000378801200043 PM 27348220 ER PT J AU Wang, RH Zhao, TR Cui, KR Hu, GQ Chen, Q Chen, WP Wang, XW Soto-Gutierrez, A Zhao, KJ Deng, CX AF Wang, Rui-Hong Zhao, Tingrui Cui, Kairong Hu, Gangqing Chen, Qiang Chen, Weiping Wang, Xin-Wei Soto-Gutierrez, Alejandro Zhao, Keji Deng, Chu-Xia TI Negative reciprocal regulation between Sirt1 and Per2 modulates the circadian clock and aging SO SCIENTIFIC REPORTS LA English DT Article ID LIFE-SPAN; TUMOR-SUPPRESSOR; CALORIE RESTRICTION; DEACETYLASE SIRT1; MUTANT MICE; DNA-DAMAGE; P53; METABOLISM; RHYTHMS; PROTEIN AB Sirtuin 1 (SIRT1) is involved in both aging and circadian-clock regulation, yet the link between the two processes in relation to SIRT1 function is not clear. Using Sirt1-deficient mice, we found that Sirt1 and Period 2 (Per2) constitute a reciprocal negative regulation loop that plays important roles in modulating hepatic circadian rhythmicity and aging. Sirt1-deficient mice exhibited profound premature aging and enhanced acetylation of histone H4 on lysine16 (H4K16) in the promoter of Per2, the latter of which leads to its overexpression; in turn, Per2 suppresses Sirt1 transcription through binding to the Sirt1 promoter at the Clock/Bmal1 site. This negative reciprocal relationship between SIRT1 and PER2 was also observed in human hepatocytes. We further demonstrated that the absence of Sirt1 or the ectopic overexpression of Per2 in the liver resulted in a dysregulated pace of the circadian rhythm. The similar circadian rhythm was also observed in aged wild type mice. The interplay between Sirt1 and Per2 modulates aging gene expression and circadian-clock maintenance. C1 [Wang, Rui-Hong; Chen, Qiang; Deng, Chu-Xia] Univ Macau, Fac Hlth Sci, Macau, Peoples R China. [Wang, Rui-Hong; Zhao, Tingrui; Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Cui, Kairong; Hu, Gangqing; Zhao, Keji] NHLBI, Syst Biol Ctr, Bethesda, MD 20892 USA. [Chen, Weiping] NIDDK, Genom Core Lab, Bethesda, MD 20892 USA. [Wang, Xin-Wei] NCI, Lab Human Carcinogenesis, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Soto-Gutierrez, Alejandro] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. RP Deng, CX (reprint author), Univ Macau, Fac Hlth Sci, Macau, Peoples R China.; Deng, CX (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. EM cxdeng@umac.mo RI deng, chuxia/N-6713-2016; Wang, Xin/B-6162-2009 FU Intramural Research Program of the National Institute of DIDDK, National Institutes of Health, Bethesda, MD, USA; Intramural Research Program of the National Institute of NHLBI, National Institutes of Health, Bethesda, MD, USA; Intramural Research Program of the National Institute of NCI, National Institutes of Health, Bethesda, MD, USA; Faculty of Health Sciences, University of Macau, Macau SAR, China FX We gratefully acknowledge members of the Deng laboratory for helpful discussions. The ChIP-Seq libraries were sequenced by the DNA Sequencing and Computation Core facility of the National Heart, Lung, and Blood Institute (NHLBI). Freshly isolated human hepatocytes were obtained from the Liver Tissue Cell Distribution System at the University of Pittsburgh (Pittsburgh, PA). This work was supported, in part, by the Intramural Research Programs of the National Institute of DIDDK, NHLBI, and NCI, National Institutes of Health, Bethesda, MD, USA, as well as the Faculty of Health Sciences, University of Macau, Macau SAR, China. NR 57 TC 1 Z9 2 U1 3 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 27 PY 2016 VL 6 AR 28633 DI 10.1038/srep28633 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP5DD UT WOS:000378515300001 PM 27346580 ER PT J AU White, CL Kessler, PM Dickerman, BK Ozato, K Sen, GC AF White, Christine L. Kessler, Patricia M. Dickerman, Benjamin K. Ozato, Keiko Sen, Ganes C. TI Interferon Regulatory Factor 8 (IRF8) Impairs Induction of Interferon Induced with Tetratricopeptide Repeat Motif (IFIT) Gene Family Members SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE gene regulation; interferon; interferon regulatory factor (IRF); promoter; transcription regulation ID SEQUENCE-BINDING-PROTEIN; INDUCIBLE HUMAN GENES; RIG-I; TRANSCRIPTION FACTOR; ALPHA; MOUSE; ACTIVATION; EXPRESSION; COMPLEX; RNA AB The chromosomally clustered interferon-induced with tetratricopeptide repeat motif (IFIT) gene family members share structural features at the gene and protein levels. Despite these similarities, different IFIT genes have distinct inducer- and cell type-specific induction patterns. Here, we investigated the mechanism for the observed differential induction of the mouse Ifit1, Ifit2, and Ifit3 genes in B cells and demonstrated that the repressive effect of the transcription factor interferon regulatory factor 8 (IRF8), which is highly expressed in B cells, played an essential role in this regulation. Although IRF8 could impair induction of all three IFIT genes following stimulation of retinoic acid-inducible gene I (RIG-I), it could selectively impair the induction of the Ifit1 gene following IFN stimulation. The above properties could be imparted to IRF8-non-expressing cells by ectopic expression of the protein. Induction of reporter genes, driven by truncated Ifit1 promoters, identified the regions that mediate the repression, and a chromatin immunoprecipitation assay revealed that more IRF8 bound to the IFN-stimulated response element of the Ifit1 gene than to those of the Ifit2 and the Ifit3 genes. Mutational analyses of IRF8 showed that its ability to bind DNA, interact with other proteins, and undergo sumoylation were all necessary to selectively repress Ifit1 gene induction in response to IFN. Our study revealed a new role for IRFs in differentially regulating the induction patterns of closely related IFN-stimulated genes that are located adjacent to one another in the mouse genome. C1 [White, Christine L.; Kessler, Patricia M.; Dickerman, Benjamin K.; Sen, Ganes C.] Cleveland Clin, Lerner Res Inst, Dept Mol Genet, Cleveland, OH 44195 USA. [Dickerman, Benjamin K.; Sen, Ganes C.] Case Western Reserve Univ, Grad Program Mol Virol, Cleveland, OH 44106 USA. [Ozato, Keiko] NICHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Dickerman, Benjamin K.] Burnet Inst Med Res, Melbourne, Vic 3004, Australia. RP White, CL (reprint author), Hudson Inst Med Res, Ctr Canc Res, 27-31 Wright St, Clayton, Vic 3168, Australia.; Sen, GC (reprint author), Cleveland Clin, Dept Immunol NE20, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM christine.white@hudson.org.au; seng@ccf.org OI White, Christine/0000-0002-5920-0029 FU National Institutes of Health [CA068782, CA062220, AI073303] FX This work was supported by National Institutes of Health Grants CA068782, CA062220, and AI073303 (to G. C. S.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 40 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 24 PY 2016 VL 291 IS 26 BP 13535 EP 13545 DI 10.1074/jbc.M115.705467 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DR2YZ UT WOS:000379771100012 PM 27137933 ER PT J AU Graham, BS AF Graham, Barney S. TI Vaccines against respiratory syncytial virus: The time has finally come SO VACCINE LA English DT Article DE RSV; Immunization; Vaccination; Structure-based vaccine design; Fusion; Neutralization; Vaccine-enhanced illness; Bronchiolitis; Pneumonia; Infants; Elderly; Th2; Eosinophilia; Subunit vaccine; Vaccine vector; Wheezing; Asthma; Protein conformation; Epitope ID FUSION GLYCOPROTEIN; NEUTRALIZING ANTIBODY; RSV INFECTION; COTTON RATS; STRUCTURAL-ANALYSIS; ANTIGENIC STRUCTURE; DISEASE SEVERITY; ATYPICAL MEASLES; PRETERM INFANTS; FIELD TRIAL AB Respiratory syncytial virus causes a significant public health burden, particularly in very young infants and the frail elderly. The legacy of enhanced RSV disease (ERD) from a whole formalin-inactivated RSV vaccine, and the complex biology of the virus and the neonate have delayed the development of effective vaccines. However, new insights into factors associated with ERD and breakthroughs in understanding the antigenic structure of the fusion (F) glycoprotein have increased optimism that vaccine development is possible. This has led to investment of time and resources by industry, regulatory authorities, governments, and nonprofit organizations to develop the infrastructure needed to make the advanced clinical development of RSV vaccine candidates a reality. Published by Elsevier Ltd. C1 [Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Graham, BS (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bgraham@nih.gov FU Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by intramural funding from the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH. The author is a named inventor on patents for RSV vaccines involving subunit F proteins and gene-based vector delivery of F. I thank Jason Gall and Kaitlyn Morabito for thoughtful editorial comments on the manuscript. NR 93 TC 9 Z9 9 U1 7 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JUN 24 PY 2016 VL 34 IS 30 BP 3535 EP 3541 DI 10.1016/j.vaccine.2016.04.083 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DQ1IT UT WOS:000378955400015 PM 27182820 ER PT J AU Pine, PS Munro, SA Parsons, JR McDaniel, J Lucas, AB Lozach, J Myers, TG Su, Q Jacobs-Helber, SM Salit, M AF Pine, P. Scott Munro, Sarah A. Parsons, Jerod R. McDaniel, Jennifer Lucas, Anne Bergstrom Lozach, Jean Myers, Timothy G. Su, Qin Jacobs-Helber, Sarah M. Salit, Marc TI Evaluation of the External RNA Controls Consortium (ERCC) reference material using a modified Latin square design SO BMC BIOTECHNOLOGY LA English DT Article DE ERCC; Gene expression; Microarray; RNA controls; RNA sequencing; RNA-Seq; Spike-in controls ID GENE-EXPRESSION; SEQ EXPERIMENTS; DIFFERENTIAL GENE; DNA MICROARRAYS; TRANSCRIPTOME; AMPLIFICATION; PERFORMANCE; MODELS; NOISE; CELLS AB Background: Highly multiplexed assays for quantitation of RNA transcripts are being used in many areas of biology and medicine. Using data generated by these transcriptomic assays requires measurement assurance with appropriate controls. Methods to prototype and evaluate multiple RNA controls were developed as part of the External RNA Controls Consortium (ERCC) assessment process. These approaches included a modified Latin square design to provide a broad dynamic range of relative abundance with known differences between four complex pools of ERCC RNA transcripts spiked into a human liver total RNA background. Results: ERCC pools were analyzed on four different microarray platforms: Agilent 1- and 2-color, Illumina bead, and NIAID lab-made spotted microarrays; and two different second-generation sequencing platforms: the Life Technologies 5500xl and the Illumina HiSeq 2500. Individual ERCC controls were assessed for reproducible performance in signal response to concentration among the platforms. Most demonstrated linear behavior if they were not located near one of the extremes of the dynamic range. Performance issues with any individual ERCC transcript could be attributed to detection limitations, platform-specific target probe issues, or potential mixing errors. Collectively, these pools of spike-in RNA controls were evaluated for suitability as surrogates for endogenous transcripts to interrogate the performance of the RNA measurement process of each platform. The controls were useful for establishing the dynamic range of the assay, as well as delineating the useable region of that range where differential expression measurements, expressed as ratios, would be expected to be accurate. Conclusions: The modified Latin square design presented here uses a composite testing scheme for the evaluation of multiple performance characteristics: linear performance of individual controls, signal response within dynamic range pools of controls, and ratio detection between pairs of dynamic range pools. This compact design provides an economical sample format for the evaluation of multiple external RNA controls within a single experiment per platform. These results indicate that well-designed pools of RNA controls, spiked into samples, provide measurement assurance for endogenous gene expression studies. C1 [Pine, P. Scott; Munro, Sarah A.; Parsons, Jerod R.; McDaniel, Jennifer; Salit, Marc] NIST, Joint Initiat Metrol Biol, 443 Via Ortega, Stanford, CA 94305 USA. [Lucas, Anne Bergstrom] Agilent Technol, Genom Res & Dev, Santa Clara, CA 95051 USA. [Lozach, Jean] Illumina Inc, San Diego, CA 92122 USA. [Myers, Timothy G.; Su, Qin] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Jacobs-Helber, Sarah M.] AIBioTech Inc, Richmond, VA 23235 USA. [Jacobs-Helber, Sarah M.] GENETWORx LLC, Glen Allen, VA USA. RP Pine, PS (reprint author), NIST, Joint Initiat Metrol Biol, 443 Via Ortega, Stanford, CA 94305 USA. EM p.scott.pine@nist.gov FU Intramural Research Program of the NIH, NIAID FX This research was supported in part by the Intramural Research Program of the NIH, NIAID. NR 42 TC 1 Z9 1 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6750 J9 BMC BIOTECHNOL JI BMC Biotechnol. PD JUN 24 PY 2016 VL 16 AR 54 DI 10.1186/s12896-016-0281-x PG 15 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DP6FB UT WOS:000378591200003 PM 27342544 ER PT J AU Krushkal, J Zhao, YD Hose, C Monks, A Doroshow, JH Simon, R AF Krushkal, Julia Zhao, Yingdong Hose, Curtis Monks, Anne Doroshow, James H. Simon, Richard TI Concerted changes in transcriptional regulation of genes involved in DNA methylation, demethylation, and folate-mediated one-carbon metabolism pathways in the NCI-60 cancer cell line panel in response to cancer drug treatment SO CLINICAL EPIGENETICS LA English DT Article DE Gene expression; DNA methylation; Folate metabolism; Cancer drug treatment; Epigenetic analysis; NCI-60 cell lines ID LUNG-CANCER; COLORECTAL-CANCER; PROSTATE-CANCER; OVARIAN-CANCER; CISPLATIN RESISTANCE; BREAST-CANCER; HEPATOCELLULAR-CARCINOMA; EXPRESSION SIGNATURES; 1-CARBON METABOLISM; METHYLTRANSFERASE AB Background: Aberrant patterns of DNA methylation are abundant in cancer, and epigenetic pathways are increasingly being targeted in cancer drug treatment. Genetic components of the folate-mediated one-carbon metabolism pathway can affect DNA methylation and other vital cell functions, including DNA synthesis, amino acid biosynthesis, and cell growth. Results: We used a bioinformatics tool, the Transcriptional Pharmacology Workbench, to analyze temporal changes in gene expression among epigenetic regulators of DNA methylation and demethylation, and one-carbon metabolism genes in response to cancer drug treatment. We analyzed gene expression information from the NCI-60 cancer cell line panel after treatment with five antitumor agents, 5-azacytidine, doxorubicin, vorinostat, paclitaxel, and cisplatin. Each antitumor agent elicited concerted changes in gene expression of multiple pathway components across the cell lines. Expression changes of FOLR2, SMUG1, GART, GADD45A, MBD1, MTR, MTHFD1, and CTH were significantly correlated with chemosensitivity to some of the agents. Among many genes with concerted expression response to individual antitumor agents were genes encoding DNA methyltransferases DNMT1, DNMT3A, and DNMT3B, epigenetic and DNA repair factors MGMT, GADD45A, and MBD1, and one-carbon metabolism pathway members MTHFD1, TYMS, DHFR, MTR, MAT2A, SLC19A1, ATIC, and GART. Conclusions: These transcriptional changes are likely to influence vital cellular functions of DNA methylation and demethylation, cellular growth, DNA biosynthesis, and DNA repair, and some of them may contribute to cytotoxic and apoptotic action of the drugs. This concerted molecular response was observed in a time-dependent manner, which may provide future guidelines for temporal selection of genetic drug targets for combination drug therapy treatment regimens. C1 [Krushkal, Julia; Zhao, Yingdong; Simon, Richard] NCI, Biometr Res Program, Div Canc Treatment & Diag, 9609 Med Ctr Dr, Rockville, MD 20850 USA. [Hose, Curtis; Monks, Anne] Leidos Biomed Res Inc, Mol Pharmacol Grp, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Doroshow, James H.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Simon, R (reprint author), NCI, Biometr Res Program, Div Canc Treatment & Diag, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM richard.simon@nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 131 TC 0 Z9 0 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1868-7083 J9 CLIN EPIGENETICS JI Clin. Epigenetics PD JUN 24 PY 2016 VL 8 AR 73 DI 10.1186/s13148-016-0240-3 PG 24 WC Oncology SC Oncology GA DP6GN UT WOS:000378595400001 PM 27347216 ER PT J AU Anson, ER Bigelow, RT Carey, JP Xue, QL Studenski, S Schubert, MC Agrawal, Y AF Anson, Eric R. Bigelow, Robin T. Carey, John P. Xue, Qian-Li Studenski, Stephanie Schubert, Michael C. Agrawal, Yuri TI VOR Gain Is Related to Compensatory Saccades in Healthy Older Adults SO FRONTIERS IN AGING NEUROSCIENCE LA English DT Article DE VOR; compensatory saccades; healthy aging; head impulse test; vestibular ID HEAD IMPULSE TEST; CATCH-UP SACCADES; VESTIBULOOCULAR REFLEX; VIDEO-OCULOGRAPHY; EYE-MOVEMENTS; DISORDERS; NYSTAGMUS; RESPONSES; ACCURACY; SIGN AB Objective: Vestibulo-ocular reflex (VOR) gain is well-suited for identifying rotational vestibular dysfunction, but may miss partial progressive decline in age-related vestibular function. Since compensatory saccades might provide an alternative method for identifying subtle vestibular decline, we describe the relationship between VOR gain and compensatory saccades in healthy older adults. Methods: Horizontal VOR gain was measured in 243 subjects age 60 and older from the Baltimore Longitudinal Study of Aging using video head impulse testing (HIT). Saccades in each HIT were identified as either "compensatory" or "compensatory backup," i.e., same or opposite direction as the VOR response respectively. Saccades were also classified as "covert" (occurring during head movement) and "overt" (occurring after head movement). The relationship between VOR gain and percentage of HITs with saccades, as well as the relationship between VOR gain and saccade latency and amplitude, were evaluated using regression analyses adjusting for age, gender, and race. Results: In adjusted analyses, the percentage of HITs with compensatory saccades increased 4.5% for every 0.1 decrease in VOR gain (p < 0.0001). Overt compensatory saccade amplitude decreased 0.6 (p 0.005) and latency increased 90 ms (p < 0.001) for every 0.1 increase in VOR gain. Covert back-up compensatory saccade amplitude increased 0.4 for every 0.1 increase in VOR gain. Conclusion: We observed significant relationships between VOR gain and compensatory saccades in healthy older adults. Lower VOR gain was associated with larger amplitude, shorter latency compensatory saccades. Compensatory saccades reflect underlying rotational vestibular hypofunction, and may be particularly useful at identifying partial vestibular deficits as occur in aging adults. C1 [Anson, Eric R.; Bigelow, Robin T.; Carey, John P.; Schubert, Michael C.; Agrawal, Yuri] Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. [Xue, Qian-Li] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Xue, Qian-Li] Johns Hopkins Med Inst, Ctr Aging & Hlth, Baltimore, MD 21205 USA. [Studenski, Stephanie] NIA, Longitudinal Studies Sect, Baltimore, MD 21224 USA. RP Anson, ER (reprint author), Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. EM eanson1@jhmi.edu FU NIDCD [K23 DC013056, T32 DC000023] FX Supported in part by NIDCD K23 DC013056 and NIDCD T32 DC000023. NR 30 TC 1 Z9 1 U1 1 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1663-4365 J9 FRONT AGING NEUROSCI JI Front. Aging Neurosci. PD JUN 24 PY 2016 VL 8 AR 150 DI 10.3389/fnagi.2016.00150 PG 10 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA DP5KJ UT WOS:000378534800001 PM 27445793 ER PT J AU Zou, SM Caler, L Colombini-Hatch, S Glynn, S Srinivas, P AF Zou, Shimian Caler, Lis Colombini-Hatch, Sandra Glynn, Simone Srinivas, Pothur TI Research on the human virome: where are we and what is next SO MICROBIOME LA English DT Article DE Microbiome; Virome; Heart; Lung; Blood; HIV ID PARVOVIRUS B19 INFECTION; BLOOD SAFETY; NATIONAL HEART; ENTERIC VIROME; DISEASE; TRANSFUSION; VIRUSES; PROGRESS; DONOR; LUNG AB The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health convened a Working Group on the Microbiome in Cardiovascular, Pulmonary and Hematologic Health and Diseases from June 25, 2014, to June 26, 2014. The Working Group's central goal was to define what major microbiome research areas warranted additional study in the context of heart, lung, and blood (HLB) diseases. The Working Group identified studies of the human virome a key priority. C1 [Zou, Shimian; Caler, Lis; Colombini-Hatch, Sandra; Glynn, Simone; Srinivas, Pothur] NHLBI, NIH, 6701,Rockledge Dr,Room 9144, Bethesda, MD 20892 USA. RP Zou, SM (reprint author), NHLBI, NIH, 6701,Rockledge Dr,Room 9144, Bethesda, MD 20892 USA. EM shimian.zou@nih.gov NR 41 TC 1 Z9 1 U1 10 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2049-2618 J9 MICROBIOME JI Microbiome PD JUN 24 PY 2016 VL 4 AR 32 DI 10.1186/s40168-016-0177-y PG 4 WC Microbiology SC Microbiology GA DP6QG UT WOS:000378622000002 PM 27341799 ER PT J AU Hosseini-Vasoukolaei, N Idali, F Khamesipour, A Yaghoobi-Ershadi, MR Kamhawi, S Valenzuela, JG Edalatkhah, H Arandian, MH Mirhendi, H Emami, S Jafari, R Saeidi, Z Jeddi-Tehrani, M Akhavan, AA AF Hosseini-Vasoukolaei, Nasibeh Idali, Farah Khamesipour, Ali Yaghoobi-Ershadi, Mohammad Reza Kamhawi, Shaden Valenzuela, Jesus G. Edalatkhah, Haleh Arandian, Mohammad Hossein Mirhendi, Hossein Emami, Shaghayegh Jafari, Reza Saeidi, Zahra Jeddi-Tehrani, Mahmood Akhavan, Amir Ahmad TI Differential expression profiles of the salivary proteins SP15 and SP44 from Phlebotomus papatasi SO PARASITES & VECTORS LA English DT Article DE Salivary gene expression; Phlebotomus papatasi; PpSP15; PpSP44; Iran ID ZOONOTIC CUTANEOUS LEISHMANIASIS; LUTZOMYIA-LONGIPALPIS COMPLEX; SAND-FLY SALIVA; JORDAN VALLEY; VISCERAL LEISHMANIASIS; IMMUNE-RESPONSE; GLAND PROTEINS; ENDEMIC AREA; CENTRAL IRAN; PSYCHODIDAE AB Background: Sand fly saliva has been shown to help parasite establishment and to induce immune responses in vertebrate hosts. In the current study, we investigated the pattern of expression of two Phlebotomus papatasi salivary transcripts in specific physiological and seasonal conditions at a hyperendemic area of zoonotic cutaneous leishmaniasis (ZCL) in Iran. Methods: Sand flies were collected during 2012-2013, and grouped according to physiological stages such as unfed, fed, semi-gravid, gravid, parous, nulliparous, infected or non-infected with Leishmania major and also based on the season in which they were collected. Quantitative Real-Time PCR was applied for assessment of the expression of two relevant salivary transcripts, PpSP15 and PpSP44, associated to protection from and exacerbation of ZCL, respectively. Results: The expression of PpSP15 and PpSP44 transcripts was significantly up-regulated (1.74 and 1.4 folds, respectively) in blood fed compared to unfed flies. Among four groups of fed, unfed, semi-gravid and gravid flies, the lowest levels of PpSP15 and PpSP44 expression were observed in gravid flies. Additionally, the expression levels of both PpSP15 and PpSP44 transcripts in P. papatasi collected during summer were significantly up-regulated (3.7 and 4.4 folds, respectively) compared to spring collections. In addition, the PpSP15 transcript exhibited a significant up-regulation (P < 0.05) in non-infected flies compared to those infected with L. major. Conclusions: This study contributes to our knowledge of the differential expression of salivary genes among different groups within a P. papatasi population under natural field conditions. Cutaneous and visceral leishmaniasis are of public health importance in many parts of Iran and neighbouring countries where P. papatasi is the proven and dominant sand fly vector for ZCL, the most prevalent and endemic form of the disease in Iran. Therefore, the current study could be helpful in understanding the influence of salivary genes on Leishmania transmission by phlebotomine sand flies. Our findings demonstrate the differential expression of salivary transcripts under various physiological conditions potentially influencing the sand fly capacity for parasite transmission as well as the outcome of disease. C1 [Hosseini-Vasoukolaei, Nasibeh; Yaghoobi-Ershadi, Mohammad Reza; Saeidi, Zahra; Akhavan, Amir Ahmad] Univ Tehran Med Sci, Sch Publ Hlth, Dept Med Entomol & Vector Control, Tehran, Iran. [Hosseini-Vasoukolaei, Nasibeh] Mazandaran Univ Med Sci, Fac Hlth, Dept Med Entomol & Vector Control, Hlth Sci Res Ctr, Sari, Iran. [Idali, Farah] ACECR, Avicenna Res Inst, Reprod Immunol Res Ctr, Tehran, Iran. [Khamesipour, Ali] Univ Tehran Med Sci, Ctr Res & Training Skin Dis & Leprosy, Tehran, Iran. [Kamhawi, Shaden; Valenzuela, Jesus G.] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Edalatkhah, Haleh] ACECR, Avicenna Res Inst, Reprod Biotechnol Res Ctr, Tehran, Iran. [Arandian, Mohammad Hossein; Jafari, Reza] Univ Tehran Med Sci, Natl Inst Hlth Res, Esfahan Hlth Res Stn, Esfahan, Iran. [Mirhendi, Hossein] Isfahan Univ Med Sci, Sch Med, Dept Med Mycol & Parasitol, Esfahan, Iran. [Emami, Shaghayegh; Jeddi-Tehrani, Mahmood] ACECR, Avicenna Res Inst, Monoclonal Antibody Res Ctr, Tehran, Iran. RP Akhavan, AA (reprint author), Univ Tehran Med Sci, Sch Publ Hlth, Dept Med Entomol & Vector Control, Tehran, Iran.; Jeddi-Tehrani, M (reprint author), ACECR, Avicenna Res Inst, Monoclonal Antibody Res Ctr, Tehran, Iran. EM mahjed@avicenna.ac.ir; aaakhavan@tums.ac.ir FU Tehran University of Medical Sciences (TUMS) [18511/16.5.2012]; Avicenna Research Institute; ACECR [910206-018] FX This work was supported by Research deputy of Tehran University of Medical Sciences (TUMS), Project No. 18511/16.5.2012 and Avicenna Research Institute, ACECR, Project No. 910206-018. We thank Dr. Shabani for his helpful comments, Ms. Babaei, Ms. Balaei and Mr. Hadavi for their technical support, from Avicenna Research Institute, ACECR. We are very grateful to Ms. Shareghi, Esfahan Health Research Station, National Institute of Health Research, TUMS, for her assistance in the project. We are grateful to Ms. Ahmadi and Ms. Bolandian, School of Public Health, TUMS, for their assistance in sand fly rearing. NR 46 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD JUN 24 PY 2016 VL 9 AR 357 DI 10.1186/s13071-016-1633-z PG 10 WC Parasitology SC Parasitology GA DP9RC UT WOS:000378833500001 PM 27342811 ER PT J AU Long, MT Pedley, A Massaro, JM Hoffmann, U Fox, CS AF Long, Michelle T. Pedley, Alison Massaro, Joseph M. Hoffmann, Udo Fox, Caroline S. TI The Association between Non-Invasive Hepatic Fibrosis Markers and Cardiometabolic Risk Factors in the Framingham Heart Study SO PLOS ONE LA English DT Article ID FATTY LIVER-DISEASE; INCREASED ARTERIAL STIFFNESS; PULSE PRESSURE; NONALCOHOLIC STEATOHEPATITIS; DIAGNOSIS; BIOPSY; ADULTS AB Background & Aims Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular related death, particularly in those with hepatic fibrosis. We determined the prevalence of predicted fibrosis based on non-invasive fibrosis markers and the association of hepatic fibrosis with cardiovascular risk factors. Methods Cross-sectional study of 575 Framingham Heart Study participants with NAFLD based on computed tomography. We determined the prevalence of predicted fibrosis based on the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, AST to platelet ratio index (APRI), the Fibrosis-4 score (FIB4), and the NAFLD Fibrosis Score (NFS). Using multivariable logistic regression models, we examined the association between low, indeterminate, or high risk for fibrosis according to the NFS and various cardiometabolic risk factors. Results The predicted risk of fibrosis was 12%, 4%, 5%, and 32% for the NFS, FIB4, APRI, and AST/ALT ratio, respectively. In multivariable models, participants with a high risk for advanced fibrosis by the NFS had a wider pulse pressure (adjusted mean difference = 6.87 mm Hg; p = 0.0002) and an increased odds of hypertension (OR 2.92; p = 0.007) compared to those with low risk of fibrosis. There were no statistically significant differences between other cardiovascular risk factors for those with a high versus low risk of fibrosis. Conclusions The AST/ALT ratio, APRI, and NFS give widely disparate predictions of liver fibrosis. Participants with a high risk for fibrosis based on NFS had wider pulse pressure and increased odds of hypertension. Whether modifying these risk factors impacts cardiovascular endpoints in NAFLD patients remains unknown. C1 [Long, Michelle T.] Boston Univ, Sch Med, Div Gastroenterol, Boston Med Ctr, Boston, MA 02118 USA. [Long, Michelle T.; Pedley, Alison; Massaro, Joseph M.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Pedley, Alison] Merck Res Labs, Kenilworth, NJ USA. [Massaro, Joseph M.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol Hypertens & Metab, Boston, MA 02115 USA. RP Long, MT (reprint author), Boston Univ, Sch Med, Div Gastroenterol, Boston Med Ctr, Boston, MA 02118 USA.; Long, MT (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA. EM mtlong@bu.edu OI Long, Michelle/0000-0001-6131-3981 FU Boston University School of Medicine; National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195, HHSN268201500001I]; Division of Intramural Research of the National Heart, Lung, and Blood Institute FX This work was supported by the Boston University School of Medicine and the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract N01-HC-25195 and HHSN268201500001I), and the Division of Intramural Research of the National Heart, Lung, and Blood Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Alison Pedley is an employee of Merck. The funder provided support in the form of salaries for authors [AP], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. NR 31 TC 2 Z9 2 U1 2 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 24 PY 2016 VL 11 IS 6 AR e0157517 DI 10.1371/journal.pone.0157517 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP3KZ UT WOS:000378393600008 PM 27341207 ER PT J AU Heman-Ackah, SM Bassett, AR Wood, MJA AF Heman-Ackah, Sabrina Mahalia Bassett, Andrew Roger Wood, Matthew John Andrew TI Precision Modulation of Neurodegenerative Disease-Related Gene Expression in Human iPSC-Derived Neurons SO SCIENTIFIC REPORTS LA English DT Article ID PLURIPOTENT STEM-CELLS; ALPHA-SYNUCLEIN LOCUS; FAMILIAL PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; LEWY BODIES; CAS9; CRISPR; SPECIFICITY; ACTIVATION; DEMENTIA AB The ability to reprogram adult somatic cells into induced pluripotent stem cells (iPSCs) and the subsequent development of protocols for their differentiation into disease-relevant cell types have enabled in-depth molecular analyses of multiple disease states as hitherto impossible. Neurons differentiated from patient-specific iPSCs provide a means to recapitulate molecular phenotypes of neurodegenerative diseases in vitro. However, it remains challenging to conduct precise manipulations of gene expression in iPSC-derived neurons towards modeling complex human neurological diseases. The application of CRISPR/Cas9 to mammalian systems is revolutionizing the utilization of genome editing technologies in the study of molecular contributors to the pathogenesis of numerous diseases. Here, we demonstrate that CRISPRa and CRISPRi can be used to exert precise modulations of endogenous gene expression in fate-committed iPSC-derived neurons. This highlights CRISPRa/i as a major technical advancement in accessible tools for evaluating the specific contributions of critical neurodegenerative disease-related genes to neuropathogenesis. C1 [Heman-Ackah, Sabrina Mahalia; Wood, Matthew John Andrew] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QX, England. [Heman-Ackah, Sabrina Mahalia] NIH, NIH Oxford Cambridge Scholars Program, Bldg 10, Bethesda, MD 20892 USA. [Heman-Ackah, Sabrina Mahalia] Univ N Carolina, UNC MD PhD Program, Chapel Hill, NC 27599 USA. [Bassett, Andrew Roger] Univ Oxford, Sir William Dunn Sch Pathol, Genome Engn Oxford, S Parks Rd, Oxford OX1 3RE, England. [Bassett, Andrew Roger] Wellcome Trust Sanger Inst, Wellcome Genome Campus, Cambridge CB10 1SA, England. RP Heman-Ackah, SM (reprint author), Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QX, England.; Heman-Ackah, SM (reprint author), NIH, NIH Oxford Cambridge Scholars Program, Bldg 10, Bethesda, MD 20892 USA.; Heman-Ackah, SM (reprint author), Univ N Carolina, UNC MD PhD Program, Chapel Hill, NC 27599 USA. EM hemanackah.sabrina@gmail.com FU NIH Oxford-Cambridge Scholars Program; University of North Carolina at Chapel Hill MD-PhD Program; Oxford University John Fell Fund; Cure Parkinson's Trust; Wellcome Trust Institutional Strategic Support Fund (ISSF) FX The authors would like to thank Wilfried Haerty for help with analysis of CAGE data and Natasha Gromak and Nick Proudfoot for helpful discussions. We would also like to acknowledge the NIH Center for Regenerative Medicine (NIH CRM) for providing valuable study materials, including NCRM-1 (NIH CRM), NCRM-5 (NIH CRM), ND34391G (Coriell) and ND38477C (Coriell) iPSCs and NCRM-5 iPSC-derived NSCs. NHDF-1 iPSCs were a kind gift from Sally Cowley of the James Martin Stem Cell Facility. The pAC154-dual-dCas9VP160-sgExpression vector was a gift from Rudolf Jaenisch (Addgene #48240), and the SP-dCas9-VPR vector was a gift from George Church (Addgene #63798). S.M.H.-A. is supported by the NIH Oxford-Cambridge Scholars Program and the University of North Carolina at Chapel Hill MD-PhD Program. Awards to S.M.H.-A. and M.J.A.W. from the Oxford University John Fell Fund and Cure Parkinson's Trust provided core support for this project. Awards to A.R.B. from the Oxford University John Fell Fund and Wellcome Trust Institutional Strategic Support Fund (ISSF) further supported the work presented in this manuscript. NR 58 TC 2 Z9 2 U1 4 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 24 PY 2016 VL 6 AR 28420 DI 10.1038/srep28420 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP4QF UT WOS:000378479900001 PM 27341390 ER PT J AU Devambatla, RKV Namjoshi, OA Choudhary, S Hamel, E Shaffer, CV Rohena, CC Mooberry, SL Gangjee, A AF Devambatla, Ravi Kumar Vyas Namjoshi, Ojas A. Choudhary, Shruti Hamel, Ernest Shaffer, Corena V. Rohena, Cristina C. Mooberry, Susan L. Gangjee, Aleem TI Design, Synthesis, and Preclinical Evaluation of 4-Substituted-5-methyl-furo[2,3-d]pyrimidines as Microtubule Targeting Agents That Are Effective against Multidrug Resistant Cancer Cells SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID III BETA-TUBULIN; COMBRETASTATIN A4 PHOSPHATE; I CLINICAL-TRIAL; BREAST-CANCER; LUNG-CANCER; COLCHICINE SITE; OVARIAN-CANCER; BINDING-SITE; ANTICANCER DRUGS; ANTITUMOR AGENTS AB The design, synthesis, and biological evaluations of eight 4-substituted 5-methyl-furo[2,3-d]pyrimidines are reported. Synthesis involved N-4-alkylation of N-aryl-5-methylfuro[2,3-d]pyrimidin-4-amines, obtained from Ullmann coupling of 4-amino-5-methylfuro[2,3-d]pyrimidine and appropriate aryl iodides. Compounds 3, 4, and 9 showed potent microtubule depolymerizing activities, while compounds 6-8 had slightly lower potency. Compounds 4, 6, 7, and 9 inhibited tubulin assembly with IC50 values comparable to that of combretastatin A-4 (CA-4). Compounds 3, 4, and 6-9 circumvented Pgp and beta III-tubulin mediated drug resistance, mechanisms that can limit the efficacy of paclitaxel, docetaxel, and the vinca alkaloids. In the NCI 60-cell line panel, compound 3 exhibited GI(50) values less than 10 nM in 47 of the cell lines. In an MDA-MB-435 xenograft model, compound 3 had statistically significant antitumor effects. The biological effects of 3 identify it as a novel, potent microtubule depolymerizing agent with antitumor activity. C1 [Devambatla, Ravi Kumar Vyas; Namjoshi, Ojas A.; Choudhary, Shruti; Gangjee, Aleem] Duquesne Univ, Grad Sch Pharmaceut Sci, Div Med Chem, 600 Forbes Ave, Pittsburgh, PA 15282 USA. [Shaffer, Corena V.; Rohena, Cristina C.; Mooberry, Susan L.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, Dept Pharmacol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. [Hamel, Ernest] NCI, Screening Technol Branch,Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, NIH, Frederick, MD 21702 USA. [Namjoshi, Ojas A.] RTI Int, Ctr Drug Discovery, 3040 E Cornwallis Rd, Res Triangle Pk, NC 27709 USA. RP Gangjee, A (reprint author), Duquesne Univ, Grad Sch Pharmaceut Sci, Div Med Chem, 600 Forbes Ave, Pittsburgh, PA 15282 USA. EM mooberry@uthscsa.edu; gangjee@duq.edu FU National Institutes of Health, National Cancer Institute [CA142868]; President's Council Research Excellence Award; Duquesne University Adrian Van Kaam Chair in Scholarly Excellence; CTRC Cancer Center Support Grant [P30 CA054174]; Flow Cytometry Shared Resource; NSF [NMR: CHE 0614785] FX We acknowledge the National Cancer Institute Developmental Therapeutics Program for performing the in vitro evaluation in the NCI 60-cell line panel. This work was supported, in part, by a grant from the National Institutes of Health, National Cancer Institute (CA142868 (to A.G., S.L.M.)); by the President's Council Research Excellence Award (to S.L.M.), Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (to A.G.); the CTRC Cancer Center Support Grant P30 CA054174 and the Flow Cytometry Shared Resource; and by an NSF equipment grant for NMR instrumentation (NMR: CHE 0614785). We thank Mr. Arpit Doshi, Duquesne University, for the NMR analysis of compound 2. NR 51 TC 2 Z9 2 U1 14 U2 19 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD JUN 23 PY 2016 VL 59 IS 12 BP 5752 EP 5765 DI 10.1021/acs.jmedchem.6b00237 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DP7EV UT WOS:000378662900012 PM 27213719 ER PT J AU Domanova, W Krycer, J Chaudhuri, R Yang, PY Vafaee, F Fazakerley, D Humphrey, S James, D Kuncic, Z AF Domanova, Westa Krycer, James Chaudhuri, Rima Yang, Pengyi Vafaee, Fatemeh Fazakerley, Daniel Humphrey, Sean James, David Kuncic, Zdenka TI Unraveling Kinase Activation Dynamics Using Kinase-Substrate Relationships from Temporal Large-Scale Phosphoproteomics Studies SO PLOS ONE LA English DT Article ID INSULIN-RESISTANCE; ELONGATION-FACTOR-2 KINASE; PHOSPHORYLATION NETWORKS; PROTEIN; REVEALS; PATTERNS; SURVIVAL; DATABASE; COMPLEX; SITES AB In response to stimuli, biological processes are tightly controlled by dynamic cellular signaling mechanisms. Reversible protein phosphorylation occurs on rapid time-scales (milliseconds to seconds), making it an ideal carrier of these signals. Advances in mass spectrometry-based proteomics have led to the identification of many tens of thousands of phosphorylation sites, yet for the majority of these the kinase is unknown and the underlying network topology of signaling networks therefore remains obscured. Identifying kinase substrate relationships (KSRs) is therefore an important goal in cell signaling research. Existing consensus sequence motif based prediction algorithms do not consider the biological context of KSRs, and are therefore insensitive to many other mechanisms guiding kinase-substrate recognition in cellular contexts. Here, we use temporal information to identify biologically relevant KSRs from Large-scale In Vivo Experiments (KSR-LIVE) in a data-dependent and automated fashion. First, we used available phosphorylation databases to construct a repository of existing experimentally-predicted KSRs. For each kinase in this database, we used time-resolved phosphoproteomics data to examine how its substrates changed in phosphorylation over time. Although substrates for a particular kinase clustered together, they often exhibited a different temporal pattern to the phosphorylation of the kinase. Therefore, although phosphorylation regulates kinase activity, our findings imply that substrate phosphorylation likely serve as a better proxy for kinase activity than kinase phosphorylation. KSR-LIVE can thereby infer which kinases are regulated within a biological context. Moreover, KSR-LIVE can also be used to automatically generate positive training sets for the subsequent prediction of novel KSRs using machine learning approaches. We demonstrate that this approach can distinguish between Akt and Rps6kb1, two kinases that share the same linear consensus motif, and provide evidence suggesting IRS-1 S265 as a novel Akt site. KSR-LIVE is an open-access algorithm that allows users to dissect phosphorylation signaling within a specific biological context, with the potential to be included in the standard analysis workflow for studying temporal high-throughput signal transduction data. C1 [Domanova, Westa; Krycer, James; Chaudhuri, Rima; Vafaee, Fatemeh; Fazakerley, Daniel; James, David; Kuncic, Zdenka] Univ Sydney, Charles Perkins Ctr, Sydney, NSW 2006, Australia. [Domanova, Westa; Kuncic, Zdenka] Univ Sydney, Sch Phys, Sydney, NSW 2006, Australia. [Krycer, James; Chaudhuri, Rima; Fazakerley, Daniel; James, David] Univ Sydney, Sch Life & Environm Sci, Sydney, NSW 2006, Australia. [Yang, Pengyi] NIEHS, NIH, Durham, NC 27709 USA. [Vafaee, Fatemeh] Univ Sydney, Sch Math & Stat, Sydney, NSW 2006, Australia. [Humphrey, Sean] Max Planck Inst Biochem, Dept Prote & Signal Transduct, Klopferspitz 18A, D-82152 Martinsried, Germany. [James, David] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. RP James, D; Kuncic, Z (reprint author), Univ Sydney, Charles Perkins Ctr, Sydney, NSW 2006, Australia.; Kuncic, Z (reprint author), Univ Sydney, Sch Phys, Sydney, NSW 2006, Australia.; James, D (reprint author), Univ Sydney, Sch Life & Environm Sci, Sydney, NSW 2006, Australia.; James, D (reprint author), Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. EM david.james@sydney.edu.au; zdenka.kuncic@sydney.edu.au OI Yang, Pengyi/0000-0003-1098-3138 FU NHMRC [GNT1061122]; Australian Postgraduate Award scholarship FX This work is supported by the NHMRC (project grant GNT1061122). DJ is an NHMRC Senior Principal Research Fellow. JK is an NHMRC Early Career Fellow. WD is supported by an Australian Postgraduate Award scholarship. NR 42 TC 1 Z9 1 U1 8 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 23 PY 2016 VL 11 IS 6 AR e0157763 DI 10.1371/journal.pone.0157763 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP3JL UT WOS:000378389200041 PM 27336693 ER PT J AU Ho, R Siddiqui, MM George, AK Frye, T Kilchevsky, A Fascelli, M Shakir, NA Chelluri, R Abboud, SF Walton-Diaz, A Sankineni, S Merino, MJ Turkbey, B Choyke, PL Wood, BJ Pinto, PA AF Ho, Richard Siddiqui, Mohummad M. George, Arvin K. Frye, Thomas Kilchevsky, Amichai Fascelli, Michele Shakir, Nabeel A. Chelluri, Raju Abboud, Steven F. Walton-Diaz, Annerleim Sankineni, Sandeep Merino, Maria J. Turkbey, Baris Choyke, Peter L. Wood, Bradford J. Pinto, Peter A. TI Preoperative Multiparametric Magnetic Resonance Imaging Predicts Biochemical Recurrence in Prostate Cancer after Radical Prostatectomy SO PLOS ONE LA English DT Article ID ANTIGEN RECURRENCE; OUTCOMES; RISK; GUIDELINES; MORTALITY; FAILURE; UTILITY; BIOPSY; MRI AB Objectives To evaluate the utility of preoperative multiparametric magnetic resonance imaging (MP-MRI) in predicting biochemical recurrence (BCR) following radical prostatectomy (RP). Materials/Methods From March 2007 to January 2015, 421 consecutive patients with prostate cancer (PCa) underwent preoperative MP-MRI and RP. BCR-free survival rates were estimated using the Kaplan-Meier method. Cox proportional hazards models were used to identify clinical and imaging variables predictive of BCR. Logistic regression was performed to generate a nomogram to predict three-year BCR probability. Results Of the total cohort, 370 patients met inclusion criteria with 39 (10.5%) patients experiencing BCR. On multivariate analysis, preoperative prostate-specific antigen (PSA) (p = 0.01), biopsy Gleason score (p = 0.0008), MP-MRI suspicion score (p = 0.03), and extracapsular extension on MP-MRI (p = 0.03) were significantly associated with time to BCR. A nomogram integrating these factors to predict BCR at three years after RP demonstrated a c-index of 0.84, outperforming the predictive value of Gleason score and PSA alone (c-index 0.74, p = 0.02). Conclusion The addition of MP-MRI to standard clinical factors significantly improves prediction of BCR in a post-prostatectomy PCa cohort. This could serve as a valuable tool to support clinical decision-making in patients with moderate and high-risk cancers. C1 [Ho, Richard; Siddiqui, Mohummad M.; George, Arvin K.; Frye, Thomas; Kilchevsky, Amichai; Fascelli, Michele; Shakir, Nabeel A.; Chelluri, Raju; Abboud, Steven F.; Walton-Diaz, Annerleim; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Sankineni, Sandeep; Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Wood, Bradford J.] NCI, Ctr Intervent Oncol, NIH, Bethesda, MD 20892 USA. [Siddiqui, Mohummad M.] Univ Maryland, Dept Surg, Div Urol, Baltimore, MD 21201 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 FU Center for Cancer Research; Center for Interventional Oncology; NIH; Intramural Research Program of the National Institutes of Health, National Cancer Institute; Pfizer Inc.; Doris Duke Charitable Foundation; Alexandria Real Estate Equities, Inc.; Howard Hughes Medical Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, the Center for Cancer Research, and the Center for Interventional Oncology. NIH and Philips Healthcare/Invivo Corp. have a cooperative research and development agreement. NIH and Philips share intellectual property in the field. This research was also made possible through the National Institutes of Health Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc., The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities, Inc. and Mr. and Mrs. Joel S. Marcus, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the Foundation website at: http://fnih.org/what-we-do/current-education-and-training-programs/mrsp. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 1 Z9 1 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 23 PY 2016 VL 11 IS 6 AR e0157313 DI 10.1371/journal.pone.0157313 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP3JL UT WOS:000378389200015 PM 27336392 ER PT J AU Malachowa, N Kobayashi, SD Porter, AR Braughton, KR Scott, DP Gardner, DJ Missiakas, DM Schneewind, O Deleo, FR AF Malachowa, Natalia Kobayashi, Scott D. Porter, Adeline R. Braughton, Kevin R. Scott, Dana P. Gardner, Donald J. Missiakas, Dominique M. Schneewind, Olaf Deleo, Frank R. TI Contribution of Staphylococcus aureus Coagulases and Clumping Factor A to Abscess Formation in a Rabbit Model of Skin and Soft Tissue Infection SO PLOS ONE LA English DT Article ID FACTOR-BINDING-PROTEIN; INTRAVENOUS INJECTION; VASCULAR-PERMEABILITY; CUTANEOUS INFECTIONS; IMMUNE-RESPONSES; MOUSE MODEL; FACTOR-I; VIRULENCE; SURFACE; ROLES AB Staphylococcus aureus produces numerous factors that facilitate survival in the human host. S. aureus coagulase (Coa) and von Willebrand factor-binding protein (vWbp) are known to clot plasma through activation of prothrombin and conversion of fibrinogen to fibrin. In addition, S. aureus clumping factor A (ClfA) binds fibrinogen and contributes to platelet aggregation via a fibrinogen-or complement-dependent mechanism. Here, we evaluated the contribution of Coa, vWbp and ClfA to S. aureus pathogenesis in a rabbit model of skin and soft tissue infection. Compared to skin abscesses caused by the Newman wild-type strain, those caused by isogenic coa, vwb, or clfA deletion strains, or a strain deficient in coa and vwb, were significantly smaller following subcutaneous inoculation in rabbits. Unexpectedly, we found that fibrin deposition and abscess capsule formation appear to be independent of S. aureus coagulase activity in the rabbit infection model. Similarities notwithstanding, S. aureus strains deficient in coa and vwb elicited reduced levels of several proinflammatory molecules in human blood in vitro. Although a specific mechanism remains to be determined, we conclude that S. aureus Coa, vWbp and ClfA contribute to abscess formation in rabbits. C1 [Malachowa, Natalia; Kobayashi, Scott D.; Porter, Adeline R.; Braughton, Kevin R.; Deleo, Frank R.] NIAID, Bacteriol Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Scott, Dana P.; Gardner, Donald J.] NIAID, Rocky Mt Vet Branch, Rocky Mt Labs, NIH, Hamilton, MT USA. [Missiakas, Dominique M.; Schneewind, Olaf] Univ Chicago, Dept Microbiol, Chicago, IL 60637 USA. RP Deleo, FR (reprint author), NIAID, Bacteriol Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX Support was provided by Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 53 TC 1 Z9 1 U1 2 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 23 PY 2016 VL 11 IS 6 AR e0158293 DI 10.1371/journal.pone.0158293 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP3JL UT WOS:000378389200129 PM 27336691 ER PT J AU Spensieri, F Siena, E Borgogni, E Zedda, L Cantisani, R Chiappini, N Schiavetti, F Rosa, D Castellino, F Montomoli, E Bodinham, CL Lewis, DJ Medini, D Bertholet, S Del Giudice, G AF Spensieri, Fabiana Siena, Emilio Borgogni, Erica Zedda, Luisanna Cantisani, Rocco Chiappini, Nico Schiavetti, Francesca Rosa, Domenico Castellino, Flora Montomoli, Emanuele Bodinham, Caroline L. Lewis, David J. Medini, Duccio Bertholet, Sylvie Del Giudice, Giuseppe TI Early Rise of Blood T Follicular Helper Cell Subsets and Baseline Immunity as Predictors of Persisting Late Functional Antibody Responses to Vaccination in Humans SO PLOS ONE LA English DT Article ID CXC CHEMOKINE RECEPTOR-5; MEMORY TFH CELLS; GERMINAL-CENTERS; H1N1 VACCINE; B-CELLS; INFLUENZA; EXPRESSION; NONRESPONDERS; CORRELATE; TRIAL AB CD4(+) T follicular helper cells (T-FH) have been identified as the T-cell subset specialized in providing help to B cells for optimal activation and production of high affinity antibody. We recently demonstrated that the expansion of peripheral blood influenza-specific CD4(+) IL-21(+) ICOS1(+) T helper (T-H) cells, three weeks after vaccination, associated with and predicted the rise of protective neutralizing antibodies to avian H5N1. In this study, healthy adults were vaccinated with plain seasonal trivalent inactivated influenza vaccine (TIIV), MF59 (R)-adjuvanted TIIV (ATIIV), or saline placebo. Frequencies of circulating CD4(+) T(FH)1 ICOS+ T-FH cells and H1N1-specific CD4(+-) IL-21(+) ICOS+ CXCR5(+) T-FH and CXCR5-T-H cell subsets were determined at various time points after vaccination and were then correlated with hemagglutination inhibition (HI) titers. All three CD4(+) T cell subsets expanded in response to TIIV and ATIIV, and peaked 7 days after vaccination. To demonstrate that these T-FH cell subsets correlated with functional antibody titers, we defined an alternative endpoint metric, decorrelated HI (DHI), which removed any correlation between day 28/day 168 and day 0 HI titers, to control for the effect of preexisting immunity to influenza vaccine strains. The numbers of total circulating CD4(+) T(FH)1 ICOS+ cells and of H1N1-specific CD4(+)IL-21(+)ICOS(+)CXCR5(+), measured at day 7, were significantly associated with day 28, and day 28 and 168 DHI titers, respectively. Altogether, our results show that CD4(+) T-FH subsets may represent valuable biomarkers of vaccine-induced long-term functional immunity. C1 [Spensieri, Fabiana; Siena, Emilio; Borgogni, Erica; Zedda, Luisanna; Cantisani, Rocco; Chiappini, Nico; Schiavetti, Francesca; Rosa, Domenico; Castellino, Flora; Medini, Duccio; Bertholet, Sylvie; Del Giudice, Giuseppe] Novartis Vaccines & Diagnost Srl, Siena, Italy. [Montomoli, Emanuele] Univ Siena, Dept Mol & Dev Med, Siena, Italy. [Montomoli, Emanuele] VisMederi Srl, Siena, Italy. [Bodinham, Caroline L.; Lewis, David J.] Univ Surrey, Surrey Clin Res Ctr, Guildford GU2 5XH, Surrey, England. [Spensieri, Fabiana; Siena, Emilio; Borgogni, Erica; Zedda, Luisanna; Chiappini, Nico; Schiavetti, Francesca; Rosa, Domenico; Medini, Duccio; Bertholet, Sylvie; Del Giudice, Giuseppe] GSK Vaccines Srl, Siena, Italy. [Cantisani, Rocco] Univ Hosp, Lab Immunohematol, Pisa, Italy. [Castellino, Flora] NHLBI, Ctr Human Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Bertholet, S (reprint author), Novartis Vaccines & Diagnost Srl, Siena, Italy.; Bertholet, S (reprint author), GSK Vaccines Srl, Siena, Italy. EM sylvie.c.bertholet-girardin@gsk.com RI Medini, Duccio/Q-9556-2016 OI Medini, Duccio/0000-0001-6041-2603 FU Innovative Medicines Initiative Joint Undertaking [115308]; European Union's Seventh Framework Programme; EFPIA companies' FX These studies were funded by the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115308, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in kind contribution. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 1 Z9 1 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 23 PY 2016 VL 11 IS 6 AR e0157066 DI 10.1371/journal.pone.0157066 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP3JL UT WOS:000378389200009 PM 27336786 ER PT J AU Roschewski, M Roschewski, M Staudt, LM Wilson, WH AF Roschewski, Mark Roschewski, Mark Staudt, Louis M. Wilson, Wyndham H. TI Dynamic monitoring of circulating tumor DNA in non-Hodgkin lymphoma SO BLOOD LA English DT Article ID B-CELL LYMPHOMA; MINIMAL RESIDUAL DISEASE; CANCER-PATIENTS; FOLLICULAR LYMPHOMA; PROGNOSTIC VALUE; FDG-PET; THERAPY; REMISSION; BLOOD; CT AB Response assessment in lymphoma relies on imaging scans that do not capture biologic processes at the molecular level. Monitoring circulating tumor DNA(ctDNA) with next-generation sequencing-based assays can detect recurrent disease prior to scans and "liquid biopsies" for somatic mutations address tumor heterogeneity, clonal evolution, and mechanisms of resistance to guide precision treatment. Preanalytic collection and processing procedures should be validated and standardized. We describe emerging applications of ctDNA monitoring including real-time analysis of tumor dynamics, preclinical disease detection, and precision-directed treatment paradigms. C1 [Roschewski, Mark; Roschewski, Mark; Staudt, Louis M.; Wilson, Wyndham H.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10,Room 4N-115, Bethesda, MD 20892 USA. RP Roschewski, M (reprint author), NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10,Room 4N-115, Bethesda, MD 20892 USA. EM mark.roschewski@nih.gov FU National Institutes of Health FX We acknowledge support from the intramural research program of the National Institutes of Health, especially Kieron Dunleavy and the research team. Alan Hoofring and S. Peter Wu are acknowledged for illustration support. NR 44 TC 5 Z9 5 U1 7 U2 15 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUN 23 PY 2016 VL 127 IS 25 BP 3127 EP 3132 DI 10.1182/blood-2016-03-635219 PG 6 WC Hematology SC Hematology GA DP2RK UT WOS:000378337700006 PM 27081097 ER PT J AU Toubiana, J Okada, S Hiller, J Oleastro, M Gomez, ML Becerra, JCA Ouachee-Chardin, M Fouyssac, F Girisha, KM Etzioni, A Van Montfrans, J Camcioglu, Y Kerns, LA Belohradsky, B Blanche, S Bousfiha, A Rodriguez-Gallego, C Meyts, I Kisand, K Reichenbach, J Renner, ED Rosenzweig, S Grimbacher, B van de Veerdonk, FL Traidl-Hoffmann, C Picard, C Marodi, L Morio, T Kobayashi, M Lilic, D Milner, JD Holland, S Casanova, JL Puel, A AF Toubiana, Julie Okada, Satoshi Hiller, Julia Oleastro, Matias Lagos Gomez, Macarena Aldave Becerra, Juan Carlos Ouachee-Chardin, Marie Fouyssac, Fanny Girisha, Katta Mohan Etzioni, Amos Van Montfrans, Joris Camcioglu, Yildiz Kerns, Leigh Ann Belohradsky, Bernd Blanche, Stephane Bousfiha, Aziz Rodriguez-Gallego, Carlos Meyts, Isabelle Kisand, Kai Reichenbach, Janine Renner, Ellen D. Rosenzweig, Sergio Grimbacher, Bodo van de Veerdonk, Frank L. Traidl-Hoffmann, Claudia Picard, Capucine Marodi, Laszlo Morio, Tomohiro Kobayashi, Masao Lilic, Desa Milner, Joshua D. Holland, Steven Casanova, Jean-Laurent Puel, Anne CA STAT1 Gain Function Study Grp TI Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype SO BLOOD LA English DT Article ID CHRONIC MUCOCUTANEOUS CANDIDIASIS; HYPER-IGE SYNDROME; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; AICARDI-GOUTIERES-SYNDROME; FUNCTION SIGNAL TRANSDUCER; HOMOZYGOUS CARD9 MUTATION; AUTOSOMAL-DOMINANT GAIN; CYTOKINE GM-CSF; SYNDROME TYPE-I; INBORN-ERRORS AB Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-Guerin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism(22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms(6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis. C1 [Toubiana, Julie] Necker Enfants Malades Hosp, AP HP, Dept Gen Pediat & Pediat Infect Dis, Paris, France. [Toubiana, Julie; Blanche, Stephane; Casanova, Jean-Laurent; Puel, Anne] Paris Descartes Univ, Sorbonne Paris Cite, Inst Imagine, Paris, France. [Toubiana, Julie; Picard, Capucine; Casanova, Jean-Laurent; Puel, Anne] Necker Med Sch, Lab Human Genet Infect Dis, Necker Branch, INSERM,UMR1163, Paris, France. [Toubiana, Julie; Blanche, Stephane; Picard, Capucine] Necker Enfants Malades Hosp, AP HP, Pediat Hematol Immunol Rheumatol Unit, Paris, France. [Okada, Satoshi; Casanova, Jean-Laurent; Puel, Anne] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA. [Okada, Satoshi; Kobayashi, Masao] Hiroshima Univ, Grad Sch Biomed & Hlth Sci, Dept Pediat, Hiroshima, Japan. [Hiller, Julia; Traidl-Hoffmann, Claudia] Tech Univ, UNIKA T, Inst Environm Med, Augsburg, Germany. [Hiller, Julia; Traidl-Hoffmann, Claudia] Helmholtz Ctr Munich, Augsburg, Germany. [Hiller, Julia; Traidl-Hoffmann, Claudia] CK CARE, Davos, Switzerland. [Oleastro, Matias] Juan Pedro Garrahan Natl Hosp Pediat, Immunol & Reumatholoy Dept, Buenos Aires, DF, Argentina. [Lagos Gomez, Macarena] Univ Valparaiso, Sch Med, Dept Preclin, Valparaiso, Chile. [Lagos Gomez, Macarena] Padre Hurtado Clin Alemana Santiago Hosp, Valparaiso, Chile. [Aldave Becerra, Juan Carlos] Edgardo Rebagliati Martins Natl Hosp, Allergy & Immunol Div, Lima, Peru. [Ouachee-Chardin, Marie] Robert Debre Hosp, AP HP, Pediat Hematol Oncol Unit, Paris, France. [Fouyssac, Fanny] Children Hosp, Pediat Oncol & Hematol Unit, Vandoeuvre Les Nancy, France. [Girisha, Katta Mohan] Manipal Univ, Kasturba Med Coll, Dept Med Genet, Manipal, India. [Etzioni, Amos] Meyer Childrens Hosp, Haifa, Israel. [Van Montfrans, Joris] Univ Utrecht, Med Ctr, Dept Pediat Immunol Hematol & Infect Dis, Utrecht, Netherlands. [Camcioglu, Yildiz] Istanbul Univ, Cerrahpasa Med Sch, Infect Dis Clin Immunol & Allergy Div, Dept Pediat, Istanbul, Turkey. [Kerns, Leigh Ann] Rainbow Babies & Childrens Hosp, Case Med Ctr, Div Pediat Pulmonol Allergy Immunol & Sleep Med, 2101 Adelbert Rd, Cleveland, OH 44106 USA. [Belohradsky, Bernd; Renner, Ellen D.] Univ Munich, Dr von Hauner Childrens Hosp, Munich, Germany. [Bousfiha, Aziz] King Hassan II Univ, Ibn Rochd Hosp, Dept Pediat Infect Dis, Clin Immunol Unit, Casablanca, Morocco. [Rodriguez-Gallego, Carlos] Son Espases Univ Hosp, Dept Immunol, Palma de Mallorca, Spain. [Meyts, Isabelle] Leuven Univ Hosp, Dept Pediat, Leuven, Belgium. [Kisand, Kai] Univ Tartu, Inst Biomed & Translat Med, Ulikooli 18, EE-50090 Tartu, Estonia. [Reichenbach, Janine] Univ Zurich, Univ Childrens Hosp, Div Immunol, Zurich, Switzerland. [Reichenbach, Janine] Univ Zurich, Childrens Res Ctr, Zurich, Switzerland. [Rosenzweig, Sergio; Holland, Steven] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Grimbacher, Bodo] Univ Freiburg, Med Ctr, Ctr Chron Immunodeficiency, Hugstetter Str 55, D-79106 Freiburg, Germany. [Grimbacher, Bodo] Univ Freiburg, Hugstetter Str 55, D-79106 Freiburg, Germany. [van de Veerdonk, Frank L.] Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis, Dept Internal Med, NL-6525 ED Nijmegen, Netherlands. [Picard, Capucine] Necker Enfants Malades Hosp, AP HP, Study Ctr Immunodeficiencies, Paris, France. [Marodi, Laszlo] Univ Debrecen, Fac Med, Dept Infect Dis & Pediat Immunol, Debrecen, Hungary. [Morio, Tomohiro] Tokyo Med & Dent Univ, Dept Pediat & Dev Biol, Tokyo, Japan. [Lilic, Desa] Newcastle Univ, Inst Cellular Med, Primary Immunodeficiency Grp, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Milner, Joshua D.] NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Casanova, Jean-Laurent] Howard Hughes Med Inst, New York, NY USA. [Puel, Anne] Necker Enfants Malades Hosp, AP HP, Dept Infect & Trop Dis, Paris, France. RP Puel, A (reprint author), Necker Enfants Malades Hosp, AP HP, Dept Infect & Trop Dis, Paris, France.; Puel, A (reprint author), Necker Enfants Malades Hosp, Lab Human Genet Infect Dis, Necker Branch, INSERM,UMR1163,Imagine Inst, 24 Blvd Montparnasse, F-75015 Paris, France. EM anne.puel@inserm.fr RI Okada, Satoshi/B-8901-2011; Kisand, Kai/J-3483-2015; OI Okada, Satoshi/0000-0002-4622-5657; Kisand, Kai/0000-0002-5426-4648; Traidl-Hoffmann, Claudia/0000-0001-5085-5179 FU French National Research Agency (ANR) under the "Investments for the future" program [ANR-10-IAHU-01]; French National Research Agency (ANR) under GENCMCD grant [ANR-11-BSV3-005-01]; French National Research Agency (ANR) under HGDIFD [ANR-14-CE15-0006]; French National Research Agency (ANR) under Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases [ANR-10-LABX-62-IBEID]; INSERM; University Paris Descartes; Jeffrey Modell Foundation-Translational Research Program; Jeffrey Modell Centers Network; Rockefeller University; St. Giles Foundation; National Institute of Allergy and Infectious Diseases, National Institutes of Health [U01AI109697]; ERA-Net for Research Programmes on Rare Diseases "E-RARE EURO CMC" [ANR-14-RARE-0005-02]; Helmholtz Center grant DZIF [8000805-3_TTU_IICH 07.801]; Gebert Ruf Stiftung-programme Rare Diseases-New Approaches, EUFP7 CELL-PID, EUFP7 NET4CGD, ZIHP; Ministerio de Sanidad, Spain from the Regional Development Fund-European Social Fund (FEDER-FSE) [PI13/1456] FX The Laboratory of Human Genetics of Infectious Diseases was supported by the French National Research Agency (ANR) under the "Investments for the future" program (ANR-10-IAHU-01), GENCMCD grant (ANR-11-BSV3-005-01), HGDIFD (ANR-14-CE15-0006), and Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases (#ANR-10-LABX-62-IBEID); INSERM; University Paris Descartes; the Jeffrey Modell Foundation-Translational Research Program; the Jeffrey Modell Centers Network; the Rockefeller University; the St. Giles Foundation; and the National Institute of Allergy and Infectious Diseases, National Institutes of Health (grant U01AI109697). This work was also supported by the ERA-Net for Research Programmes on Rare Diseases "E-RARE EURO CMC" (ANR-14-RARE-0005-02). B.G. was supported by the Helmholtz Center grant DZIF (8000805-3_TTU_IICH 07.801). J.R. was supported by Gebert Ruf Stiftung-programme Rare Diseases-New Approaches, EUFP7 CELL-PID, EUFP7 NET4CGD, ZIHP. C.R.-G. was supported by the Ministerio de Sanidad, Spain (grant PI13/1456), from the Regional Development Fund-European Social Fund (FEDER-FSE). NR 88 TC 13 Z9 13 U1 3 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUN 23 PY 2016 VL 127 IS 25 BP 3154 EP 3164 DI 10.1182/blood-2015-11-679902 PG 11 WC Hematology SC Hematology GA DP2RK UT WOS:000378337700009 PM 27114460 ER PT J AU Le Gall, SM Szabo, R Lee, M Kirchhofer, D Craik, CS Bugge, TH Camerer, E AF Le Gall, Sylvain M. Szabo, Roman Lee, Melody Kirchhofer, Daniel Craik, Charles S. Bugge, Thomas H. Camerer, Eric TI Matriptase activation connects tissue factor-dependent coagulation initiation to epithelial proteolysis and signaling SO BLOOD LA English DT Article ID SERINE-PROTEASE MATRIPTASE; HEPATOCYTE GROWTH-FACTOR; EPIDERMAL BARRIER FUNCTION; FACTOR CYTOPLASMIC DOMAIN; NEURAL-TUBE CLOSURE; CANINE KIDNEY-CELLS; ENDOTHELIAL-CELLS; FACTOR VIIA; RECEPTOR 2; BLOOD-COAGULATION AB The coagulation cascade is designed to sense tissue injury by physical separation of the membrane-anchored cofactor tissue factor (TF) from inactive precursors of coagulation proteases circulating in plasma. Once TF on epithelial and other extravascular cells is exposed to plasma, sequential activation of coagulation proteases coordinates hemostasis and contributes to host defense and tissue repair. Membrane-anchored serine proteases (MASPs) play critical roles in the development and homeostasis of epithelial barrier tissues; how MASPs are activated in mature epithelia is unknown. We here report that proteases of the extrinsic pathway of blood coagulation transactivate the MASP matriptase, thus connecting coagulation initiation to epithelial proteolysis and signaling. Exposure of TF-expressing cells to factors (F) VIIa and Xa triggered the conversion of latent pro-matriptase to an active protease, which in turn cleaved the pericellular substrates protease-activated receptor-2 (PAR2) and pro-urokinase. An activation pathway-selective PAR2 mutant resistant to direct cleavage by TF: FVIIa and FXa was activated by these proteases when cells co-expressed pro-matriptase, and matriptase transactivation was necessary for efficient cleavage and activation of wild-type PAR2 by physiological concentrations of TF: FVIIa and FXa. The coagulation initiation complex induced rapid and prolonged enhancement of the barrier function of epithelial monolayers that was dependent on matriptase transactivation andPAR2signaling. These observations suggest that the coagulation cascade engages matriptase to help coordinate epithelial defense and repair programs after injury or infection, and that matriptase may contribute to TF-driven pathogenesis in cancer and inflammation. C1 [Le Gall, Sylvain M.; Camerer, Eric] Paris Cardiovasc Res Ctr, INSERM, U970, 56 Rue Leblanc, F-75015 Paris, France. [Le Gall, Sylvain M.; Camerer, Eric] Univ Paris 05, Paris, France. [Szabo, Roman; Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Lee, Melody; Craik, Charles S.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA USA. [Kirchhofer, Daniel] Genentech Inc, Dept Early Discovery Biochem, San Francisco, CA 94080 USA. RP Camerer, E (reprint author), Paris Cardiovasc Res Ctr, INSERM, U970, 56 Rue Leblanc, F-75015 Paris, France. EM eric.camerer@inserm.fr FU INSERM Avenir; Marie Curie Actions [IRG-249193]; French National Research Agency [ANR-10-MIDI-0003, ANR-15-CE14-0009]; Ile-de-France Region; US Department of Defense [PC 11318]; National Institute of Dental and Craniofacial Research Intramural Research Program FX This work was funded by INSERM Avenir, Marie Curie Actions (IRG-249193), the French National Research Agency (ANR-10-MIDI-0003, ANR-15-CE14-0009), the Ile-de-France Region (E.C.), the US Department of Defense PC 11318 (C.S.C.) and by the National Institute of Dental and Craniofacial Research Intramural Research Program (T.H.B.). NR 81 TC 2 Z9 2 U1 4 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUN 23 PY 2016 VL 127 IS 25 BP 3260 EP 3269 DI 10.1182/blood-2015-11-683110 PG 10 WC Hematology SC Hematology GA DP2RK UT WOS:000378337700019 PM 27114461 ER PT J AU Zhao, WD Hamid, E Shin, W Wen, PJ Krystofiak, ES Villarreal, SA Chiang, HC Kachar, B Wu, LG AF Zhao, Wei-Dong Hamid, Edaeni Shin, Wonchul Wen, Peter J. Krystofiak, Evan S. Villarreal, Seth A. Chiang, Hsueh-Cheng Kachar, Bechara Wu, Ling-Gang TI Hemi-fused structure mediates and controls fusion and fission in live cells SO NATURE LA English DT Article ID MEMBRANE FISSION; CHROMAFFIN CELLS; CA2+-TRIGGERED EXOCYTOSIS; SNARE COMPLEX; PORES; VESICLES; ENDOCYTOSIS; TOMOGRAPHY; PROTEINS; INTERMEDIATE AB Membrane fusion and fission are vital for eukaryotic life(1-5). For three decades, it has been proposed that fusion is mediated by fusion between the proximal leaflets of two bilayers (hemi-fusion) to produce a hemi-fused structure, followed by fusion between the distal leaflets, whereas fission is via hemi-fission, which also produces a hemi-fused structure, followed by full fission(1,4,6-10). This hypothesis remained unsupported owing to the lack of observation of hemi-fusion or hemi-fission in live cells. A competing fusion hypothesis involving protein-lined pore formation has also been proposed(2,11-15). Here we report the observation of a hemi-fused Omega-shaped structure in live neuroendocrine chromaffin cells and pancreatic beta-cells, visualized using confocal and super-resolution stimulated emission depletion microscopy. This structure is generated from fusion pore opening or closure (fission) at the plasma membrane. Unexpectedly, the transition to full fusion or fission is determined by competition between fusion and calcium/dynamin-dependent fission mechanisms, and is notably slow (seconds to tens of seconds) in a substantial fraction of the events. These results provide key missing evidence in support of the hemi-fusion and hemi-fission hypothesis in live cells, and reveal the hemi-fused intermediate as a key structure controlling fusion and fission, as fusion and fission mechanisms compete to determine the transition to fusion or fission. C1 [Zhao, Wei-Dong; Hamid, Edaeni; Shin, Wonchul; Wen, Peter J.; Villarreal, Seth A.; Chiang, Hsueh-Cheng; Wu, Ling-Gang] NINDS, 35 Convent Dr,Room 2B-1012, Bethesda, MD 20892 USA. [Krystofiak, Evan S.; Kachar, Bechara] NIDCD, 35A Convent Dr,Room 3D-824, Bethesda, MD 20892 USA. [Chiang, Hsueh-Cheng] Natl Cheng Kung Univ, Dept Pharmacol, Coll Med, 1 Univ Rd, Tainan 701, Taiwan. RP Wu, LG (reprint author), NINDS, 35 Convent Dr,Room 2B-1012, Bethesda, MD 20892 USA. EM wul@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke Intramural Research Program [ZIA NS003009-13, ZIA NS003105-08]; National Institute on Deafness and Other Communication Disorders (NIDCD) Intramural Research Program [Z01-DC000002]; National Institute on Deafness and Other Communication Disorders (NIDCD) Intramural Research Program (NIDCD Advanced Imaging Core ZIC) [DC000081] FX We thank T. Balla, G. Miesenbock, and D.-S. Wang for providing the construct containing the GFP-fused PH domain of PLC delta 1, the VAMP2-pHluorin construct, and dynamin siRNA, respectively; C. Smith for technical support with STED microscopy; and S. Cheng and V. Crocker for their electron microscopy technical support. This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program (ZIA NS003009-13 and ZIA NS003105-08) and National Institute on Deafness and Other Communication Disorders (NIDCD) Intramural Research Program (Z01-DC000002 and NIDCD Advanced Imaging Core ZIC DC000081). NR 34 TC 9 Z9 9 U1 13 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUN 23 PY 2016 VL 534 IS 7608 BP 548 EP + DI 10.1038/nature18598 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP1SS UT WOS:000378270300053 PM 27309816 ER PT J AU Gottschalk, RA Martins, AJ Angermann, BR Dutta, B Ng, CE Uderhardt, S Tsang, JS Fraser, IDC Meier-Schellersheim, M Germain, RN AF Gottschalk, Rachel A. Martins, Andrew J. Angermann, Bastian R. Dutta, Bhaskar Ng, Caleb E. Uderhardt, Stefan Tsang, John S. Fraser, Iain D. C. Meier-Schellersheim, Martin Germain, Ronald N. TI Distinct NF-kappa B and MAPK Activation Thresholds Uncouple Steady- State Microbe Sensing from Anti-pathogen Inflammatory Responses SO CELL SYSTEMS LA English DT Article ID GENOME-WIDE ASSOCIATION; BOWEL-DISEASE; SUSCEPTIBILITY LOCI; COLORECTAL-CANCER; IMMUNE ACTIVATION; INNATE IMMUNITY; TNF; RECOGNITION; PATHWAYS; LIPOPOLYSACCHARIDE AB The innate immune system distinguishes low-level homeostatic microbial stimuli from those of invasive pathogens, yet we lack understanding of how qualitatively similar microbial products yield context-specific macrophage functional responses. Using quantitative approaches, we found that NF-kappa B and MAPK signaling was activated at different concentrations of a stimulatory TLR4 ligand in both mouse and human macrophages. Above a threshold of ligand, MAPK were activated in a switch-like manner, facilitating production of inflammatory mediators. At ligand concentrations below this threshold, NF-kappa B signaling occurred, promoting expression of a restricted set of genes and macrophage priming. Among TLR-induced genes, we observed an inverse correlation between MAPK dependence and ligand sensitivity, highlighting the role of this signaling dichotomy in partitioning innate responses downstream of a single receptor. Our study reveals an evolutionarily conserved innate immune response system in which danger discrimination is enforced by distinct thresholds for NF-kappa B and MAPK activation, which provide sequential barriers to inflammatory mediator production. C1 [Gottschalk, Rachel A.; Dutta, Bhaskar; Ng, Caleb E.; Uderhardt, Stefan; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Martins, Andrew J.; Tsang, John S.] NIAID, Syst Genom & Bioinformat Unit, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Angermann, Bastian R.; Meier-Schellersheim, Martin] NIAID, Computat Biol Sect, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ng, Caleb E.] Univ Penn, Immunol Grad Grp, Philadelphia, PA 19104 USA. [Fraser, Iain D. C.] NIAID, Signaling Syst Unit, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Dutta, Bhaskar] AstraZeneca, Adv Analyt Ctr, Gaithersburg, MD 20878 USA. RP Gottschalk, RA; Germain, RN (reprint author), NIAID, Lymphocyte Biol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gottschalkra@niaid.nih.gov; rgermain@niaid.nih.gov FU Intramural Research Program of National Institute of Allergy and Infectious Diseases, NIH FX We thank M. Narayanan, A. Nita-Lazar, V. Sjoelund, S.J. Vayttaden, and members of the R.N.G. laboratory and the Laboratory of Systems Biology for helpful discussions. This work was supported by the Intramural Research Program of National Institute of Allergy and Infectious Diseases, NIH. NR 52 TC 2 Z9 2 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2405-4712 EI 2405-4720 J9 CELL SYST JI Cell Syst. PD JUN 22 PY 2016 VL 2 IS 6 BP 378 EP 390 DI 10.1016/j.cels.2016.04.016 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EL1DN UT WOS:000394360800006 PM 27237739 ER PT J AU Pettit, SD Lipshultz, SE Cleeland, CS Roberts, S Davis, M Berridge, BR Kirch, RA AF Pettit, Syril D. Lipshultz, Steven E. Cleeland, Charles S. Roberts, Samantha Davis, Myrtle Berridge, Brian R. Kirch, Rebecca A. TI Enhancing quality of life as a goal for anticancer therapeutics SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material ID CLINICAL ONCOLOGY; AMERICAN SOCIETY; CANCER C1 [Pettit, Syril D.] HESI, ILSI, Washington, DC 20005 USA. [Lipshultz, Steven E.] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Lipshultz, Steven E.] Wayne State Univ, Sch Med, Pediat, Detroit, MI 48202 USA. [Lipshultz, Steven E.] Univ Pediatricians, Detroit, MI USA. [Lipshultz, Steven E.] Childrens Res Ctr Michigan, Detroit, MI 48201 USA. [Cleeland, Charles S.] Univ Texas MD Anderson Canc Ctr, Canc Res, Dept Symptom Res, Div Internal Med, Houston, TX 77030 USA. [Roberts, Samantha] Friends Canc Res, Sci Affairs, Washington, DC 20036 USA. [Davis, Myrtle] US NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Berridge, Brian R.] GlaxoSmithKline, Worldwide Anim Res Strategy, King Of Prussia, PA 19406 USA. [Kirch, Rebecca A.] Natl Patient Advocate Fdn, Healthcare Qual & Value, Washington, DC 20005 USA. RP Pettit, SD (reprint author), HESI, ILSI, Washington, DC 20005 USA. EM spettit@hesiglobal.org FU NCI NIH HHS [P30 CA016672] NR 7 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUN 22 PY 2016 VL 8 IS 344 AR 344ed9 DI 10.1126/scitranslmed.aag0382 PG 2 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DP8HJ UT WOS:000378738500001 PM 27334258 ER PT J AU Warren, BL Mendoza, MP Cruz, FC Leao, RM Caprioli, D Rubio, FJ Whitaker, LR McPherson, KB Bossert, JM Shaham, Y Hope, BT AF Warren, Brandon L. Mendoza, Michael P. Cruz, Fabio C. Leao, Rodrigo M. Caprioli, Daniele Rubio, F. Javier Whitaker, Leslie R. McPherson, Kylie B. Bossert, Jennifer M. Shaham, Yavin Hope, Bruce T. TI Distinct Fos-Expressing Neuronal Ensembles in the Ventromedial Prefrontal Cortex Mediate Food Reward and Extinction Memories SO JOURNAL OF NEUROSCIENCE LA English DT Article DE Daun02 inactivation; food reward; operant conditioning; RNAscope; vmPFC ID COCAINE-SEEKING BEHAVIOR; CONTEXT-INDUCED REINSTATEMENT; STRESS-INDUCED REINSTATEMENT; INFRALIMBIC CORTEX; NUCLEUS-ACCUMBENS; METHAMPHETAMINE SEEKING; OPTOGENETIC INHIBITION; ALCOHOL-SEEKING; FEMALE RATS; INCUBATION AB In operant learning, initial reward-associated memories are thought to be distinct from subsequent extinction-associated memories. Memories formed during operant learning are thought to be stored in "neuronal ensembles." Thus, we hypothesize that different neuronal ensembles encode reward-and extinction-associated memories. Here, we examined prefrontal cortex neuronal ensembles involved in the recall of reward and extinction memories of food self-administration. We first trained rats to lever press for palatable food pellets for 7 d (1 h/d) and then exposed them to 0, 2, or 7 daily extinction sessions in which lever presses were not reinforced. Twenty-four hours after the last training or extinction session, we exposed the rats to either a short 15 min extinction test session or left them in their homecage (a control condition). We found maximal Fos (a neuronal activity marker) immunoreactivity in the ventral medial prefrontal cortex of rats that previously received 2 extinction sessions, suggesting that neuronal ensembles in this area encode extinction memories. We then used the Daun02 inactivation procedure to selectively disrupt ventral medial prefrontal cortex neuronal ensembles that were activated during the 15 min extinction session following 0 (no extinction) or 2 prior extinction sessions to determine the effects of inactivating the putative food reward and extinction ensembles, respectively, on subsequent nonreinforced food seeking 2 d later. Inactivation of the food reward ensembles decreased food seeking, whereas inactivation of the extinction ensembles increased food seeking. Our results indicate that distinct neuronal ensembles encoding operant reward and extinction memories intermingle within the same cortical area. C1 [Warren, Brandon L.; Mendoza, Michael P.; Cruz, Fabio C.; Leao, Rodrigo M.; Caprioli, Daniele; Rubio, F. Javier; Whitaker, Leslie R.; McPherson, Kylie B.; Bossert, Jennifer M.; Shaham, Yavin; Hope, Bruce T.] NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. RP Hope, BT (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM bhope@intra.nida.nih.gov RI Hope, Bruce/A-9223-2010; OI Hope, Bruce/0000-0001-5804-7061; McPherson, Kylie/0000-0002-5196-098X FU Intramural Research Program/National Institute on Drug Abuse/National Institutes of Health FX This work was supported by the Intramural Research Program/National Institute on Drug Abuse/National Institutes of Health. NR 57 TC 5 Z9 5 U1 2 U2 8 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 22 PY 2016 VL 36 IS 25 BP 6691 EP 6703 DI 10.1523/JNEUROSCI.0140-16.2016 PG 13 WC Neurosciences SC Neurosciences & Neurology GA DQ2FQ UT WOS:000379018100009 PM 27335401 ER PT J AU Tada, N Jansen, DJ Mower, MP Blewett, MM Umotoy, JC Cravatt, BF Wolan, DW Shenvi, RA AF Tada, Norihiro Jansen, Daniel J. Mower, Matthew P. Blewett, Megan M. Umotoy, Jeffrey C. Cravatt, Benjamin F. Wolan, Dennis W. Shenvi, Ryan A. TI Synthesis and Sulfur Electrophilicity of the Nuphar Thiaspirane Pharmacophore SO ACS CENTRAL SCIENCE LA English DT Article ID DIMERIC SESQUITERPENE THIOALKALOIDS; STRUCTURAL REQUIREMENTS; HYDROGEN-SULFIDE; ALKALOIDS; LUTEUM; NEOTHIOBINUPHARIDINE; APOPTOSIS; PUMILUM; THIOBINUPHARIDINE; SULFOXIDES AB We describe a general method to synthesize the iminium tetrahydrothiophene embedded in the dimeric Nuphar alkaloids. In contrast to prior studies, the sulfur atom of the thiaspirane pharmacophore is shown to be electrophilic. This a-thioether reacts with thiophenol or glutathione at ambient temperature to cleave the C-S bond and form a disulfide. Rates of conversion are proportional to the corresponding ammonium ion pK(a) and exhibit half-lives less than 5 h at a 5 mM concentration of thiol. A simple thiophane analogue of the Nuphar dimers causes apoptosis at single-digit micromolar concentration and labels reactive cysteines at similar levels as the unsaturated iminium "warhead". Our experiments combined with prior observations suggest the sulfur of the Nuphar dimers can react as an electrophile in cellular environments and that sulfur-triggered retrodimerization can occur in the cell. C1 [Tada, Norihiro; Jansen, Daniel J.; Mower, Matthew P.; Blewett, Megan M.; Umotoy, Jeffrey C.; Cravatt, Benjamin F.; Wolan, Dennis W.; Shenvi, Ryan A.] Scripps Res Inst, Dept Chem, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA. [Jansen, Daniel J.] NIH, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA. RP Shenvi, RA (reprint author), Scripps Res Inst, Dept Chem, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA. EM rshenvi@scripps.edu OI Shenvi, Ryan/0000-0001-8353-6449; Wolan, Dennis/0000-0001-9879-8353 FU NIGMS NIH HHS [R01 GM105766] NR 64 TC 2 Z9 2 U1 7 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 2374-7943 EI 2374-7951 J9 ACS CENTRAL SCI JI ACS Central Sci. PD JUN 22 PY 2016 VL 2 IS 6 BP 401 EP 408 DI 10.1021/acscentsci.6b00113 PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA DP7OZ UT WOS:000378690000009 PM 27413784 ER PT J AU Wheeler, AR Fulton, KA Gaudette, JE Simmons, RA Matsuo, I Simmons, JA AF Wheeler, Alyssa R. Fulton, Kara A. Gaudette, Jason E. Simmons, Ryan A. Matsuo, Ikuo Simmons, James A. TI Echolocating Big Brown Bats, Eptesicus fuscus, Modulate Pulse Intervals to Overcome Range Ambiguity in Cluttered Surroundings SO FRONTIERS IN BEHAVIORAL NEUROSCIENCE LA English DT Article DE echolocation; sonar; clutter; bat; range ambiguity ID ADAPTIVE ECHOLOCATION; AUDITORY SCENE; SONAR IMAGES; BEHAVIOR; BIOSONAR; SIGNALS; TARGET; AVOIDANCE; DESIGN; CALLS AB Big brown bats (Eptesicus fuscus) emit trains of brief, wideband frequency-modulated (FM) echolocation sounds and use echoes of these sounds to orient, find insects, and guide flight through vegetation. They are observed to emit sounds that alternate between short and long inter-pulse intervals (IPIs), forming sonar sound groups. The occurrence of these strobe groups has been linked to flight in cluttered acoustic environments, but how exactly bats use sonar sound groups to orient and navigate is still a mystery. Here, the production of sound groups during clutter navigation was examined. Controlled flight experiments were conducted where the proximity of the nearest obstacles was systematically decreased while the extended scene was kept constant. Four bats flew along a corridor of varying widths (100, 70, and 40 cm) bounded by rows of vertically hanging plastic chains while in-flight echolocation calls were recorded. Bats shortened their IPIs for more rapid spatial sampling and also grouped their sounds more tightly when flying in narrower corridors. Bats emitted echolocation calls with progressively shorter IPIs over the course of a flight, and began their flights by emitting shorter starting IPI calls when clutter was denser. The percentage of sound groups containing 3 or more calls increased with increasing clutter proximity. Moreover, IPI sequences having internal structure become more pronounced when corridor width narrows. A novel metric for analyzing the temporal organization of sound sequences was developed, and the results indicate that the time interval between echolocation calls depends heavily on the preceding time interval. The occurrence of specific IPI patterns were dependent upon clutter, which suggests that sonar sound grouping may be an adaptive strategy for coping with pulse-echo ambiguity in cluttered surroundings. C1 [Wheeler, Alyssa R.; Fulton, Kara A.; Gaudette, Jason E.; Simmons, James A.] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. [Fulton, Kara A.] NINDS, Circuit Dynam & Connect Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Gaudette, Jason E.] US Navy, Undersea Warfare Ctr, Sensors & Sonar Syst Dept, Newport, RI USA. [Simmons, Ryan A.] Duke Univ, Sch Med, Dept Biostat & Bioinformat, Durham, NC USA. [Matsuo, Ikuo] Tohoku Gakuin Univ, Dept Informat Sci, Sendai, Miyagi 980, Japan. RP Wheeler, AR (reprint author), Brown Univ, Dept Neurosci, Providence, RI 02912 USA. EM alyssa_wheeler@alumni.brown.edu FU ONR Grant [N00014-14-1-05880] FX The authors thank Aidan Leonard and Uday Shriram for work in the control room, Laura Kloepper for help in the flight room, and Andrea Simmons for suggestions that improved the manuscript. This work was supported by ONR Grant N00014-14-1-05880 to JS and internal investments by NUWC Division Newport to JG. NR 43 TC 1 Z9 1 U1 8 U2 18 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5153 J9 FRONT BEHAV NEUROSCI JI Front. Behav. Neurosci. PD JUN 22 PY 2016 VL 10 AR 125 DI 10.3389/fnbeh.2016.00125 PG 13 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DP4ZA UT WOS:000378504600001 PM 27445723 ER PT J AU Gichohi-Wainaina, WN Tanaka, T Towers, GW Verhoef, H Veenemans, J Talsma, EF Harryvan, J Boekschoten, MV Feskens, EJ Melse-Boonstra, A AF Gichohi-Wainaina, Wanjiku N. Tanaka, Toshiko Towers, G. Wayne Verhoef, Hans Veenemans, Jacobien Talsma, Elise F. Harryvan, Jan Boekschoten, Mark V. Feskens, Edith J. Melse-Boonstra, Alida TI Associations between Common Variants in Iron-Related Genes with Haematological Traits in Populations of African Ancestry SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; BLOOD-CELL TRAITS; DEFICIENCY ANEMIA; SERUM IRON; TRANSFERRIN SATURATION; HEMOGLOBIN LEVELS; TMPRSS6; AMERICANS; CHILDREN; FERRITIN AB Background Large genome-wide association (GWA) studies of European ancestry individuals have identified multiple genetic variants influencing iron status. Studies on the generalizability of these associations to African ancestry populations have been limited. These studies are important given interethnic differences in iron status and the disproportionate burden of iron deficiency among African ancestry populations. Methods We tested the associations of 20 previously identified iron status-associated single nucleotide polymorphisms (SNPs) in 628 Kenyans, 609 Tanzanians, 608 South Africans and 228 African Americans. In each study, we examined the associations present between 20 SNPs with ferritin and haemoglobin, adjusting for age, sex and CRP levels. Results In the meta analysis including all 4 African ancestry cohorts, we replicated previously reported associations with lowered haemoglobin concentrations for rs2413450 (beta = -0.19, P = 0.02) and rs4820268 (beta = -0.16, P = 0.04) in TMPRSS6. An association with increased ferritin concentrations was also confirmed for rs1867504 in TF (beta = 1.04, P = <0.0001) in the meta analysis including the African cohorts only. Conclusions In all meta analyses, we only replicated 4 of the 20 single nucleotide polymorphisms reported to be associated with iron status in large GWA studies of European ancestry individuals. While there is now evidence for the associations of a number of genetic variants with iron status in both European and African ancestry populations, the considerable lack of concordance highlights the importance of continued ancestry-specific studies to elucidate the genetic underpinnings of iron status in ethnically diverse populations. C1 [Gichohi-Wainaina, Wanjiku N.; Harryvan, Jan; Feskens, Edith J.; Melse-Boonstra, Alida] Wageningen Univ, Div Human Nutr, NL-6700 AP Wageningen, Netherlands. [Gichohi-Wainaina, Wanjiku N.] IITA, Dar Es Salaam, Tanzania. [Tanaka, Toshiko] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Towers, G. Wayne] North West Univ, Ctr Excellence Nutr, Potchefstroom Campus, Potchefstroom, South Africa. [Verhoef, Hans] Wageningen Univ, Cell Biol & Immunol Grp, NL-6700 AP Wageningen, Netherlands. [Verhoef, Hans] London Sch Hyg & Trop Med, MRC, Int Nutr Grp, London WC1, England. [Verhoef, Hans] Med Res Council Banjul, Banjul, Gambia. [Veenemans, Jacobien] Amphia Hosp, Lab Microbiol & Infect Control, Breda, Netherlands. [Veenemans, Jacobien] Admiraal De Ruyter Hosp, Dept Med Microbiol & Immunol, Goes, Netherlands. [Talsma, Elise F.] CIAT, HarvestPlus, Cali, Colombia. [Boekschoten, Mark V.] Wageningen Univ, Div Human Nutr, Nutr Metab & Genom Grp, NL-6700 AP Wageningen, Netherlands. RP Gichohi-Wainaina, WN (reprint author), Wageningen Univ, Div Human Nutr, NL-6700 AP Wageningen, Netherlands.; Gichohi-Wainaina, WN (reprint author), IITA, Dar Es Salaam, Tanzania. EM wngichohi@gmail.com FU European Union's Seventh Framework Programme [FP7] [211484]; Netherlands Organisation for Scientific Research (NWO)/WOTRO [W93-413, WAO93-441, WIZ93-465]; UNICEF; Cornelis Visser Foundation; Wageningen University (Interdisciplinary Research and Education Fund); South African Medical Research Council (Self-Initiated Research Grants), Cape Town, South Africa; Unilever R&D, Vlaardingen, The Netherlands; European Union (EU) [MC-IRSES-2008-230786]; Intramural Research Program of the NIH; National Institute on Aging FX The Kenyan cohort research was conducted within the framework of INSTAPA Project, funded by the European Union's Seventh Framework Programme [FP7/2007-2013] under grant agreement nr 211484. The Tanzanian cohort research was supported through funding from the Netherlands Organisation for Scientific Research (NWO)/WOTRO [W93-413, WAO93-441, as well as WIZ93-465, UNICEF, Cornelis Visser Foundation and Wageningen University (Interdisciplinary Research and Education Fund). The PURE study was supported through grants provided by the South African Medical Research Council (Self-Initiated Research Grants), Cape Town, South Africa, with further support from a fellowship provided by Unilever R&D, Vlaardingen, The Netherlands, and from the European Union (EU) funded staff exchange European-South African Partnership in Nutrition Research program (grant MC-IRSES-2008-230786). The BLSA was supported through funding by the Intramural Research Program of the NIH, National Institute on Aging. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 0 Z9 0 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 22 PY 2016 VL 11 IS 6 AR e0157996 DI 10.1371/journal.pone.0157996 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP0WX UT WOS:000378212800065 PM 27332551 ER PT J AU Gorgolewski, KJ Auer, T Calhoun, VD Craddock, RC Das, S Duff, EP Flandin, G Ghosh, SS Glatard, T Halchenko, YO Handwerker, DA Hanke, M Keator, D Li, XR Michael, Z Maumet, C Nichols, BN Nichols, TE Pellman, J Poline, JB Rokem, A Schaefer, G Sochat, V Triplett, W Tumer, JA Varoquaux, G Poldrack, RA AF Gorgolewski, Krzysztof J. Auer, Tibor Calhoun, Vince D. Craddock, R. Cameron Das, Samir Duff, Eugene P. Flandin, Guillaume Ghosh, Satrajit S. Glatard, Tristan Halchenko, Yaroslav O. Handwerker, Daniel A. Hanke, Michael Keator, David Li, Xiangrui Michael, Zachary Maumet, Camille Nichols, B. Nolan Nichols, Thomas E. Pellman, John Poline, Jean-Baptiste Rokem, Ariel Schaefer, Gunnar Sochat, Vanessa Triplett, William Tumer, Jessica A. Varoquaux, Gael Poldrack, Russell A. TI The brain imaging data structure, a format for organizing and describing outputs of neuroimaging experiments SO SCIENTIFIC DATA LA English DT Article ID MANAGEMENT; PROVENANCE; STORAGE AB The development of magnetic resonance imaging (MRI) techniques has defined modern neuroimaging. Since its inception, tens of thousands of studies using techniques such as functional MRI and diffusion weighted imaging have allowed for the non-invasive study of the brain. Despite the fact that MRI is routinely used to obtain data for neuroscience research, there has been no widely adopted standard for organizing and describing the data collected in an imaging experiment. This renders sharing and reusing data (within or between labs) difficult if not impossible and unnecessarily complicates the application of automatic pipelines and quality assurance protocols. To solve this problem, we have developed the Brain Imaging Data Structure (BIDS), a standard for organizing and describing MRI datasets. The BIDS standard uses file formats compatible with existing software, unifies the majority of practices already common in the field, and captures the metadata necessary for most common data processing operations. C1 [Gorgolewski, Krzysztof J.; Schaefer, Gunnar; Triplett, William; Poldrack, Russell A.] Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. [Auer, Tibor] MRC, Cognit & Brain Sci Unit, Cambridge CB2 7EF, England. [Calhoun, Vince D.; Tumer, Jessica A.] Mind Res Network, Albuquerque, NM 87131 USA. [Calhoun, Vince D.] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87106 USA. [Craddock, R. Cameron] Nathan S Kline Inst Psychiat Res, Computat Neuroimaging Lab, Ctr Biomed Imaging & Neuromodulat, Orangeburg, NY 10962 USA. [Craddock, R. Cameron; Pellman, John] Child Mind Inst, Ctr Developing Brain, New York, NY 10022 USA. [Das, Samir; Glatard, Tristan] Montreal Neurol Inst, McGill Ctr Integrat Neurosci, Ludmer Ctr, Montreal, PQ H3A 2B4, Canada. [Duff, Eugene P.] Univ Oxford, FMRIB Ctr, Oxford OX3 9DU, England. [Flandin, Guillaume] UCL, Wellcome Trust Ctr Neuroimaging, London WC1N 3BG, England. [Ghosh, Satrajit S.] MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Ghosh, Satrajit S.] Harvard Med Sch, Dept Otol & Laryngol, Boston, MA 02114 USA. [Glatard, Tristan] Univ Claude Bernard Lyon 1, Univ Lyon, CNRS UMR5220, CREATIS,Inserm U1044,INSA Lyon, F-69100 Villeurbanne, France. [Halchenko, Yaroslav O.] Dartmouth Coll, Dept Psychol & Brain Sci, Hanover, NH 03755 USA. [Handwerker, Daniel A.] NIH, Intramural Res Program, Bethesda, MD 20814 USA. [Hanke, Michael] Otto Von Guericke Univ, Dept Psychol, D-39016 Magdeburg, Germany. [Hanke, Michael] Ctr Behav Brain Sci, D-39118 Magdeburg, Germany. [Keator, David] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92697 USA. [Li, Xiangrui] Ohio State Univ, Ctr Cognit & Behav Brain Imaging, Columbus, OH 43210 USA. [Michael, Zachary] Squishymedia, Portland, OR 97232 USA. [Maumet, Camille; Nichols, Thomas E.] Univ Warwick, WMG, Coventry CV4 7AL, W Midlands, England. [Nichols, B. Nolan] SRI Int, Ctr Hlth Sci, Menlo Pk, CA 94025 USA. [Nichols, B. Nolan] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94304 USA. [Nichols, Thomas E.] Univ Warwick, Dept Stat, Coventry CV4 7AL, W Midlands, England. [Poline, Jean-Baptiste] Univ Calif Berkeley, Helen Wills Neurosci Inst, Henry Wheeler Jr Brain Imaging Ctr, Berkeley, CA 94720 USA. [Rokem, Ariel] Univ Washington, eSci Inst, Seattle, WA 98195 USA. [Schaefer, Gunnar] Flywheel Exchange LLC, Minneapolis, MN 55405 USA. [Sochat, Vanessa] Stanford Univ, Program Biomed Informat, Stanford, CA 94305 USA. [Tumer, Jessica A.] Georgia State Univ, Dept Psychol, Atlanta, GA 30302 USA. [Tumer, Jessica A.] Georgia State Univ, Neurosci Inst, Atlanta, GA 30302 USA. [Varoquaux, Gael] INRIA Saclay, Parietal Team, F-91120 Palaiseau, France. RP Gorgolewski, KJ (reprint author), Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. EM krzysztof.gorgolewski@gmail.com RI Glatard, Tristan/H-3656-2014; OI Duff, Eugene/0000-0001-8795-5472; Ghosh, Satrajit/0000-0002-5312-6729; Hanke, Michael/0000-0001-6398-6370; Craddock, Cameron/0000-0002-4950-1303; Nichols, Nolan/0000-0003-1099-3328 FU International Neuroinformatics Coordinating Facility (INCF); Laura and John Arnold Foundation; NIH [P20GM103472]; Wellcome Trust; NIH NIAAA [1 U01 AA021697]; NIH NIAAA OD [1 U01 AA021697-04S1]; Intramural Research Program of the NIMH; German federal state of Sachsen-Anhalt; European Regional Development Fund (ERDF); Medical Research Council (United Kingdom) [MC-A060-53144]; NSF [1429999] FX This work has been supported by the International Neuroinformatics Coordinating Facility (INCF) and by the Laura and John Arnold Foundation. V.D.C. has been supported by in part by NIH P20GM103472. T.E.N. and C.M. have been supported by the Wellcome Trust. N.N. has been supported by NIH NIAAA [1 U01 AA021697]. J.-B.P., B.N.N., and R.A.P. have been supported by NIH NIAAA OD [1 U01 AA021697-04S1]. D.A.H. was supported by the Intramural Research Program of the NIMH. M.H. was supported by the German federal state of Sachsen-Anhalt and the European Regional Development Fund (ERDF), project: Center for Behavioral Brain Sciences (CBBS). T.A. was supported by the Medical Research Council (United Kingdom) [MC-A060-53144]. Y.O.H. has been supported by in part by NSF [1429999]. NR 29 TC 15 Z9 15 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2052-4463 J9 SCI DATA JI Sci. Data PD JUN 21 PY 2016 VL 3 AR UNSP 160044 DI 10.1038/sdata.2016.44 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF3JI UT WOS:000390220200004 PM 27326542 ER PT J AU Zeng, C Guo, XY Long, JR Kuchenbaecker, KB Droit, A Michailidou, K Ghoussaini, M Kar, S Freeman, A Hopper, JL Milne, RL Bolla, MK Wang, Q Dennis, J Agata, S Ahmed, S Aittomaki, K Andrulis, IL Anton-Culver, H Antonenkova, NN Arason, A Arndt, V Arun, BK Arver, B Bacot, F Barrowdale, D Baynes, C Beeghly-Fadiel, A Benitez, J Bermisheva, M Blomqvist, C Blot, WJ Bogdanova, NV Bojesen, SE Bonanni, B Borresen-Dale, AL Brand, JS Brauch, H Brennan, P Brenner, H Broeks, A Bruning, T Burwinkel, B Buys, SS Cai, QY Caldes, T Campbell, I Carpenter, J Chang-Claude, J Choi, JY Claes, KBM Clarke, C Cox, A Cross, SS Czene, K Daly, MB de la Hoya, M De Leeneer, K Devilee, P Diez, O Domchek, SM Doody, M Dorfling, CM Dork, T dos-Santos-Silva, I Dumont, M Dwek, M Dworniczak, B Egan, K Eilber, U Einbeigi, Z Ejlertsen, B Ellis, S Frost, D Lalloo, F Fasching, PA Figueroa, J Flyger, H Friedlander, M Friedman, E Gambino, G Gao, YT Garber, J Garcia-Closas, M Gehrig, A Damiola, F Lesueur, F Mazoyer, S Stoppa-Lyonnet, D Giles, GG Godwin, AK Goldgar, DE Gonzalez-Neira, A Greene, MH Guenel, P Haeberle, L Haiman, CA Hallberg, E Hamann, U Hansen, TVO Hart, S Hartikainen, JM Hartman, M Hassan, N Healey, S Hogervorst, FBL Verhoef, S Hendricks, CB Hillemanns, P Hollestelle, A Hulick, PJ Hunter, DJ Imyanitov, EN Isaacs, C Ito, H Jakubowska, A Janavicius, R Jaworska-Bieniek, K Jensen, UB John, EM Beauparlant, CJ Jones, M Kabisch, M Kang, D Karlan, BY Kauppila, S Kerin, MJ Khan, S Khusnutdinova, E Knight, JA Konstantopoulou, I Kraft, P Kwong, A Laitman, Y Lambrechts, D Lazaro, C Le Marchand, L Lee, CN Lee, MH Lester, J Li, JM Liljegren, A Lindblom, A Lophatananon, A Lubinski, J Mai, PL Mannermaa, A Manoukian, S Margolin, S Marme, F Matsuo, K McGuffog, L Meindl, A Menegaux, F Montagna, M Muir, K Mulligan, AM Nathanson, KL Neuhausen, SL Nevanlinna, H Newcomb, PA Nord, S Nussbaum, RL Offit, K Olah, E Olopade, OI Olswold, C Osorio, A Papi, L Park-Simon, TW Paulsson-Karlsson, Y Peeters, S Peissel, B Peterlongo, P Peto, J Pfeiler, G Phelan, CM Presneau, N Radice, P Rahman, N Ramus, SJ Rashid, MU Rennert, G Rhiem, K Rudolph, A Salani, R Sangrajrang, S Sawyer, EJ Schmidt, MK Schmutzler, RK Schoemaker, MJ Schurmann, P Seynaeve, C Shen, CY Shrubsole, MJ Shu, XO Sigurdson, A Singer, CF Slager, S Soucy, P Southey, M Steinemann, D Swerdlow, A Szabo, CI Tchatchou, S Teixeira, MR Teo, SH Terry, MB Tessier, DC Teule, A Thomassen, M Tihomirova, L Tischkowitz, M Toland, AE Tung, N Turnbull, C van den Ouweland, AMW van Rensburg, EJ ven den Berg, D Vijai, J Wang-Gohrke, S Weitzel, JN Whittemore, AS Winqvist, R Wong, TY Wu, AH Yannoukakos, D Yu, JC Pharoah, PDP Hall, P Chenevix-Trench, G Dunning, AM Simard, J Couch, FJ Antoniou, AC Easton, DF Zheng, W AF Zeng, Chenjie Guo, Xingyi Long, Jirong Kuchenbaecker, Karoline B. Droit, Arnaud Michailidou, Kyriaki Ghoussaini, Maya Kar, Siddhartha Freeman, Adam Hopper, John L. Milne, Roger L. Bolla, Manjeet K. Wang, Qin Dennis, Joe Agata, Simona Ahmed, Shahana Aittomaki, Kristiina Andrulis, Irene L. Anton-Culver, Hoda Antonenkova, Natalia N. Arason, Adalgeir Arndt, Volker Arun, Banu K. Arver, Brita Bacot, Francois Barrowdale, Daniel Baynes, Caroline Beeghly-Fadiel, Alicia Benitez, Javier Bermisheva, Marina Blomqvist, Carl Blot, William J. Bogdanova, Natalia V. Bojesen, Stig E. Bonanni, Bernardo Borresen-Dale, Anne-Lise Brand, Judith S. Brauch, Hiltrud Brennan, Paul Brenner, Hermann Broeks, Annegien Bruening, Thomas Burwinkel, Barbara Buys, Saundra S. Cai, Qiuyin Caldes, Trinidad Campbell, Ian Carpenter, Jane Chang-Claude, Jenny Choi, Ji-Yeob Claes, Kathleen B. M. Clarke, Christine Cox, Angela Cross, Simon S. Czene, Kamila Daly, Mary B. de la Hoya, Miguel De Leeneer, Kim Devilee, Peter Diez, Orland Domchek, Susan M. Doody, Michele Dorfling, Cecilia M. Doerk, Thilo dos-Santos-Silva, Isabel Dumont, Martine Dwek, Miriam Dworniczak, Bernd Egan, Kathleen Eilber, Ursula Einbeigi, Zakaria Ejlertsen, Bent Ellis, Steve Frost, Debra Lalloo, Fiona Fasching, Peter A. Figueroa, Jonine Flyger, Henrik Friedlander, Michael Friedman, Eitan Gambino, Gaetana Gao, Yu-Tang Garber, Judy Garcia-Closas, Montserrat Gehrig, Andrea Damiola, Francesca Lesueur, Fabienne Mazoyer, Sylvie Stoppa-Lyonnet, Dominique Giles, Graham G. Godwin, Andrew K. Goldgar, David E. Gonzalez-Neira, Anna Greene, Mark H. Guenel, Pascal Haeberle, Lothar Haiman, Christopher A. Hallberg, Emily Hamann, Ute Hansen, Thomas V. O. Hart, Steven Hartikainen, Jaana M. Hartman, Mikael Hassan, Norhashimah Healey, Sue Hogervorst, Frans B. L. Verhoef, Senno Hendricks, Carolyn B. Hillemanns, Peter Hollestelle, Antoinette Hulick, Peter J. Hunter, David J. Imyanitov, Evgeny N. Isaacs, Claudine Ito, Hidemi Jakubowska, Anna Janavicius, Ramunas Jaworska-Bieniek, Katarzyna Jensen, Uffe Birk John, Esther M. Beauparlant, Charles Joly Jones, Michael Kabisch, Maria Kang, Daehee Karlan, Beth Y. Kauppila, Saila Kerin, Michael J. Khan, Sofia Khusnutdinova, Elza Knight, Julia A. Konstantopoulou, Irene Kraft, Peter Kwong, Ava Laitman, Yael Lambrechts, Diether Lazaro, Conxi Le Marchand, Loic Lee, Chuen Neng Lee, Min Hyuk Lester, Jenny Li, Jingmei Liljegren, Annelie Lindblom, Annika Lophatananon, Artitaya Lubinski, Jan Mai, Phuong L. Mannermaa, Arto Manoukian, Siranoush Margolin, Sara Marme, Frederik Matsuo, Keitaro McGuffog, Lesley Meindl, Alfons Menegaux, Florence Montagna, Marco Muir, Kenneth Mulligan, Anna Marie Nathanson, Katherine L. Neuhausen, Susan L. Nevanlinna, Heli Newcomb, Polly A. Nord, Silje Nussbaum, Robert L. Offit, Kenneth Olah, Edith Olopade, Olufunmilayo I. Olswold, Curtis Osorio, Ana Papi, Laura Park-Simon, Tjoung-Won Paulsson-Karlsson, Ylva Peeters, Stephanie Peissel, Bernard Peterlongo, Paolo Peto, Julian Pfeiler, Georg Phelan, Catherine M. Presneau, Nadege Radice, Paolo Rahman, Nazneen Ramus, Susan J. Rashid, Muhammad Usman Rennert, Gad Rhiem, Kerstin Rudolph, Anja Salani, Ritu Sangrajrang, Suleeporn Sawyer, Elinor J. Schmidt, Marjanka K. Schmutzler, Rita K. Schoemaker, Minouk J. Schuermann, Peter Seynaeve, Caroline Shen, Chen-Yang Shrubsole, Martha J. Shu, Xiao-Ou Sigurdson, Alice Singer, Christian F. Slager, Susan Soucy, Penny Southey, Melissa Steinemann, Doris Swerdlow, Anthony Szabo, Csilla I. Tchatchou, Sandrine Teixeira, Manuel R. Teo, Soo H. Terry, Mary Beth Tessier, Daniel C. Teule, Alex Thomassen, Mads Tihomirova, Laima Tischkowitz, Marc Toland, Amanda E. Tung, Nadine Turnbull, Clare van den Ouweland, Ans M. W. van Rensburg, Elizabeth J. ven den Berg, David Vijai, Joseph Wang-Gohrke, Shan Weitzel, Jeffrey N. Whittemore, Alice S. Winqvist, Robert Wong, Tien Y. Wu, Anna H. Yannoukakos, Drakoulis Yu, Jyh-Cherng Pharoah, Paul D. P. Hall, Per Chenevix-Trench, Georgia Dunning, Alison M. Simard, Jacques Couch, Fergus J. Antoniou, Antonis C. Easton, Douglas F. Zheng, Wei CA EMBRACE GEMO Study Collaborators HEBON KConFab AOCS Investigators TI Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus SO BREAST CANCER RESEARCH LA English DT Article DE Fine-scale mapping; Genetic risk factor; PTHLH; CCDC91; Breast cancer; BRAC1 mutation carriers ID HORMONE-RELATED PROTEIN; GENOME-WIDE ASSOCIATION; BRCA2 MUTATION CARRIERS; SUSCEPTIBILITY LOCI; GENETIC MODIFIERS; OVARIAN-CANCER; LOCALIZATION; METASTASIS; EXPRESSION; ENHANCERS AB Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk. C1 [Zeng, Chenjie; Guo, Xingyi; Long, Jirong; Beeghly-Fadiel, Alicia; Blot, William J.; Cai, Qiuyin; Shrubsole, Martha J.; Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA. [Kuchenbaecker, Karoline B.; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Barrowdale, Daniel; Ellis, Steve; Frost, Debra; McGuffog, Lesley; Pharoah, Paul D. P.; Antoniou, Antonis C.; Easton, Douglas F.; EMBRACE] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Droit, Arnaud; Hall, Per] Univ Laval, Prote Ctr, CHU Quebec Res Ctr, Quebec City, PQ G1K 7P4, Canada. [Droit, Arnaud; Hall, Per] Univ Laval, Dept Mol Med, Quebec City, PQ G1K 7P4, Canada. [Ghoussaini, Maya; Kar, Siddhartha] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Freeman, Adam] St Vincent Hosp, Dept Surg, Melbourne, Vic, Australia. [Hopper, John L.; Milne, Roger L.; Giles, Graham G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. [Milne, Roger L.; Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Godwin, Andrew K.; Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Agata, Simona; Montagna, Marco] IRCCS, IOV, Immunol & Mol Oncol Unit, Padua, Italy. [Ahmed, Shahana; Baynes, Caroline; Pharoah, Paul D. P.; Dunning, Alison M.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Aittomaki, Kristiina] Univ Helsinki, Helsinki Univ Hosp, Dept Clin Genet, Helsinki, Finland. [Andrulis, Irene L.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Antonenkova, Natalia N.] NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, Byelarus. [Arason, Adalgeir] Landspitali Univ Hosp, Dept Pathol, Reykjavik, Iceland. [Arason, Adalgeir] Univ Iceland, Fac Med, BMC Biomed Ctr, Reykjavik, Iceland. [Arndt, Volker; Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Arun, Banu K.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. 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[Egan, Kathleen] H Lee Moffitt Canc Ctr & Res Inst, Div Populat Sci, Tampa, FL USA. [Einbeigi, Zakaria] Sahlgrens Univ Hosp, Dept Oncol, Gothenburg, Sweden. [Ejlertsen, Bent] Copenhagen Univ Hosp, Rigshosp, Dept Oncol, Copenhagen, Denmark. [Lalloo, Fiona] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Genet Med, Manchester, Lancs, England. [Fasching, Peter A.; Haeberle, Lothar] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Gynecol & Obstet, Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Herlev, Denmark. [Friedlander, Michael] Australia New Zealand GOG, ANZ GOTG Coordinating Ctr, Camperdown, NSW, Australia. [Friedman, Eitan; Laitman, Yael] Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel. [Gambino, Gaetana] Univ Pisa, Deparment Lab Med, Sect Genet Oncol, Pisa, Italy. [Gambino, Gaetana] Univ Hosp Pisa, Pisa, Italy. [Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Garber, Judy] Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02115 USA. [Garcia-Closas, Montserrat; Jones, Michael; Schoemaker, Minouk J.; Swerdlow, Anthony] Inst Canc Res, Div Genet & Epidemiol, London, England. [Gehrig, Andrea] Univ Wurzburg, Inst Human Genet, Wurzburg, Germany. [Damiola, Francesca; Mazoyer, Sylvie; Steinemann, Doris] Univ Lyon, CNRS, INSERM, Ctr Rech Cancerol Lyon,U1052,UMR5286, Lyon, France. [Lesueur, Fabienne] Mines ParisTech, Inst Curie, INSERM, Genet Epidemiol Canc Team,U900, F-75248 Paris, France. [Stoppa-Lyonnet, Dominique] Inst Curie, Dept Tumor Biol, Paris, France. [Stoppa-Lyonnet, Dominique] INSERM, Inst Curie, U830, Paris, France. [Stoppa-Lyonnet, Dominique] Univ Paris 05, Sorbonne Paris Cite, Paris, France. [GEMO Study Collaborators] UNICANC Genet Grp, Natl Canc Genet Network, GEMO Study, Paris, France. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Goldgar, David E.] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Dermatol, Salt Lake City, UT USA. [Greene, Mark H.; Mai, Phuong L.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Guenel, Pascal; Menegaux, Florence] INSERM, Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc, Villejuif, France. [Guenel, Pascal; Menegaux, Florence] Univ Paris 11, Villejuif, France. [Haiman, Christopher A.; ven den Berg, David; Wu, Anna H.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Hallberg, Emily; Hart, Steven; Olswold, Curtis; Slager, Susan] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Hamann, Ute; Kabisch, Maria; Rashid, Muhammad Usman] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany. [Hansen, Thomas V. O.] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, Copenhagen, Denmark. [Hartikainen, Jaana M.; Mannermaa, Arto] Kuopio Univ Hosp, Ctr Canc, Kuopio, Finland. [Hartikainen, Jaana M.; Mannermaa, Arto] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland. [Hartikainen, Jaana M.; Mannermaa, Arto] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, Kuopio, Finland. [Hartman, Mikael; Lee, Chuen Neng] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Hartman, Mikael] Natl Univ Hlth Syst, Dept Surg, Singapore, Singapore. [Hassan, Norhashimah; Teo, Soo H.] Canc Res Initiat Fdn, Subang Jaya, Selangor, Malaysia. [Hassan, Norhashimah; Teo, Soo H.] Univ Malaya, Med Ctr, Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur, Malaysia. [Healey, Sue] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia. [Hogervorst, Frans B. L.; Verhoef, Senno] Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands. [HEBON] Netherlands Canc Inst, Coordinating Ctr, Hereditary Breast & Ovarian Canc Res Grp Netherla, Amsterdam, Netherlands. [Hendricks, Carolyn B.] Suburban Hosp, Bethesda, MD USA. [Hendricks, Carolyn B.] City Hope Natl Med Ctr, Clin Canc Genet Community Res Network, Duarte, CA USA. [Hollestelle, Antoinette; Seynaeve, Caroline] Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [Hulick, Peter J.] NorthShore Univ HealthSyst, Ctr Med Genet, Evanston, IL USA. [Hunter, David J.; Kraft, Peter] Harvard Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA. [Hunter, David J.; Kraft, Peter] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Imyanitov, Evgeny N.] NN Petrov Inst Oncol, St Petersburg, Russia. [Isaacs, Claudine] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Ito, Hidemi] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan. [Jakubowska, Anna; Jaworska-Bieniek, Katarzyna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Janavicius, Ramunas] State Res Inst, Ctr Innovat Med, Vilnius, Lithuania. [Jensen, Uffe Birk] Aarhus Univ Hosp, Dept Clin Genet, Aarhus N, Denmark. [John, Esther M.] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA USA. [John, Esther M.; Whittemore, Alice S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA. [John, Esther M.; Whittemore, Alice S.] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA. [Beauparlant, Charles Joly] Ctr Hosp Univ Quebec Res Ctr, Genom Ctr, Quebec City, PQ, Canada. [Beauparlant, Charles Joly] Univ Laval, Quebec City, PQ, Canada. [Karlan, Beth Y.; Lester, Jenny] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Kauppila, Saila] Univ Oulu, Oulu Univ Hosp, Dept Pathol, Oulu, Finland. [Kerin, Michael J.] Natl Univ Ireland, Sch Med, Galway, Ireland. [Khan, Sofia; Nevanlinna, Heli] Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland. [Khusnutdinova, Elza] Bashkir State Univ, Dept Genet & Fundamental Med, Ufa, Russia. [Knight, Julia A.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON, Canada. [Knight, Julia A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada. [Konstantopoulou, Irene] Natl Ctr Sci Res Demokritos, IRRP, Mol Diagnost Lab, Athens, Greece. [Kwong, Ava] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China. [Kwong, Ava] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Lambrechts, Diether] Vesalius Res Ctr, Leuven, Belgium. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Lazaro, Conxi] Catalan Inst Oncol, IDIBELL Bellvitge Biomed Res Inst, Hereditary Canc Program, Mol Diagnost Unit, Barcelona, Spain. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI USA. [Lee, Min Hyuk] Soonchunhyang Univ & Hosp, Dept Surg, Seoul, South Korea. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Lophatananon, Artitaya; Muir, Kenneth] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry, W Midlands, England. [Manoukian, Siranoush; Peissel, Bernard] INT, Fdn IRCCS Ist Ricovero Cura Carattere Sci, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Marme, Frederik] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Matsuo, Keitaro] Kyushu Univ, Fac Med Sci, Dept Prevent Med, Fukuoka, Japan. [Meindl, Alfons] Tech Univ Munich, Div Gynaecol & Obstet, Munich, Germany. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Mulligan, Anna Marie] Univ Hlth Network, Lab Med Program, Toronto, ON, Canada. [Mulligan, Anna Marie] Univ Toronto, Dept Lab Med & Pathol, Toronto, ON, Canada. [Neuhausen, Susan L.] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA USA. [Newcomb, Polly A.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [Newcomb, Polly A.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA USA. [Nussbaum, Robert L.] Univ Calif San Francisco, Dept Med Genet, San Francisco, CA 94143 USA. [Offit, Kenneth; Vijai, Joseph] Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, Clin Genet Res Lab, 1275 York Ave, New York, NY 10021 USA. [Olah, Edith] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary. [Olopade, Olufunmilayo I.] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA. [Osorio, Ana] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Human Genet Grp, Madrid, Spain. [Osorio, Ana] Biomed Network Rare Dis CIBERER, Madrid, Spain. [Papi, Laura] Univ Florence, Dept Biomed Expt & Clin Sci, Unit Med Genet, Florence, Italy. [Paulsson-Karlsson, Ylva] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Peeters, Stephanie] Univ Hosp Gasthuisberg, Leuven, Belgium. [Peterlongo, Paolo] Fdn Ist FIRC Italian Fdn Canc Res Oncol Mol, IFOM, Milan, Italy. [Pfeiler, Georg] Med Univ Vienna, Dept Obstet & Gynecol, Vienna, Austria. [Pfeiler, Georg] Med Univ Vienna, Ctr Comprehens Canc, Vienna, Austria. [Phelan, Catherine M.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Radice, Paolo] INT, Fdn IRCCS Ist Ricovero & Cura Carattere Sci, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy. [Rahman, Nazneen; Turnbull, Clare] Inst Canc Res, Sect Canc Genet, London, England. [Ramus, Susan J.] Univ Southern Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Rashid, Muhammad Usman] SKMCH & RC, Dept Basic Sci, Lahore, Pakistan. [Rennert, Gad] Clalit Natl Israeli Canc Control Ctr, Haifa, Israel. [Rennert, Gad] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel. [Rennert, Gad] B Rappaport Fac Med, Haifa, Israel. [Rhiem, Kerstin] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Dept Obstet & Gynaecol, Cologne, Germany. [Rhiem, Kerstin] Univ Hosp Cologne, CIO, CMMC, Cologne, Germany. [Salani, Ritu] Ohio State Univ, Coll Med, Obstet & Gynecol, Columbus, OH 43210 USA. [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok, Thailand. [Sawyer, Elinor J.] Kings Coll London, Guys Hosp, Res Oncol, London, England. [Schmutzler, Rita K.] Univ Hosp Cologne, Dept Obstet & Gynaecol, Div Mol Gynecooncol, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Mol Med, Cologne, Germany. [Shen, Chen-Yang] China Med Univ, Sch Publ Hlth, Taichung, Taiwan. [Shen, Chen-Yang] Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei, Taiwan. [Singer, Christian F.] Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, Vienna, Austria. [Soucy, Penny] Ctr Hosp Univ Quebec Res Ctr, Quebec City, PQ, Canada. [Soucy, Penny] Univ Laval, Quebec City, PQ, Canada. [Southey, Melissa] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic, Australia. [Steinemann, Doris] Hannover Med Sch, Hannover, Germany. [Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, London, England. [Szabo, Csilla I.] NHGRI, NIH, Bethesda, MD 20892 USA. [Tchatchou, Sandrine] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Teixeira, Manuel R.] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal. [Teixeira, Manuel R.] Univ Porto, Biomed Sci Inst ICBAS, Oporto, Portugal. [Terry, Mary Beth] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Teule, Alex] Catalan Inst Oncol, IDIBELL Bellvitge Biomed Res Inst, Hereditary Canc Program, Genet Counseling Unit, Barcelona, Spain. [Thomassen, Mads] Odense Univ Hosp, Dept Clin Genet, Odense C, Denmark. [Tihomirova, Laima] Latvian Biomed Res & Study Ctr, Riga, Latvia. [Tischkowitz, Marc] McGill Univ, Program Canc Genet, Dept Human Genet, Montreal, PQ, Canada. [Tischkowitz, Marc] McGill Univ, Dept Oncol, Montreal, PQ, Canada. [Tischkowitz, Marc] Univ Cambridge, Sch Med, Cambridge, England. [Toland, Amanda E.] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH USA. [Tung, Nadine] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA. [van den Ouweland, Ans M. W.] Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands. [Offit, Kenneth; Vijai, Joseph] Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, 1275 York Ave, New York, NY 10021 USA. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, Ulm, Germany. [Weitzel, Jeffrey N.] City Hope Natl Med Ctr, Clin Canc Genet Community Res Network, Clin Canc Genet, Duarte, CA USA. [Winqvist, Robert] Univ Oulu, Lab Canc Genet & Tumor Biol, Dept Clin Chem, Oulu, Finland. [Winqvist, Robert] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Winqvist, Robert] Ctr NordLab Oulu, Northern Finland Lab, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Wong, Tien Y.] Natl Univ Singapore, Singapore Eye Res Inst, Singapore, Singapore. [Yannoukakos, Drakoulis] Aristotle Univ Thessaloniki, Sch Med, Papageorgiou Hosp, Dept Med Oncol, Thessaloniki, Greece. [Yu, Jyh-Cherng] Natl Taiwan Univ Hosp, Dept Surg, Taipei, Taiwan. [Chenevix-Trench, Georgia; KConFab] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld, Australia. [Chenevix-Trench, Georgia; AOCS Investigators] Univ Melbourne, Peter MacCallum Canc Inst, Melbourne, Vic, Australia. RP Zheng, W (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA. EM wei.zheng@vanderbilt.edu RI Peissel, Bernard/E-8187-2017; manoukian, siranoush/E-7132-2017; Bruning, Thomas/G-8120-2015; Hartikainen, Jaana/E-6256-2015; Osorio, Ana/I-4324-2014; Li, Jingmei/I-2904-2012; Teo, Soo-hwang/H-2353-2014; Dork, Thilo/J-8620-2012; Knight, Julia/A-6843-2012; Zheng, Wei/O-3351-2013; Nord, Silje/R-5212-2016; Khusnutdinova, Elza/A-4810-2013; Brenner, Hermann/B-4627-2017; Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011 OI Peissel, Bernard/0000-0001-9233-3571; Khan, Sofia/0000-0003-4185-8882; Yannoukakos, Drakoulis/0000-0001-7509-3510; Dunning, Alison Margaret/0000-0001-6651-7166; Evans, Gareth/0000-0002-8482-5784; manoukian, siranoush/0000-0002-6034-7562; Bruning, Thomas/0000-0001-9560-5464; Osorio, Ana/0000-0001-8124-3984; Li, Jingmei/0000-0001-8587-7511; Zheng, Wei/0000-0003-1226-070X; Nord, Silje/0000-0002-3271-5356; Brenner, Hermann/0000-0002-6129-1572; FU charity Against Breast Cancer [1121258]; Deutsche Krebshilfe; NHMRC; National Breast Cancer Foundation, Cancer Australia; National Institute of Health (USA); Breakthrough Breast Cancer; Institute of Cancer Research; NHS; National Cancer Institute grants [CA 27469]; GOG Statistical and Data Center [CA 37517]; GOG Cancer Prevention and Control Committee [CA 101165]; Intramural Research Program; NCI; ISCIII (Spain) [RD12/00369/0006, 12/00539]; European Regional Development FEDER funds; Dutch Cancer Society [NKI1998-1854, NKI2004-3088, NKI2007-3756, NKI 2007-3839, 2009 4363]; Netherlands Organization of Scientific Research [NWO 91109024]; Pink Ribbon [110005, 2014-187.WO76]; BBMRI [NWO 184.021.007/CP46]; Transcan [JTC 2012]; Singapore Breast Cancer Study; HUKM-HKL; Malaysian Ministry of Science, Technology and Innovation, Ministry of Higher Education [UM.C/HIR/MOHE/06]; Cancer Research Initiatives Foundation; NIH [R37CA070867]; Cancer Research UK [C1287/A10118, C1287/A12014, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565, C8620/A8372, C8620/A8857]; European Community Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; National Institutes of Health [CA128978, R01 CA77398]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR); Komen Foundation; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; National Cancer Institute (USA) [UM1 CA164920]; National Health and Medical Research Council of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Victorian Breast Cancer Research Consortium; BBMRI-NL; Dutch government [NWO 184.021.007]; Dutch National Genomics Initiative; Cancer Institute NSW; National Breast Cancer Foundation; Breast Cancer Research Trust, UK; ELAN-Fond of the University Hospital of Erlangen; Cancer Research UK; National Cancer Research Network (NCRN); NIHR Comprehensive Biomedical Research Centre; Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, UK; Oxford Biomedical Research Centre; US Military Acquisition (ACQ) Activity, Era of Hope Award [W81XWH-05-1-0204]; Institute of Cancer Research (UK); Medical Research Council (UK) Clinical Research Fellowship; Dietmar-Hopp Foundation; Helmholtz Society; German Cancer Research Center (DKFZ); Fondation de France; Institut National du Cancer (INCa); Ligue Nationale contre le Cancer; Ligue contre le Cancer Grand Ouest; Agence Nationale de Securit, Sanitaire (ANSES); Agence Nationale de la Recherche (ANR); Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council and Herlev Hospital; Instituto de Salud Carlos III; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra el Cancer; Fondo de Investigacion Sanitario [PI11/ 00923, PI12/00070]; California Breast Cancer Act; California Breast Cancer Research Fund [97-10500]; California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section [103885]; Lon V Smith Foundation [LVS39420]; Against Breast Cancer Registered Charity [1121258]; Baden Wrettemberg Minister of Sciences, Research and Arts; German Cancer Aid (Deutsche Krebshilfe); Deutsche Krebshilfe [107 352]; Federal Ministry of Education and Research (BMBF) Germany grants [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114]; Robert Bosch Foundation; Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance; Institute of the Ruhr University Bochum (IPA), Bochum; Department of Internal Medicine; Evangelische Kliniken Bonn gGmbH; Johanniter Krankenhaus, Bonn, Germany; Deutsche Krebshilfe e. V. [70492]; Hannover Medical School; Helsinki University Central Hospital Research Fund; Academy of Finland [266528]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; Ministry of Education, Science, Sports, Culture and Technology of Japan; Ministry of Health, Labor and Welfare of Japan; Health and Labor Sciences Research Grants for Research on Applying Health Technology from the Ministry Health, Labor and Welfare of Japan; National Cancer Center Research and Development Fund; Takeda Health Foundation; Friends of Hannover Medical School; Rudolf Bartling Foundation; German Federal Ministry of Research and Education [RUS08/017]; Stockholm County Council; Karolinska Institutet; Swedish Cancer Society; Gustav V Jubilee foundation; Bert von Kantzows foundation; special Government Funding (EVO) of Kuopio University Hospital grants; Cancer Fund of North Savo; Finnish Cancer Organizations and strategic funding of the University of Eastern Finland; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; Cancer Foundation of Western Australia; United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]; Cancer Council Victoria; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; National Health and Medical Research Council of Australia (NHMRC) [400413, 400281, 199600]; California Breast Cancer Research Program [1RB-0287, 3 PB-0102, 5 PB-0018, 10 PB-0098]; California Department of Health; National Cancer Institute Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program [N01CN25403]; Stichting tegen Kanker [232-2008, 196-2010]; FWO; Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419]; Hamburg Cancer Society; Federal Ministry of Education and Research (BMBF) Germany [01KH0402]; Italian Association for Cancer Research (AIRC); Italian citizens [5/1000]; NIH grants [CA128978, CA116167, CA176785, CA116201, CA63464, CA54281, CA098758, CA132839]; Ting Tsung and Wei Fong Chao Foundation; VicHealth and Cancer Council Victoria; Australian NHMRC grants [209057, 251553, 504711]; Robert and Kate Niehaus Clinical Cancer Genetics Initiative; Quebec Breast Cancer Foundation; Canadian Institutes of Health Research for the CIHR Team in Familial Risks of Breast Cancer program [CRN-87521]; Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]; Malaysian Ministry of Science, Technology and Innovation (MOSTI); Malaysian Ministry of Higher Education [UM.C/HlR/MOHE/06]; Cancer Research Initiatives Foundation (CARIF); Biomedical Research Council, Singapore [BMRC08/1/35/19/550]; National medical Research Council, Singapore [NMRC/CG/SERI/2010]; K.G. Jebsen Centre for Breast Cancer Research; Research Council of Norway grant [193387/V50, 193387/H10]; South Eastern Norway Health Authority [39346]; Norwegian Cancer Society; NIH grant [R01CA100374, CA87969, R01CA64277, R01CA148667, R37CA70867]; Finnish Cancer Foundation; Center of Excellence grant [251314]; University of Oulu; University of Oulu Support Foundation; special Governmental EVO funds; Biobanking and Biomolecular Resources Research Infrastructure [BBMRI-NL CP16]; Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA; Marit and Hans Rausings Initiative Against Breast Cancer; Agency for Science, Technology and Research of Singapore (A*STAR); US National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; Genetic Associations and Mechanisms in Oncology (GAME-ON) Network [U19 CA148065]; Yorkshire Cancer Research [S295, S299, S305PA]; Sheffield Experimental Cancer Medicine Centre; National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC); UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; BRL (Basic Research Laboratory) programme through the National Research Foundation of Korea - Ministry of Education, Science and Technology [2012-0000347]; NUS start-up Grant; National University Cancer Institute Singapore (NCIS) Centre Grant; NMRC Clinician Scientist Award; Biomedical Research Council [05/1/21/19/425]; DKFZ; National Cancer Institute Thailand; Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; Stefanie Spielman Breast Cancer fund; OSU Comprehensive Cancer Center; Hellenic Cooperative Oncology Group research grant [HR R_BG/04]; Greek General Secretary for Research and Technology (GSRT) Program; Research Excellence II; European Union (European Social Fund - ESF); Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - ARISTEIA; Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan; Institute of Cancer Research (ICR), London; Massachusetts [R01CA47305]; Wisconsin [R01 CA47147]; New Hampshire centres [R01CA69664]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institutes of Health; U.S. Department of Health and Human Services; National Cancer Institute [CA164920]; Lithuania (BFBOCC-LT), Research Council of Lithuania grant [LIG-07/2012]; Cancer Association of South Africa (CANSA); Morris and Horowitz Families Endowed Professorship; NEYE Foundation; Spanish Association against Cancer [AECC08]; RTICC [06/0020/1060, FISPI08/1120]; Mutua Madrilena Foundation (FMMA) [SAF2010-20493]; Office of the Director, National Institutes of Health; Fondazione IRCCS Istituto Nazionale Tumori [5x1000]; FiorGen Foundation for Pharmacogenomics; Cancer Research UK grants [C1287/A10118, C12292/A11174]; NHMRC Program Grant; Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research Technology [SYN11_10_19 NBCA]; NIHR grant; NIHR support; Royal Marsden NHS Foundation Trust; University of Kansas Cancer Center [P30 CA168524]; Kansas Bioscience Authority Eminent Scholar Program; Chancellors Distinguished Chair in Biomedical Sciences Professorship; German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC); German Cancer Aid [109076]; Center for Molecular Medicine Cologne (CMMC); Association "Le cancer du sein, parlons-en!" Award; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program; French National Institute of Cancer (INCa); Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI) [P30-CA051008]; Fisher Center for Familial Cancer Research; Swing For the Cure; GOA grant [BOF10/GOA/019]; Ghent University Hospital; Helsinki University Hospital Research Fund; Dutch Cancer Society grants [NKI1998-1854, NKI2004-3088, NKI2007-3756]; Netherlands Organization of Scientific Research grant [NWO 91109024]; Pink Ribbon grant [110005]; BBMRI grant NWO [184.021.007/CP46]; Hong Kong Hereditary Breast Cancer Family Registry; Dr. Ellen Li Charitable Foundation, Hong Kong; Hungarian Research Grants [KTIA-OTKA CK-80745, OTKA K-112228]; Norwegian EEA Financial Mechanism [Hu0115/NA/2008-3/OP-9]; ICO: contract grant sponsor; ISCIIIRETIC [RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290, 2014SGR364]; Icelandic Association "Walking for Breast Cancer Research"; Landspitali University Hospital Research Fund; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" programme; Canadian Breast Cancer Research Alliance-grant [019511]; Ministry of Economic Development, Innovation and Export Trade - grant [PSR-SIIRI-701]; Ministero della Salute and Istituto Oncologico Veneto grant [5x1000]; Liga Portuguesa Contra o Cancro; National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea [1020350]; NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; U.S. Department of Defence Ovarian Cancer Idea award [W81XWH-10-1-0341]; MH CZ - DRO (MMCI) [00209805]; European Regional Development Fund; State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]; Charles University in Prague project [UNCE204024]; Andrew Sabin Research Fund; Intramural Research Program of the US National Cancer Institute, NIH; Westat Inc, Rockville [NO2-CP-11019-50, N02-CP-65504]; Clalit Health Services in Israel; Israel Cancer Association; Breast Cancer Research Foundation (BCRF), NY; Russian Federation for Basic Research [13-04-92613, 14-04-93959, 15-04-01744]; National Cancer Institute grants; Tissue Bank [CA 27469]; NRG Oncology Statistical and Data Center [CA 37517]; NRG Oncology's Cancer Prevention and Control Committee [CA 101165]; Intramural Research Program, NCI; Ohio State University Comprehensive Cancer Center; ITT (Istituto Toscano Tumori) grants; Ministry of Science, Technology and Innovation, Ministry of Higher Education [UM.C/HlR/MOHE/06]; Ralph and Marion Falk Medical Research Trust; Entertainment Industry Fund National Women's Cancer Research Alliance; Jonsson Comprehensive Cancer Center Foundation; UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center; CRUK; National Institutes of Health (NIH) [R01-CA102776, R01-CA083855]; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA; Frieda G. and Saul F. Shapira BRCA-Associated Cancer Research Program; Ovarian Cancer Research Fund (OCRF) grant [258807]; Ann Schreiber Program of Excellence award from the Ovarian Cancer Research Fund [POE/USC/01.12]; National Institute of Health [5 U19 CA148112-02]; Cancer Center Support Grant from the National Cancer Institute [P30 CA014089]; Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation; American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; National Center for Advancing Translational Sciences (NCATS) [UL1TR000124]; [KULPFV/10/016-SymBioSysII]; [P30 CA68485]; [PBZ_KBN_122/P05/2004]; [5U01CA113916]; [R01CA140323] FX We thank all the individuals who took part in these studies and all the researchers, study staff, clinicians and other healthcare providers, technicians and administrative staff who have enabled this work to be carried out. In particular, we would like to thank Terence Jack Martin (St Vincents Institute, Melbourne, Australia) for carefully reviewing this manuscript. COGS would not have been possible without the contributions of the following: Andrew Berchuck (OCAC), Rosalind A. Eeles, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Lesley McGuffog, Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Javier Benitez, Anna Gonzalez-Neira and the staff of the CNIO genotyping unit, and Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissiere and Frederic Robidoux and the staff of the McGill University and Genome Quebec Innovation Centre, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility. ABCFS wishes to thank Maggie Angelakos, Judi Maskiell and Gillian Dite. ABCS wishes to thank Sten Cornelissen, Richard van Hien, Linde Braaf, Frans Hogervorst, Senno Verhoef, Laura van t Veer, Emiel Rutgers, C Ellen van der Schoot and Femke Atsma. ABCTB wishes to thank Christine Clarke, Rosemary Balleine, Robert Baxter, Stephen Braye, Jane Carpenter, Jane Dahlstrom, John Forbes, Soon Lee, Debbie Marsh, Adrienne Morey, Nirmala Pathmanathan, Rodney Scott, Allan Spigelman, Nicholas Wilcken and Desmond Yip. Samples are made available to researchers on a non-exclusive basis. The ACP study wishes to thank the participants in the Thai Breast Cancer study. Special thanks also go to the Thai Ministry of Public Health (MOPH), doctors and nurses who helped with the data collection process. Finally, the ACP study would like to thank Dr. Prat Boonyawongviroj, the former Permanent Secretary of MOPH and Dr. Pornthep Siriwanarungsan, the Department Director-General of Disease Control who have supported the study throughout. BBCS wishes to thank Eileen Williams, Elaine Ryder-Mills and Kara Sargus. BIGGS wishes to thank Niall McInerney, Gabrielle Colleran, Andrew Rowan and Angela Jones. BOCS wishes to thank The Wellcome Trust Case Control Consortium (see the WTCCC website for a full list of contributing investigators). BSUCH wishes to thank Peter Bugert and Medical Faculty Mannheim. CGPS wishes to thank staff and participants of the Copenhagen General Population Study, and Dorthe Uldall Andersen, Maria Birna Arnadottir, Anne Bank and Dorthe Kjeldgard Hansenor for the excellent technical assistance. CNIO-BCS thanks Guillermo Pita, Charo Alonso, Daniel Herrero, Nuria Alvarez, Pilar Zamora, Primitiva Menendez and the Human Genotyping-CEGEN Unit (CNIO). The CTS Steering Committee includes Leslie Bernstein, Susan Neuhausen, James Lacey, Sophia Wang, Huiyan Ma, Yani Lu and Jessica Clague DeHart at the Beckman Research Institute of City of Hope, Dennis Deapen, Rich Pinder, Eunjung Lee, and Fred Schumacher at the University of Southern California, Pam Horn-Ross, Peggy Reynolds, Christina Clarke Dur and David Nelson at the Cancer Prevention Institute of California, and Hoda Anton-Culver, Argyrios Ziogas and Hannah Park at the University of California Irvine. DIETCOMPLY thanks the patients, nurses and clinical staff involved in the study.; The University of Westminster Against Breast Cancer Research Unit acknowledges funding from the charity Against Breast Cancer (Registered Charity Number 1121258). ESTHER thanks Hartwig Ziegler, Sonja Wolf and Volker Hermann. GC-HBOC thanks Heide Hellebrand, Stefanie Engert and GC-HBOC (Supported by Deutsche Krebshilfe). GENICA thanks Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tubingen, Germany (HB, Wing-Yee Lo, Christina Justenhoven), German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) (HB), Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany (Yon-Dschun Ko, Christian Baisch), Institute of Pathology, University of Bonn, Germany (Hans-Peter Fischer), Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany (Ute Hamann), Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany (TB, Beate Pesch, Sylvia Rabstein, Anne Lotz) and Institute of Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany (Volker Harth). GESBC thanks Ursula Eilber. HABCS wishes to thank Michael Bremer. HEBCS wishes to thank Kirsimari Aaltonen, Karl von Smitten, Sofia Khan, Tuomas Heikkinen and Irja Erkkila. HMBCS wishes to thank Peter Hillemanns, Hans Christiansen and Johann H. Karstens. KBCP wishes to thank Eija Myohanen and Helena Kemilainen. kConFab/AOCS wishes to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics and the clinical follow up study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab. LAABC thanks all the study participants and the entire data collection team, especially Annie Fung and June Yashiki. LMBC wishes to thank Gilian Peuteman, Dominiek Smeets, Thomas Van Brussel and Kathleen Corthouts. MARIE wishes to thank Petra Seibold, Dieter Flesch-Janys, Judith Heinz, Nadia Obi, Alina Vrieling, Sabine Behrens, Ursula Eilber, Muhabbet Celik, Til Olchers and Stefan Nickels. MBCSG wishes to thank Daniela Zaffaroni of the Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Monica Barile and Irene Feroce of the Istituto Europeo di Oncologia (IEO) and the personnel of the Cogentech Cancer Genetic Test Laboratory. MSKCC thanks Marina Corines and Lauren Jacobs. MTLGEBCS would like to thank Martine Tranchant (CHU de Quebec Research Center), Marie-France Valois, Annie Turgeon and Lea Heguy (McGill University Health Center, Royal Victoria Hospital, McGill University) for DNA extraction, sample management and skillful technical assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. MYBRCA wishes to thank Phuah Sze Yee, Peter Kang, Kang In Nee, Kavitta Sivanandan, Shivaani Mariapun, Yoon Sook-Yee, Daphne Lee, Teh Yew Ching and Nur Aishah Mohd Taib for DNA extraction and patient recruitment. NBCS wishes to thank Dr. Kristine Kleivi, PhD (K.G. Jebsen Centre for Breast Cancer Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway and Department of Research, Vestre Viken, Drammen, Norway), Dr. Lars Ottestad, MD (Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway), Prof. Em.; Rolf Karesen, MD (Department of Oncology, Oslo University Hospital and Faculty of Medicine, University of Oslo, Oslo, Norway), Dr. Anita Langerod, PhD (Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway), Dr. Ellen Schlichting, MD (Department for Breast and Endocrine Surgery, Oslo University Hospital Ullevaal, Oslo, Norway), Dr. Marit Muri Holmen, MD (Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway), Prof. Toril Sauer, MD (Department of Pathology at Akershus University hospital, Lorenskog, Norway), Dr. Vilde Haakensen, MD (Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway), Dr. Olav Engebraten, MD (Institute for Clinical Medicine, Faculty of Medicine, University of Oslo and Department of Oncology, Oslo University Hospital, Oslo, Norway), Prof. Bjorn Naume, MD (Division of Cancer Medicine and Radiotherapy, Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway), Dr. Cecile E. Kiserud, MD (National Advisory Unit on Late Effects after Cancer Treatment, Department of Oncology, Oslo University Hospital, Oslo, Norway and Department of Oncology, Oslo University Hospital, Oslo, Norway), Dr. Kristin V. Reinertsen, MD (National Advisory Unit on Late Effects after Cancer Treatment, Department of Oncology, Oslo University Hospital, Oslo, Norway and Department of Oncology, Oslo University Hospital, Oslo, Norway), Assoc. Prof. Aslaug Helland, MD (Department of Genetics, Institute for Cancer Research and Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway), Dr. Margit Riis, MD (Dept of Breast- and Endocrine Surgery, Oslo University Hospital, Ulleval, Oslo, Norway), Dr. Ida Bukholm, MD (Department of Breast-Endocrine Surgery, Akershus University Hospital, Oslo, Norway and Department of Oncology, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway), Prof. Per Eystein Lonning, MD (Section of Oncology, Institute of Medicine, University of Bergen and Department of Oncology, Haukeland University Hospital, Bergen, Norway), and Grethe I. Grenaker Alnaes, M.Sc. (Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway). NBHS wishes to thank study participants and research staff for their contributions and commitment to this study. OBCS thanks Meeri Otsukka and Kari Mononen. OFBCR wishes to thank Teresa Selander and Nayana Weerasooriya. ORIGO wishes to thank E. Krol-Warmerdam and J. Blom for patient accrual, administering questionnaires and managing clinical information. The LUMC survival data were retrieved from the Leiden hospital-based cancer registry system (ONCDOC) with the help of Dr. J. Molenaar. PBCS wishes to thank Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao and Michael Stagner. pKARMA wishes to thank the Swedish Medical Research Counsel. RBCS wishes to thank Petra Bos, Jannet Blom, Ellen Crepin, Elisabeth Huijskens, Annette Heemskerk and the Erasmus MC Family Cancer Clinic. SASBAC thanks the Swedish Medical Research Counsel. SBCGS wishes to thank the study participants and research staff for their contributions and commitment to this study. SBCS wishes to thank Sue Higham, Helen Cramp, Ian Brock, Sabapathy Balasubramanian and Dan Connley. SEARCH wishes to thank the SEARCH and EPIC teams. SGBCC wishes to thank the participants and research coordinator Kimberley Chua.; SKKDKFZS wishes to thank all study participants, clinicians, family doctors, researchers and technicians for their contributions and commitment to this study. TNBCC wishes to thank Robert Pilarski and Charles Shapiro who were instrumental in the formation of the OSU Breast Cancer Tissue Bank. We thank the Human Genetics Sample Bank for processing of samples and providing OSU Columbus area control samples. UCIBCS wishes to thank Irene Masunaka. UKBGS wishes to thank Breakthrough Breast Cancer and the Institute of Cancer Research for support and funding of the Breakthrough Generations Study, and the study participants, study staff, and the doctors, nurses and other health care providers and health information sources who have contributed to the study. We acknowledge NHS funding to the Royal Marsden/ICR NIHR Biomedical Research Centre.; CIMBA studies acknowledge the following. BCFR-AU wishes to thank Maggie Angelakos, Judi Maskiell, Gillian Dite and Helen Tsimiklis. BCFR-NY wishes to thank members and participants in the New York site of the Breast Cancer Family Registry for their contributions to the study. BCFR-ON wishes to thank members and participants in the Ontario Familial Breast Cancer Registry for their contributions to the study. BFBOCC-LT acknowledges Vilius Rudaitis, Laimonas Griskevicius, Ramunas Janavicius. BFBOCC-LV acknowledges Drs. Janis Eglitis, Anna Krilova and Aivars Stengrevics. BMBSA wishes to thank the families who contribute to the BMBSA study. BRICOH wishes to thank Yuan Chun Ding and Linda Steele for their work in participant enrollment and biospecimen and data management. CNIO wishes to thank Alicia Barroso, Rosario Alonso and Guillermo Pita for their assistance. The CONSIT TEAM wishes to thank Maria Grazia Tibiletti of the Ospedale di Circolo-Universitu dellInsubria,Varese, Italy, Giulietta Scuvera of the Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Gabriele Capone of the University of Florence, Florence, Italy, Alessandra Viel and Riccardo Dolcetti of the CRO Aviano National Cancer Institute, Aviano, Italy, Aline Martayan of the Istituto Nazionale Tumori Regina Elena, Rome, Italy, Stefania Tommasi e Brunella Pilato of the Istituto Nazionale Tumori "Giovanni Paolo II", Bari, Italy, Liliana Varesco of the IRCCS, AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy, Laura Cortesi of the University of Modena and Reggio Emilia, Modena, Italy and Laura Ottini of the University La Sapienza, Rome, Italy. FCCC thanks Ms. JoEllen Weaver and Dr. Betsy Bove for their technical support. Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO) study: National Cancer Genetics Network (UNICANCER Genetic Group), France. We wish to thank all the GEMO collaborating groups for their contribution to this study. GEMO Collaborating Centers are: Coordinating Centres, Unite Mixte de Genetique Constitutionnelle des Cancers Frequents, Hospices Civils de Lyon - Centre Leon Berard & Equipe, Genetique du cancer du sein, Centre de Recherche en Cancerologie de Lyon: Olga Sinilnikova dagger, Sylvie Mazoyer, Francesca Damiola, Laure Barjhoux, Carole Verny-Pierre, Melanie Leone, Nadia Boutry-Kryza, Alain Calender, Sophie Giraud; and Service de Genetique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Etienne Rouleau, Lisa Golmard, Agnes Collet, Virginie Moncoutier, Cedrick Lefol, Muriel Belotti, Antoine de Pauw, Camille Elan, Catherine Nogues, Emmanuelle Fourme, Anne-Marie Birot. Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Olivier Caron, Marine Guillaud-Bataille. Centre Jean Perrin, Clermont-Ferrand: Yves-Jean Bignon, Nancy Uhrhammer. Centre Leon Berard, Lyon: Christine Lasset, Valerie Bonadona, Sandrine Handallou. Centre Francois Baclesse, Caen: Agnes Hardouin, Pascaline Berthet, Dominique Vaur, Laurent Castera. Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Audrey Remenieras, Francois Eisinger. CHU Arnaud-de-Villeneuve, Montpellier: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Joelle Fournier, Francoise Revillion, Philippe Vennin dagger, Claude Adenis. Centre Paul Strauss, Strasbourg: Daniele Muller, Jean-Pierre Fricker. Institut Bergonie, Bordeaux: Emmanuelle Barouk-Simonet, Francoise Bonnet, Virginie Bubien, Nicolas Sevenet, Michel Longy.; Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel. CHU Grenoble: Dominique Leroux, Helene Dreyfus, Christine Rebischung, Magalie Peysselon. CHU Dijon: Fanny Coron, Laurence Faivre. CHU St-Etienne: Fabienne Prieur, Marine Lebrun, Caroline Kientz. Hotel Dieu Centre Hospitalier, Chambery: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice: Marc Frenay. CHU Limoges: Laurence Venat-Bouvet. CHU Nantes: Capucine Delnatte. CHU Bretonneau, Tours: Isabelle Mortemousque. Groupe Hospitalier Pitie-Salpetriere, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier, Mathilde Warcoin. CHU Vandoeuvre-les-Nancy: Johanna Sokolowska, Myriam Bronner. CHU Besancon: Marie-Agnes Collonge-Rame, Alexandre Damette. Creighton University, Omaha, USA: Henry T. Lynch, Carrie L. Snyder. G-FAST wishes to thank the technical support of Ilse Coene en Brecht Crombez. GOG: this study was supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office and Tissue Bank (CA 27469), the GOG Statistical and Data Center (CA 37517), and the GOG Cancer Prevention and Control Committee (CA 101165). Drs. Greene, Mai and Savage were supported by funding from the Intramural Research Program, NCI. HCSC was supported by a grant RD12/00369/0006 and 12/00539 from ISCIII (Spain), partially supported by European Regional Development FEDER funds. We acknowledge Alicia Tosar for her technical assistance. HCSC wishes to thank the technical support of Ilse Coene en Brecht Crombez. HEBCS would like to thank Dr. Kristiina Aittomaki, Taru A. Muranen, Drs. Carl Blomqvist and Kirsimari Aaltonen and RNs Irja Erkkila and Virpi Palola for their help with the HEBCS data and samples. The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, N.S. Russell, J.L. de Lange, R. Wijnands; Erasmus Medical Center, Rotterdam, NL: J.M. Collee, A.M.W. van den Ouweland, M.J. Hooning, C. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center, NL: C.J. van Asperen, J.T. Wijnen, R.A.E.M. Tollenaar, P. Devilee, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: C.M. Kets, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, R.B. van der Luijt, C.C. van der Pol; Amsterdam Medical Center, NL: C.M. Aalfs, T.A.M. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht, NL: E.B. Gomez-Garcia, M.J. Blok; University Medical Center Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Foundation for the detection of hereditary tumours, Leiden, NL: H.F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J.Verloop; The Dutch Pathology Registry (PALGA): L.I.H. Overbeek. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46 and the Transcan grant JTC 2012 Cancer 12-054. HEBON thanks the registration teams of IKNL and PALGA for part of the data collection. HRBCP wishes to thank Hong Kong Sanatoriuma and Hospital for their continual support.; HUNBOCS wishes to thank the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Tibor Vaszko, Aniko Bozsik, Timea Pocza, Judit Franko, Maria Balogh, Gabriella Domokos and Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study. HVH wishes to thank the Oncogenetics Group (VHIO), and the High Risk and Cancer Prevention Unit of the University Hospital Vall dHebron. ICO wishes to thank the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella. INHERIT would like to thank Dr. Martine Dumont, Martine Tranchant for sample management and skillful technical assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. J.S. and P.S. were part of the QC and Genotyping coordinating group of iCOGS (http://ccge.medschl.cam.ac.uk/research/consortia/icogs/) (BCAC and CIMBA). IPOBCS wishes to thank Drs. Ana Peixoto, Catarina Santos, Patricia Rocha and Pedro Pinto for their skillful contribution to the study. KCONFAB wishes to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the clinical follow up study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab. The Modifier Study of Quantitative Effects on Disease (MODSQUAD) acknowledges ModSQuaD members Csilla Szabo (National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA); Lenka Foretova and Eva Machackova (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic) and Michal Zikan, Petr Pohlreich and Zdenek Kleibl (Oncogynecologic Center and Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic). MSKCC wishes to thank Anne Lincoln and Lauren Jacobs. NICCC wishes to thank the NICCC National Familial Cancer Consultation Service team led by Sara Dishon, the laboratory team led by Dr. Flavio Lejbkowicz, and the research field operations team led by Dr. Mila Pinchev. NRG Oncology thanks the investigators of the Australia New Zealand NRG Oncology group. OCGN wishes to thank members and participants in the Ontario Cancer Genetics Network for their contributions to the study. SEABASS would like to thank Yip Cheng Har, Nur Aishah Mohd Taib, Phuah Sze Yee, Norhashimah Hassan and all the research nurses, research assistants and doctors involved in the MyBrCa Study for assistance in patient recruitment, data collection and sample preparation. In addition, we thank Philip Iau, Sng Jen-Hwei and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL study respectively. The Malaysian Breast Cancer Genetic Study is funded by research grants from the Malaysian Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HIR/MOHE/06) and charitable funding from the Cancer Research Initiatives Foundation. The SMC team wishes to acknowledge the assistance of the Meirav Comprehensive breast cancer center team at the Sheba Medical Center for assistance in this study.; Swedish scientists participating as SWE-BRCA collaborators are: Ake Borg, Hakan Olsson, Helena Jernstrom, Karin Henriksson, Katja Harbst, Maria Soller and Ulf Kristoffersson from Lund University and University Hospital; Anna Ofverholm, Margareta Nordling, Per Karlsson and Zakaria Einbeigi from Gothenburg Sahlgrenska University Hospital; Anna von Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza and Johanna Rantala from Stockholm and Karolinska University Hospital; Beatrice Melin, Christina Edwinsdotter Ardnor and Monica Emanuelsson from Umea University Hospital; Hans Ehrencrona, Maritta Hellstrom Pigg and Richard Rosenquist from Uppsala University; and Marie Stenmark-Askmalm and Sigrun Liedgren from Linkoping University Hospital. UCHICAGO wishes to thank Cecilia Zvocec, Qun Niu, the physicians, genetic counselors, research nurses and staff of the Cancer Risk Clinic for their contributions to this resource and the many families who contribute to our program. UCLA thanks Joyce Seldon, MSGC and Lorna Kwan, MPH, for assembling the data for this study. UCSF would like to thank Dr. Robert Nussbaum and the following genetic counselors for participant recruitment: Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin Lee, Amie Blanco and Peggy Conrad, and Ms. Salina Chan for data management. UKFOCR thanks Paul Pharoah, Simon Gayther, Susan Ramus, Carole Pye, Patricia Harrington and Eva Wozniak for their contributions towards the UKFOCR. UPENN wishes to thank the Breast Cancer Research Foundation, Susan G. Komen Foundation for the cure and Basser Research Center for BRCA. VFCTG wishes to thank Geoffrey Lindeman, Marion Harris and Martin Delatycki of the Victorian Familial Cancer Trials Group. VFCTG also thanks Sarah Sawyer and Rebecca Driessen for assembling these data and Ella Thompson for performing all DNA amplification. Funding was as follows: the work conducted for this project at Vanderbilt Epidemiology Center is supported in part by NIH grant R37CA070867 and endowment funds for the Ingram Professorship and Anne Potter Wilson Chair. BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community Seventh Framework Programme under grant agreement number 223175 (HEALTH-F2-2009-223175) (COGS). Funding for the iCOGS infrastructure came from the European Community Seventh Framework Programme under grant agreement number 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA14811he GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR.; The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Australia Fellow and a Victorian Breast Cancer Research Consortium Group Leader. M.C.S. is a NHMRC Senior Research Fellow and a Victorian Breast Cancer Research Consortium Group Leader. The ABCS study was supported by the Dutch Cancer Society (grants NKI 2007-3839; 2009 4363); BBMRI-NL, which is a research infrastructure financed by the Dutch government (NWO 184.021.007); and the Dutch National Genomics Initiative. The Australian Breast Cancer Tissue Bank is generously supported by the National Health and Medical Research Council of Australia, The Cancer Institute NSW and the National Breast Cancer Foundation. The ACP study is funded by the Breast Cancer Research Trust, UK. The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). ES is supported by NIHR Comprehensive Biomedical Research Centre, Guys & St. Thomas NHS Foundation Trust in partnership with Kings College London, UK. IT is supported by the Oxford Biomedical Research Centre. BOCS is supported by funds from Cancer Research UK (C8620/A8372 and C8620/A8857), a US Military Acquisition (ACQ) Activity, Era of Hope Award (W81XWH-05-1-0204) and the Institute of Cancer Research (UK). C.T. is funded by a Medical Research Council (UK) Clinical Research Fellowship. BOCS acknowledges NHS funding to the Royal Marsden/Institute of Cancer Research NIHR Specialist Cancer Biomedical Research Centre. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CECILE study was funded by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Ligue contre le Cancer Grand Ouest, Agence Nationale de Securite Sanitaire (ANSES) and Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The CNIO-BCS was supported by the Instituto de Salud Carlos III, the Red Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario (PI11/00923 and PI12/00070). The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. HAC receives support from the Lon V Smith Foundation (LVS39420). The University of Westminster curates the DietCompLyf database created by and funded by Against Breast Cancer Registered Charity No. 1121258. The ESTHER study was supported by a grant from the Baden Wurttemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe).; The GC-HBOC was supported by Deutsche Krebshilfe (107 352). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, and the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, and Johanniter Krankenhaus, Bonn, Germany. The GESBC was supported by the Deutsche Krebshilfe e. V. [70492] and the German Cancer Research Center (DKFZ). The HABCS study was supported by an intramural grant from Hannover Medical School. The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation. The HERPACC was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from Ministry of Health, Labor and Welfare of Japan, by Health and Labor Sciences Research Grants for Research on Applying Health Technology from the Ministry Health, Labor and Welfare of Japan, National Cancer Center Research and Development Fund and Grant form Takeda Health Foundation. The HMBCS was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. The HUBCS was supported by a grant from the German Federal Ministry of Research and Education (RUS08/017). Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and and Bert von Kantzows foundation. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations and strategic funding of the University of Eastern Finland. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command (DAMD17-01-1-0729), Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; 400413, 400281, 199600). G.C.T. and P.W. are supported by the NHMRC. RB was a Cancer Institute NSW Clinical Research Fellow. LAABC is supported by grants (1RB-0287, 3 PB-0102, 5 PB-0018, 10 PB-0098) from the California Breast Cancer Research Program. Incident breast cancer cases were collected by the USC Cancer Surveillance Program (CSP) which is supported under subcontract by the California Department of Health. The CSP is also part of the National Cancer Institute Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403.; LMBC is supported by the Stichting tegen Kanker (232-2008 and 196-2010). Diether Lambrechts is supported by the FWO and the KULPFV/10/016-SymBioSysII. The MARIE study was supported by the Deutsche Krebshilfe e.V. (70-2892-BR I, 106332, 108253, 108419), the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany (01KH0402). MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "5x1000"). The MCBCS was supported by the NIH grants CA128978, CA116167, CA176785 an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR). The MEC was supported by NIH grants CA63464, CA54281, CA098758 and CA132839. MSKCC is supported by grants from the Breast Cancer Research Foundation and Robert and Kate Niehaus Clinical Cancer Genetics Initiative. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the CIHR Team in Familial Risks of Breast Cancer program, grant number CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade, grant number PSR-SIIRI-701. MYBRCA is funded by research grants from the Malaysian Ministry of Science, Technology and Innovation (MOSTI), Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation (CARIF). Additional controls were recruited by the Singapore Eye Research Institute, which was supported by a grant from the Biomedical Research Council (BMRC08/1/35/19/550), Singapore and the National medical Research Council, Singapore (NMRC/CG/SERI/2010). The NBCS has received funding from the K.G. Jebsen Centre for Breast Cancer Research, the Research Council of Norway grant 193387/V50 (to A-L Borresen-Dale and V.N. Kristensen) and grant 193387/H10 (to A-L Borresen-Dale and V.N. Kristensen), South Eastern Norway Health Authority (grant 39346 to A-L Borresen-Dale) and the Norwegian Cancer Society (to A-L Borresen-Dale and V.N. Kristensen). The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted using the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The Northern California Breast Cancer Family Registry (NC-BCFR) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The NHS was funded by NIH grant CA87969.; The OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation and the special Governmental EVO funds for Oulu University Hospital-based research activities. The Ontario Familial Breast Cancer Registry (OFBCR) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The pKARMA study was supported by Marit and Hans Rausings Initiative Against Breast Cancer. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. The SBCGS was supported primarily by NIH grants R01CA64277, R01CA148667 and R37CA70867. Biological sample preparation was conducted using the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The scientific development and funding of this project were, in part, supported by the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network U19 CA148065. The SBCS was supported by Yorkshire Cancer Research S295, S299, S305PA and Sheffield Experimental Cancer Medicine Centre. The SCCS is supported by a grant from the National Institutes of Health (R01 CA092447). Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry, Lexington, KY; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; Arkansas Department of Health, Cancer Registry, 4815 W. Markham, Little Rock, AR 72205. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. SEARCH is funded by a programme grant from Cancer Research UK (C490/A10124) and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge.; SEBCS was supported by the BRL (Basic Research Laboratory) programme through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347). SGBCC is funded by the NUS start-up Grant, National University Cancer Institute Singapore (NCIS) Centre Grant and the NMRC Clinician Scientist Award. Additional controls were recruited by the Singapore Consortium of Cohort Studies-Multi-ethnic cohort (SCCS-MEC), which was funded by the Biomedical Research Council, grant number 05/1/21/19/425. SKKDKFZS is supported by the DKFZ. The SZBCS was supported by grant PBZ_KBN_122/P05/2004. The TBCS was funded by The National Cancer Institute Thailand. The TNBCC was supported by a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation, the Stefanie Spielman Breast Cancer fund and the OSU Comprehensive Cancer Center, the Hellenic Cooperative Oncology Group research grant (HR R_BG/04) and the Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II, the European Union (European Social Fund - ESF), and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - ARISTEIA. The TWBCS is supported by the Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan. The UCIBCS component of this research was supported by the NIH (CA58860, CA92044) and the Lon V Smith Foundation (LVS39420). The UKBGS is funded by Breakthrough Breast Cancer and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The US3SS study was supported by Massachusetts (K.M.E., R01CA47305), Wisconsin (P.A.N., R01 CA47147) and New Hampshire (L.T.-E., R01CA69664) centres, and Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The USRT study was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services. Support for CIMBA studies: BCFR was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names and commercial products, or organizations imply endorsement by the US Government or the BCFR. BFBOCC is partly supported by Lithuania (BFBOCC-LT), Research Council of Lithuania grant LIG-07/2012; BIDMC is supported by the Breast Cancer Research Foundation. BRCA-gene mutations and breast cancer in South African women (BMBSA) was supported by grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg; SLN was partially supported by the Morris and Horowitz Families Endowed Professorship. The CBCS was supported by the NEYE Foundation. CNIO was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrilena Foundation (FMMA) and SAF2010-20493. City of Hope Clinical Cancer Genetics Community Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J.; Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funds for CONSIT TEAM were from Italian citizens who allocated the 5x1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects 5x1000) to SM and from FiorGen Foundation for Pharmacogenomics to LP. The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. SH is supported by an NHMRC Program Grant to GCT. ACA is a Cancer Research UK Senior Cancer Research Fellow. GCT is an NHMRC Senior Principal Research Fellow. The DEMOKRITOS has been co-financed by the European Union (European Social Fund - ESF) and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund. The DKFZ study was supported by the DKFZ. EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eelses is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC was supported by The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 109076, Rita K. Schmutzler) and by the Center for Molecular Medicine Cologne (CMMC). The GEMO study was supported by the Ligue Nationale Contre le Cancer; the Association "Le cancer du sein, parlons-en!" Award; the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program and the French National Institute of Cancer (INCa). GEORGETOWN (CI) received support from the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Familial Cancer Research, and Swing For the Cure. Kim De Leeneer (the G-FAST study) is supported by GOA grant BOF10/GOA/019 (Ghent University) and spearhead financing of Ghent University Hospital. The HCSC was supported by a grant RD12/00369/0006 and 12/00539 from ISCIII (Spain), partially supported by European Regional Development FEDER funds. HEBCS was financially supported by the Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation.; The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grant 110005 and the BBMRI grant NWO 184.021.007/CP46. HEBON thanks the registration teams of the Comprehensive Cancer Centre Netherlands and Comprehensive Centre South (together the Netherlands Cancer Registry) and PALGA (Dutch Pathology Registry) for part of the data collection. HRBCP is supported by The Hong Kong Hereditary Breast Cancer Family Registry and the Dr. Ellen Li Charitable Foundation, Hong Kong. The Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grants KTIA-OTKA CK-80745, OTKA K-112228 and the Norwegian EEA Financial Mechanism Hu0115/NA/2008-3/OP-9. ICO: contract grant sponsor, Asociacion Espanola Contra el Cancer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia. Contract grant numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290 and 2014SGR364. The IHCC was supported by Grant PBZ_KBN_122/P05/2004. The ILUH group was supported by the Icelandic Association "Walking for Breast Cancer Research" and by the Landspitali University Hospital Research Fund. INHERIT was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" programme, the Canadian Breast Cancer Research Alliance-grant 019511 and the Ministry of Economic Development, Innovation and Export Trade - grant PSR-SIIRI-701. IOVHBOCS is supported by Ministero della Salute and "5x1000" Istituto Oncologico Veneto grant. The IPOBCS study was in part supported by Liga Portuguesa Contra o Cancro. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. KOHBRA is supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1020350). MAYO is supported by NIH grants CA116167, CA128978 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation. Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. MODSQUAD was supported by MH CZ - DRO (MMCI, 00209805) and by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101) to LF, and by Charles University in Prague project UNCE204024 (MZ). MSKCC is supported by grants from the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, and the Andrew Sabin Research Fund. NAROD was supported by NIH grant:1R01 CA149429-01. The research of Drs. MH Greene and PL Mai was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat Inc, Rockville, MD. NICCC is supported by Clalit Health Services in Israel.; Some of its activities are supported by the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. NNPIO has been supported by the Russian Federation for Basic Research (grants 13-04-92613, 14-04-93959 and 15-04-01744). NRG Oncology was supported by National Cancer Institute grants to the NRG Oncology Administrative Office and Tissue Bank (CA 27469), the NRG Oncology Statistical and Data Center (CA 37517), and NRG Oncologys Cancer Prevention and Control Committee (CA 101165). Drs. Greene, Mai and Savage were supported by funding from the Intramural Research Program, NCI. OSUCCG is supported by the Ohio State University Comprehensive Cancer Center. PBCS was supported by the ITT (Istituto Toscano Tumori) grants 2011-2013. SEABASS was supported by the Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. SMC was partially funded through a grant by the Israel cancer association and the funding for the Israeli Inherited Breast Cancer Consortium. SWE-BRCA collaborators are supported by the Swedish Cancer Society. UCHICAGO is supported by NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Womens Cancer Research Alliance and the Breast Cancer research Foundation. OIO is an ACS Clinical Research Professor. UCLA was supported by the Jonsson Comprehensive Cancer Center Foundation, Breast Cancer Research Foundation. UCSF was supported by the UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UKFOCR was supported by a project grant from CRUK to Paul Pharoah. UPENN was supported by National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855; Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA. UPITT/MWH was supported by the Frieda G. and Saul F. Shapira BRCA-Associated Cancer Research Program, Hackers for Hope Pittsburgh. Kate Lawrenson is funded by Ovarian Cancer Research Fund (OCRF) grant number 258807 and an Ann Schreiber Program of Excellence award from the Ovarian Cancer Research Fund (POE/USC/01.12). Janet Lee and Howard Shen are funded by National Institute of Health grant number 5 U19 CA148112-02. Tassja Spindler is funded by National Institute of Health grant number CA173531-01. Work was performed within the USC Norris Comprehensive Cancer Center which is supported by a Cancer Center Support Grant (award number P30 CA014089) from the National Cancer Institute. VFCTG was supported by the Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. Dr. Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. NR 45 TC 1 Z9 1 U1 22 U2 32 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD JUN 21 PY 2016 VL 18 AR 64 DI 10.1186/s13058-016-0718-0 PG 21 WC Oncology SC Oncology GA DR9CE UT WOS:000380193900001 PM 27459855 ER PT J AU Wang, SJ Chu, CH Guo, MR Jiang, LL Nie, H Zhang, W Wilson, B Yang, L Stewart, T Hong, JS Zhang, J AF Wang, Shijun Chu, Chun-Hsien Guo, Mingri Jiang, Lulu Nie, Hui Zhang, Wei Wilson, Belinda Yang, Li Stewart, Tessandra Hong, Jau-Shyong Zhang, Jing TI Identification of a specific alpha-synuclein peptide (alpha-Syn 29-40) capable of eliciting microglial superoxide production to damage dopaminergic neurons SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE alpha-Synuclein; gp91(phox); Superoxide; Neuronal damage; Microglia ID POINT MUTATIONS A30P; PARKINSONS-DISEASE; NADPH OXIDASE; IN-VIVO; ACTIVATION; NEURODEGENERATION; AGGREGATION; PHOSPHORYLATION; NEUROTOXICITY; A53T AB Background: Misfolded alpha-synuclein (alpha-Syn) aggregates participate in the pathogenesis of synucleinopathies, such as Parkinson's disease. Whereas much is known about how the various domains within full-length alpha-Syn (FL-alpha-Syn) contribute to the formation of alpha-Syn aggregates and therefore to their neurotoxicity, little is known about whether the individual peptides that can be generated from alpha-syn, possibly as intermediate metabolites during degradation of misfolded alpha-Syn aggregates, are neurotoxic themselves. Methods: A series of synthesized alpha-Syn peptides, corresponding to the locus in FL-alpha-Syn containing alanine 30, substitution of which with a proline causes a familial form of Parkinson's disease, were examined for their capacity of inducing release of microglial superoxide. The neurotoxicity of these peptides was measured according to their influence on the ability of neuroglial cultures deficient in gp91(phox), the catalytic unit of NADPH oxidase (Nox2), or wild-type cultures to take up 3H-labeled dopamine and on the number of tyrosine hydroxylase-staining-positive neurons. Western blots and confocal images were utilized to analyze membrane translocation of p47(phox) and p67(phox), phosphorylation of p47phox and Erk1/2 kinase, and binding of alpha-Syn peptides to gp91(phox). Activation of brain microglia in mice injected with alpha-Syn peptides was demonstrated by immunostaining for major histocompatibility complex (MHC)-II along with qPCR for Ib alpha-1 and MHC-II. Results: We report alpha-Syn (29-40) as a specific peptide capable of activating microglial Nox2 to produce superoxide and cause dopaminergic neuronal damage. Administered to mice, this peptide also activated brain microglia to increase expression of MHC-II and Ib alpha-1 and stimulated oxidation reaction. Exploring the underlying mechanisms showed that alpha-Syn (29-40) peptide triggered Nox2 to generate extracellular superoxide and its metabolite H2O2 by binding to the catalytic unit gp91(phox) of Nox2; diffusing into cytosol, H2O2 activated Erk1/2 kinase to phosphorylate p47(phox) and p67(phox) and further activated Nox2, establishing a positive feedback loop to amplify the Nox2-mediated response. Conclusions: Collectively, our study suggests novel information regarding how alpha-Syn causes neuronal injury, possibly including mechanisms involving abnormal metabolites of alpha -Syn aggregates. C1 [Wang, Shijun; Chu, Chun-Hsien; Guo, Mingri; Jiang, Lulu; Nie, Hui; Wilson, Belinda; Hong, Jau-Shyong] NIEHS, Neuropharmacol Sect, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Wang, Shijun; Yang, Li; Stewart, Tessandra; Zhang, Jing] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98104 USA. [Chu, Chun-Hsien] Natl Cheng Kung Univ, Inst Mol Med, Tainan 70101, Taiwan. [Guo, Mingri] Tianjin Med Univ, Tianjin Haihe Hosp, Tianjin Inst Resp Dis, Dept Lab Med, Tianjin 300350, Peoples R China. [Jiang, Lulu] Shandong Univ, Sch Publ Hlth, Inst Toxicol, Jinan 250012, Shandong, Peoples R China. [Zhang, Wei] Capital Med Univ, Beijing Tiantan Hosp, Dept Geriatr, Beijing 100050, Peoples R China. [Zhang, Jing] Peking Univ, Hlth Sci Ctr, Dept Pathol, Beijing 100083, Peoples R China. RP Hong, JS (reprint author), NIEHS, Neuropharmacol Sect, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA.; Zhang, J (reprint author), Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98104 USA.; Zhang, J (reprint author), Peking Univ, Hlth Sci Ctr, Dept Pathol, Beijing 100083, Peoples R China. EM hong3@niehs.nih.gov; zhangj@uw.edu FU NIEHS; National Institutes of Health [R01 ES019277, R01 ES016873] FX This study was supported by the intramural funding from the NIEHS (to JSH) and the National Institutes of Health Grants R01 ES019277 and R01 ES016873 (to JZ). NR 46 TC 0 Z9 0 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD JUN 21 PY 2016 VL 13 AR 158 DI 10.1186/s12974-016-0606-7 PG 19 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DQ0BS UT WOS:000378863300002 PM 27329107 ER PT J AU Burg, AR Quigley, L Jones, AV O'Connor, GM Boelte, K McVicar, DW Orr, SJ AF Burg, Ashley R. Quigley, Laura Jones, Adam V. O'Connor, Geraldine M. Boelte, Kimberly McVicar, Daniel W. Orr, Selinda J. TI Orally administered beta-glucan attenuates the Th2 response in a model of airway hypersensitivity SO SPRINGERPLUS LA English DT Article DE beta-Glucan; Th2; Airway inflammation; Eosinophils ID TUMOR-BEARING MICE; T-CELL RESPONSES; DENDRITIC CELLS; MONOCLONAL-ANTIBODIES; MOUSE MODELS; ASTHMA; DECTIN-1; RECEPTOR; DISEASE; MACROPHAGES AB beta-Glucan is a polysaccharide that can be extracted from fungal cell walls. Wellmune WGP (R), a preparation of beta-1,3/1,6-glucans, is a dietary supplement that has immunomodulating properties. Here we investigated the effect WGP had on a mouse model of asthma. OVA-induced asthma in mice is characterized by infiltration of eosinophils into the lung, production of Th2 cytokines and IgE. Daily oral administration of WGP (400 mu g) significantly reduced the influx of eosinophils into the lungs of OVA-challenged mice compared to control mice. In addition, WGP inhibited pulmonary production of Th2 cytokines (IL-4, IL-5, IL-13), however serum IgE levels were unaffected by WGP treatment. These data indicate that WGP could potentially be useful as an oral supplement for some asthma patients, however, it would need to be combined with therapies that target other aspects of the disease such as IgE levels. As such, further studies that examine the potential of WGP in combination with other therapies should be explored. C1 [Orr, Selinda J.] Cardiff Univ, Sch Med, Div Infect & Immun, Tenovus Bldg,Heath Pk, Cardiff CF14 4XN, S Glam, Wales. [Burg, Ashley R.; Quigley, Laura; O'Connor, Geraldine M.; Boelte, Kimberly; McVicar, Daniel W.; Orr, Selinda J.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Burg, Ashley R.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35205 USA. [Jones, Adam V.] Cardiff & Vale Univ Hlth Board, Univ Dent Hosp, Cardiff CF14 4XY, S Glam, Wales. [O'Connor, Geraldine M.] Univ Chester, Dept Biol Sci, Chester CH1 4BJ, Cheshire, England. RP Orr, SJ (reprint author), Cardiff Univ, Sch Med, Div Infect & Immun, Tenovus Bldg,Heath Pk, Cardiff CF14 4XN, S Glam, Wales.; Orr, SJ (reprint author), NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. EM OrrS@cardiff.ac.uk FU NIH Office of Dietary Supplements; Intramural Research Program of the NIH, National Cancer Institute; Royal Society [099953/Z/12/Z]; Wellcome Trust FX This research was supported in part by the NIH Office of Dietary Supplements and in part by the Intramural Research Program of the NIH, National Cancer Institute. SJO is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 099953/Z/12/Z). We would like to thank Megan Karwan, Kelli Czarra and Grace Williams for animal care for this project. NR 31 TC 1 Z9 1 U1 1 U2 2 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 2193-1801 J9 SPRINGERPLUS JI SpringerPlus PD JUN 21 PY 2016 VL 5 AR 815 DI 10.1186/s40064-016-2501-1 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP4OE UT WOS:000378474400029 PM 27390655 ER PT J AU Jochems, C Fantini, M Fernando, RI Kwilas, AR Donahue, RN Lepone, LM Grenga, I Kim, YS Brechbiel, MW Gulley, JL Madan, RA Heery, CR Hodge, JW Newton, R Schlom, J Tsang, KY AF Jochems, Caroline Fantini, Massimo Fernando, Romaine I. Kwilas, Anna R. Donahue, Renee N. Lepone, Lauren M. Grenga, Italia Kim, Young-Seung Brechbiel, Martin W. Gulley, James L. Madan, Ravi A. Heery, Christopher R. Hodge, James W. Newton, Robert Schlom, Jeffrey Tsang, Kwong Y. TI The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumor antigen-specific T cells SO ONCOTARGET LA English DT Article DE IDO inhibitor; dendritic cells; T cells; indoleamine-2,3-dioxygenase (IDO); Tregs ID INDOLEAMINE 2,3-DIOXYGENASE EXPRESSION; HUMAN CARCINOEMBRYONIC ANTIGEN; ARYL-HYDROCARBON RECEPTOR; DRAINING LYMPH-NODES; TRYPTOPHAN CATABOLISM; RESISTANCE MECHANISM; NK CELLS; CANCER; IMMUNOTHERAPY; CONVERSION AB Epacadostat is a novel inhibitor of indoleamine-2,3-dioxygenase-1 (IDO1) that suppresses systemic tryptophan catabolism and is currently being evaluated in ongoing clinical trials. We investigated the effects of epacadostat on (a) human dendritic cells (DCs) with respect to maturation and ability to activate human tumor antigen-specific cytotoxic T-cell (CTL) lines, and subsequent T-cell lysis of tumor cells, (b) human regulatory T cells (Tregs), and (c) human peripheral blood mononuclear cells (PBMCs) in vitro. Simultaneous treatment with epacadostat and IFN-gamma plus lipopolysaccharide (LPS) did not change the phenotype of matured human DCs, and as expected decreased the tryptophan breakdown and kynurenine production. Peptide-specific T-cell lines stimulated with DCs pulsed with peptide produced significantly more IFN-gamma, TNF alpha, GM-CSF and IL-8 if the DCs were treated with epacadostat. These T cells also displayed higher levels of tumor cell lysis on a per cell basis. Epacadostat also significantly decreased Treg proliferation induced by IDO production from IFN-gamma plus LPS matured human DCs, although the Treg phenotype did not change. Multicolor flow cytometry was performed on human PBMCs treated with epacadostat; analysis of 123 discrete immune cell subsets revealed no changes in major immune cell types, an increase in activated CD83(+) conventional DCs, and a decrease in immature activated Tim3(+) NK cells. These studies show for the first time several effects of epacadostat on human DCs, and subsequent effects on CTL and Tregs, and provide a rationale as to how epacadostat could potentially increase the efficacy of immunotherapeutics, including cancer vaccines. C1 [Jochems, Caroline; Fantini, Massimo; Fernando, Romaine I.; Kwilas, Anna R.; Donahue, Renee N.; Lepone, Lauren M.; Grenga, Italia; Heery, Christopher R.; Hodge, James W.; Schlom, Jeffrey; Tsang, Kwong Y.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kim, Young-Seung; Brechbiel, Martin W.] NCI, Radioimmune Inorgan Chem Sect, Radiat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Gulley, James L.; Madan, Ravi A.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Newton, Robert] Incyte Corp, Wilmington, DE USA. RP Schlom, J (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Gulley, James/K-4139-2016; Hodge, James/D-5518-2015; OI Gulley, James/0000-0002-6569-2912; Hodge, James/0000-0001-5282-3154; Fantini, Massimo/0000-0002-8164-2587 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; National Cancer Institute; Incyte Corporation FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, as well as through a Cooperative Research and Development Agreement (CRADA) between the National Cancer Institute and Incyte Corporation. NR 46 TC 4 Z9 4 U1 13 U2 17 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUN 21 PY 2016 VL 7 IS 25 BP 37762 EP 37772 DI 10.18632/oncotarget.9326 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DP1CW UT WOS:000378229100027 PM 27192116 ER PT J AU Flanders, KC Yang, YA Herrmann, M Chen, JQ Mendoza, N Mirza, AM Wakefield, LM AF Flanders, Kathleen C. Yang, Yu-an Herrmann, Michelle Chen, JinQiu Mendoza, Nerissa Mirza, Amer M. Wakefield, Lalage M. TI Quantitation of TGF-beta proteins in mouse tissues shows reciprocal changes in TGF-beta 1 and TGF-beta 3 in normal vs neoplastic mammary epithelium SO ONCOTARGET LA English DT Article DE TGF-beta isoforms; protein; quantitation; mouse tissues; mammary gland ID TRANSFORMING-GROWTH-FACTOR; INDUCED PULMONARY-FIBROSIS; BREAST-CANCER; IMMUNOHISTOCHEMICAL LOCALIZATION; GROWTH-FACTOR-BETA-1 GENE; EXPRESSION PATTERNS; TRANSGENIC MICE; MESSENGER-RNA; TUMOR; DISEASE AB Transforming growth factor-beta s (TGF-beta s) regulate tissue homeostasis, and their expression is perturbed in many diseases. The three isoforms (TGF-beta 1, -beta 2, and -beta 3) have similar bioactivities in vitro but show distinct activities in vivo. Little quantitative information exists for expression of TGF-beta isoform proteins in physiology or disease. We developed an optimized method to quantitate protein levels of the three isoforms, using a Luminex (R) xMAP (R)-based multianalyte assay following acid-ethanol extraction of tissues. Analysis of multiple tissues and plasma from four strains of adult mice showed that TGF-beta 1 is the predominant isoform with TGF-beta 2 being similar to 10-fold lower. There were no sex-specific differences in isoform expression, but some tissues showed inter-strain variation, particularly for TGF-beta 2. The only adult tissue expressing appreciable TGF-beta 3 was the mammary gland, where its levels were comparable to TGF-beta 1. In situ hybridization showed the luminal epithelium as the major source of all TGF-beta isoforms in the normal mammary gland. TGF-beta 1 protein was 3-8-fold higher in three murine mammary tumor models than in normal mammary gland, while TGF-beta 3 protein was 2-3-fold lower in tumors than normal tissue, suggesting reciprocal regulation of these isoforms in mammary tumorigenesis. C1 [Flanders, Kathleen C.; Yang, Yu-an; Herrmann, Michelle; Chen, JinQiu; Wakefield, Lalage M.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Mendoza, Nerissa; Mirza, Amer M.] Xoma Corp, Berkeley, CA 94710 USA. RP Flanders, KC (reprint author), NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. EM flanderk@mail.nih.gov FU Intramural Research Program of the NCI, NIH [ZIA BC 010881] FX Funding came from the Intramural Research Program of the NCI, NIH, project ZIA BC 010881. NR 65 TC 0 Z9 0 U1 0 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUN 21 PY 2016 VL 7 IS 25 BP 38164 EP 38179 DI 10.18632/oncotarget.9416 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DP1CW UT WOS:000378229100060 PM 27203217 ER PT J AU Jiao, XD Kabir, F Irum, B Khan, AO Wang, QW Li, D Khan, AA Husnain, T Akram, J Riazuddin, S Hejtmancik, JF Riazuddin, SA AF Jiao, Xiaodong Kabir, Firoz Irum, Bushra Khan, Arif O. Wang, Qiwei Li, David Khan, Asma A. Husnain, Tayyab Akram, Javed Riazuddin, Sheikh Hejtmancik, J. Fielding Riazuddin, S. Amer TI A Common Ancestral Mutation in CRYBB3 Identified in Multiple Consanguineous Families with Congenital Cataracts SO PLOS ONE LA English DT Article ID AUTOSOMAL RECESSIVE CATARACT; PAKISTANI FAMILIES; NONSENSE MUTATION; LOCUS; GENE; LENS; BLINDNESS; PROTEINS; MAPS AB Purpose This study was performed to investigate the genetic determinants of autosomal recessive congenital cataracts in large consanguineous families. Methods Affected individuals underwent a detailed ophthalmological examination and slit-lamp photographs of the cataractous lenses were obtained. An aliquot of blood was collected from all participating family members and genomic DNA was extracted from white blood cells. Initially, a genome-wide scan was performed with genomic DNAs of family PKCC025 followed by exclusion analysis of our familial cohort of congenital cataracts. Protein-coding exons of CRYBB1, CRYBB2, CRYBB3, and CRYBA4 were sequenced bidirectionally. A haplotype was constructed with SNPs flanking the causal mutation for affected individuals in all four families, while the probability that the four familial cases have a common founder was estimated using EM and CHM-based algorithms. The expression of Crybb3 in the developing murine lens was investigated using TaqMan assays. Results The clinical and ophthalmological examinations suggested that all affected individuals had nuclear cataracts. Genome-wide linkage analysis localized the causal phenotype in family PKCC025 to chromosome 22q with statistically significant two-point logarithm of odds (LOD) scores. Subsequently, we localized three additional families, PKCC063, PKCC131, and PKCC168 to chromosome 22q. Bidirectional Sanger sequencing identified a missense variation: c.493G>C (p.Gly165Arg) in CRYBB3 that segregated with the disease phenotype in all four familial cases. This variation was not found in ethnically matched control chromosomes, the NHLBI exome variant server, or the 1000 Genomes or dbSNP databases. Interestingly, all four families harbor a unique disease haplotype that strongly suggests a common founder of the causal mutation (p<1.64E-10). We observed expression of Crybb3 in the mouse lens as early as embryonic day 15 (E15), and expression remained relatively steady throughout development. Conclusion Here, we report a common ancestral mutation in CRYBB3 associated with autosomal recessive congenital cataracts identified in four familial cases of Pakistani origin. C1 [Jiao, Xiaodong; Wang, Qiwei; Li, David; Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Kabir, Firoz; Irum, Bushra; Riazuddin, S. Amer] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21287 USA. [Irum, Bushra; Khan, Asma A.; Husnain, Tayyab; Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore 53700, Pakistan. [Khan, Arif O.] King Khalid Eye Specialist Hosp, Riyadh 12329, Saudi Arabia. [Akram, Javed; Riazuddin, Sheikh] Univ Hlth Sci, Allama Iqbal Med Coll, Lahore 54550, Pakistan. [Akram, Javed; Riazuddin, Sheikh] Shaheed Zulfiqar Ali Bhutto Med Univ, Natl Ctr Genet Dis, Islamabad, Pakistan. RP Riazuddin, SA (reprint author), Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21287 USA. EM riazuddin@jhmi.edu FU National Eye Institute grant [1R01EY022714]; Knights Templar Eye Foundation grant; King Khaled Eye Specialist Hospital-Johns Hopkins University collaboration grant; National Academy of Sciences, Washington DC USA; Higher Education Commission, Islamabad Pakistan FX This study was supported in part by the National Eye Institute grant 1R01EY022714 (SAR), the Knights Templar Eye Foundation grant (SAR), King Khaled Eye Specialist Hospital-Johns Hopkins University collaboration grant (SAR), the National Academy of Sciences, Washington DC USA, and the Higher Education Commission, Islamabad Pakistan.; The authors are grateful to all members for their participation in this study. This study was supported in part by the National Eye Institute grant 1R01EY022714 (SAR), the Knights Templar Eye Foundation grant (SAR), King Khaled Eye Specialist Hospital-Johns Hopkins University collaboration grant (SAR), the National Academy of Sciences, Washington DC USA, and the Higher Education Commission, Islamabad Pakistan. NR 36 TC 2 Z9 2 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 21 PY 2016 VL 11 IS 6 AR e0157005 DI 10.1371/journal.pone.0157005 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP0WU UT WOS:000378212400012 PM 27326458 ER PT J AU