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. [Arver, Brita; Liljegren, Annelie] Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden. [Bacot, Francois; Tessier, Daniel C.] McGill Univ, Montreal, PQ, Canada. [Bacot, Francois; Tessier, Daniel C.] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Benitez, Javier; Gonzalez-Neira, Anna] Spanish Natl Canc Res Ctr, Human Canc Genet Program, Madrid, Spain. [Benitez, Javier] Ctr Invest Red Enfermedades Raras, Valencia, Spain. [Bermisheva, Marina; Khusnutdinova, Elza] Russian Acad Sci, Ufa Sci Ctr, Inst Biochem & Genet, Ufa, Russia. [Blomqvist, Carl] Univ Helsinki, Helsinki Univ Hosp, Dept Oncol, Helsinki, Finland. [Blot, William J.] Int Epidemiol Inst, Rockville, MD USA. [Bogdanova, Natalia V.] Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany. [Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark. [Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Bojesen, Stig E.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Bonanni, Bernardo] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy. [Borresen-Dale, Anne-Lise; Broeks, Annegien; Nord, Silje] Radiumhosp, Oslo Univ Hosp, Inst Canc Res, Dept Genet, Oslo, Norway. [Borresen-Dale, Anne-Lise] Univ Oslo, Fac Med, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, Oslo, Norway. [Brand, Judith S.; Czene, Kamila; Li, Jingmei] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Tubingen, Germany. [Brauch, Hiltrud; Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Brennan, Paul] Int Agcy Res Canc, Lyon, France. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Broeks, Annegien; Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Bruening, Thomas] Inst Ruhr Univ Bochum, Inst Prevent & Occupat Med German Social Accident, Bochum, Germany. [Burwinkel, Barbara; Marme, Frederik] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany. [Buys, Saundra S.] Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT USA. [Caldes, Trinidad; de la Hoya, Miguel] Hosp Clin San Carlos, IdISSC Inst Invest Sanitaria Hosp Clin San Carlos, Mol Oncol Lab, Madrid, Spain. [Campbell, Ian] Peter MacCallum Canc Ctr, Canc Gene Lab, Melbourne, Vic, Australia. [Carpenter, Jane] Univ Sydney, Westmead Millennium Inst, Australian Breast Canc Tissue Bank, Sydney, NSW, Australia. [Chang-Claude, Jenny; Eilber, Ursula; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, UCCH, Hamburg, Germany. [Choi, Ji-Yeob; Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Choi, Ji-Yeob; Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea. [Choi, Ji-Yeob; Kang, Daehee] Seoul Natl Univ, Canc Res Inst, Seoul, South Korea. [Claes, Kathleen B. M.; De Leeneer, Kim] Univ Ghent, Ctr Med Genet, Ghent, Belgium. [Clarke, Christine] Univ Sydney, Westmead Millenium Inst Med Res, Sydney, NSW, Australia. [Cox, Angela] Univ Sheffield, Dept Oncol, Sheffield Canc Res, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England. [Daly, Mary B.] Fox Chase Canc Ctr, Dept Clin Genet, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Diez, Orland] Univ Hosp Vall dHebron, VHIO, Oncogenet Grp, Barcelona, Spain. [Diez, Orland] Univ Autonoma Barcelona, Barcelona, Spain. [Domchek, Susan M.; Nathanson, Katherine L.] Univ Penn, Dept Med, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA. [Doody, Michele; Figueroa, Jonine; Garcia-Closas, Montserrat; Sigurdson, Alice] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Dorfling, Cecilia M.; van Rensburg, Elizabeth J.] Univ Pretoria, Dept Genet, Pretoria, South Africa. [Doerk, Thilo; Hillemanns, Peter; Park-Simon, Tjoung-Won; Schuermann, Peter] Hannover Med Sch, Clin Obstet & Gynaecol, Hannover, Germany. [dos-Santos-Silva, Isabel; Peto, Julian] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England. [Dumont, Martine; Simard, Jacques] Univ Laval, Ctr Hosp Univ Quebec Res Ctr, Genom Ctr, Quebec City, PQ, Canada. [Dwek, Miriam; Presneau, Nadege] Univ Westminster, Fac Sci & Technol, Dept Biomed Sci, London, England. [Dworniczak, Bernd] Inst Human Genet, Munster, Germany. [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 Cataisson, C Michalowski, AM Shibuya, K Ryscavage, A Klosterman, M Wright, L Dubois, W Liu, F Zhuang, A Rodrigues, KB Hoover, S Dwyer, J Simpson, MR Merlino, G Yuspa, SH AF Cataisson, Christophe Michalowski, Aleksandra M. Shibuya, Kelly Ryscavage, Andrew Klosterman, Mary Wright, Lisa Dubois, Wendy Liu, Fan Zhuang, Anne Rodrigues, Kameron B. Hoover, Shelley Dwyer, Jennifer Simpson, Mark R. Merlino, Glenn Yuspa, Stuart H. TI MET signaling in keratinocytes activates EGFR and initiates squamous carcinogenesis SO SCIENCE SIGNALING LA English DT Article ID GROWTH-FACTOR RECEPTOR; KINASE-C-ALPHA; FACTOR-TRANSGENIC MICE; HEPATOCYTE GROWTH; CELL CARCINOMA; FACTOR/SCATTER FACTOR; SERINE-PROTEASE; SKIN TUMORS; LUNG-CANCER; INTRAEPIDERMAL INFLAMMATION AB The receptor tyrosine kinase MET is abundant in many human squamous cell carcinomas (SCCs), but its functional significance in tumorigenesis is not clear. We found that the incidence of carcinogen-induced skin squamous tumors was substantially increased in transgenic MT-HGF (mouse metallothionein-hepatocyte growth factor) mice, which have increased abundance of the MET ligand HGF. Squamous tumors also erupted spontaneously on the skin of MT-HGF mice that were promoted by wounding or the application of 12-O-tetradecanoylphorbol 13-acetate, an activator of protein kinase C. Carcinogen-initiated tumors had Ras mutations, but spontaneous tumors did not. Cultured keratinocytes from MT-HGF mice and oncogenic RAS-transduced keratinocytes shared phenotypic and biochemical features of initiation that were dependent on autocrine activation of epidermal growth factor receptor (EGFR) through increased synthesis and release of EGFR ligands, which was mediated by the kinase SRC, the pseudoproteases iRhom1 and iRhom2, and the metallopeptidase ADAM17. Pharmacological inhibition of EGFR caused the regression of MT-HGF squamous tumors that developed spontaneously in orthografts of MT-HGF keratinocytes combined with dermal fibroblasts and implanted onto syngeneic mice. The global gene expression profile in MET-transformed keratinocytes was highly concordant with that in RAS-transformed keratinocytes, and a core RAS/MET coexpression network was activated in precancerous and cancerous human skin lesions. Tissue arrays revealed that many human skin SCCs have abundant HGF at both the transcript and protein levels. Thus, through the activation of EGFR, MET activation parallels a RAS pathway to contribute to human and mouse cutaneous cancers. C1 [Cataisson, Christophe; Michalowski, Aleksandra M.; Shibuya, Kelly; Ryscavage, Andrew; Klosterman, Mary; Wright, Lisa; Dubois, Wendy; Liu, Fan; Zhuang, Anne; Rodrigues, Kameron B.; Hoover, Shelley; Dwyer, Jennifer; Simpson, Mark R.; Merlino, Glenn; Yuspa, Stuart H.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Yuspa, SH (reprint author), NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM yuspas@mail.nih.gov OI Rodrigues, Kameron/0000-0002-0270-3688 FU intramural program of the Center for Cancer Research of the NCI FX This work was funded by the intramural program of the Center for Cancer Research of the NCI. NR 96 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 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD JUN 21 PY 2016 VL 9 IS 433 AR ra62 DI 10.1126/scisignal.aaf5106 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DP2RU UT WOS:000378339500002 PM 27330189 ER PT J AU Vasan, RS Benjamin, EJ AF Vasan, Ramachandran S. Benjamin, Emelia J. TI The Future of Cardiovascular Epidemiology SO CIRCULATION LA English DT Article DE cardiovascular diseases; epidemiology ID AMERICAN-HEART-ASSOCIATION; LARGE SOCIAL NETWORK; UNITED-STATES; PUBLIC-HEALTH; PHYSICAL-ACTIVITY; NATIONAL HEART; WORKING GROUP; HUMAN GENOME; DISEASE; POPULATION C1 [Vasan, Ramachandran S.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Evans Dept Med, Boston, MA 02215 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Prevent Med Sect, Boston, MA 02215 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02215 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Ste 2, Framingham, MA 01702 USA. EM vasan@bu.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung, and Blood Institute, Framingham Heart Study (National Heart, Lung, and Blood Institute/NIH) [N01-HC-25195, HHSN268201500001I]; Boston University School of Medicine Evan's Scholar Award; [1P50HL120163] FX This work was supported by the National Heart, Lung, and Blood Institute, Framingham Heart Study (National Heart, Lung, and Blood Institute/NIH contracts N01-HC-25195 and HHSN268201500001I), 1P50HL120163, and the Boston University School of Medicine Evan's Scholar Award (Dr Vasan). NR 65 TC 0 Z9 0 U1 6 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JUN 21 PY 2016 VL 133 IS 25 BP 2626 EP 2633 DI 10.1161/CIRCULATIONAHA.116.023528 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DO9LT UT WOS:000378108800006 PM 27324358 ER PT J AU MacRae, CA Vasan, RS AF MacRae, Calum A. Vasan, Ramachandran S. TI The Future of Genetics and Genomics Closing the Phenotype Gap in Precision Medicine SO CIRCULATION LA English DT Article DE genetics; genomics; phenotyping ID CONGENITAL HEART-DISEASE; MISSING HERITABILITY; HIRSCHSPRUNG-DISEASE; ATRIAL-FIBRILLATION; WIDE ASSOCIATION; EXOME DATA; VARIANTS; RISK; LOCI; CARDIOMYOPATHY C1 [MacRae, Calum A.] Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. [MacRae, Calum A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [MacRae, Calum A.] Broad Inst Harvard & MIT, Boston, MA USA. [Vasan, Ramachandran S.] NHLBI, Framingham, MA USA. [Vasan, Ramachandran S.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02215 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Evans Dept Epidemiol, Boston, MA 02215 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Evans Dept Med, Boston, MA 02215 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Evans Dept Epidemiol, Boston, MA 02215 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02215 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02215 USA. RP MacRae, CA (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM camacrae@bics.bwh.harvard.edu FU National Health, Lung, and Blood Institute, Framingham Heart Study (National Health, Lung, and Blood Institute/National Institutes of Health) [N01-HC-25195, HHSN268201500001I]; National Human Genome Research Institute [U01 HG007690, U01 HG006500] FX This work was supported by the National Health, Lung, and Blood Institute, Framingham Heart Study (National Health, Lung, and Blood Institute/National Institutes of Health contracts N01-HC-25195 and HHSN268201500001I), and National Human Genome Research Institute (U01 HG007690, U01 HG006500). NR 42 TC 0 Z9 0 U1 3 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JUN 21 PY 2016 VL 133 IS 25 BP 2634 EP 2639 DI 10.1161/CIRCULATIONAHA.116.022547 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DO9LT UT WOS:000378108800007 PM 27324359 ER PT J AU Kanellopoulou, C Muljo, SA AF Kanellopoulou, Chrysi Muljo, Stefan A. TI Fine-Tuning Th17 Cells: To Be or Not To Be Pathogenic? SO IMMUNITY LA English DT Editorial Material ID PROGRESSIVE HEARING-LOSS; T(H)17 CELLS; DIFFERENTIATION; INDUCTION; MIR-96; SGK1 AB Like the story of Jekyll and Hyde, Th17 cells have two guises. One helps with host immunity, but the other can cause immunopathology. In this issue of Immunity, Dong and colleagues report that three microRNAs, miR183, miR-96, and miR-182, can enhance the pathogenicity of Th17 cells (Ichiyama et al., 2016). C1 [Kanellopoulou, Chrysi; Muljo, Stefan A.] NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Muljo, SA (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM stefan.muljo@nih.gov NR 10 TC 1 Z9 1 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JUN 21 PY 2016 VL 44 IS 6 BP 1241 EP 1243 DI 10.1016/j.immuni.2016.06.003 PG 3 WC Immunology SC Immunology GA DP2SE UT WOS:000378341200001 PM 27332724 ER PT J AU Voss, OH Murakami, Y Pena, MY Lee, HN Tian, LJ Margulies, DH Street, JM Yuen, PST Qi, CF Krzewski, K Coligan, JE AF Voss, Oliver H. Murakami, Yousuke Pena, Mirna Y. Lee, Ha-Na Tian, Linjie Margulies, David H. Street, Jonathan M. Yuen, Peter S. T. Qi, Chen-Feng Krzewski, Konrad Coligan, John E. TI Lipopolysaccharide-Induced CD300b Receptor Binding to Toll-like Receptor 4 Alters Signaling to Drive Cytokine Responses that Enhance Septic Shock SO IMMUNITY LA English DT Article ID APOPTOTIC CELLS; AMPLIFIES INFLAMMATION; ACTIVATING RECEPTOR; IL-10 PRODUCTION; IMMUNE-SYSTEM; PROTECTS MICE; CD14; LPS; SEPSIS; MACROPHAGES AB Receptor CD300b is implicated in regulating the immune response to bacterial infection by an unknown mechanism. Here, we identified CD300b as a lipopolysaccharide (LPS)-binding receptor and determined the mechanism underlying CD300b augmentation of septic shock. In vivo depletion and adoptive transfer studies identified CD300b-expressing macrophages as the key cell type augmenting sepsis. We showed that CD300b, and its adaptor DAP12, associated with Toll-like receptor 4 (TLR4) upon LPS binding, thereby enhancing TLR4-adaptor MyD88- and TRIF-dependent signaling that resulted in an elevated pro-inflammatory cytokine storm. LPS engagement of the CD300b-TLR4 complex led to the recruitment and activation of spleen tyrosine kinase (Syk) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K). This resulted in an inhibition of the ERK1/2 protein kinase-and NF-kappa B transcription factor-mediated signaling pathways, which subsequently led to a reduced interleukin-10 (IL-10) production. Collectively, our data describe a mechanism of TLR4 signaling regulated by CD300b in myeloid cells in response to LPS. C1 [Voss, Oliver H.; Murakami, Yousuke; Pena, Mirna Y.; Lee, Ha-Na; Tian, Linjie; Krzewski, Konrad; Coligan, John E.] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Margulies, David H.] NIAID, Mol Biol Sect, Immunol Lab, NIH, Bethesda, MD 20814 USA. [Street, Jonathan M.; Yuen, Peter S. T.] NIDDK, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD 20814 USA. [Qi, Chen-Feng] NIAID, Pathol Core, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Coligan, JE (reprint author), NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM jcoligan@niaid.nih.gov RI Yuen, Peter/B-1954-2008 OI Yuen, Peter/0000-0001-9557-3909 FU intramural programs of the National Institute of Allergy and Infectious Diseases (NIAID) FX We thank Robert Star (NIAID/NIH) for providing us with the CLP methodology. We further thank Kannan Natarajan and Lisa Boyd for assistance with the SPR analyses. We also thank Herbert Morse III, Susan Pierce, and Louis Thomas for their critical comments and advice. This study was supported by the intramural programs of the National Institute of Allergy and Infectious Diseases (NIAID). NR 40 TC 3 Z9 3 U1 6 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JUN 21 PY 2016 VL 44 IS 6 BP 1365 EP 1378 DI 10.1016/j.immuni.2016.05.005 PG 14 WC Immunology SC Immunology GA DP2SE UT WOS:000378341200015 PM 27261276 ER PT J AU Knudsen, AB Zauber, AG Rutter, CM Naber, SK Doria-Rose, VP Pabiniak, C Johanson, C Fischer, SE Lansdorp-Vogelaar, I Kuntz, KM AF Knudsen, Amy B. Zauber, Ann G. Rutter, Carolyn M. Naber, Steffie K. Doria-Rose, V. Paul Pabiniak, Chester Johanson, Colden Fischer, Sara E. Lansdorp-Vogelaar, Iris Kuntz, Karen M. TI Estimation of Benefits, Burden, and Harms of Colorectal Cancer Screening Strategies Modeling Study for the US Preventive Services Task Force SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID FECAL-OCCULT-BLOOD; RANDOMIZED CONTROLLED-TRIAL; COST-EFFECTIVENESS ANALYSIS; FLEXIBLE SIGMOIDOSCOPY; CT COLONOGRAPHY; LARGE-INTESTINE; LARGE-BOWEL; NEGATIVE COLONOSCOPY; POPULATION; MORTALITY AB IMPORTANCE The US Preventive Services Task Force (USPSTF) is updating its 2008 colorectal cancer (CRC) screening recommendations. OBJECTIVE To inform the USPSTF by modeling the benefits, burden, and harms of CRC screening strategies; estimating the optimal ages to begin and end screening; and identifying a set of model-recommendable strategies that provide similar life-years gained (LYG) and a comparable balance between LYG and screening burden. DESIGN, SETTING, AND PARTICIPANTS Comparative modeling with 3 microsimulation models of a hypothetical cohort of previously unscreened US 40-year-olds with no prior CRC diagnosis. EXPOSURES Screening with sensitive guaiac-based fecal occult blood testing, fecal immunochemical testing (FIT), multitarget stool DNA testing, flexible sigmoidoscopy with or without stool testing, computed tomographic colonography (CTC), or colonoscopy starting at age 45, 50, or 55 years and ending at age 75, 80, or 85 years. Screening intervals varied by modality. Full adherence for all strategies was assumed. MAIN OUTCOMES AND MEASURES Life-years gained compared with no screening (benefit), lifetime number of colonoscopies required (burden), lifetime number of colonoscopy complications (harms), and ratios of incremental burden and benefit (efficiency ratios) per 1000 40-year-olds. RESULTS The screening strategies provided LYG in the range of 152 to 313 per 1000 40-year-olds. Lifetime colonoscopy burden per 1000 persons ranged from fewer than 900 (FIT every 3 years from ages 55-75 years) to more than 7500 (colonoscopy screening every 5 years from ages 45-85 years). Harm from screening was at most 23 complications per 1000 persons screened. Strategies with screening beginning at age 50 years generally provided more LYG as well as more additional LYG per additional colonoscopy than strategies with screening beginning at age 55 years. There were limited empirical data to support a start age of 45 years. For persons adequately screened up to age 75 years, additional screening yielded small increases in LYG relative to the increase in colonoscopy burden. With screening from ages 50 to 75 years, 4 strategies yielded a comparable balance of screening burden and similar LYG (median LYG per 1000 across the models): colonoscopy every 10 years (270 LYG); sigmoidoscopy every 10 years with annual FIT (256 LYG); CTC every 5 years (248 LYG); and annual FIT (244 LYG). CONCLUSIONS AND RELEVANCE In this microsimulation modeling study of a previously unscreened population undergoing CRC screening that assumed 100% adherence, the strategies of colonoscopy every 10 years, annual FIT, sigmoidoscopy every 10 years with annual FIT, and CTC every 5 years performed from ages 50 through 75 years provided similar LYG and a comparable balance of benefit and screening burden. C1 [Zauber, Ann G.; Fischer, Sara E.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 485 Lexington Ave,Second Floor, New York, NY 10017 USA. [Knudsen, Amy B.; Johanson, Colden] Massachusetts Gen Hosp, Dept Radiol, Inst Technol Assessment, Boston, MA USA. [Rutter, Carolyn M.] RAND Corp, Santa Monica, CA USA. [Naber, Steffie K.; Lansdorp-Vogelaar, Iris] Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Doria-Rose, V. Paul] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Pabiniak, Chester] Grp Hlth Res Inst, Seattle, WA USA. [Kuntz, Karen M.] Univ Minnesota, Sch Publ Hlth, Dept Hlth Policy & Management, Minneapolis, MN USA. [Johanson, Colden] Optum, Boston, MA USA. RP Zauber, AG (reprint author), Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 485 Lexington Ave,Second Floor, New York, NY 10017 USA. EM zaubera@mskcc.org OI Doria-Rose, Vincent/0000-0002-8802-5143 FU National Cancer Institute (NCI) of the National Institutes of Health (NIH) [U01CA152959]; NCI Cancer Center Support Grant [P30CA008748] FX This analysis was supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) (through a supplement from the Agency for Healthcare Research and Quality [AHRQ]) under award U01CA152959. Dr Zauber was also supported in part by a NCI Cancer Center Support Grant under award P30CA008748. NR 69 TC 15 Z9 15 U1 2 U2 4 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 21 PY 2016 VL 315 IS 23 BP 2595 EP 2609 DI 10.1001/jama.2016.6828 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA DP2GQ UT WOS:000378306700022 PM 27305518 ER PT J AU Kamhawi, S Coutinho-Abreu, IV AF Kamhawi, Shaden Coutinho-Abreu, Iliano V. TI VSG overcomes an early barrier to survival of African trypanosomes in tsetse flies SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID SAND FLY VECTORS; PHLEBOTOMUS-PAPATASI; PERITROPHIC MATRIX; PARASITE CHITINASE; NATURAL VECTOR; AEDES-AEGYPTI; MIDGUT; TRANSMISSION C1 [Kamhawi, Shaden; Coutinho-Abreu, Iliano V.] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Kamhawi, S (reprint author), NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM skamhawi@niaid.nih.gov NR 20 TC 0 Z9 0 U1 6 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 21 PY 2016 VL 113 IS 25 BP 6821 EP 6823 DI 10.1073/pnas.1607008113 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP1TN UT WOS:000378272400026 PM 27286826 ER PT J AU Werner-Allen, JW DuMond, JF Levine, RL Bax, A AF Werner-Allen, Jon W. DuMond, Jenna F. Levine, Rodney L. Bax, Ad TI Toxic Dopamine Metabolite DOPAL Forms an Unexpected Dicatechol Pyrrole Adduct with Lysines of alpha-Synuclein SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE amyloid disease; covalent modification; oxidative stress; Paal-Knorr synthesis; Parkinson's disease ID PARKINSONS-DISEASE; IN-VIVO; AGGREGATION; 3,4-DIHYDROXYPHENYLACETALDEHYDE; PRODUCTS; PROTEINS AB Parkinson's disease has long been known to involve the loss of dopaminergic neurons in the substantia nigra and the coincidental appearance of Lewy bodies containing oligomerized forms of alpha-synuclein. The "catecholaldehyde hypothesis" posits a causal link between these two central pathologies mediated by 3,4-dihydroxyphenylacetaldehyde (DOPAL), the most toxic dopamine metabolite. Here we determine the structure of the dominant product in reactions between DOPAL and alpha-synuclein, a dicatechol pyrrole lysine adduct. This novel modification results from the addition of two DOPAL molecules to the Lys sidechain amine through their aldehyde moieties and the formation of a new carbon-carbon bond between their alkyl chains to generate a pyrrole ring. The product is detectable at low concentrations of DOPAL and its discovery should provide a valuable chemical basis for future studies of DOPAL-induced crosslinking of alpha-synuclein. C1 [Werner-Allen, Jon W.; Bax, Ad] NIDDK, Chem Phys Lab, Bethesda, MD 20892 USA. [DuMond, Jenna F.; Levine, Rodney L.] NHLBI, Biochem Lab, NIH, Bldg 3, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, Bethesda, MD 20892 USA.; Levine, RL (reprint author), NHLBI, Biochem Lab, NIH, Bldg 3, Bethesda, MD 20892 USA. EM rlevine@nih.gov; bax@nih.gov RI Levine, Rodney/D-9885-2011 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, National Institutes of Health FX We thank Jinfa Ying for technical help, Daniel Mulvihill (University of Kent) for the NatB acetyltransferase construct, the NIDDK Advanced Spectrometry Core for preliminary data collection, and Richard Glass (University of Arizona), S. Bruce King (Wake Forest University), Kenneth Kirk, Vincent Cole, and Rolf Swenson (National Institutes of Health), and Sanford Markey, W. Gary Mallard, and Edward White (National Institutes of Standards and Technology) for their advice. This work was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, National Institutes of Health. NR 22 TC 1 Z9 1 U1 4 U2 5 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD JUN 20 PY 2016 VL 55 IS 26 BP 7374 EP 7378 DI 10.1002/anie.201600277 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA DV6WI UT WOS:000383077400007 PM 27158766 ER PT J AU Cilli, P Ventura, I Minoprio, A Meccia, E Martire, A Wilson, SH Bignami, M Mazzei, F AF Cilli, Piera Ventura, Ilenia Minoprio, Anna Meccia, Ettore Martire, Alberto Wilson, Samuel H. Bignami, Margherita Mazzei, Filomena TI Oxidized dNTPs and the OGG1 and MUTYH DNA glycosylases combine to induce CAG/CTG repeat instability SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BASE EXCISION-REPAIR; PURINE NUCLEOSIDE TRIPHOSPHATASE; KNOCK-IN MICE; HUNTINGTONS-DISEASE; OXIDATIVE DAMAGE; POLYMERASE-BETA; CAG REPEAT; MISMATCH RECOGNITION; REPLICATION FIDELITY; SECONDARY STRUCTURE AB DNA trinucleotide repeat (TNR) expansion underlies several neurodegenerative disorders including Huntington's disease (HD). Accumulation of oxidized DNA bases and their inefficient processing by base excision repair (BER) are among the factors suggested to contribute to TNR expansion. In this study, we have examined whether oxidation of the purine dNTPs in the dNTP pool provides a source of DNA damage that promotes TNR expansion. We demonstrate that during BER of 8-oxoguanine (8-oxodG) in TNR sequences, DNA polymerase beta (POL beta) can incorporate 8-oxodGMP with the formation of 8-oxodG:C and 8-oxodG:A mispairs. Their processing by the OGG1 and MUTYH DNA glycosylases generates closely spaced incisions on opposite DNA strands that are permissive for TNR expansion. Evidence in HD model R6/2 mice indicates that these DNA glycosylases are present in brain areas affected by neurodegeneration. Consistent with prevailing oxidative stress, the same brain areas contained increased DNA 8-oxodG levels and expression of the p53-inducible ribonucleotide reductase. Our in vitro and in vivo data support a model where an oxidized dNTPs pool together with aberrant BER processing contribute to TNR expansion in non-replicating cells. C1 [Cilli, Piera; Ventura, Ilenia; Minoprio, Anna; Meccia, Ettore; Bignami, Margherita; Mazzei, Filomena] Ist Super Sanita, Dept Environm & Primary Prevent, I-00161 Rome, Italy. [Cilli, Piera] Univ Rome Tre, Dept Sci, I-00154 Rome, Italy. [Martire, Alberto] Ist Super Sanita, Dept Drug Safety & Evaluat, I-00161 Rome, Italy. [Wilson, Samuel H.] NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Bignami, M; Mazzei, F (reprint author), Ist Super Sanita, Dept Environm & Primary Prevent, I-00161 Rome, Italy. EM Margherita.bignami@gmail.com; filomena.mazzei@iss.it FU Associazione Italiana Ricerca sul Cancro [11755]; Ministry of Health, Project 'Malattie Rare'; Intramural Research Program of the US National Institutes of Health, NIEHS [Z01 ES050158, ES050159]; Istituto Superiore di Sanita FX Associazione Italiana Ricerca sul Cancro [11755]; Ministry of Health, Project 'Malattie Rare' (to M.B. and F.M.); Intramural Research Program of the US National Institutes of Health, NIEHS [Z01 ES050158, ES050159 to S.H.W.]. Funding for open access charge: Istituto Superiore di Sanita NR 58 TC 2 Z9 2 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUN 20 PY 2016 VL 44 IS 11 BP 5190 EP 5203 DI 10.1093/nar/gkw170 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DR2SB UT WOS:000379753100028 PM 26980281 ER PT J AU Henriksen, S Read, JCA AF Henriksen, Sid Read, Jenny C. A. TI Visual Perception: A Novel Difference Channel in Binocular Vision SO CURRENT BIOLOGY LA English DT Editorial Material ID ADAPTATION AB A recent study provides compelling evidence that binocular vision uses two separate channels; one channel adds the images from the two eyes, and the other subtracts them. C1 [Henriksen, Sid; Read, Jenny C. A.] Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Henriksen, Sid] NEI, Sensorimotor Res Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Henriksen, S; Read, JCA (reprint author), Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England.; Henriksen, S (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM sid.henriksen@gmail.com; jenny.read@ncl.ac.uk OI Read, Jenny/0000-0002-9029-5185 NR 14 TC 0 Z9 0 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD JUN 20 PY 2016 VL 26 IS 12 BP R500 EP R503 DI 10.1016/j.cub.2016.04.049 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DP7EK UT WOS:000378661800009 PM 27326711 ER PT J AU Ondov, BD Treangen, TJ Melsted, P Mallonee, AB Bergman, NH Koren, S Phillippy, AM AF Ondov, Brian D. Treangen, Todd J. Melsted, Pall Mallonee, Adam B. Bergman, Nicholas H. Koren, Sergey Phillippy, Adam M. TI Mash: fast genome and metagenome distance estimation using MinHash SO GENOME BIOLOGY LA English DT Article DE Comparative genomics; Genomic distance; Alignment; Sequencing; Nanopore; Metagenomics ID SEQUENCING DATA; ALIGNMENT; RECONSTRUCTION; SIMILARITY; ALGORITHM; MATCHES; SEARCH AB Mash extends the MinHash dimensionality-reduction technique to include a pairwise mutation distance and P value significance test, enabling the efficient clustering and search of massive sequence collections. Mash reduces large sequences and sequence sets to small, representative sketches, from which global mutation distances can be rapidly estimated. We demonstrate several use cases, including the clustering of all 54,118 NCBI RefSeq genomes in 33 CPU h; real-time database search using assembled or unassembled Illumina, Pacific Biosciences, and Oxford Nanopore data; and the scalable clustering of hundreds of metagenomic samples by composition. Mash is freely released under a BSD license (https://github.com/marbl/mash). C1 [Ondov, Brian D.; Treangen, Todd J.; Mallonee, Adam B.; Bergman, Nicholas H.] Natl Biodef Anal & Countermeasures Ctr, Frederick, MD USA. [Melsted, Pall] Univ Iceland, Fac Ind Engn, Mech Engn & Comp Sci, Reykjavik, Iceland. [Koren, Sergey; Phillippy, Adam M.] NHGRI, Genome Informat Sect, Computat & Stat Genom Branch, NIH, Bethesda, MD 20892 USA. RP Phillippy, AM (reprint author), NHGRI, Genome Informat Sect, Computat & Stat Genom Branch, NIH, Bethesda, MD 20892 USA. EM adam.phillippy@nih.gov FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health; Department of Homeland Security (DHS) Science and Technology Directorate (S&T) for the management and operation of the National Biodefense Analysis and Countermeasures Center (NBACC) [HSHQDC-07-C-00020] FX This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, and under Contract No. HSHQDC-07-C-00020 awarded by the Department of Homeland Security (DHS) Science and Technology Directorate (S&T) for the management and operation of the National Biodefense Analysis and Countermeasures Center (NBACC), a Federally Funded Research and Development Center. The views and conclusions contained in this document are those of the authors and should not be interpreted as necessarily representing the official policies, either expressed or implied, of the DHS or S&T. In no event shall the DHS, NBACC, S&T, or Battelle National Biodefense Institute (BNBI) have any responsibility or liability for any use, misuse, inability to use, or reliance upon the information contained herein. DHS does not endorse any products or commercial services mentioned in this publication. NR 55 TC 6 Z9 6 U1 6 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-760X J9 GENOME BIOL JI Genome Biol. PD JUN 20 PY 2016 VL 17 AR 132 DI 10.1186/s13059-016-0997-x PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DQ0OZ UT WOS:000378900700001 PM 27323842 ER PT J AU Levin, L Srour, S Gartner, J Kapitansky, O Qutob, N Dror, S Golan, T Dayan, R Brener, R Ziv, T Khaled, M Schueler-Furman, O Samuels, Y Levy, C AF Levin, Lotan Srour, Shani Gartner, Jared Kapitansky, Oxana Qutob, Nouar Dror, Shani Golan, Tamar Dayan, Roy Brener, Ronen Ziv, Tamar Khaled, Mehdi Schueler-Furman, Ora Samuels, Yardena Levy, Carmit TI Parkin Somatic Mutations Link Melanoma and Parkinson's Disease SO JOURNAL OF GENETICS AND GENOMICS LA English DT Article DE Melanoma; Parkinson's disease; Parkin; Mutation ID UBIQUITIN-PROTEIN LIGASE; INDEPENDENT UBIQUITINATION; MALIGNANT-MELANOMA; BREAST-CANCER; GENES; DEGRADATION; ACTIVATION; LANDSCAPE; DELETIONS; DOPAMINE AB Epidemiological studies suggest a direct link between melanoma and Parkinson's disease (PD); however, the underlying molecular basis is unknown. Since mutations in Parkin are the major driver of early-onset PD and Parkin was recently reported to play a role in cancer development, we hypothesized that Parkin links melanoma and PD. By analyzing whole exome/genome sequencing of Parkin from 246 melanoma patients, we identified five non-synonymous mutations, three synonymous mutations, and one splice region variant in Parkin in 3.6% of the samples. In vitro analysis showed that wild-type Parkin plays a tumor suppressive role in melanoma development resulting in cell-cycle arrest, reduction of metabolic activity, and apoptosis. Using a mass spectrometry-based analysis, we identified potential Parkin substrates in melanoma and generated a functional protein association network. The activity of mutated Parkin was assessed by protein structure modeling and examination of Parkin E3 ligase activity. The Parkin-E28K mutation impairs Parkin ubiquitination activity and abolishes its tumor suppressive effect. Taken together, our analysis of genomic sequence and in vitro data indicate that Parkin is a potential link between melanoma and Parkinson's disease. Our findings suggest new approaches for early diagnosis and treatment against both diseases. C1 [Levin, Lotan; Srour, Shani; Kapitansky, Oxana; Dror, Shani; Golan, Tamar; Dayan, Roy; Levy, Carmit] Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Biochem, IL-69978 Tel Aviv, Israel. [Gartner, Jared] NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Qutob, Nouar; Samuels, Yardena] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. [Brener, Ronen] Edith Wolfson Med Ctr, Inst Oncol, IL-5822012 Holon, Israel. [Ziv, Tamar] Technion Israel Inst Technol, Fac Biol, Technion Smoler Prote Ctr, IL-32000 Haifa, Israel. [Khaled, Mehdi] Inst Gustave Roussy, INSERM, U753, F-94805 Villejuif, France. [Schueler-Furman, Ora] Hebrew Univ Jerusalem, Fac Med, Dept Microbiol & Mol Genet, Inst Med Res Israel Canada, IL-91120 Jerusalem, Israel. RP Levy, C (reprint author), Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Biochem, IL-69978 Tel Aviv, Israel. EM carmitlevy@post.tau.ac.il RI khaled, mehdi/C-4854-2012 FU I-CORE [41/11]; Israel Cancer Association (ICA) [20150101]; Israel Cancer Research Fund (ICRF) [RCBA-11706]; Fritz Thyssen Stiftung [AZ.10.12.1.188]; Marie Curie Career Integration Grants (CIG) [293594]; Dalya Gridinger Fund; Fingerhot Carol and Lionara Fund; Shtacher Family award FX We would like to thank Drs. Meenhard Herlyn, Levi Garraway, and Carl Novina for supplying melanoma cultures and the Smoler Proteomics Center at the Technion for mass spectroscopy analyses. C.L. gratefully acknowledges grant support from I-CORE (grant number 41/11), Mr. David Brown through the Israel Cancer Association (ICA) (grant number 20150101), Israel Cancer Research Fund (ICRF) (grant number RCBA-11706), Fritz Thyssen Stiftung (grant number AZ.10.12.1.188), Marie Curie Career Integration Grants (CIG) (grant number 293594), Dalya Gridinger Fund, Fingerhot Carol and Lionara Fund, and the Shtacher Family award. NR 49 TC 1 Z9 1 U1 4 U2 11 PU SCIENCE PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1673-8527 EI 1873-5533 J9 J GENET GENOMICS JI J. Genet. Genomics PD JUN 20 PY 2016 VL 43 IS 6 BP 369 EP 379 DI 10.1016/j.jgg.2016.05.005 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DP5MT UT WOS:000378542400002 PM 27297116 ER PT J AU Jiang, JS Promchan, K Jiang, H Awasthi, P Marshall, H Harned, A Natarajan, V AF Jiang, Jiangsong Promchan, Kanyarat Jiang, Hong Awasthi, Parirokh Marshall, Heather Harned, Adam Natarajan, Ven TI Depletion of BBS Protein LZTFL1 Affects Growth and Causes Retinal Degeneration in Mice SO JOURNAL OF GENETICS AND GENOMICS LA English DT Article DE LZTFL1; Cilium; BBSome; BBS17; Retina; AP-1 ID BARDET-BIEDL-SYNDROME; INTRAFLAGELLAR TRANSPORT; CILIA FUNCTION; SYNDROME GENES; CORE COMPLEX; MOUSE MODEL; T-CELLS; IFT; TRAFFICKING; PHENOTYPES AB Bardet-Biedl syndrome (BBS) is a heterogeneous disease characterized by deficiencies in various organs that are caused by defects in genes involved in the genesis, structural maintenance, and protein trafficking of cilia. Leucine zipper transcription factor-like 1 (LZTFL1) has been identified as a BBS protein (BBS17), because patients with mutations in this gene exhibit the common BBS phenotypes. In this study, we generated a knockout mouse model to investigate the effects of LZTFL1 depletion. Lztfl1 knockout mice were born with low birth weight, reached similar weight to those of wild-type mice at 10 weeks of age, and later gained more weight than their wild-type counterparts. LZTFL1 was localized to the primary cilium of kidney cells, and the absence of LZTFL1 increased the ciliary localization of BBS9. Moreover, in the retinas of Lztfl1 knockout mice, the photoreceptor outer segment was shortened, the distal axoneme of photoreceptor connecting cilium was significantly enlarged, and rhodopsin was targeted to the outer nuclear layer. TUNEL assay showed that many of these abnormal photoreceptor cells in Lztfl1 knockout mice underwent apoptosis. Interestingly, the absence of LZTFL1 caused an abnormal increase of the adaptor protein complex 1 (AP1) in some photoreceptor cells. Based on these data, we conclude that LZTFL1 is a cilium protein and regulates animal weight and photoreceptor connecting cilium function probably by controlling microtubule assembly and protein trafficking in cilia. C1 [Jiang, Jiangsong; Promchan, Kanyarat; Jiang, Hong; Marshall, Heather; Natarajan, Ven] Leidos Biomed Res Inc, Mol Cell Biol Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Awasthi, Parirokh] Leidos Biomed Res Inc, Transgen Mouse Model Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Harned, Adam] Leidos Biomed Res Inc, Electron Microscopy Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Jiang, Hong] Univ Kentucky, Grad Ctr Toxicol, Lucille P Markey Canc Ctr, Lexington, KY 40536 USA. RP Jiang, JS; Natarajan, V (reprint author), Leidos Biomed Res Inc, Mol Cell Biol Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM jiangj2@mail.nih.gov; Vnatarajan@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases FX This work has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract (HHSN261200800001E), and also 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 organizations imply endorsement by the U.S. Government. We would like to thank Kunio Nagashima for help with electron microscope analysis, as well as Mohammad Ishaq and other members of the Laboratory of Molecular Cell Biology for valuable suggestions. NR 48 TC 1 Z9 1 U1 2 U2 3 PU SCIENCE PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1673-8527 EI 1873-5533 J9 J GENET GENOMICS JI J. Genet. Genomics PD JUN 20 PY 2016 VL 43 IS 6 BP 381 EP 391 DI 10.1016/j.jgg.2015.11.006 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DP5MT UT WOS:000378542400003 PM 27312011 ER PT J AU Halilovic, A Schmedt, T Benischke, AS Hamill, C Chen, YM Santos, JH Jurkunas, UV AF Halilovic, Adna Schmedt, Thore Benischke, Anne-Sophie Hamill, Cecily Chen, Yuming Santos, Janine Hertzog Jurkunas, Ula V. TI Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID INDUCED OXIDATIVE STRESS; CELL-DEATH; INDUCED APOPTOSIS; MORPHOLOGY; EXPRESSION; PROTECTS; FUSION; CLUSTERIN; DIVISION; DYNAMICS AB Aims: Fuchs endothelial corneal dystrophy (FECD), a leading cause of age-related corneal edema requiring transplantation, is characterized by rosette formation of corneal endothelium with ensuing apoptosis. We sought to determine whether excess of mitochondrial reactive oxygen species leads to chronic accumulation of oxidative DNA damage and mitochondrial dysfunction, instigating cell death. Results: We modeled the pathognomonic rosette formation of postmitotic corneal cells by increasing endogenous cellular oxidative stress with menadione (MN) and performed a temporal analysis of its effect in normal (HCEnC, HCECi) and FECD (FECDi) cells and ex vivo specimens. FECDi and FECD ex vivo specimens exhibited extensive mtDNA and nDNA damage as detected by quantitative PCR. Exposure to MN triggered an increase in mitochondrial superoxide levels and led to mtDNA and nDNA damage, while DNA amplification was restored with NAC pretreatment. Furthermore, MN exposure led to a decrease in Delta Psi m and adenosine triphosphate levels in normal cells, while FECDi exhibited mitochondrial dysfunction at baseline. Mitochondrial fragmentation and cytochrome c release were detected in FECD tissue and after MN treatment of HCEnCs. Furthermore, cleavage of caspase-9 and caspase-3 followed MN-induced cytochrome c release in HCEnCs. Innovation: This study provides the first line of evidence that accumulation of oxidative DNA damage leads to rosette formation, loss of functionally intact mitochondria via fragmentation, and subsequent cell death during postmitotic cell degeneration of ocular tissue. Conclusion: MN induced rosette formation, along with mtDNA and nDNA damage, mitochondrial dysfunction, and fragmentation, leading to activation of the intrinsic apoptosis via caspase cleavage and cytochrome c release. C1 [Halilovic, Adna; Schmedt, Thore; Benischke, Anne-Sophie; Hamill, Cecily; Chen, Yuming; Jurkunas, Ula V.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. [Santos, Janine Hertzog] Rutgers State Univ, New Jersey Med Sch Rutgers, Dept Physiol & Pharmacol, Piscataway, NJ 08855 USA. [Santos, Janine Hertzog] NIEHS, Epigenet & Stem Cell Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. RP Jurkunas, UV (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM ula_jurkunas@meei.harvard.edu FU NEI/NIH [R01 EY020581] FX This work was supported by NEI/NIH R01 EY020581. NR 47 TC 2 Z9 2 U1 4 U2 7 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JUN 20 PY 2016 VL 24 IS 18 BP 1072 EP 1083 DI 10.1089/ars.2015.6532 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DP2RE UT WOS:000378336900004 PM 26935406 ER PT J AU Kim, JW Yang, HJ Oel, AP Brooks, MJ Jia, L Plachetzki, DC Li, W Allison, WT Swaroop, A AF Kim, Jung-Woong Yang, Hyun-Jin Oel, Adam Phillip Brooks, Matthew John Jia, Li Plachetzki, David Charles Li, Wei Allison, William Ted Swaroop, Anand TI Recruitment of Rod Photoreceptors from Short-Wavelength-Sensitive Cones during the Evolution of Nocturnal Vision in Mammals SO DEVELOPMENTAL CELL LA English DT Article ID MOUSE RETINA; VERTEBRATE PHOTORECEPTORS; TRANSCRIPTION FACTORS; TEMPORAL EXPRESSION; VISUAL PIGMENTS; COLOR-VISION; CELLS; NRL; PRECURSORS; ZEBRAFISH AB Vertebrate ancestors had only cone-like photoreceptors. The duplex retina evolved in jawless vertebrates with the advent of highly photosensitive rod-like photoreceptors. Despite cones being the arbiters of high-resolution color vision, rods emerged as the dominant photoreceptor in mammals during a nocturnal phase early in their evolution. We investigated the evolutionary and developmental origins of rods in two divergent vertebrate retinas. In mice, we discovered genetic and epigenetic vestiges of short-wavelength cones in developing rods, and cell-lineage tracing validated the genesis of rods from S cones. Curiously, rods did not derive from S cones in zebrafish. Our study illuminates several questions regarding the evolution of duplex retina and supports the hypothesis that, in mammals, the S-cone lineage was recruited via the Maf-family transcription factor NRL to augment rod photoreceptors. We propose that this developmental mechanism allowed the adaptive exploitation of scotopic niches during the nocturnal bottleneck early in mammalian evolution. C1 [Kim, Jung-Woong; Yang, Hyun-Jin; Brooks, Matthew John; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Kim, Jung-Woong] Chung Ang Univ, Coll Nat Sci, Dept Life Sci, Seoul 156756, South Korea. [Oel, Adam Phillip; Allison, William Ted] Univ Alberta, Dept Biol Sci, Edmonton, AB T6G 2E9, Canada. [Jia, Li; Li, Wei] NEI, Retinal Neurophysiol Sect, NIH, Bethesda, MD 20892 USA. [Plachetzki, David Charles] Univ New Hampshire, Dept Mol Cellular & Biomed Sci, Durham, NH 03824 USA. RP Swaroop, A (reprint author), NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA.; Allison, WT (reprint author), Univ Alberta, Dept Biol Sci, Edmonton, AB T6G 2E9, Canada. EM ted.allison@ualberta.ca; swaroopa@nei.nih.gov OI Allison, Ted/0000-0002-8461-4864 FU Intramural Research Program of the National Eye Institute [EY000450, EY000474]; Natural Sciences & Engineering Research Council of Canada; National Research Foundation of Korea [NRF-2015 R1C1A1A01055466] FX We are grateful to Douglas Forrest for advice and discussions, Tudor Badea for Rosa26-iAP mouse, Rafael Vilasmil for flow cytometry, and Robert Farris for imaging support. We thank Alexis Boleda, Sam Perez, and Genomatix (Claudia Gugenmus, Tanja Druke, Martin Seifert) for assistance in some of the next-generation sequencing data analysis. We acknowledge Hao Wang and Michele DuVal for generating transgenic zebrafish. This research was supported by the Intramural Research Program of the National Eye Institute (EY000450, EY000474), a Discovery Accelerator Grant from the Natural Sciences & Engineering Research Council of Canada, and the National Research Foundation of Korea (NRF-2015 R1C1A1A01055466). This work utilized the high-performance computational resources of the HPC Biowulf cluster at NIH (http://hpc.nih.gov). NR 74 TC 8 Z9 8 U1 7 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD JUN 20 PY 2016 VL 37 IS 6 BP 520 EP 532 DI 10.1016/j.devcel.2016.05.023 PG 13 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA DP0UB UT WOS:000378204200007 PM 27326930 ER PT J AU Ahmad, F Chung, YW Tang, Y Hockman, SC Liu, SW Khan, Y Huo, K Billings, E Amar, MJ Remaley, AT Manganiello, VC AF Ahmad, Faiyaz Chung, Youn Wook Tang, Yan Hockman, Steven C. Liu, Shiwei Khan, Yusuf Huo, Kevin Billings, Eric Amar, Marcelo J. Remaley, Alan T. Manganiello, Vincent C. TI Phosphodiesterase 3B (PDE3B) regulates NLRP3 inflammasome in adipose tissue SO SCIENTIFIC REPORTS LA English DT Article ID ACTIVATED PROTEIN-KINASE; GAMMA-INDUCING FACTOR; SMOOTH-MUSCLE-CELLS; NF-KAPPA-B; INSULIN-RESISTANCE; ENERGY HOMEOSTASIS; OBESE MICE; BETA; MACROPHAGES; SENSITIVITY AB Activation of inflammation in white adipose tissue (WAT), includes infiltration/expansion of WAT macrophages, contributes pathogenesis of obesity, insulin resistance, and metabolic syndrome. The inflammasome comprises an intracellular sensor (NLR), caspase-1 and the adaptor ASC. Inflammasome activation leads to maturation of caspase-1 and processing of IL1 beta, contributing to many metabolic disorders and directing adipocytes to a more insulin-resistant phenotype. Ablation of PDE3B in WAT prevents inflammasome activation by reducing expression of NLRP3, caspase-1, ASC, AIM2, TNF alpha, IL1 beta and proinflammatory genes. Following IP injection of lipopolysaccharide (LPS), serum levels of IL1 beta and TNF alpha were reduced in PDE3B(-/-)mice compared to WT. Activation of signaling cascades, which mediate inflammasome responses, were modulated in PDE3B(-/-)mice WAT, including smad, NFAT, NFkB, and MAP kinases. Moreover, expression of chemokine CCL2, MCP-1 and its receptor CCR2, which play an important role in macrophage chemotaxis, were reduced in WAT of PDE3B(-/-)mice. In addition, atherosclerotic plaque formation was significantly reduced in the aorta of apoE(-/-)/PDE3B(-/-) and LDL-R-/-/PDE3B(-/-)mice compared to apoE(-/-) and LDL-R(-/-)mice, respectively. Obesity-induced changes in serum-cholesterol were blocked in PDE3B(-/-)mice. Collectively, these data establish a role for PDE3B in modulating inflammatory response, which may contribute to a reduced inflammatory state in adipose tissue. C1 [Ahmad, Faiyaz; Chung, Youn Wook; Tang, Yan; Hockman, Steven C.; Liu, Shiwei; Khan, Yusuf; Huo, Kevin; Amar, Marcelo J.; Remaley, Alan T.; Manganiello, Vincent C.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Billings, Eric] NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Ahmad, F (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM AhmadF@NHLBI.NIH.gov FU Intramural Research Program, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA FX These studies were supported by the Intramural Research Program, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. The manuscript was completed following Dr. Manganiello's death. Dr. Joel Moss (NHLBI, NIH) assumed responsibility for its content. We also thank Dr. Matthew Movsesian for his careful reading of the manuscript and providing constructive comments. NR 53 TC 0 Z9 0 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 20 PY 2016 VL 6 AR 28056 DI 10.1038/srep28056 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP1CD UT WOS:000378227100001 PM 27321128 ER PT J AU Mullooly, M Pfeiffer, RM Nyante, SJ Heckman-Stoddard, BM Perloff, M Jatoi, I Brinton, LA Bowles, EJA Hoover, RN Glass, A de Gonzalez, AB Sherman, ME Gierach, GL AF Mullooly, Maeve Pfeiffer, Ruth M. Nyante, Sarah J. Heckman-Stoddard, Brandy M. Perloff, Marjorie Jatoi, Ismail Brinton, Louise A. Bowles, Erin J. Aiello Hoover, Robert N. Glass, Andrew de Gonzalez, Amy Berrington Sherman, Mark E. Gierach, Gretchen L. TI Mammographic Density as a Biosensor of Tamoxifen Effectiveness in Adjuvant Endocrine Treatment of Breast Cancer: Opportunities and Implications SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID WOMEN; RISK; TRIAL; CYP2D6; REDUCTION; THERAPY C1 [Mullooly, Maeve; Pfeiffer, Ruth M.; Heckman-Stoddard, Brandy M.; Perloff, Marjorie; Brinton, Louise A.; Hoover, Robert N.; de Gonzalez, Amy Berrington; Sherman, Mark E.; Gierach, Gretchen L.] NCI, Bethesda, MD 20892 USA. [Nyante, Sarah J.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Jatoi, Ismail] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Bowles, Erin J. Aiello] Grp Hlth Res Inst, Seattle, WA USA. [Glass, Andrew] Kaiser Permanente Northwest Ctr Hlth Res, Portland, OR USA. RP Mullooly, M (reprint author), NCI, Bethesda, MD 20892 USA. RI Gierach, Gretchen/E-1817-2016 OI Gierach, Gretchen/0000-0002-0165-5522 NR 30 TC 1 Z9 1 U1 2 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2016 VL 34 IS 18 BP 2093 EP + DI 10.1200/JCO.2015.64.4492 PG 7 WC Oncology SC Oncology GA DN9DU UT WOS:000377380300006 PM 27022110 ER PT J AU Henriksen, S Tanabe, S Cumming, B AF Henriksen, Sid Tanabe, Seiji Cumming, Bruce TI Disparity processing in primary visual cortex SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE binocular disparity; striate cortex; depth perception ID CAT STRIATE CORTEX; STEREOSCOPIC DEPTH-PERCEPTION; LATERAL GENICULATE-NUCLEUS; BINOCULAR DISPARITY; COMPLEX CELLS; V1 NEURONS; HORIZONTAL DISPARITY; RECEPTIVE-FIELDS; ENERGY-MODEL; MACAQUE V1 AB The first step in binocular stereopsis is to match features on the left retina with the correct features on the right retina, discarding 'false' matches. The physiological processing of these signals starts in the primary visual cortex, where the binocular energy model has been a powerful framework for understanding the underlying computation. For this reason, it is often used when thinking about how binocular matching might be performed beyond striate cortex. But this step depends critically on the accuracy of the model, and real V1 neurons show several properties that suggest they may be less sensitive to false matches than the energy model predicts. Several recent studies provide empirical support for an extended version of the energy model, in which the same principles are used, but the responses of single neurons are described as the sum of several subunits, each of which follows the principles of the energy model. These studies have significantly improved our understanding of the role played by striate cortex in the stereo correspondence problem. This article is part of the themed issue 'Vision in our three-dimensional world'. C1 [Henriksen, Sid; Cumming, Bruce] NEI, Lab Sensorimotor Res, NIH, Bethesda, MD 20892 USA. [Tanabe, Seiji] Univ Virginia, EEG Lab, Hlth Syst, Charlottesville, VA USA. RP Cumming, B (reprint author), NEI, Lab Sensorimotor Res, NIH, Bethesda, MD 20892 USA. EM bgc@lsr.nei.nih.gov FU National Institutes of Health, National Eye Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Eye Institute. NR 49 TC 3 Z9 3 U1 4 U2 5 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD JUN 19 PY 2016 VL 371 IS 1697 AR 20150255 DI 10.1098/rstb.2015.0255 PG 12 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DO3TQ UT WOS:000377704900004 ER PT J AU Murphy, AP Leopold, DA Humphreys, GW Welchman, AE AF Murphy, Aidan P. Leopold, David A. Humphreys, Glyn W. Welchman, Andrew E. TI Lesions to right posterior parietal cortex impair visual depth perception from disparity but not motion cues SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE depth perception; binocular vision; structure from motion; bistable; parietal cortex ID STRUCTURE-FROM-MOTION; COST FUNCTION MASKING; BINOCULAR-RIVALRY; BISTABLE PERCEPTION; STEREOSCOPIC VISION; PREFRONTAL CORTEX; HUMAN BRAIN; SPATIAL NORMALIZATION; PSYCHOMETRIC FUNCTION; DOMINANCE DURATIONS AB The posterior parietal cortex (PPC) is understood to be active when observers perceive three-dimensional (3D) structure. However, it is not clear howcentral this activity is in the construction of 3D spatial representations. Here, we examine whether PPC is essential for two aspects of visual depth perception by testing patients with lesions affecting this region. First, we measured subjects' ability to discriminate depth structure in various 3D surfaces and objects using binocular disparity. Patients with lesions to right PPC (N = 3) exhibited marked perceptual deficits on these tasks, whereas those with left hemisphere lesions (N = 2) were able to reliably discriminate depth as accurately as control subjects. Second, we presented an ambiguous 3D stimulus defined by structure from motion to determine whether PPC lesions influence the rate of bistable perceptual alternations. Patients' percept durations for the 3D stimulus were generally within a normal range, although the two patients with bilateral PPC lesions showed the fastest perceptual alternation rates in our sample. Intermittent stimulus presentation reduced the reversal rate similarly across subjects. Together, the results suggest that PPC plays a causal role in both inferring and maintaining the perception of 3D structure with stereopsis supported primarily by the right hemisphere, but do not lend support to the view that PPC is a critical contributor to bistable perceptual alternations. This article is part of the themed issue 'Vision in our three-dimensional world'. C1 [Murphy, Aidan P.; Leopold, David A.] NIMH, Sect Cognit Neurophysiol & Imaging, Neuropsychol Lab, Bethesda, MD 20838 USA. [Murphy, Aidan P.; Humphreys, Glyn W.; Welchman, Andrew E.] Univ Birmingham, Sch Psychol, Birmingham B15 2TT, W Midlands, England. [Humphreys, Glyn W.] Univ Oxford, Dept Expt Psychol, S Parks Rd, Oxford OX1 3UD, England. [Welchman, Andrew E.] Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England. RP Murphy, AP (reprint author), NIMH, Sect Cognit Neurophysiol & Imaging, Neuropsychol Lab, Bethesda, MD 20838 USA.; Murphy, AP (reprint author), Univ Birmingham, Sch Psychol, Birmingham B15 2TT, W Midlands, England. EM murphyap@mail.nih.gov OI Leopold, David/0000-0002-1345-6360 FU Wellcome Trust-NIH [WT091467MA]; Wellcome Trust [095183/Z/10/Z]; MRC; Stroke Association; National Institutes of Health FX This research was supported by a Wellcome Trust-NIH PhD studentship (WT091467MA) to A.P.M., a Wellcome Trust Fellowship (095183/Z/10/Z) to A.E.W., and grants from the MRC and the Stroke Association to G.W.H. D.A.L. and A.P.M. are supported by the Intramural program of the National Institutes of Health. NR 116 TC 2 Z9 2 U1 3 U2 4 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD JUN 19 PY 2016 VL 371 IS 1697 AR 20150263 DI 10.1098/rstb.2015.0263 PG 17 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DO3TQ UT WOS:000377704900012 ER PT J AU Krebs, SJ Slike, BM Sithinamsuwan, P Allen, IE Chalermchai, T Tipsuk, S Phanuphak, N Jagodzinski, L Kim, JH Ananworanich, J Marovich, MA Valcour, VG AF Krebs, Shelly J. Slike, Bonnie M. Sithinamsuwan, Pasiri Allen, Isabel E. Chalermchai, Thep Tipsuk, Somporn Phanuphak, Nittaya Jagodzinski, Linda Kim, Jerome H. Ananworanich, Jintanat Marovich, Mary A. Valcour, Victor G. CA SEARCH 011 Study Team TI Sex differences in soluble markers vary before and after the initiation of antiretroviral therapy in chronically HIV-infected individuals SO AIDS LA English DT Article DE cognition; cytokines; HIV; neopterin; sCD14; sex; soluble factors ID IMMUNODEFICIENCY-VIRUS-INFECTION; CENTRAL-NERVOUS-SYSTEM; CEREBROSPINAL-FLUID; IMMUNE ACTIVATION; PREDICT MORTALITY; T-CELLS; C VIRUS; AIDS; NEOPTERIN; INFLAMMATION AB Objective: To evaluate differences in soluble inflammatory markers between chronically HIV-infected men and women, with or without cognitive impairment, and in response to treatment. Design: Soluble biomarkers were measured in cryopreserved plasma and cerebrospinal fluid (CSF) of 60 treatment-nave individuals (25 men and 35 women) with chronic HIV infection and 18 HIV-uninfected controls (9 men and 9 women) from Thailand. Following enrollment, participants began combination antiretroviral therapy and were evaluated for expression of these markers after 48 weeks. Methods: Plasma and CSF levels of 19 soluble biomarkers (IFN-gamma TNF alpha, TN F-RII, IL-1 alpha, IL-1 beta, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-15, MCP-1, t-Tau, IP-10, neopterin, IFN alpha, I-FABP, and sCD14) were measured using either a multiparameter or standard ELISA assay. Results: Prior to combination antiretroviral therapy, women with impaired cognition had elevated levels of neopterin and TNF-RII compared with women with normal cognition in both the plasma and CSF; however, levels did not differ between cognitively impaired or normal men. In a secondary outcome-hypothesis generating analysis, sex differences were also pronounced in plasma levels of MCP-1, IL-10, I-FABP, and sCD14 in response to treatment. Neopterin, IP-10, TNF alpha, IFN alpha, MCP-1, IL-8, I-FABP, and sCD14 plasma levels remained elevated following 48 weeks of therapy in both sexes compared with uninfected controls. Conclusion: We provide evidence of sustained immune activation after 48 weeks of treatment and identify possible sex differences in biomarkers previously linked to cognitive impairment, chronic inflammation, and gut integrity that may contribute to immunological differences between sexes in relationship to disease progression and response to therapy. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Krebs, Shelly J.; Slike, Bonnie M.; Jagodzinski, Linda; Ananworanich, Jintanat; Marovich, Mary A.] US Mil HIV Res Program, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. [Krebs, Shelly J.; Slike, Bonnie M.; Ananworanich, Jintanat] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA. [Sithinamsuwan, Pasiri] Phramongkutklao Hosp, Bangkok, Thailand. [Allen, Isabel E.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Chalermchai, Thep; Tipsuk, Somporn; Phanuphak, Nittaya; Ananworanich, Jintanat] SEARCH, Thai Red Cross AIDS Res Ctr, Bangkok, Thailand. [Kim, Jerome H.] Int Vaccine Inst, Seoul, South Korea. [Ananworanich, Jintanat] Chulalongkorn Univ, Bangkok, Thailand. [Marovich, Mary A.] NIH, Vaccine Res & Dev Sect, Div Aids, Bldg 10, Bethesda, MD 20892 USA. [Valcour, Victor G.] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA USA. RP Krebs, SJ (reprint author), US Mil HIV Res Program, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. EM skrebs@hivresearch.org FU NIH [R01NS061696]; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. [W81XWH-11-2-0174]; US Department of Defense [W81XWH-11-2-0174] FX The authors thank the SEARCH 011 Study Group volunteers for their participation, and the physicians who cared for the volunteers. The SEARCH 011 Study group includes Nitiya Chomchey, Somprartthana Rattanamanee, James L. K. Fletcher, Duanghathai Sutthichom, and Pairoa Praihirunkit from SEARCH/TRCARC; Nijasri Charnnarong and Sukalaya Lerdlum from Chulalongkorn University; Yotin Chinvarun from Phramongkutklao Medical Center; Mark de Souza, Alexandra Schuetz, and Rapee Trichavaroj from the Armed Forces Research Institute of Medical Sciences; Supunee Jirajariyavej from Taksin Hospital; Elijah Mun, Stephanie Chiao, Akash Desai, Edgar Busovaca, Nicholas Hutchings, Collin Adams, Katherine Clifford, and Lauren Wendelken from UCSF. The authors also thank Matthew Creegan and Roger Faubel for technical support and Michael Eller for critical review of this manuscript. The views expressed are those of the authors and should not be construed to represent the positions of the US Army or the Department of Defense. This work was supported by R01NS061696 (NIH) and a cooperative agreement (W81XWH-11-2-0174) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. and the US Department of Defense. NR 41 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JUN 19 PY 2016 VL 30 IS 10 BP 1533 EP 1542 DI 10.1097/QAD.0000000000001096 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DN9SD UT WOS:000377419500004 PM 26990631 ER PT J AU Yanik, EL Katki, HA Engels, EA AF Yanik, Elizabeth L. Katki, Hormuzd A. Engels, Eric A. TI Cancer risk among the HIV-infected elderly in the United States SO AIDS LA English DT Article DE aging; cancer; epidemiology; HIV ID ANTIRETROVIRAL THERAPY; LUNG-CANCER; INDIVIDUALS; PEOPLE; AIDS; IMMUNODEFICIENCY; METAANALYSIS; SMOKING; COHORT AB Objective: HIV-infected people and elderly people have higher cancer risk, but the combined effects of aging and HIV are not well described. We aimed to evaluate the magnitude of cancer risk in the HIV-infected elderly population. Design: We conducted a case-cohort study including a 5% sample of U.S. Medicare enrollees and all cancer cases aged at least 65 in linked cancer registries. Methods: HIV was identified through Medicare claims. Among the HIV-infected, absolute cancer risk was calculated accounting for the competing risk of death. Associations between HIV and cancer were estimated with weighted Cox regression adjusting for demographic characteristics. Results: Among 469 954 people in the 5% sample, 0.08% had an HIV diagnosis. Overall, 825 776 cancer cases were identified in cancer registries. Over 5 years, 10.1% of the HIV-infected elderly developed cancer, the most common diagnoses comprising lung (5-year cumulative incidence=2.2%), prostate (2.7%, among men), and colorectal cancer (0.9%), and non-Hodgkin lymphoma (0.8%). HIV was strongly associated with incidence of Kaposi sarcoma [adjusted hazard ratio (aHR)=94.4, 95% confidence interval (95%CI)=54.6-1631, anal cancer (aHR=34.2, 95%CI=23.9-49.0) and Hodgkin lymphoma (aH R=6.3, 95%CI=2.8-14.3). HIV was also associated with incidence of liver cancer, non-Hodgkin lymphoma and lung cancer (aHR=3.4, 2.6, and 1.6, respectively). Conclusion: In the elderly, HIV infection is associated with higher risk for many cancers, although some associations were weaker than expected, perhaps reflecting effects of non-HIV pathways on cancer development. Due to the effects of HIV and aging, the HIV-infected elderly have a sizeable absolute risk, highlighting a need for cancer prevention. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Yanik, Elizabeth L.; Katki, Hormuzd A.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Yanik, EL (reprint author), NCI, 9609 Med Ctr Dr,Rm 6E-216, Bethesda, MD 20892 USA. EM elizabeth.yanik@nih.gov OI Yanik, Elizabeth/0000-0002-5835-0201 FU National Cancer Institute at the National Institutes of Health; Office of AIDS Research at the National Institutes of Health FX E.L.Y., H.A.K., and E.A.E. were supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. E.L.Y. was also supported by an Intramural AIDS Research Fellowship Award from the Office of AIDS Research at the National Institutes of Health NR 23 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JUN 19 PY 2016 VL 30 IS 10 BP 1663 EP 1668 DI 10.1097/QAD.0000000000001077 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DN9SD UT WOS:000377419500016 PM 26950314 ER PT J AU Arbore, G West, EE Spolski, R Robertson, AAB Klos, A Rheinheimer, C Dutow, P Woodruff, TM Yu, ZX O'Neill, LA Coll, RC Sher, A Leonard, WJ Kohl, J Monk, P Cooper, MA Arno, M Afzali, B Lachmann, HJ Cope, AP Mayer-Barber, KD Kemper, C AF Arbore, Giuseppina West, Erin E. Spolski, Rosanne Robertson, Avril A. B. Klos, Andreas Rheinheimer, Claudia Dutow, Pavel Woodruff, Trent M. Yu, Zu Xi O'Neill, Luke A. Coll, Rebecca C. Sher, Alan Leonard, Warren J. Koehl, Jorg Monk, Pete Cooper, Matthew A. Arno, Matthew Afzali, Behdad Lachmann, Helen J. Cope, Andrew P. Mayer-Barber, Katrin D. Kemper, Claudia TI T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4(+) T cells SO SCIENCE LA English DT Article ID INNATE LYMPHOID-CELLS; C5A RECEPTOR CD88; INTESTINAL INFLAMMATION; IFN-GAMMA; DIFFERENTIATION; ACTIVATION; C5L2; CYTOKINE; DISEASE; ANTAGONISTS C1 [Arbore, Giuseppina; Afzali, Behdad; Kemper, Claudia] Kings Coll London, Div Transplant Immunol & Mucosal Biol, MRC Ctr Transplantat, London SE1 9RT, England. [West, Erin E.; Spolski, Rosanne; Leonard, Warren J.; Kemper, Claudia] NHLBI, Lab Mol Immunol, Bldg 10, Bethesda, MD 20892 USA. [Robertson, Avril A. B.; Woodruff, Trent M.; Coll, Rebecca C.; Cooper, Matthew A.] Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia. [Klos, Andreas; Rheinheimer, Claudia; Dutow, Pavel] Hannover Med Sch, Inst Med Microbiol & Hosp Epidemiol, D-30625 Hannover, Germany. [Yu, Zu Xi] NHLBI, Pathol Core, Bldg 10, Bethesda, MD 20892 USA. [O'Neill, Luke A.] Univ Dublin Trinity Coll, Sch Biochem & Immunol, Dublin 2, Ireland. [Sher, Alan] NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. [Koehl, Jorg] Med Univ Lubeck, Inst Syst Inflammat Res, D-23538 Lubeck, Germany. [Koehl, Jorg] Cincinnati Childrens Hosp Med Ctr, Div Immunobiol, Cincinnati, OH 45229 USA. [Koehl, Jorg] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Monk, Pete] Univ Sheffield, Dept Infect & Immun, Sheffield S10 2RX, S Yorkshire, England. [Arno, Matthew] Kings Coll London, Fac Life Sci & Med, Genom Ctr, London SE1 9NH, England. [Afzali, Behdad] NIAMSD, Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. [Lachmann, Helen J.] UCL, Div Med, UK Natl Amyloidosis Ctr, Royal Free Campus, London NW3 2PF, England. [Cope, Andrew P.] Kings Coll London, Div Immunol Infect & Inflammatory Dis, Acad Dept Rheumatol, London SE1 1UL, England. [Mayer-Barber, Katrin D.] NIAID, Lab Clin Infect Dis, Inflammat & Innate Immun Unit, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Kemper, C (reprint author), Kings Coll London, Div Transplant Immunol & Mucosal Biol, MRC Ctr Transplantat, London SE1 9RT, England.; Kemper, C (reprint author), NHLBI, Lab Mol Immunol, Bldg 10, Bethesda, MD 20892 USA. EM claudia.kemper@kcl.ac.uk RI Monk, Peter/C-6155-2008; Woodruff, Trent/B-4861-2009; Coll, Rebecca/J-2124-2014; Robertson, Avril/A-4043-2012; Koehl, Joerg/C-8531-2011; OI Monk, Peter/0000-0003-4637-3059; Woodruff, Trent/0000-0003-1382-911X; Coll, Rebecca/0000-0002-7359-6023; Robertson, Avril/0000-0002-9652-8357; Koehl, Joerg/0000-0003-1121-3178; Cooper, Matthew/0000-0003-3147-3460 FU British Heart Foundation [PG/09/018/25279]; Intramural NIH HHS [Z99 AI999999, ZIA AI001207-01]; Medical Research Council [MR/J006742/1]; Wellcome Trust NR 59 TC 20 Z9 20 U1 0 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JUN 17 PY 2016 VL 352 IS 6292 AR aad1210 DI 10.1126/science.aad1210 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO7PV UT WOS:000377975400040 PM 27313051 ER PT J AU Vemu, A Atherton, J Spector, JO Szyk, A Moores, CA Roll-Mecak, A AF Vemu, Annapurna Atherton, Joseph Spector, Jeffrey O. Szyk, Agnieszka Moores, Carolyn A. Roll-Mecak, Antonina TI Structure and Dynamics of Single-isoform Recombinant Neuronal Human Tubulin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MICROTUBULE PLUS-END; ALPHA-BETA-TUBULIN; IN-VITRO; ELECTRON CRYOMICROSCOPY; GTP HYDROLYSIS; RESOLUTION; INSTABILITY; MICROSCOPY; RECONSTRUCTIONS; ISOTYPES AB Microtubules are polymers that cycle stochastically between polymerization and depolymerization, i.e. they exhibit "dynamic instability." This behavior is crucial for cell division, motility, and differentiation. Although studies in the last decade have made fundamental breakthroughs in our understanding of how cellular effectors modulate microtubule dynamics, analysis of the relationship between tubulin sequence, structure, and dynamics has been held back by a lack of dynamics measurements with and structural characterization of homogeneous isotypically pure engineered tubulin. Here, we report for the first time the cryo-EM structure and in vitro dynamics parameters of recombinant isotypically pure human tubulin. alpha 1A/beta III is a purely neuronal tubulin isoform. The 4.2-angstrom structure of post-translationally unmodified human alpha 1A/beta III microtubules shows overall similarity to that of heterogeneous brain microtubules, but it is distinguished by subtle differences at polymerization interfaces, which are hot spots for sequence divergence between tubulin isoforms. In vitro dynamics assays show that, like mosaic brain microtubules, recombinant homogeneous microtubules undergo dynamic instability, but they polymerize slower and have fewer catastrophes. Interestingly, we find that epitaxial growth of alpha 1A/beta III microtubules from heterogeneous brain seeds is inefficient but can be fully rescued by incorporating as little as 5% of brain tubulin into the homogeneous alpha 1A/beta III lattice. Our study establishes a system to examine the structure and dynamics of mammalian microtubules with well defined tubulin species and is a first and necessary step toward uncovering how tubulin genetic and chemical diversity is exploited to modulate intrinsic microtubule dynamics. C1 [Vemu, Annapurna; Spector, Jeffrey O.; Szyk, Agnieszka; Roll-Mecak, Antonina] NINDS, Cell Biol & Biophys Unit, Bethesda, MD 20892 USA. [Roll-Mecak, Antonina] NHLBI, Ctr Biophys, NIH, Bethesda, MD 20892 USA. [Atherton, Joseph; Moores, Carolyn A.] Univ London, Inst Struct & Mol Biol, Dept Biol Sci, Birkbeck Coll, London WC1E, England. RP Moores, CA (reprint author), Birkbeck Coll, Inst Struct & Mol Biol, London WC1E 7HX, England.; Roll-Mecak, A (reprint author), NIH, Cell Biol & Biophys Unit, Porter Neurosci Res Ctr, Bldg 35,Rm 3B-203,35 Convent Dr,MSC 3700, Bethesda, MD 20892 USA. EM c.moores@mail.cryst.bbk.ac.uk; Antonina@mail.nih.gov FU Medical Research Council, United Kingdom; NINDS; NHLBI, National Institutes of Health FX This work was supported by grants from the Medical Research Council, United Kingdom (to J. A. and C. A. M.), and by the Intramural Programs of the NINDS and the NHLBI, National Institutes of Health (to A. V., J. O. S., A. S. and A. R.-M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 51 TC 1 Z9 1 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 17 PY 2016 VL 291 IS 25 BP 12907 EP + DI 10.1074/jbc.C116.731133 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DR2YT UT WOS:000379770500002 PM 27129203 ER PT J AU Navarro, G Aguinaga, D Angelats, E Medrano, M Moreno, E Mallol, J Cortes, A Canela, EI Casado, V McCormick, PJ Lluis, C Ferre, S AF Navarro, Gemma Aguinaga, David Angelats, Edgar Medrano, Mireia Moreno, Estefania Mallol, Josefa Cortes, Antonio Canela, Enric I. Casado, Vicent McCormick, Peter J. Lluis, Carme Ferre, Sergi TI A Significant Role of the Truncated Ghrelin Receptor GHS-R1b in Ghrelin-induced Signaling in Neurons SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; CELL-SURFACE EXPRESSION; ALLOSTERIC INTERACTIONS; POLYPEPTIDE GHS-R1B; INSULIN-RELEASE; HETEROTETRAMER; HETERODIMERS; ACTIVATION; ATTENUATE; PATHWAYS AB The truncated non-signaling ghrelin receptor growth hormone secretagogue R1b (GHS-R1b) has been suggested to simply exert a dominant negative role in the trafficking and signaling of the full and functional ghrelin receptor GHS-R1a. Here we reveal a more complex modulatory role of GHS-R1b. Differential co-expression of GHS-R1a and GHS-R1b, both in HEK-293T cells and in striatal and hippocampal neurons in culture, demonstrates that GHS-R1b acts as a dual modulator of GHS-R1a function: low relative GHS-R1b expression potentiates and high relative GHS-R1b expression inhibits GHS-R1a function by facilitating GHS-R1a trafficking to the plasma membrane and by exerting a negative allosteric effect on GHS-R1a signaling, respectively. We found a preferential G(i/o) coupling of the GHS-R1a-GHS-R1b complex in HEK-293T cells and, unexpectedly, a preferential G(s/olf) coupling in both striatal and hippocampal neurons in culture. A dopamine D-1 receptor (D1R) antagonist blocked ghrelin-induced cAMP accumulation in striatal but not hippocampal neurons, indicating the involvement of D1R in the striatal GHS-R1a-G(s/olf) coupling. Experiments in HEK-293T cells demonstrated that D1R co-expression promotes a switch in GHS-R1a-G protein coupling from G(i/o) to G(s/olf), but only upon co-expression of GHS-R1b. Furthermore, resonance energy transfer experiments showed that D1R interacts with GHS-R1a, but only in the presence of GHS-R1b. Therefore, GHS-R1b not only determines the efficacy of ghrelin-induced GHS-R1a-mediated signaling but also determines the ability of GHS-R1a to form oligomeric complexes with other receptors, promoting profound qualitative changes in ghrelin-induced signaling. C1 [Navarro, Gemma; Aguinaga, David; Angelats, Edgar; Medrano, Mireia; Moreno, Estefania; Mallol, Josefa; Cortes, Antonio; Canela, Enric I.; Casado, Vicent; Lluis, Carme] Univ Barcelona, Fac Biol, Dept Biochem & Mol Biol, Diagonal 645, E-08028 Barcelona, Spain. [Navarro, Gemma; Aguinaga, David; Angelats, Edgar; Medrano, Mireia; Moreno, Estefania; Mallol, Josefa; Cortes, Antonio; Canela, Enric I.; Casado, Vicent; Lluis, Carme] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona 08028, Spain. [McCormick, Peter J.] Univ East Anglia, Sch Pharm, Norwich Res Pk, Norwich NR4 7TJ, Norfolk, England. [Ferre, Sergi] NIDA, Integrat Neurobiol Sect, Intramural Res Program, Baltimore, MD 21224 USA. RP Navarro, G (reprint author), Univ Barcelona, Fac Biol, Dept Biochem & Mol Biol, Diagonal 645, E-08028 Barcelona, Spain.; Ferre, S (reprint author), NIDA, Integrat Neurobiol Sect, Intramural Res Program, NIH, Triad Technol Bldg,333 Cassell Dr, Baltimore, MD 21224 USA. EM dimartts@hotmail.com; sferre@intra.nida.nih.gov RI Ferre, Sergi/K-6115-2014; Canela, Enric I./M-8726-2013 OI Ferre, Sergi/0000-0002-1747-1779; Canela, Enric I./0000-0003-4992-7440 FU Spanish Ministerio de Ciencia y Tecnologia [SAF2011-23813]; government of Catalonia [2014-SGR-1236]; Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas Grant [CB06/05/0064]; National Institute on Drug Abuse; Ramon y Cajal fellowship FX This work was supported by Spanish Ministerio de Ciencia y Tecnologia Grant SAF2011-23813, government of Catalonia Grant 2014-SGR-1236, Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas Grant CB06/05/0064, and intramural funds of the National Institute on Drug Abuse. The authors declare that they have no conflicts of interest with the contents of this article.; Supported by a Ramon y Cajal fellowship. NR 29 TC 1 Z9 1 U1 2 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 17 PY 2016 VL 291 IS 25 BP 13048 EP 13062 DI 10.1074/jbc.M116.715144 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DR2YT UT WOS:000379770500014 PM 27129257 ER PT J AU Lu, JX Bayro, MJ Tycko, R AF Lu, Jun-Xia Bayro, Marvin J. Tycko, Robert TI Major Variations in HIV-1 Capsid Assembly Morphologies Involve Minor Variations in Molecular Structures of Structurally Ordered Protein Segments SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; SOLID-STATE NMR; NUCLEAR-MAGNETIC-RESONANCE; ANGLE-SPINNING NMR; CHEMICAL-SHIFTS; GAG POLYPROTEIN; TERMINAL DOMAIN; DIMERIZATION DOMAIN; CRYSTAL-STRUCTURE; LATTICE FORMATION AB We present the results of solid state nuclear magnetic resonance (NMR) experiments on HIV-1 capsid protein (CA) assemblies with three different morphologies, namely wild-type CA (WT-CA) tubes with 35-60 nm diameters, planar sheets formed by the Arg(18)-Leu mutant (R18L-CA), and R18L-CA spheres with 20-100 nm diameters. The experiments are intended to elucidate molecular structural variations that underlie these variations in CA assembly morphology. We find that multidimensional solid state NMR spectra of N-15, C-13-labeled CA assemblies are remarkably similar for the three morphologies, with only small differences in N-15 and C-13 chemical shifts, no significant differences in NMR line widths, and few differences in the number of detectable NMR cross-peaks. Thus, the pronounced differences in morphology do not involve major differences in the conformations and identities of structurally ordered protein segments. Instead, morphological variations are attributable to variations in conformational distributions within disordered segments, which do not contribute to the solid state NMR spectra. Variations in solid state NMR signals from certain amino acid side chains are also observed, suggesting differences in the intermolecular dimerization interface between curved and planar CA lattices, as well as possible differences in intramolecular helix-helix packing. C1 [Lu, Jun-Xia; Bayro, Marvin J.; Tycko, Robert] NIDKK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Lu, Jun-Xia] ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China. RP Tycko, R (reprint author), Bldg 5,Rm 112, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov RI Bayro, Marvin/Q-4643-2016 OI Bayro, Marvin/0000-0003-1482-9381 FU NIDDK, National Institutes of Health [DK075032]; National Institutes of Health FX This work was supported by the Intramural Research Program of the NIDDK, National Institutes of Health, under project DK075032, and by the Intramural AIDS Targeted Antiviral Program of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare that they have no conflicts of interest with the contents of this article. NR 58 TC 3 Z9 3 U1 1 U2 7 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 17 PY 2016 VL 291 IS 25 BP 13098 EP + DI 10.1074/jbc.M116.720557 PG 30 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DR2YT UT WOS:000379770500018 PM 27129282 ER PT J AU Celik, H Bulut, G Han, J Graham, GT Minas, TZ Conn, EJ Hong, SH Pauly, GT Hayran, M Li, X Ozdemirli, M Ayhan, A Rudek, MA Toretsky, JA Uren, A AF Celik, Haydar Bulut, Gulay Han, Jenny Graham, Garrett T. Minas, Tsion Z. Conn, Erin J. Hong, Sung-Hyeok Pauly, Gary T. Hayran, Mutlu Li, Xin Ozdemirli, Metin Ayhan, Ayse Rudek, Michelle A. Toretsky, Jeffrey A. Uren, Aykut TI Ezrin Inhibition Up-regulates Stress Response Gene Expression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID METASTATIC PHENOTYPE; ERM PROTEINS; OSTEOSARCOMA METASTASIS; ENDOPLASMIC-RETICULUM; CARCINOMA-CELLS; MURINE MODEL; LINKER EZRIN; CANCER; METABOLISM; PATHWAY AB Ezrin is a member of the ERM (ezrin/radixin/moesin) family of proteins that links cortical cytoskeleton to the plasma membrane. High expression of ezrin correlates with poor prognosis and metastasis in osteosarcoma. In this study, to uncover specific cellular responses evoked by ezrin inhibition that can be used as a specific pharmacodynamic marker(s), we profiled global gene expression in osteosarcoma cells after treatment with small molecule ezrin inhibitors, NSC305787 and NSC668394. We identified and validated several up-regulated integrated stress response genes including PTGS2, ATF3, DDIT3, DDIT4, TRIB3, and ATF4 as novel ezrin-regulated transcripts. Analysis of transcriptional response in skin and peripheral blood mononuclear cells from NSC305787-treated mice compared with a control group revealed that, among those genes, the stress gene DDIT4/REDD1 may be used as a surrogate pharmacodynamic marker of ezrin inhibitor compound activity. In addition, we validated the anti-metastatic effects of NSC305787 in reducing the incidence of lung metastasis in a genetically engineered mouse model of osteosarcoma and evaluated the pharmacokinetics of NSC305787 and NSC668394 in mice. In conclusion, our findings suggest that cytoplasmic ezrin, previously considered a dormant and inactive protein, has important functions in regulating gene expression that may result in down-regulation of stress response genes. C1 [Celik, Haydar; Bulut, Gulay; Han, Jenny; Graham, Garrett T.; Minas, Tsion Z.; Conn, Erin J.; Hong, Sung-Hyeok; Toretsky, Jeffrey A.; Uren, Aykut] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. [Ozdemirli, Metin] Georgetown Univ, Med Ctr, Dept Pathol, Washington, DC 20007 USA. [Bulut, Gulay] Bahcesehir Univ, Fac Engn & Nat Sci, Dept Mol Biol & Genet, TR-34349 Istanbul, Turkey. [Pauly, Gary T.] NCI, Biol Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Hayran, Mutlu] Hacettepe Univ, Inst Canc, Dept Prevent Oncol, TR-06800 Ankara, Turkey. [Li, Xin] Georgetown Univ, Dept Biostat Bioinformat & Biomath, Washington, DC 20057 USA. [Ayhan, Ayse] Seirei Mikatahara Hosp, Dept Pathol, Hamamatsu, Shizuoka, Japan. [Ayhan, Ayse] Hamamatsu Univ Sch Med, Hamamatsu, Shizuoka, Japan. [Ayhan, Ayse] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21218 USA. [Rudek, Michelle A.] Johns Hopkins Univ, Sch Med, Div Clin Pharmacol, Dept Oncol, Baltimore, MD 21218 USA. [Rudek, Michelle A.] Johns Hopkins Univ, Sch Med, Div Clin Pharmacol, Dept Med, Baltimore, MD 21218 USA. Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21218 USA. RP Uren, A (reprint author), Georgetown Univ, Med Ctr, Dept Oncol, Dept Biochem & Mol & Cellular Biol,NRB, 3970 Reservoir Rd NW,Rm E312, Washington, DC 20057 USA. EM au26@georgetown.edu OI Graham, Garrett/0000-0002-1097-0962 FU National Cancer Institute [P30CA51008] FX We thank the Animal Models Shared Resource, Histopathology & Tissue Shared Resource and the Genomics & Epigenomics Shared Resource at the Lombardi Comprehensive Cancer Center (Georgetown University), which are supported by a grant P30CA51008 from the National Cancer Institute. We thank Dr. Chand Khanna from National Cancer Institute (NCI/NIH, Bethesda, MD) for providing human MG63.3 osteosarcoma and mouse K7M2 osteosarcoma cell lines. We thank Dr. Douglas H. Thamm (Colorado State University, Fort Collins, CO) for providing MCKOS, SKKOS and CSKOS canine osteosarcoma cell lines. We thank Dr. Stuart H. Orkin and Dr. Katherine A. Janeway (Harvard Medical School, Boston, MA) for providing mice to generate the Osx-Cre + p53fl/flpRBfl/fl transgenic mouse model of osteosarcoma and helpful discussion. We thank the Brandon Carrington Lee Foundation and Children's Cancer Foundation for continuous support of our research program. NR 48 TC 0 Z9 0 U1 2 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 17 PY 2016 VL 291 IS 25 BP 13257 EP 13270 DI 10.1074/jbc.M116.718189 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DR2YT UT WOS:000379770500030 PM 27137931 ER PT J AU Castelnuovo, B Kiragga, A Mubiru, F Kambugu, A Kamya, M Reynolds, SJ AF Castelnuovo, Barbara Kiragga, Agnes Mubiru, Frank Kambugu, Andrew Kamya, Moses Reynolds, Steven J. TI First-line antiretroviral therapy durability in a 10-year cohort of naive adults started on treatment in Uganda SO JOURNAL OF THE INTERNATIONAL AIDS SOCIETY LA English DT Article DE antiretroviral treatment; treatments failure; long term outcomes ID RESOURCE-LIMITED SETTINGS; PRESIDENTS EMERGENCY PLAN; HIV DRUG-RESISTANCE; TREATMENT FAILURE; VIRAL FAILURE; SOUTH-AFRICA; AIDS RELIEF; PREDICTORS; INFECTION; ADHERENCE AB Introduction: The majority of studies from resource-limited settings only report short-term virological outcomes of patients on antiretroviral treatment (ART). We aim to describe the long-term durability of first-line ART and identify factors associated with long-term virological outcomes. Methods: At the Infectious Diseases Institute in Kampala, Uganda, 559 adult patients starting ART in 2004 were enrolled into a research cohort and monitored with viral load (VL) testing every six months for 10 years. We report the proportion and cumulative probability of 1) achieving virologic suppression (at least one VL <400 copies/ml); 2) experiencing virologic failure in patients who achieved suppression (two consecutive VLs >1000 copies/ml or one VL >5000, for those without a subsequent one); 3) treatment failure (not attaining virologic suppression or experiencing virologic failure). We used Cox regression methods to determine the characteristics associated with treatment failure. We included gender, baseline age, WHO stage, body mass index, CD4 count, propensity score for initial ART regimen, VL, time-dependent CD4 count and adherence. Results: Of the 559 patients enrolled, 472 (84.8%) had at least one VL (67 died, 13 were lost to follow-up, 4 transferred, 2 had no VL available); 73.6% started on d4T/3TC/nevirapine and 26.4% on AZT/3TC/efavirenz. Patients in the two groups had similar characteristics, except for the higher proportion of patients in WHO Stage 3/4 and higher VL in the efavirenz-based group. Four hundred thirty-nine (93%) patients achieved virologic suppression with a cumulative probability of 0.94 (confidence interval (CI): 0.92-0.96); 74/439 (16.9%) experienced virologic failure with a cumulative probability of 0.18 (CI: 0.15-0.22). In the multivariate analysis, initial d4T/3TC/ nevirapine regimen (hazard ratio (HR): 3.02; CI: 3.02 (1.66-5.44, p < 0.001)) and baseline VL >= 5 log10 copies/ml (HR: 2.29; CI: 1.29-4.04) were associated with treatment failures; patients of older age (HR: 0.87 per five-year increase; CI: 0.77-0.99), with adherence >95% (HR: 0.04; CI: 0.02-0.11) and with higher time-dependent CD4 count (HR: 0.94 per 50 cells/mu l increase; CI: 0.92-0.99, p < 0.001) were less likely to experience treatment failure. Conclusions: The long-term virological outcomes from this cohort are promising and comparable to those from research-rich settings. Our results provide further evidence that efavirenz is associated with better virological outcomes. C1 [Castelnuovo, Barbara; Kiragga, Agnes; Mubiru, Frank; Kambugu, Andrew] Makerere Univ, Infect Dis Inst, Kampala, Uganda. [Kamya, Moses] Makerere Univ, Sch Med, Kampala, Uganda. [Reynolds, Steven J.] NIAID, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Reynolds, Steven J.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Castelnuovo, B (reprint author), Mulago Hosp, Infect Dis Inst, Kampala, Uganda. EM bcastelnuovo@idi.co.ug FU Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health FX This study was supported in part (SJR) by the Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health. NR 37 TC 0 Z9 0 U1 1 U2 1 PU INT AIDS SOCIETY PI GENEVA PA AVENUE DE FRANCE 23, GENEVA, 1202, SWITZERLAND SN 1758-2652 J9 J INT AIDS SOC JI J. Int. AIDS Soc. PD JUN 17 PY 2016 VL 19 AR 20773 DI 10.7448/IAS.19.1.20773 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DP1AW UT WOS:000378223600001 PM 27319742 ER PT J AU Carlier, J Scheidweiler, KB Wohlfarth, A Salmeron, BD Baumann, MH Huestis, MA AF Carlier, Jeremy Scheidweiler, Karl B. Wohlfarth, Ariane Salmeron, Bonita D. Baumann, Michael H. Huestis, Marilyn A. TI Quantification of [1-(5-fluoropentyl)-1H-indol-3-yl](naphthalene-1-yl)methanone (AM-2201) and 13 metabolites in human and rat plasma by liquid chromatography-tandem mass spectrometry SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE AM-2201; Synthetic cannabinoid; Metabolites; Plasma; Liquid chromatography-tandem mass spectrometry ID SYNTHETIC CANNABINOIDS; HUMAN URINE; DRUGS; ABUSE; MS/MS AB AM-2201 is a popular synthetic cannabinoid first synthesized in 2000. AM-2201 pharmacokinetic and pharmacodynamic data are scarce, requiring further investigation. We developed a sensitive method for quantifying AM-2201 and 13 metabolites in plasma to provide a tool to further metabolic, pharmacolcinetic and pharmacodynamic studies. Analysis was performed by liquid chromatography-tandem mass spectrometry. Chromatographic separation was performed by gradient elution on a biphenyl column with 0.1% formic acid in water/0.1% formic acid in acetonitrile:methanol 50:50 (v/v) mobile phase. Sample preparation (75 mu L) consisted of an enzymatic hydrolysis and a supported liquid extraction. The method was validated with human plasma with a 0.025 or 0.050-50 mu g/L, working range, and cross validated for rat plasma. Analytical recovery was 88.8-110.1% of target concentration, and intra- (n = 30) and inter-day (n = 30) imprecision <11.9% coefficient of variation. Method recoveries and matrix effects ranged from 58.4-84.4% and -62.1 to -15.6%, respectively. AM-2201 and metabolites were stable (+/- 20%) at room temperature for 24 h, at 4 degrees C for 72 h, and after three freeze-thaw cycles, and for 72 h in the autosampler after extraction. The method was developed for pharmacodynamic and pharmacokinetic studies with controlled administration in rats but is applicable for pre-clinical and clinical research and forensic investigations. Rat plasma specimen analysis following subcutaneous AM-2201 administration demonstrated the suitability of the method. AM-2201, JWH-018 N-(5-hydroxypentyl), and JWH-018 N-pentanoic acid concentrations were 4.8 +/- 1.0, 0.15 +/- 0.03, and 0.34 +/- 0.07 mu g/L, respectively, 8h after AM-2201 administration at 0.3 mg/kg (n = 5). Published by Elsevier B.V. C1 [Carlier, Jeremy; Scheidweiler, Karl B.; Wohlfarth, Ariane; Huestis, Marilyn A.] NIDA, Clin Pharmacol & Therapeut Res Branch, Chem & Drug Metab Sect, Intramural Res Program,NIH, 251 Bayview Blvd Suite 200, Baltimore, MD 21224 USA. [Salmeron, Bonita D.; Baumann, Michael H.] NIDA, Designer Drug Res Unit, Intramural Res Program, NIH, 333 Cassell Dr Suite 4400, Baltimore, MD 21224 USA. [Wohlfarth, Ariane] Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Artillerigatan 12, SE-58758 Linkoping, Sweden. [Wohlfarth, Ariane] Linkoping Univ, Dept Med & Hlth Sci, Div Drug Res, SE-58158 Linkoping, Sweden. [Huestis, Marilyn A.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. RP Scheidweiler, KB (reprint author), NIDA, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program, NIH, 251 Bayview Blvd Suite 200,Room BRC 05A729, Baltimore, MD 21224 USA. EM KScheidweiler@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH) FX This study was supported by the Intramural Research Program of the National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH). NR 35 TC 0 Z9 0 U1 7 U2 17 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 JUN 17 PY 2016 VL 1451 BP 97 EP 106 DI 10.1016/j.chroma.2016.05.020 PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DO4BD UT WOS:000377725900012 PM 27208987 ER PT J AU Hinnebusch, AG Ivanov, IP Sonenberg, N AF Hinnebusch, Alan G. Ivanov, Ivaylo P. Sonenberg, Nahum TI Translational control by 5 '-untranslated regions of eukaryotic mRNAs SO SCIENCE LA English DT Review ID OPEN READING FRAMES; START CODON SELECTION; CAP-INDEPENDENT TRANSLATION; INTEGRATED STRESS-RESPONSE; GENOME-WIDE ANALYSIS; SECONDARY STRUCTURE; 5' UTR; MODULATES AUTOREGULATION; NUCLEOTIDE RESOLUTION; INITIATION-FACTORS AB The eukaryotic 5' untranslated region (UTR) is critical for ribosome recruitment to the messenger RNA (mRNA) and start codon choice and plays a major role in the control of translation efficiency and shaping the cellular proteome. The ribosomal initiation complex is assembled on the mRNA via a cap-dependent or cap-independent mechanism. We describe various mechanisms controlling ribosome scanning and initiation codon selection by 5' upstream open reading frames, translation initiation factors, and primary and secondary structures of the 5' UTR, including particular sequence motifs. We also discuss translational control via phosphorylation of eukaryotic initiation factor 2, which is implicated in learning and memory, neurodegenerative diseases, and cancer. C1 [Hinnebusch, Alan G.; Ivanov, Ivaylo P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Grp Cell Regulat & Dev, NIH, Bethesda, MD USA. [Sonenberg, Nahum] McGill Univ, Dept Biochem, Montreal, PQ H3A 1A3, Canada. [Sonenberg, Nahum] McGill Univ, Goodman Canc Ctr, Montreal, PQ H3A 1A3, Canada. RP Sonenberg, N (reprint author), McGill Univ, Dept Biochem, Montreal, PQ H3A 1A3, Canada.; Sonenberg, N (reprint author), McGill Univ, Goodman Canc Ctr, Montreal, PQ H3A 1A3, Canada. EM nahum.sonenberg@mcgill.ca NR 60 TC 18 Z9 18 U1 13 U2 35 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JUN 17 PY 2016 VL 352 IS 6292 BP 1413 EP 1416 DI 10.1126/science.aad9868 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO7PV UT WOS:000377975400038 PM 27313038 ER PT J AU Bott, LC Salomons, FA Maric, D Liu, YH Merry, D Fischbeck, KH Dantuma, NP AF Bott, Laura C. Salomons, Florian A. Maric, Dragan Liu, Yuhong Merry, Diane Fischbeck, Kenneth H. Dantuma, Nico P. TI The polyglutamine-expanded androgen receptor responsible for spinal and bulbar muscular atrophy inhibits the APC/C-Cdh1 ubiquitin ligase complex SO SCIENTIFIC REPORTS LA English DT Article ID ANAPHASE-PROMOTING COMPLEX/CYCLOSOME; TRANSGENIC MOUSE MODEL; PROTEASOME SYSTEM; NEURODEGENERATIVE DISEASES; MOTOR-NEURONS; AXONAL GROWTH; CELLS; MUSCLE; IMPAIRMENT; 5-ALPHA-DIHYDROTESTOSTERONE AB Polyglutamine expansion in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA), an X-linked neuromuscular disease that is fully manifest only in males. It has been suggested that proteins with expanded polyglutamine tracts impair ubiquitin-dependent proteolysis due to their propensity to aggregate, but recent studies indicate that the overall activity of the ubiquitin-proteasome system is preserved in SBMA models. Here we report that AR selectively interferes with the function of the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C), which, together with its substrate adaptor Cdh1, is critical for cell cycle arrest and neuronal architecture. We show that both wild-type and mutant AR physically interact with the APC/C-Cdh1 complex in a ligand-dependent fashion without being targeted for proteasomal degradation. Inhibition of APC/C-Cdh1 by mutant but not wild-type AR in PC12 cells results in enhanced neurite outgrowth which is typically followed by rapid neurite retraction and mitotic entry. Our data indicate a role of AR in neuronal differentiation through regulation of APC/C-Cdh1 and suggest abnormal cell cycle reactivation as a pathogenic mechanism in SBMA. C1 [Bott, Laura C.; Salomons, Florian A.; Dantuma, Nico P.] Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden. [Bott, Laura C.; Fischbeck, Kenneth H.] Natl Inst Neurol Disorders & Stroke, Neurogenet Branch, Bethesda, MD 20892 USA. [Maric, Dragan] Natl Inst Neurol Disorders & Stroke, Flow Cytometry Core Facil, Bethesda, MD 20892 USA. [Liu, Yuhong; Merry, Diane] Thomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USA. [Bott, Laura C.] Northwestern Univ, Dept Mol Biosci, Rice Inst Biomed Res, Evanston, IL 60208 USA. RP Dantuma, NP (reprint author), Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden. EM nico.dantuma@ki.se FU Swedish Cancer Society; Swedish Research Council; intramural NINDS research funds [1ZIA NS003037]; KI-NIH Graduate Partnership Program in Neuroscience FX We would like to thank Dr. Jacques Neefjes and Amilcar Flores-Morales for providing reagents. This work was supported by the Swedish Cancer Society (N.P.D.), the Swedish Research Council (N.P.D.), and intramural NINDS research funds (1ZIA NS003037; K.H.F.). L.C.B. was supported by the KI-NIH Graduate Partnership Program in Neuroscience. NR 65 TC 0 Z9 0 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 17 PY 2016 VL 6 AR 27703 DI 10.1038/srep27703 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO8NF UT WOS:000378039600001 PM 27312068 ER PT J AU Myers, JM Cooper, LT Kem, DC Stavrakis, S Kosanke, SD Shevach, EM Fairweather, D Stoner, JA Cox, CJ Cunningham, MW AF Myers, Jennifer M. Cooper, Leslie T. Kem, David C. Stavrakis, Stavros Kosanke, Stanley D. Shevach, Ethan M. Fairweather, DeLisa Stoner, Julie A. Cox, Carol J. Cunningham, Madeleine W. TI Cardiac myosin-Th17 responses promote heart failure in human myocarditis SO JCI INSIGHT LA English DT Article ID REGULATORY T-CELLS; EXPERIMENTAL AUTOIMMUNE MYOCARDITIS; GROWTH-FACTOR-BETA; COXSACKIEVIRUS B3-INDUCED MYOCARDITIS; ROR-GAMMA-T; CYTOKINE GM-CSF; TH17 CELLS; DILATED CARDIOMYOPATHY; VIRAL MYOCARDITIS; T(H)17 CELLS AB In human myocarditis and its sequela dilated cardiomyopathy (DCM), the mechanisms and immune phenotype governing disease and subsequent heart failure are not known. Here, we identified a Th17 cell immunophenotype of human myocarditis/DCM with elevated CD4(+) IL17(+) T cells and Th17-promoting cytokines IL-6, TGF-beta, and IL-23 as well as GM-CSF-secreting CD4(+) T cells. The Th17 phenotype was linked with the effects of cardiac myosin on CD14(+) monocytes, TLR2, and heart failure. Persistent heart failure was associated with high percentages of IL-17-producing T cells and IL-17-promoting cytokines, and the myocarditis/DCM phenotype included significantly low percentages of FOXP3(+) Tregs, which may contribute to disease severity. We demonstrate a potentially novel mechanism in human myocarditis/DCM in which TLR2 peptide ligands from human cardiac myosin stimulated exaggerated Th17-related cytokines including TGF-beta, IL-6, and IL-23 from myocarditic CD14(+) monocytes in vitro, and an anti-TLR2 antibody abrogated the cytokine response. Our translational study explains how an immune phenotype may be initiated by cardiac myosin TLR ligand stimulation of monocytes to generate Th17-promoting cytokines and development of pathogenic Th17 cells in human myocarditis and heart failure, and provides a rationale for targeting IL-17A as a therapeutic option. C1 [Myers, Jennifer M.; Cox, Carol J.; Cunningham, Madeleine W.] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73190 USA. [Cooper, Leslie T.; Fairweather, DeLisa] Mayo Clin, Dept Cardiovasc Dis, Jacksonville, FL 32224 USA. [Kem, David C.] Univ Oklahoma, Hlth Sci Ctr, Dept Med Endocrinol, Oklahoma City, OK USA. [Stavrakis, Stavros] Univ Oklahoma, Hlth Sci Ctr, Med Cardiol, Oklahoma City, OK USA. [Kosanke, Stanley D.] Univ Oklahoma, Hlth Sci Ctr, Pathol, Oklahoma City, OK USA. [Shevach, Ethan M.] NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Fairweather, DeLisa] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Stoner, Julie A.] Univ Oklahoma, Hlth Sci Ctr, Dept Biostat & Epidemiol, Oklahoma City, OK USA. RP Cunningham, MW (reprint author), Univ Oklahoma, Hlth Sci Ctr, 975 NE 10th St, Oklahoma City, OK 73104 USA. EM madeleine-cunningham@ouhsc.edu NR 87 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD JUN 16 PY 2016 VL 1 IS 9 AR e85851 DI 10.1172/jci.insight.85851 PG 19 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1LG UT WOS:000387112700001 ER PT J AU Heuston, EF AF Heuston, Elisabeth F. TI The potential of a single enhancer SO BLOOD LA English DT Editorial Material ID C/EBP-ALPHA; MICE; AML C1 [Heuston, Elisabeth F.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Heuston, EF (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUN 16 PY 2016 VL 127 IS 24 BP 2943 EP 2944 DI 10.1182/blood-2016-03-706218 PG 2 WC Hematology SC Hematology GA DP2RG UT WOS:000378337100002 PM 27313321 ER PT J AU Maxson, JE Ries, RE Wang, YC Gerbing, RB Kolb, EA Thompson, SL Auvil, JMG Marra, MA Ma, Y Zong, ZS Mungall, AJ Moore, R Long, W Gesuwan, P Davidsen, TM Hermida, LC Hughes, SB Farrar, JE Radich, JP Smith, MA Gerhard, DS Gamis, AS Alonzo, TA Meshinchi, S AF Maxson, Julia E. Ries, Rhonda E. Wang, Yi-Cheng Gerbing, Robert B. Kolb, E. Anders Thompson, Sarah L. Auvil, Jaime M. Guidry Marra, Marco A. Ma, Yussanne Zong, Zusheng Mungall, Andrew J. Moore, Richard Long, William Gesuwan, Patee Davidsen, Tanja M. Hermida, Leandro C. Hughes, Seamus B. Farrar, Jason E. Radich, Jerald P. Smith, Malcolm A. Gerhard, Daniela S. Gamis, Alan S. Alonzo, Todd A. Meshinchi, Soheil TI CSF3R mutations have a high degree of overlap with CEBPA mutations in pediatric AML SO BLOOD LA English DT Letter ID COLONY-STIMULATING FACTOR; ACUTE MYELOID-LEUKEMIA; CHRONIC NEUTROPHILIC LEUKEMIA; SEVERE CONGENITAL NEUTROPENIA; BINDING-PROTEIN-ALPHA; SRC KINASE LYN; FACTOR-RECEPTOR; TRANSCRIPTION FACTOR; T618I MUTATION; ATYPICAL CML C1 [Maxson, Julia E.; Ries, Rhonda E.; Thompson, Sarah L.; Hughes, Seamus B.; Radich, Jerald P.; Meshinchi, Soheil] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Wang, Yi-Cheng; Gerbing, Robert B.; Gamis, Alan S.; Alonzo, Todd A.; Meshinchi, Soheil] Childrens Oncol Grp, Monrovia, CA USA. [Kolb, E. Anders] Alfred I duPont Hosp Children, Nemours Ctr Canc & Blood Disorders, Wilmington, DE USA. [Auvil, Jaime M. Guidry; Gesuwan, Patee; Davidsen, Tanja M.; Hermida, Leandro C.; Gerhard, Daniela S.] NCI, Off Canc Genom, Bethesda, MD 20892 USA. [Marra, Marco A.; Ma, Yussanne; Zong, Zusheng; Mungall, Andrew J.; Moore, Richard; Long, William] British Columbia Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4E6, Canada. [Farrar, Jason E.] Univ Arkansas Med Sci, Arkansas Childrens Hosp, Res Inst, Little Rock, AR 72205 USA. [Farrar, Jason E.] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Gamis, Alan S.] Childrens Mercy Hosp & Clin, Div Hematol Oncol Bone Marrow Transplantat, Kansas City, MO USA. [Alonzo, Todd A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. RP Meshinchi, S (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,D5-380, Seattle, WA 98109 USA. EM smeshinc@fredhutch.org RI Marra, Marco/B-5987-2008 FU NCI NIH HHS [R01 CA114563, U10 CA180899]; NIH HHS [S10 OD020069] NR 23 TC 6 Z9 6 U1 2 U2 3 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 16 PY 2016 VL 127 IS 24 BP 3094 EP + DI 10.1182/blood-2016-04-709899 PG 5 WC Hematology SC Hematology GA DP2RG UT WOS:000378337100024 PM 27143256 ER PT J AU Lin, BR Le, DJ Chen, YB Wang, QW Chung, DD Frausto, RF Croasdale, C Yee, RW Hejtmancik, FJ Aldave, AJ AF Lin, Benjamin R. Le, Derek J. Chen, Yabin Wang, Qiwei Chung, D. Doug Frausto, Ricardo F. Croasdale, Christopher Yee, Richard W. Hejtmancik, Fielding J. Aldave, Anthony J. TI Whole Exome Sequencing and Segregation Analysis Confirms That a Mutation in COL17A1 Is the Cause of Epithelial Recurrent Erosion Dystrophy in a Large Dominant Pedigree Previously Mapped to Chromosome 10q23-q24 SO PLOS ONE LA English DT Article ID BEHNKE CORNEAL-DYSTROPHY; INDIVIDUAL PHENOTYPIC VARIANCES; GENE; PREDICTION; EXCLUSION; COLLAGEN; FAMILY; CDB2; XVII AB Purpose To report identification of a COL17A1 mutation in a family with a corneal dystrophy previously mapped to chromosome 10q23-q24. Methods Whole-exome sequencing was performed on DNA samples from five affected family members and two unrelated, unaffected individuals. Identified variants were filtered for those that were: located in the linked interval on chromosome 10q23-q24; novel or rare (minor allele frequency <= 0.01); heterozygous; present in all affected individuals and not in controls; and present in genes that encode proteins expressed in human corneal epithelial cells (reads per kilobase per million >= 1). Sanger sequencing of identified variants (SNVs) was performed in additional family members. In silico analysis was used to predict the functional impact of non-synonymous variants. Results Three SNVs located in two genes were identified that met the filtering criteria: one rare synonymous c.3156C>T variant in the collagen, type XVII, alpha I (COL17A1) gene; and two rare variants, one synonymous and one missense, in the dynamin binding protein (DNMBP) gene. Sanger sequencing of additional family members determined that only the COL17A1 variant segregates with the affected phenotype. In silico analysis predicts that the missense variant in DNMBP would be tolerated. Conclusions The corneal dystrophy mapped to chromosome 10q23-q24 is associated with the c.3156C>T variant in COL17A1. As this variant has recently been identified in five other families with early onset recurrent corneal erosions, and has been shown in vitro to introduce a cryptic splice donor site, this dystrophy is likely caused by aberrant splicing of COL17A1 and should be classified as epithelial recurrent erosion dystrophy. C1 [Lin, Benjamin R.; Le, Derek J.; Chung, D. Doug; Frausto, Ricardo F.; Aldave, Anthony J.] Univ Calif Los Angeles, David Geffen Sch Med, Stein Eye Inst, Los Angeles, CA 90095 USA. [Chen, Yabin; Wang, Qiwei; Hejtmancik, Fielding J.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Croasdale, Christopher] Davis Duehr Dean Clin, Madison, WI USA. [Yee, Richard W.] Cross Ophthalmol Associates, Houston, TX USA. RP Aldave, AJ (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Stein Eye Inst, Los Angeles, CA 90095 USA. EM aldave@jsei.ucla.edu FU National Eye Institute [R01EY022082, Z01EY000272]; National Institute of Health [P30 EY000331]; Research to Prevent Blindness (Stein Eye Institute) FX The work was supported by the following: National Eye Institute Grants R01EY022082 (A.J.A.) and Z01EY000272 (F.J.H.), https://nei.nih.gov/; National Institute of Health grant P30 EY000331 (core grant to Stein Eye Institute), http://www.nih.gov/; unrestricted grant from Research to Prevent Blindness (Stein Eye Institute), no grant #, https://www.rpbusa.org/rpb/?. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 16 PY 2016 VL 11 IS 6 AR e0157418 DI 10.1371/journal.pone.0157418 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO8JO UT WOS:000378029800069 PM 27309958 ER PT J AU Rosenberg, AZ Palmer, M Merlino, L Troost, JP Gasim, A Bagnasco, S Avila-Casado, C Johnstone, D Hodgin, JB Conway, C Gillespie, BW Nast, CC Barisoni, L Hewitt, SM AF Rosenberg, Avi Z. Palmer, Matthew Merlino, Lino Troost, Jonathan P. Gasim, Adil Bagnasco, Serena Avila-Casado, Carmen Johnstone, Duncan Hodgin, Jeffrey B. Conway, Catherine Gillespie, Brenda W. Nast, Cynthia C. Barisoni, Laura Hewitt, Stephen M. TI The Application of Digital Pathology to Improve Accuracy in Glomerular Enumeration in Renal Biopsies SO PLOS ONE LA English DT Article ID VIRTUAL MICROSCOPY; NEPHROTIC SYNDROME; NETWORK NEPTUNE; IGA NEPHROPATHY; CLASSIFICATION; DENSITY; REPRODUCIBILITY; MULTICENTER; NEPHRITIS; DISEASE AB Background In renal biopsy reporting, quantitative measurements, such as glomerular number and percentage of globally sclerotic glomeruli, is central to diagnostic accuracy and prognosis. The aim of this study is to determine the number of glomeruli and percent globally sclerotic in renal biopsies by means of registration of serial tissue sections and manual enumeration, compared to the numbers in pathology reports from routine light microscopic assessment. Design We reviewed 277 biopsies from the Nephrotic Syndrome Study Network (NEPTUNE) digital pathology repository, enumerating 9,379 glomeruli by means of whole slide imaging. Glomerular number and the percentage of globally sclerotic glomeruli are values routinely recorded in the official renal biopsy pathology report from the 25 participating centers. Two general trends in reporting were noted: total number per biopsy or average number per level/section. Both of these approaches were assessed for their accuracy in comparison to the analogous numbers of annotated glomeruli on WSI. Results The number of glomeruli annotated was consistently higher than those reported (p<0.001); this difference was proportional to the number of glomeruli. In contrast, percent globally sclerotic were similar when calculated on total glomeruli, but greater in FSGS when calculated on average number of glomeruli (p<0.01). The difference in percent globally sclerotic between annotated and those recorded in pathology reports was significant when global sclerosis is greater than 40%. Conclusions Although glass slides were not available for direct comparison to whole slide image annotation, this study indicates that routine manual light microscopy assessment of number of glomeruli is inaccurate, and the magnitude of this error is proportional to the total number of glomeruli. C1 [Rosenberg, Avi Z.] Childrens Natl Med Ctr, Dept Pathol, Washington, DC 20010 USA. [Rosenberg, Avi Z.] NIDDK, NIH, Bethesda, MD 20892 USA. [Palmer, Matthew] Univ Penn, Dept Pathol, Philadelphia, PA 19104 USA. [Merlino, Lino; Barisoni, Laura] Univ Miami, Dept Pathol, Miami, FL USA. [Troost, Jonathan P.] Univ Michigan, Dept Pediat, Div Pediat Nephrol, Ann Arbor, MI 48109 USA. [Gasim, Adil] Univ N Carolina, Dept Pathol, Chapel Hill, NC USA. [Bagnasco, Serena] Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD USA. [Avila-Casado, Carmen] Toronto Gen Hosp, Dept Pathol, Toronto, ON, Canada. [Johnstone, Duncan] Temple Univ, Dept Med, Sect Nephrol Hypertens & Kidney Transplantat, Philadelphia, PA 19122 USA. [Hodgin, Jeffrey B.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Conway, Catherine; Hewitt, Stephen M.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Gillespie, Brenda W.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Nast, Cynthia C.] Cedars Sinai Med Ctr, Dept Pathol, Los Angeles, CA 90048 USA. RP Hewitt, SM (reprint author), NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM genejock@helix.nih.gov FU Office of Rare Diseases Research, NCATS [U54-DK-083912]; National Institute of Diabetes, Digestive, and Kidney Diseases [U54-DK-083912]; University of Michigan; NephCure Kidney International; Halpin Foundation; NephCure-ASN Foundation; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; [K08-DK088944] FX The Nephrotic Syndrome Study Network Consortium (U54-DK-083912) is a part of the National Center for Advancing Translational Sciences, Rare Disease Clinical Research Network, supported through a collaboration between the Office of Rare Diseases Research, NCATS, and the National Institute of Diabetes, Digestive, and Kidney Diseases. Additional funding and/or programmatic support for this project has also been provided by the University of Michigan, NephCure Kidney International, and the Halpin Foundation. Dr. Jeffrey Hodgin is supported by K08-DK088944 and the NephCure-ASN Foundation. Additional support in part was provided by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 22 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 16 PY 2016 VL 11 IS 6 AR e0156441 DI 10.1371/journal.pone.0156441 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO8JO UT WOS:000378029800005 PM 27310011 ER PT J AU Wenger, DS Kawut, SM Ding, JZ Bluemke, DA Hough, CL Kronmal, RA Lima, JA Leary, PJ AF Wenger, David S. Kawut, Steven M. Ding, Jingzhong Bluemke, David A. Hough, Catherine L. Kronmal, Richard A. Lima, Joao A. Leary, Peter J. TI Pericardial Fat and Right Ventricular Morphology: The Multi-Ethnic Study of Atherosclerosis-Right Ventricle Study (MESA-RV) SO PLOS ONE LA English DT Article ID EPICARDIAL ADIPOSE-TISSUE; RIGHT-HEART-FAILURE; METABOLIC SYNDROME; CARDIOVASCULAR-DISEASE; MOLECULAR-MECHANISMS; RISK-FACTORS; ADULTS; ASSOCIATION; VOLUME; PLAQUE AB Background Pericardial fat has been implicated in the pathogenesis of obesity-related cardiovascular disease. Proposed mechanisms may be relevant in right heart failure, but relationships between pericardial fat and right ventricular (RV) morphology have not been explored. Methods The Multi-Ethnic Study of Atherosclerosis is a prospective cohort that enrolled participants without clinical cardiovascular disease. Pericardial fat was measured using computed tomography and RV parameters using cardiac MRI. Linear regression estimated associations of pericardial fat with RV mass, RV end diastolic volume (RV-EDV), RV end systolic volume (RV-ESV), RV stroke volume (RV-SV), and RV ejection fraction (RV-EF). Limited models adjusted for age, gender, race, height, and study site with and without weight. Fully adjusted models also accounted for socioeconomic parameters and health behaviors. Adjustment for left ventricular morphology, metabolic syndrome, and systemic inflammation was also performed. Results The study sample included 3988 participants with complete assessment of RV morphology, pericardial fat and all covariates. Greater pericardial fat volume was associated with reduced RV mass (-0.3g per 40 cm(3) increase in pericardial fat, p<0.001), smaller RV-EDV (-3.7ml per 40 cm(3) increase in pericardial fat, p<0.001), smaller RV-ESV (-1.0ml per 40cm(3) increase in pericardial fat, p<0.001), and smaller RV-SV (-2.7mL per 40 cm(3) increase in pericardial fat, p<0.001) in participants after adjustment for weight. Associations were unchanged when accounting for health behaviors, markers of systemic inflammation, and the metabolic syndrome. Conclusions Greater pericardial fat was associated with reduced RV mass, smaller RV-EDV, smaller RV-ESV, and smaller RV-SV in participants after adjustment for weight. Relationships between pericardial fat and RV morphology could be relevant to diseases of right heart failure. C1 [Wenger, David S.] Univ Washington, Dept Gen Internal Med, Seattle, WA 98195 USA. [Kawut, Steven M.] Univ Penn, Perelman Sch Med, Div Pulm & Crit Care Med, Dept Med & Epidemiol, Philadelphia, PA 19104 USA. [Ding, Jingzhong] Wake Forest Univ, Dept Gen Internal Med, Winston Salem, NC 27109 USA. [Bluemke, David A.] NIH, Dept Radiol, Div Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Hough, Catherine L.; Leary, Peter J.] Univ Washington, Dept Gen Internal Med, Div Pulm & Crit Care, Seattle, WA 98195 USA. [Kronmal, Richard A.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Lima, Joao A.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. RP Leary, PJ (reprint author), Univ Washington, Dept Gen Internal Med, Div Pulm & Crit Care, Seattle, WA 98195 USA. EM learyp@uw.edu OI Bluemke, David/0000-0002-8323-8086; Leary, Peter/0000-0001-5716-248X FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; NCRR [UL1-TR-000040, UL1-TR-001079]; National Center for Advancing Translational Sciences [KL2TR000421] FX This research was supported by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169 from the National Heart, Lung, and Blood Institute and by grants UL1-TR-000040 and UL1-TR-001079 from NCRR, and KL2TR000421 from the National Center for Advancing Translational Sciences. NR 30 TC 1 Z9 1 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 16 PY 2016 VL 11 IS 6 AR e0157654 DI 10.1371/journal.pone.0157654 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO8JO UT WOS:000378029800116 PM 27311062 ER PT J AU Dayan, E Laor-Maayany, R Censor, N AF Dayan, Eran Laor-Maayany, Rony Censor, Nitzan TI Reward disrupts reactivated human skill memory SO SCIENTIFIC REPORTS LA English DT Article ID LONG-TERM-MEMORY; PREDICTION ERROR; MOTOR CORTEX; FEAR MEMORY; RECONSOLIDATION; BRAIN; RETRIEVAL; CONSOLIDATION; INTERFERENCE; SYSTEMS AB Accumulating evidence across species and memory domains shows that when an existing memory is reactivated, it becomes susceptible to modifications. However, the potential role of reward signals in these mechanisms underlying human memory dynamics is unknown. Leaning on a wealth of findings on the role of reward in reinforcing memory, we tested the impact of reinforcing a skill memory trace with monetary reward following memory reactivation, on strengthening of the memory trace. Reinforcing reactivated memories did not strengthen the memory, but rather led to disruption of the memory trace, breaking down the link between memory reactivation and subsequent memory strength. Statistical modeling further revealed a strong mediating role for memory reactivation in linking between memory encoding and subsequent memory strength only when the memory was replayed without reinforcement. We suggest that, rather than reinforcing the existing memory trace, reward creates a competing memory trace, impairing expression of the original reward-free memory. This mechanism sheds light on the processes underlying skill acquisition, having wide translational implications. C1 [Dayan, Eran] NINDS, NIH, Bethesda, MD 20892 USA. [Laor-Maayany, Rony; Censor, Nitzan] Tel Aviv Univ, Sch Psychol Sci, IL-69978 Tel Aviv, Israel. [Laor-Maayany, Rony; Censor, Nitzan] Tel Aviv Univ, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel. RP Censor, N (reprint author), Tel Aviv Univ, Sch Psychol Sci, IL-69978 Tel Aviv, Israel.; Censor, N (reprint author), Tel Aviv Univ, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel. EM censornitzan@post.tau.ac.il FU intramural program of the National Institute of Neurological Disorders and Stroke; I-CORE program of the Planning and Budgeting Committee; ISF [51/11] FX Eran Dayan was supported by the intramural program of the National Institute of Neurological Disorders and Stroke. Nitzan Censor was supported by the I-CORE program of the Planning and Budgeting Committee and The ISF (grant 51/11). NR 49 TC 1 Z9 1 U1 2 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 16 PY 2016 VL 6 AR 28270 DI 10.1038/srep28270 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO9LO UT WOS:000378108100001 PM 27306380 ER PT J AU Torn, C Liu, X Hagopian, W Lernmark, A Simell, O Rewers, M Ziegler, AG Schatz, D Akolkar, B Onengut-Gumuscu, S Chen, WM Toppari, J Mykkanen, J Ilonen, J Rich, SS She, JX Sharma, A Steck, A Krischer, J AF Torn, Carina Liu, Xiang Hagopian, William Lernmark, Ake Simell, Olli Rewers, Marian Ziegler, Anette-G Schatz, Desmond Akolkar, Beena Onengut-Gumuscu, Suna Chen, Wei-Min Toppari, Jorma Mykkanen, Juha Ilonen, Jorma Rich, Stephen S. She, Jin-Xiong Sharma, Ashok Steck, Andrea Krischer, Jeffrey CA TEDDY Study Grp TI Complement gene variants in relation to autoantibodies to beta cell specific antigens and type 1 diabetes in the TEDDY Study SO SCIENTIFIC REPORTS LA English DT Article ID ANTIBODY STANDARDIZATION PROGRAM; SYSTEMIC-LUPUS-ERYTHEMATOSUS; GLUTAMIC-ACID DECARBOXYLASE; GENOME-WIDE ASSOCIATION; MACULAR DEGENERATION; EXTENDED HAPLOTYPES; ISLET ANTIGEN-2; CLASS-I; RISK; HLA AB A total of 15 SNPs within complement genes and present on the ImmunoChip were analyzed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. A total of 5474 subjects were followed from three months of age until islet autoimmunity (IA: n = 413) and the subsequent onset of type 1 diabetes (n = 115) for a median of 73 months (IQR 54-91). Three SNPs within ITGAM were nominally associated (p < 0.05) with IA: rs1143678 [Hazard ratio; HR 0.80; 95% CI 0.66-0.98; p = 0.032], rs1143683 [HR 0.80; 95% CI 0.65-0.98; p = 0.030] and rs4597342 [HR 1.16; 95% CI 1.01-1.32; p = 0.041]. When type 1 diabetes was the outcome, in DR3/4 subjects, there was nominal significance for two SNPs: rs17615 in CD21 [HR 1.52; 95% CI 1.05-2.20; p = 0.025] and rs4844573 in C4BPA [HR 0.63; 95% CI 0.43-0.92; p = 0.017]. Among DR4/4 subjects, rs2230199 in C3 was significantly associated [HR 3.20; 95% CI 1.75-5.85; p = 0.0002, uncorrected] a significance that withstood Bonferroni correction since it was less than 0.000833 (0.05/60) in the HLA-specific analyses. SNPs within the complement genes may contribute to IA, the first step to type 1 diabetes, with at least one SNP in C3 significantly associated with clinically diagnosed type 1 diabetes. C1 [Torn, Carina; Lernmark, Ake] Lund Univ, Dept Clin Sci, CRC, Malmo, Sweden. [Liu, Xiang; Krischer, Jeffrey] Univ S Florida, Morsani Coll Med, Hlth Informat Inst, Tampa, FL USA. [Hagopian, William] Pacific Northwest Diabet Res Inst, Seattle, WA USA. [Simell, Olli; Toppari, Jorma; Mykkanen, Juha] Turku Univ Hosp, Dept Pediat, FIN-20520 Turku, Finland. [Rewers, Marian; Steck, Andrea] Univ Colorado, Barbara Davis Ctr Childhood Diabet, Aurora, CO USA. [Ziegler, Anette-G] Helmholtz Zentrum, Diabet Res Inst, Munich, Germany. [Ziegler, Anette-G] Tech Univ Munich, Klinikum Rechts Isar, Neuherberg, Germany. [Ziegler, Anette-G] Forschergrp Diabet eV, Neuherberg, Germany. [Schatz, Desmond] Univ Florida, Dept Pediat, Gainesville, FL USA. [Akolkar, Beena] NIDDK, Bethesda, MD 20892 USA. [Onengut-Gumuscu, Suna; Chen, Wei-Min; Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Gen, Charlottesville, VA USA. [Toppari, Jorma; Mykkanen, Juha; Ilonen, Jorma] Univ Turku, Dept Phys, SF-20500 Turku, Finland. [Toppari, Jorma; Mykkanen, Juha; Ilonen, Jorma] Univ Turku, Dept Pediat, Turku, Finland. [She, Jin-Xiong; Sharma, Ashok] Augusta Univ, Med Coll Georgia, Ctr Biotechnol & Genom Med, Augusta, GA USA. RP Torn, C (reprint author), Lund Univ, Dept Clin Sci, CRC, Malmo, Sweden. EM Carina.Torn@med.lu.se RI Mykkanen, Juha/Q-1663-2015; OI Mykkanen, Juha/0000-0001-9898-2660; Chen, Wei-Min/0000-0002-2643-2333 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, HHSN267200700014C]; National Institute of Allergy and Infectious Diseases (NIAID); National Institute of Child Health and Human Development (NICHD); National Institute of Environmental Health Sciences (NIEHS); Juvenile Diabetes Research Foundation (JDRF); Centers for Disease Control and Prevention (CDC); NIH/NCATS Clinical and Translational Science Awards [UL1 TR000064, UL1 TR001082] FX Funded by U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, and UC4 DK100238, and Contract No. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Juvenile Diabetes Research Foundation (JDRF), and Centers for Disease Control and Prevention (CDC). This work supported in part by the NIH/NCATS Clinical and Translational Science Awards to the University of Florida (UL1 TR000064) and the University of Colorado (UL1 TR001082). NR 42 TC 1 Z9 1 U1 3 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 16 PY 2016 VL 6 AR 27887 DI 10.1038/srep27887 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO8JG UT WOS:000378028900001 PM 27306948 ER PT J AU Merk, A Bartesaghi, A Banerjee, S Falconieri, V Rao, P Davis, MI Pragani, R Boxer, MB Earl, LA Milne, JLS Subramaniam, S AF Merk, Alan Bartesaghi, Alberto Banerjee, Soojay Falconieri, Veronica Rao, Prashant Davis, Mindy I. Pragani, Rajan Boxer, Matthew B. Earl, Lesley A. Milne, Jacqueline L. S. Subramaniam, Sriram TI Breaking Cryo-EM Resolution Barriers to Facilitate Drug Discovery SO CELL LA English DT Article ID MUTANT ISOCITRATE DEHYDROGENASE; LARGE RIBOSOMAL-SUBUNIT; CRYOELECTRON MICROSCOPY; ELECTRON CRYOMICROSCOPY; ANGSTROM RESOLUTION; LACTATE-DEHYDROGENASE; GLUTAMATE-DEHYDROGENASE; SELECTIVE-INHIBITION; BETA-GALACTOSIDASE; MECHANISM AB Recent advances in single-particle cryoelecton microscopy (cryo-EM) are enabling generation of numerous near- atomic resolution structures for well-ordered protein complexes with sizes >= similar to 200 kDa. Whether cryo-EM methods are equally useful for high-resolution structural analysis of smaller, dynamic protein complexes such as those involved in cellular metabolism remains an important question. Here, we present 3.8 angstrom resolution cryo-EM structures of the cancer target isocitrate dehydrogenase (93 kDa) and identify the nature of conformational changes induced by binding of the allosteric small-molecule inhibitor ML309. We also report 2.8-angstrom- and 1.8-angstrom-resolution structures of lactate dehydrogenase (145 kDa) and glutamate dehydrogenase (334 kDa), respectively. With these results, two perceived barriers in single-particle cryo-EM are overcome: (1) crossing 2 angstrom resolution and (2) obtaining structures of proteins with sizes < 100 kDa, demonstrating that cryo-EM can be used to investigate a broad spectrum of drug-target interactions and dynamic conformational states. C1 [Merk, Alan; Bartesaghi, Alberto; Banerjee, Soojay; Falconieri, Veronica; Rao, Prashant; Earl, Lesley A.; Milne, Jacqueline L. S.; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Davis, Mindy I.; Pragani, Rajan; Boxer, Matthew B.] Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM ss1@nih.gov FU Center for Cancer Research, National Cancer Institute, NIH in Bethesda FX This research was supported by funds from the Center for Cancer Research, National Cancer Institute, NIH in Bethesda. We thank Kieran Moynihan, Robert Mueller, and Joe Cometa for technical assistance with electron microscopy; Fred Ulmer, Paul Mooney, and Chris Booth for advice and assistance with optimizing K2 detector performance; and Rishub Jain, Jierui Fang, and Amy Jin for assistance with data analysis. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). NR 49 TC 26 Z9 28 U1 32 U2 50 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 16 PY 2016 VL 165 IS 7 BP 1698 EP 1707 DI 10.1016/j.cell.2016.05.040 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DO8VD UT WOS:000378062000020 PM 27238019 ER PT J AU Zofall, M Smith, DR Mizuguchi, T Dhakshnamoorthy, J Grewal, SIS AF Zofall, Martin Smith, Deborah R. Mizuguchi, Takeshi Dhakshnamoorthy, Jothy Grewal, Shiv I. S. TI Taz1-Shelterin Promotes Facultative Heterochromatin Assembly at Chromosome-Internal Sites Containing Late Replication Origins SO MOLECULAR CELL LA English DT Article ID JMJC DOMAIN PROTEIN; CONTROLS DNA-REPLICATION; COMMON FRAGILE SITE; FISSION YEAST; SCHIZOSACCHAROMYCES-POMBE; BINDING-PROTEIN; HISTONE MODIFICATION; TELOMERE LENGTH; COMPLEX; RNAI AB Facultative heterochromatin regulates gene expression, but its assembly is poorly understood. Previously, we identified facultative heterochromatin islands in the fission yeast genome and found that RNA elimination machinery promotes island assembly at meiotic genes. Here, we report that Taz1, a component of the telomere protection complex Shelterin, is required to assemble heterochromatin islands at regions corresponding to late replication origins that are sites of double-strand break formation during meiosis. The loss of Taz1 or other Shelterin subunits, including Ccq1 that interacts with Clr4/Suv39h, abolishes heterochromatin at late origins and causes derepression of associated genes. Moreover, the late-origin regulator Rif1 affects heterochromatin at Taz1-dependent islands and subtelomeric regions. We explore the connection between facultative heterochromatin and replication control and show that heterochromatin machinery affects replication timing. These analyses reveal the role of Shelterin in facultative heterochromatin assembly at late origins, which has important implications for genome stability and gene regulation. C1 [Zofall, Martin; Smith, Deborah R.; Mizuguchi, Takeshi; Dhakshnamoorthy, Jothy; Grewal, Shiv I. S.] NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. [Smith, Deborah R.] Columbia Univ Coll Phys & Surg, 630 West 168th St, New York, NY 10032 USA. RP Grewal, SIS (reprint author), NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. EM grewals@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX We thank Amikam Cohen, Hisao Masukata, Fuyuki Ishikawa, Gerry Smith, and Julia Cooper for sharing strains and methods used in this study and Julia Cooper for providing anti-Taz1 antibody. We also thank Ke Zhang and Chanan Rubin for their help with some experiments, Jemima Barrowman for editing the manuscript, and members of the S.I.S.G. lab for helpful suggestions. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 61 TC 5 Z9 5 U1 2 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD JUN 16 PY 2016 VL 62 IS 6 BP 862 EP 874 DI 10.1016/j.molcel.2016.04.034 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DP1BI UT WOS:000378224900008 PM 27264871 ER PT J AU Palazzo, E Kellett, M Cataisson, C Gormley, A Bible, PW Pietroni, V Radoja, N Hwang, J Blumenberg, M Yuspa, SH Morasso, MI AF Palazzo, E. Kellett, M. Cataisson, C. Gormley, A. Bible, P. W. Pietroni, V. Radoja, N. Hwang, J. Blumenberg, M. Yuspa, S. H. Morasso, M. I. TI The homeoprotein DLX3 and tumor suppressor p53 co-regulate cell cycle progression and squamous tumor growth SO ONCOGENE LA English DT Article ID ECTODERMAL DYSPLASIAS; HUMAN KERATINOCYTES; HOMEOBOX GENE; EPIDERMAL DIFFERENTIATION; BINDING-SITES; STEM-CELLS; P63; CANCER; SKIN; EXPRESSION AB Epidermal homeostasis depends on the coordinated control of keratinocyte cell cycle. Differentiation and the alteration of this balance can result in neoplastic development. Here we report on a novel DLX3-dependent network that constrains epidermal hyperplasia and squamous tumorigenesis. By integrating genetic and transcriptomic approaches, we demonstrate that DLX3 operates through a p53-regulated network. DLX3 and p53 physically interact on the p21 promoter to enhance p21 expression. Elevating DLX3 in keratinocytes produces a G1-S blockade associated with p53 signature transcriptional profiles. In contrast, DLX3 loss promotes a mitogenic phenotype associated with constitutive activation of ERK. DLX3 expression is lost in human skin cancers and is extinguished during progression of experimentally induced mouse squamous cell carcinoma (SCC). Reinstatement of DLX3 function is sufficient to attenuate the migration of SCC cells, leading to decreased wound closure. Our data establish the DLX3-p53 interplay as a major regulatory axis in epidermal differentiation and suggest that DLX3 is a modulator of skin carcinogenesis. C1 [Palazzo, E.; Kellett, M.; Gormley, A.; Bible, P. W.; Pietroni, V.; Radoja, N.; Hwang, J.; Morasso, M. I.] NIAMS, Skin Biol Lab, NIH, Bldg 50,Room 1523, Bethesda, MD 20892 USA. [Cataisson, C.; Yuspa, S. H.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Blumenberg, M.] NYU, Dept Dermatol, New York, NY 10016 USA. RP Morasso, MI (reprint author), NIAMS, Skin Biol Lab, NIH, Bldg 50,Room 1523, Bethesda, MD 20892 USA. EM morasso@nih.gov RI Palazzo, Elisabetta/J-5287-2016; OI Palazzo, Elisabetta/0000-0002-0812-5524; Blumenberg, Miroslav/0000-0002-8672-7774 FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health [ZIA AR041124-14] FX We thank current and past members of the Laboratory of Skin Biology and members of the Laboratory of Cancer Biology and Genetics, and Dr Mark Udey for helpful discussions. We also thank Andrew Ryscavage (LCBG), Gustavo Gutierrez-Cruz (NIAMS Genome Analysis Core Facility), Dr Hong-Wei Sun (Biodata Mining and Discovery Section, NIAMS) and Kristina Zaal of the NIAMS Light Imaging Core Facility. This work was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (M.I.M. ZIA AR041124-14). NR 61 TC 2 Z9 2 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD JUN 16 PY 2016 VL 35 IS 24 BP 3114 EP 3124 DI 10.1038/onc.2015.380 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DO9GI UT WOS:000378092700004 PM 26522723 ER PT J AU Jones, DS Grady, C Lederer, SE AF Jones, David S. Grady, Christine Lederer, Susan E. TI "Ethics and Clinical Research" - The 50th Anniversary of Beecher's Bombshell SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID HUMAN-EXPERIMENTATION; INFORMED-CONSENT C1 [Jones, David S.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA USA. [Jones, David S.] Harvard Univ, Dept Hist Sci, Cambridge, MA 02138 USA. [Grady, Christine] NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Lederer, Susan E.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med Hist & Bioeth, Madison, WI 53706 USA. RP Jones, DS (reprint author), Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA USA.; Jones, DS (reprint author), Harvard Univ, Dept Hist Sci, Cambridge, MA 02138 USA. NR 49 TC 3 Z9 3 U1 1 U2 2 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 16 PY 2016 VL 374 IS 24 BP 2393 EP 2398 DI 10.1056/NEJMms1603756 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA DO5WW UT WOS:000377854600016 PM 27305197 ER PT J AU Biswas, P Chavali, VRM Agnello, G Stone, E Chakarova, C Duncan, JL Kannabiran, C Homsher, M Bhattacharya, SS Naeem, MA Kimchi, A Sharon, D Iwata, T Riazuddin, S Reddy, GB Hejtmancik, JF Georgiou, G Riazuddin, SA Ayyagari, R AF Biswas, Pooja Chavali, Venkata Ramana Murthy Agnello, Giulia Stone, Everett Chakarova, Christina Duncan, Jacque L. Kannabiran, Chitra Homsher, Melissa Bhattacharya, Shomi S. Naeem, Muhammad Asif Kimchi, Adva Sharon, Dror Iwata, Takeshi Riazuddin, Shaikh Reddy, G. Bhanuprakash Hejtmancik, J. Fielding Georgiou, George Riazuddin, S. Amer Ayyagari, Radha TI A missense mutation in ASRGL1 is involved in causing autosomal recessive retinal degeneration SO HUMAN MOLECULAR GENETICS LA English DT Article ID STATIONARY NIGHT BLINDNESS; L-ISOASPARTYL METHYLTRANSFERASE; VITELLIFORM MACULAR DYSTROPHY; LEBER CONGENITAL AMAUROSIS; RETINITIS-PIGMENTOSA; PROTEIN DAMAGE; GENE; IDENTIFICATION; REPAIR; SUBSTRATE AB Inherited retinal dystrophies are a group of genetically heterogeneous conditions with broad phenotypic heterogeneity. We analyzed a large five-generation pedigree with early-onset recessive retinal degeneration to identify the causative mutation. Linkage analysis and homozygosity mapping combined with exome sequencing were carried out to map the disease locus and identify the p.G178R mutation in the asparaginase like-1 gene (ASRGL1), segregating with the retinal dystrophy phenotype in the study pedigree. ASRGL1 encodes an enzyme that catalyzes the hydrolysis of L-asparagine and isoaspartyl-peptides. Studies on the ASRGL1 expressed in Escherichia coli and transiently transfected mammalian cells indicated that the p.G178R mutation impairs the autocatalytic processing of this enzyme resulting in the loss of functional ASRGL1 and leaving the inactive precursor protein as a destabilized and aggregation-prone protein. A zebrafish model overexpressing the mutant hASRGL1 developed retinal abnormalities and loss of cone photoreceptors. Our studies suggest that the p.G178R mutation in ASRGL1 leads to photoreceptor degeneration resulting in progressive vision loss. C1 [Biswas, Pooja; Chavali, Venkata Ramana Murthy; Ayyagari, Radha] Univ Calif San Diego, Shiley Eye Inst, 9415 Campus Point Dr,JRC 206, La Jolla, CA 92093 USA. [Chavali, Venkata Ramana Murthy; Homsher, Melissa] Univ Penn, Ophthalmol, Philadelphia, PA 19104 USA. [Agnello, Giulia; Stone, Everett; Georgiou, George] Univ Texas Austin, Sect Mol Genet & Microbiol, Dept Biomed Engn, Mol Biosci, Austin, TX 78712 USA. [Agnello, Giulia; Stone, Everett; Georgiou, George] Univ Texas Austin, Sect Mol Genet & Microbiol, Dept Chem Engn, Mol Biosci, Austin, TX 78712 USA. [Agnello, Giulia; Stone, Everett; Georgiou, George] Univ Texas Austin, Inst Cell & Mol Biol, Austin, TX 78712 USA. [Chakarova, Christina; Bhattacharya, Shomi S.] UCL Inst Ophthalmol, 11-43 Bath St, London, England. [Duncan, Jacque L.] Univ Calif San Francisco, Ophthalmol, San Francisco, CA 94143 USA. [Kannabiran, Chitra] LVPEI, Kallam Anji Reddy Mol Genet Lab, Kallam Anji Reddy Campus,LV Prasad Marg, Hyderabad 500034, Andhra Pradesh, India. [Naeem, Muhammad Asif] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Kimchi, Adva; Sharon, Dror] Hadassah Hebrew Univ, Med Ctr, Dept Ophthalmol, Jerusalem, Israel. [Iwata, Takeshi] Natl Hosp Org, Tokyo Med Ctr, Natl Inst Sensory Organs, Div Mol & Cellular Biol, Tokyo, Japan. [Riazuddin, Shaikh] Univ Hlth Sci Lahore, Allama Iqbal Med Coll, Lahore, Pakistan. [Riazuddin, Shaikh] Shaheed Zulfiqar Ali Bhutto Med Univ, Natl Ctr Genet Dis, Islamabad, Pakistan. [Reddy, G. Bhanuprakash] Natl Inst Nutr, Hyderabad 500007, Andhra Pradesh, India. [Hejtmancik, J. Fielding] NEI, OMGS OGVFB Branch, NIH, Bethesda, MD 20892 USA. [Riazuddin, S. Amer] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. RP Ayyagari, R (reprint author), Univ Calif San Diego, Shiley Eye Inst, 9415 Campus Point Dr,JRC 206, La Jolla, CA 92093 USA.; Riazuddin, SA (reprint author), Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. EM riazuddin@jhmi.edu; rayyagari@ucsd.edu FU Foundation Fighting Blindness; Research to Prevent Blindness; Bright Focus Foundation [NIH-EY21237, P30-EY22589 CPRIT RP120314] FX This work was supported by; The Foundation Fighting Blindness, Research to Prevent Blindness, Bright Focus Foundation grant, NIH-EY21237, P30-EY22589 CPRIT RP120314. NR 48 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUN 15 PY 2016 VL 25 IS 12 BP 2483 EP 2497 DI 10.1093/hmg/ddw113 PG 15 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EJ2TA UT WOS:000393062900009 PM 27106100 ER PT J AU Chen, MM O'Mara, TA Thompson, DJ Painter, JN Attia, J Black, A Brinton, L Chanock, S Chen, C Cheng, THT Cook, LS Crous-Bou, M Doherty, J Friedenreich, CM Garcia-Closas, M Gaudet, MM Gorman, M Haiman, C Hankinson, SE Hartge, P Henderson, BE Hodgson, S Holliday, EG Horn-Ross, PL Hunter, DJ Le Marchand, L Liang, XL Lissowska, J Long, JR Lu, LG Magliocco, AM Martin, L McEvoy, M Olson, SH Orlow, I Pooler, L Prescott, J Rastogi, R Rebbeck, TR Risch, H Sacerdote, C Schumacher, F Setiawan, VW Scott, RJ Sheng, X Shu, XO Turman, C Van Den Berg, D Wang, ZM Weiss, NS Wentzensen, N Xia, L Xiang, YB Yang, HP Yu, H Zheng, W Pharoah, PDP Dunning, AM Tomlinson, I Easton, DF Kraft, P Spurdle, AB De Vivo, I AF Chen, Maxine M. O'Mara, Tracy A. Thompson, Deborah J. Painter, Jodie N. Attia, John Black, Amanda Brinton, Louise Chanock, Stephen Chen, Chu Cheng, Timothy H. T. Cook, Linda S. Crous-Bou, Marta Doherty, Jennifer Friedenreich, Christine M. Garcia-Closas, Montserrat Gaudet, Mia M. Gorman, Maggie Haiman, Christopher Hankinson, Susan E. Hartge, Patricia Henderson, Brian E. Hodgson, Shirley Holliday, Elizabeth G. Horn-Ross, Pamela L. Hunter, David J. Le Marchand, Loic Liang, Xiaolin Lissowska, Jolanta Long, Jirong Lu, Lingeng Magliocco, Anthony M. Martin, Lynn McEvoy, Mark Olson, Sara H. Orlow, Irene Pooler, Loreall Prescott, Jennifer Rastogi, Radhai Rebbeck, Timothy R. Risch, Harvey Sacerdote, Carlotta Schumacher, Frederick Setiawan, Veronica Wendy Scott, Rodney J. Sheng, Xin Shu, Xiao-Ou Turman, Constance Van Den Berg, David Wang, Zhaoming Weiss, Noel S. Wentzensen, Nicholas Xia, Lucy Xiang, Yong-Bing Yang, Hannah P. Yu, Herbert Zheng, Wei Pharoah, Paul D. P. Dunning, Alison M. Tomlinson, Ian Easton, Douglas F. Kraft, Peter Spurdle, Amanda B. De Vivo, Immaculata CA ANECS Natl Study Endometrial Canc TI GWAS meta-analysis of 16 852 women identifies new susceptibility locus for endometrial cancer SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; EPITHELIAL-MESENCHYMAL TRANSITION; PROSTATE-CANCER; POOR-PROGNOSIS; COLORECTAL-CANCER; COMMON VARIANTS; FAMILY-HISTORY; LUNG-CANCER; RISK LOCI; SOX4 AB Endometrial cancer is the most common gynecological malignancy in the developed world. Although there is evidence of genetic predisposition to the disease, most of the genetic risk remains unexplained. We present the meta-analysis results of four genome-wide association studies (4907 cases and 11 945 controls total) in women of European ancestry. We describe one new locus reaching genome-wide significance (P<5 x 10(-8)) at 6p22.3 (rs1740828; P = 2.29 x 10(-8), OR = 1.20), providing evidence of an additional region of interest for genetic susceptibility to endometrial cancer. C1 [Chen, Maxine M.; Crous-Bou, Marta; Hunter, David J.; Turman, Constance; Kraft, Peter; De Vivo, Immaculata] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. [O'Mara, Tracy A.; Painter, Jodie N.; Spurdle, Amanda B.; ANECS] QIMR Berghofer Med Res Inst, Dept Genet & Computat Biol, Herston, Qld 4006, Australia. [Thompson, Deborah J.; Tomlinson, Ian; Easton, Douglas F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Attia, John; Holliday, Elizabeth G.; Scott, Rodney J.] John Hunter Hosp, Hunter Med Res Inst, Newcastle, NSW 2305, Australia. [Attia, John; McEvoy, Mark] Univ Newcastle, Sch Med & Publ Hlth, Ctr Clin Epidemiol & Biostat, Newcastle, NSW 2308, Australia. [Black, Amanda; Brinton, Louise; Chanock, Stephen; Garcia-Closas, Montserrat; Hartge, Patricia; Wang, Zhaoming; Wentzensen, Nicholas; Yang, Hannah P.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chen, Chu] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Cheng, Timothy H. T.; Gorman, Maggie; Martin, Lynn; Natl Study Endometrial Canc] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Cook, Linda S.] Univ New Mexico, Albuquerque, NM 87131 USA. [Cook, Linda S.] Alberta Hlth Serv, Dept Populat Hlth Res, Div Canc Care, Calgary, AB, Canada. [Crous-Bou, Marta; Hankinson, Susan E.; Prescott, Jennifer; De Vivo, Immaculata] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Crous-Bou, Marta; Hankinson, Susan E.; Prescott, Jennifer; De Vivo, Immaculata] Harvard Med Sch, Boston, MA 02115 USA. [Doherty, Jennifer] Dartmouth Coll, Sch Med, Lebanon, NH 03755 USA. [Friedenreich, Christine M.] Alberta Hlth Serv, Canc Control Alberta, Dept Canc Epidemiol & Prevent Res, Calgary, AB, Canada. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London, England. [Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Haiman, Christopher; Henderson, Brian E.; Pooler, Loreall; Schumacher, Frederick; Setiawan, Veronica Wendy; Sheng, Xin; Van Den Berg, David; Xia, Lucy] Univ Southern Calif, Los Angeles, CA 90033 USA. [Hankinson, Susan E.] Univ Massachusetts, Dept Biostat & Epidemiol, Amherst, MA 01003 USA. [Hodgson, Shirley] St Georges Univ London, Dept Clin Genet, London SW17 0RE, England. [Horn-Ross, Pamela L.] Canc Prevent Inst Calif, Fremont, CA 94538 USA. [Le Marchand, Loic; Yu, Herbert] Univ Hawaii, Ctr Canc, Honolulu, HI 96813 USA. [Liang, Xiaolin; Olson, Sara H.; Orlow, Irene; Rastogi, Radhai] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Lissowska, Jolanta] M Sklodowska Curie Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Long, Jirong; Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 27232 USA. [Lu, Lingeng; Risch, Harvey] Yale Univ, Sch Publ Hlth, New Haven, CT 06510 USA. [Magliocco, Anthony M.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Rebbeck, Timothy R.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Sacerdote, Carlotta] Ctr Canc Prevent CPO Piemonte, Turin, Italy. [Sacerdote, Carlotta] Human Genet Fdn HuGeF, Turin, Italy. [Scott, Rodney J.] John Hunter Hosp, Hunter Area Pathol Serv, Newcastle, NSW 2305, Australia. [Scott, Rodney J.] Univ Newcastle, Sch Biomed Sci & Pharm, Newcastle, NSW 2308, Australia. [Weiss, Noel S.] Univ Washington, Seattle, WA 19024 USA. [Xiang, Yong-Bing] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Pharoah, Paul D. P.; Dunning, Alison M.; Easton, Douglas F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge CB1 8RN, England. RP De Vivo, I (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA.; De Vivo, I (reprint author), Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.; De Vivo, I (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM nhidv@channing.harvard.edu FU National Health and Medical Research Council of Australia [339435]; Cancer Council Queensland [4196615]; Cancer Council Tasmania [403031, 457636]; Cancer Research UK [C490/A10124]; National Health and Medical Research Council [552402]; Medical Research Council [G0000934]; Wellcome Trust [068545/Z/02, 085475]; EU FP7 CHIBCHA grant; CORGI by Cancer Research UK; National Health and Medical Research Council of Australia (NHMRC); NHMRC [APP1031333]; National Health and Medical Research Council (NHMRC); Joseph Mitchell Trust; Cancer Research UK; Oxford Comprehensive Biomedical Research Centre; NCI [5T32CA009001-38]; NCI, NIH [UM1 CA186107, P01 CA087969, R01 CA49449, 1R01 CA134958, 2R01 CA082838, CA54281, CA128008, R01 CA91019, R01 CA77398]; NIH [RO1 CA105212, RO1 CA 87538, RO1 CA75977, RO3 CA80636, NO1 HD23166, R35 CA39779, KO5 CA92002]; Fred Hutchinson Cancer Research Center; California Breast Cancer Research Fund [97-10500]; Intramural Research Program of the NCI; Extramural and the Intramural Research Programs of the NCI FX ANECS recruitment was supported by project grants from the National Health and Medical Research Council of Australia (ID 339435), The Cancer Council Queensland (ID 4196615) and Cancer Council Tasmania (ID 403031 and ID 457636). SEARCH recruitment was funded by a programme grant from Cancer Research UK [C490/A10124]. Case genotyping was supported by the National Health and Medical Research Council (ID 552402). Control data were generated by the Wellcome Trust Case Control Consortium (WTCCC), and a full list of the investigators who contributed to the generation of the data is available from the WTCCC website. We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02-funding for this project was provided by the Wellcome Trust under award 085475. NSECG was supported by the EU FP7 CHIBCHA grant and CORGI by Cancer Research UK. Recruitment of the QIMR controls was supported by the National Health and Medical Research Council of Australia (NHMRC). The University of Newcastle, the Gladys M Brawn Senior Research Fellowship scheme, The Vincent Fairfax Family Foundation, the Hunter Medical Research Institute and the Hunter Area Pathology Service all contributed towards the costs of establishing the Hunter Community Study. T.O'M and J.N.P. are supported by NHMRC project grant (ID APP1031333). A.B.S. is supported by the National Health and Medical Research Council (NHMRC) Fellowship Scheme. D.F.E. is a Principal Research Fellow of Cancer Research UK. A.M.D. was supported by the Joseph Mitchell Trust. I.T. is supported by Cancer Research UK and the Oxford Comprehensive Biomedical Research Centre. M.M.C. is supported by training grant 5T32CA009001-38 from the NCI. The Nurses' Health Study (NHS) is supported by the NCI, NIH Grants Number UM1 CA186107, P01 CA087969, R01 CA49449, 1R01 CA134958 and 2R01 CA082838. The Connecticut Endometrial Cancer Study was supported by NCI, NIH Grant Number 2R01 CA082838. The Fred Hutchinson Cancer Research Center (FHCRC) is supported by NCI, NIH Grant Number 2R01 CA082838, NIH RO1 CA105212, RO1 CA 87538, RO1 CA75977, RO3 CA80636, NO1 HD23166, R35 CA39779, KO5 CA92002 and funds from the Fred Hutchinson Cancer Research Center. The Multiethnic Cohort Study (MEC) is supported by the NCI, NHI Grants Number CA54281, CA128008 and 2R01 CA082838. The California Teachers Study (CTS) is supported by NCI, NIH Grant Number 2R01 CA082838, R01 CA91019 and R01 CA77398, and contract 97-10500 from the California Breast Cancer Research Fund. The Polish Endometrial Cancer Study (PECS) is supported by the Intramural Research Program of the NCI. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) is supported by the Extramural and the Intramural Research Programs of the NCI. NR 64 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUN 15 PY 2016 VL 25 IS 12 BP 2612 EP 2620 DI 10.1093/hmg/ddw092 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EJ2TA UT WOS:000393062900019 PM 27008869 ER PT J AU Jin, JF Krishnamachary, B Mironchik, Y Kobayashi, H Bhujwalla, ZM AF Jin, Jiefu Krishnamachary, Balaji Mironchik, Yelena Kobayashi, Hisataka Bhujwalla, Zaver M. TI Phototheranostics of CD44-positive cell populations in triple negative breast cancer SO SCIENTIFIC REPORTS LA English DT Article ID NEAR-INFRARED PHOTOIMMUNOTHERAPY; GROWTH-FACTOR RECEPTOR; PHASE-I THERAPY; STEM-CELLS; BIVATUZUMAB MERTANSINE; TUMOR-MODEL; CARCINOMA; HEAD; NECK; THERAPEUTICS AB Triple-negative breast cancer (TNBC) is one of the most lethal subtypes of breast cancer that has limited treatment options. Its high rates of recurrence and metastasis have been associated, in part, with a subpopulation of breast cancer stem-like cells that are resistant to conventional therapies. A compendium of markers such as CD44(high)/CD24(low), and increased expression of the ABCG2 transporter and increased aldehyde dehydrogenase (ALDH1), have been associated with these cells. We developed a CD44-targeted monoclonal antibody photosensitizer conjugate for combined fluorescent detection and photoimmunotherapy (PIT) of CD44 expressing cells in TNBC. The CD44-targeted conjugate demonstrated acute cell killing of breast cancer cells with high CD44 expression. This cell death process was dependent upon CD44-specific cell membrane binding combined with near-infrared irradiation. The conjugate selectively accumulated in CD44-positive tumors and caused dramatic tumor shrinkage and efficient elimination of CD44-positive cell populations following irradiation. This novel phototheranostic strategy provides a promising opportunity for the destruction of CD44-positive populations that include cancer stem-like cells, in locally advanced primary and metastatic TNBC. C1 [Jin, Jiefu; Krishnamachary, Balaji; Mironchik, Yelena; Bhujwalla, Zaver M.] Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Div Canc Imaging Res, Sch Med, Baltimore, MD 21218 USA. [Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Bhujwalla, Zaver M.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21218 USA. RP Bhujwalla, ZM (reprint author), Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Div Canc Imaging Res, Sch Med, Baltimore, MD 21218 USA.; Bhujwalla, ZM (reprint author), Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21218 USA. EM zaver@mri.jhu.edu OI Jin, Jiefu/0000-0002-5318-1111 FU NIH [R01CA136576, R01CA138515, R01CA73850, R01CA82337, P50CA103175]; Commonwealth Foundation FX This work was supported by NIH R01CA136576, R01CA138515, R01CA73850, R01CA82337, and P50CA103175, and the Commonwealth Foundation. We thank Mr. G. Cromwell for maintaining the cell lines and inoculating tumors. We thank Dr. Marie-France Penet for assistance with the in vivo studies. We thank Drs. J.S. Lewin and K.M. Horton for their support. NR 49 TC 1 Z9 1 U1 6 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 15 PY 2016 VL 6 AR 27871 DI 10.1038/srep27871 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX8DI UT WOS:000384617900001 PM 27302409 ER PT J AU Shockley, KR AF Shockley, Keith R. TI Estimating Potency in High-Throughput Screening Experiments by Maximizing the Rate of Change in Weighted Shannon Entropy SO SCIENTIFIC REPORTS LA English DT Article ID ESTROGEN-RECEPTOR-ALPHA; STATISTICAL-ANALYSIS; CHEMICALS; TOXICITY; AGONISTS; IMPACT; CANCER; ASSAYS AB High-throughput in vitro screening experiments can be used to generate concentration-response data for large chemical libraries. It is often desirable to estimate the concentration needed to achieve a particular effect, or potency, for each chemical tested in an assay. Potency estimates can be used to directly compare chemical profiles and prioritize compounds for confirmation studies, or employed as input data for prediction modeling and association mapping. The concentration for half-maximal activity derived from the Hill equation model (i.e., AC(50)) is the most common potency measure applied in pharmacological research and toxicity testing. However, the AC(50) parameter is subject to large uncertainty for many concentration-response relationships. In this study we introduce a new measure of potency based on a weighted Shannon entropy measure termed the weighted entropy score (WES). Our potency estimator (Point of Departure, PODWES) is defined as the concentration producing the maximum rate of change in weighted entropy along a concentration-response profile. This approach provides a new tool for potency estimation that does not depend on the assumption of monotonicity or any other pre-specified concentration-response relationship. PODWES estimates potency with greater precision and less bias compared to the conventional AC(50) assessed across a range of simulated conditions. C1 [Shockley, Keith R.] NIEHS, Biostat & Computat Biol Branch, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. RP Shockley, KR (reprint author), NIEHS, Biostat & Computat Biol Branch, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM shockleykr@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [ZIA ES102865] FX I thank Dr. Raymond Tice (Biomolecular Screening Branch, NIEHS) and Dr. Grace Kissling (Biostatistics and Computational Biology Branch, NIEHS) for reviewing the manuscript and providing helpful suggestions. This work was supported [in part] by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ZIA ES102865). NR 34 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 15 PY 2016 VL 6 AR 27897 DI 10.1038/srep27897 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX7IH UT WOS:000384559800001 PM 27302286 ER PT J AU Gomez-Quiroz, LE Seo, D Lee, YH Kitade, M Gaiser, T Gillen, M Lee, SB Gutierrez-Ruiz, MC Conner, EA Factor, VM Thorgeirsson, SS Marquardt, JU AF Gomez-Quiroz, Luis E. Seo, Daekwan Lee, Yun-Han Kitade, Mitsuteru Gaiser, Timo Gillen, Matthew Lee, Seung-Bum Concepcion Gutierrez-Ruiz, Ma Conner, Elizabeth A. Factor, Valentina M. Thorgeirsson, Snorri S. Marquardt, Jens U. TI Loss of c-Met signaling sensitizes hepatocytes to lipotoxicity and induces cholestatic liver damage by aggravating oxidative stress SO TOXICOLOGY LA English DT Article DE c-Met; Oxidative stress; Cholestasis; Cholesterol ID INDUCED FATTY LIVER; GROWTH-FACTOR; ACID-METABOLISM; BILE; PATHWAY; RECEPTOR; REGENERATION; FAS; TRANSPORTERS; PROTECTION AB Recent studies confirmed a critical importance of c-Met signaling for liver regeneration by modulating redox balance. Here we used liver-specific conditional knockout mice (MetKO) and a nutritional model of hepatic steatosis to address the role of c-Met in cholesterol-mediated liver toxicity. Liver injury was assessed by histopathology and plasma enzymes levels. Global transcriptomic changes were examined by gene expression microarray, and key molecules involved in liver damage and lipid homeostasis were evaluated by Western blotting. Loss of c-Met signaling amplified the extent of liver injury in MetKO mice fed with high-cholesterol diet for 30 days as evidenced by upregulation of liver enzymes and increased synthesis of total bile acids, aggravated inflammatory response and enhanced intrahepatic lipid deposition. Global transcriptomic changes confirmed the enrichment of networks involved in steatosis and cholestasis. In addition, signaling pathways related to glutathione and lipid metabolism, oxidative stress and mitochondria dysfunction were significantly affected by the loss of c-Met function. Mechanistically, exacerbation of oxidative stress in MetKO livers was corroborated by increased lipid and protein oxidation. Western blot analysis further revealed suppression of Erk, NF-kappa B and Nrf2 survival pathways and downstream target genes (e.g. cyclin D1, SOD1, gamma-GCS), as well as up-regulation of proapoptotic signaling (e.g. p53, caspase 3). Consistent with the observed steatotic and cholestatic phenotype, nuclear receptors RAR, RXR showed increased activation while expression levels of CAR, FXR and PPAR-alpha were decreased in MetKO. Collectively, our data provide evidence for the critical involvement of c-Met signaling in cholesterol and bile acids toxicity. (C) 2016 Published by Elsevier Ireland Ltd. C1 [Gomez-Quiroz, Luis E.; Seo, Daekwan; Lee, Yun-Han; Kitade, Mitsuteru; Gillen, Matthew; Lee, Seung-Bum; Conner, Elizabeth A.; Factor, Valentina M.; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gomez-Quiroz, Luis E.; Concepcion Gutierrez-Ruiz, Ma] Univ Autonoma Metropolitana Iztapalapa, Dept Ciencias Salud, Mexico City, DF, Mexico. [Lee, Yun-Han] Yonsei Univ, Coll Med, Dept Radiat Oncol, Seoul, South Korea. [Gaiser, Timo] Univ Med Ctr Mannheim, Inst Pathol, Mannheim, Germany. [Marquardt, Jens U.] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dept Med 1, Langenbeckstr 1, D-55131 Mainz, Germany. RP Marquardt, JU (reprint author), Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dept Med 1, Langenbeckstr 1, D-55131 Mainz, Germany. EM marquarj@uni-mainz.de FU National Science Council of Mexico (CONACYT) [252942, 166042, 144805]; German Cancer Aid [DKH 110989]; Volkswagen Foundation (Lichtenberg program) FX This work was supported by National Science Council of Mexico (CONACYT) #252942, 166042 and 144805 for sabbatical support to L.E.G-Q. PRODEP 913026-1461211. The Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and J.U.M. is supported by grants from the German Cancer Aid (DKH 110989) and the Volkswagen Foundation (Lichtenberg program). We thank Tanya Hoang and Anita Ton for technical assistance. NR 41 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD JUN 15 PY 2016 VL 361 BP 39 EP 48 DI 10.1016/j.tox.2016.07.004 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA DT5SI UT WOS:000381542500004 PM 27394961 ER PT J AU Wallace, ME Grantz, KL Liu, DP Zhu, YY Kim, SS Mendola, P AF Wallace, Maeve E. Grantz, Katherine L. Liu, Danping Zhu, Yeyi Kim, Sung Soo Mendola, Pauline TI Exposure to Ambient Air Pollution and Premature Rupture of Membranes SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE ambient air pollution; premature rupture of membranes; preterm birth ID FINE PARTICULATE MATTER; TIME-SERIES-ANALYSIS; PRETERM BIRTH; OUTCOMES; RISK; OZONE; WOMEN; COMPLICATIONS; PENNSYLVANIA; INFLAMMATION AB Premature rupture of membranes (PROM) is a major factor that predisposes women to preterm delivery. Results from previous studies have suggested that there are associations between exposure to air pollution and preterm birth, but evidence of a relationship with PROM is sparse. Modified Community Multiscale Air Quality models were used to estimate mean exposures to particulate matter less than 10 A mu m or less than 2.5 A mu m in aerodynamic diameter, nitrogen oxides, carbon monoxide, sulfur dioxide, and ozone among 223,375 singleton deliveries in the Air Quality and Reproductive Health Study (2002-2008). We used log-linear models with generalized estimating equations to estimate adjusted relative risks and 95% confidence intervals for PROM per each interquartile-range increase in pollutants across the whole pregnancy, on the day of delivery, and 5 hours before delivery. Whole-pregnancy exposures to carbon monoxide and sulfur dioxide were associated with an increased risk of PROM (for carbon monoxide, relative risk (RR) = 1.09, 95% confidence interval (CI): 1.04, 1.14; for sulfur dioxide, RR = 1.15, 95% CI: 1.06, 1.25) but not preterm PROM. Ozone exposure increased the risk of PROM on the day of delivery (RR = 1.06, 95% CI: 1.02, 1.09) and 1 day prior (RR = 1.04, 95% CI: 1.01, 1.07). In the 5 hours preceding delivery, there were 3%-7% increases in risk associated with exposure to ozone and particulate matter less than 2.5 A mu m in aerodynamic diameter and inverse associations with exposure to carbon monoxide and nitrogen oxides. Acute and long-term air pollutant exposures merit further study in relation to PROM. C1 [Wallace, Maeve E.; Grantz, Katherine L.; Zhu, Yeyi; Kim, Sung Soo; Mendola, Pauline] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Rockville, MD USA. [Liu, Danping] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, Rockville, MD USA. RP Mendola, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Populat Hlth Res, 6100 Execut Blvd, Rockville, MD 20852 USA. EM Pauline.mendola@nih.gov OI Mendola, Pauline/0000-0001-5330-2844; Grantz, Katherine/0000-0003-0276-8534 FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN267200603425C]; Air Quality and Reproductive Health Study [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, including funding for the Consortium on Safe Labor (contract HHSN267200603425C) and the Air Quality and Reproductive Health Study (contract HHSN275200800002I, task order HHSN27500008). NR 34 TC 0 Z9 0 U1 4 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2016 VL 183 IS 12 BP 1114 EP 1121 DI 10.1093/aje/kwv284 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DR2IQ UT WOS:000379728600007 PM 27188941 ER PT J AU Arendt, LH Ramlau-Hansen, CH Wilcox, AJ Henriksen, TB Olsen, J Lindhard, MS AF Arendt, Linn Hakonsen Ramlau-Hansen, Cecilia Host Wilcox, Allen J. Henriksen, Tine Brink Olsen, Jorn Lindhard, Morten Sondergaard TI Placental Weight and Male Genital Anomalies: A Nationwide Danish Cohort Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE congenital abnormalities; cryptorchidism; hypospadias; placenta; pregnancy; risk factors ID GESTATIONAL-AGE; BIRTH-WEIGHT; FETAL-GROWTH; RISK-FACTORS; PROGRAMMING WINDOW; ALPHA-FETOPROTEIN; CRYPTORCHIDISM; HYPOSPADIAS; EPIDEMIOLOGY; SERUM AB The most consistently reported risk indicators for the male genital anomalies cryptorchidism and hypospadias are prematurity and low birth weight. Placental dysfunction has been hypothesized as a possible underlying cause, and an association between placental weight at birth and hypospadias has been indicated. In a population-based cohort of 388,422 Danish singleton boys born alive (1997-2008), we studied the association between placental weight and cryptorchidism and hypospadias. Missing data were handled with multiple imputation, and we estimated hazard ratios by means of Cox regression models. During follow-up, 1,713 boys were diagnosed with hypospadias and 6,878 with cryptorchidism (3,624 underwent corrective surgery). We observed an association between low placental weight and risk of both genital anomalies. Boys with a placental weight in the lowest decile (< 10%) had higher risks of both cryptorchidism (hazard ratio = 1.52, 95% confidence interval: 1.31, 1.76) and hypospadias (hazard ratio = 1.97, 95% confidence interval: 1.59, 2.45) than boys in the reference decile (50.0-59.9%). In conclusion, we found higher risks of both genital malformations in boys born with a low placental weight. The relationship seemed stronger for hypospadias than for cryptorchidism. Taken together, our data support a role for placental dysfunction in the etiology of these anomalies. C1 [Arendt, Linn Hakonsen; Ramlau-Hansen, Cecilia Host; Olsen, Jorn] Aarhus Univ, Fac Hlth, Dept Publ Hlth, Epidemiol Sect, Bartholins Alle 2, DK-8000 Aarhus C, Denmark. [Arendt, Linn Hakonsen; Henriksen, Tine Brink; Lindhard, Morten Sondergaard] Aarhus Univ Hosp, Dept Pediat, Perinatal Epidemiol Res Unit, Aarhus, Denmark. [Wilcox, Allen J.] NIEHS, Epidemiol Branch, Durham, NC USA. [Olsen, Jorn] Aarhus Univ Hosp, Dept Clin Epidemiol, Aarhus, Denmark. RP Arendt, LH (reprint author), Aarhus Univ, Fac Hlth, Dept Publ Hlth, Epidemiol Sect, Bartholins Alle 2, DK-8000 Aarhus C, Denmark. EM lha@ph.au.dk RI Lindhard, Morten/B-1963-2008; OI Lindhard, Morten/0000-0002-5685-8845; Wilcox, Allen/0000-0002-3376-1311 FU Faculty of Health, Aarhus University (Aarhus, Denmark) FX This work was supported by a grant from the Faculty of Health, Aarhus University (Aarhus, Denmark). NR 41 TC 2 Z9 2 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2016 VL 183 IS 12 BP 1122 EP 1128 DI 10.1093/aje/kwv336 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DR2IQ UT WOS:000379728600008 PM 27257113 ER PT J AU Baldi, P Przytycka, T AF Baldi, Pierre Przytycka, Teresa TI ISMB 2016 Proceedings SO BIOINFORMATICS LA English DT Editorial Material C1 [Baldi, Pierre] Univ Calif Irvine, Dept Comp Sci, Irvine, CA 92697 USA. [Przytycka, Teresa] NIH, Natl Ctr Biotechnol Informat, Bldg 10, Bethesda, MD 20892 USA. RP Baldi, P (reprint author), Univ Calif Irvine, Dept Comp Sci, Irvine, CA 92697 USA. OI Lopez, Rodrigo/0000-0003-1256-7306 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JUN 15 PY 2016 VL 32 IS 12 BP 1 EP 2 DI 10.1093/bioinformatics/btw326 PG 2 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA DR2KV UT WOS:000379734300001 ER PT J AU Wei, CH Leaman, R Lu, ZY AF Wei, Chih-Hsuan Leaman, Robert Lu, Zhiyong TI Beyond accuracy: creating interoperable and scalable text-mining web services SO BIOINFORMATICS LA English DT Article ID NAMED ENTITY RECOGNITION; BIOMEDICAL LITERATURE; NORMALIZATION; SYSTEM AB A Summary: The biomedical literature is a knowledge-rich resource and an important foundation for future research. With over 24 million articles in PubMed and an increasing growth rate, research in automated text processing is becoming increasingly important. We report here our recently developed web-based text mining services for biomedical concept recognition and normalization. Unlike most text-mining software tools, our web services integrate several state-of-the-art entity tagging systems (DNorm, GNormPlus, SR4GN, tmChem and tmVar) and offer a batch-processing mode able to process arbitrary text input (e.g. scholarly publications, patents and medical records) in multiple formats (e.g. BioC). We support multiple standards to make our service interoperable and allow simpler integration with other text-processing pipelines. To maximize scalability, we have preprocessed all PubMed articles, and use a computer cluster for processing large requests of arbitrary text. C1 [Wei, Chih-Hsuan; Leaman, Robert; Lu, Zhiyong] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Lu, ZY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM Zhiyong.Lu@nih.gov FU NIH Intramural Research Program, National Library of Medicine FX This research was supported by the NIH Intramural Research Program, National Library of Medicine. NR 27 TC 4 Z9 4 U1 2 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JUN 15 PY 2016 VL 32 IS 12 BP 1907 EP 1910 DI 10.1093/bioinformatics/btv760 PG 4 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA DR2KV UT WOS:000379734300069 PM 26883486 ER PT J AU Kamran, SC de Gonzalez, AB Ng, A Haas-Kogan, D Viswanathan, AN AF Kamran, Sophia C. de Gonzalez, Amy Berrington Ng, Andrea Haas-Kogan, Daphne Viswanathan, Akila N. TI Therapeutic radiation and the potential risk of second malignancies SO CANCER LA English DT Review DE carcinogenesis; neoplasm; radiotherapy; risk; second primary; survivors ID CHILDHOOD-CANCER SURVIVOR; BRCA2 MUTATION CARRIERS; PRIMARY BREAST-CANCER; HODGKINS-LYMPHOMA; IONIZING-RADIATION; ENDOMETRIAL CANCER; NERVOUS-SYSTEM; LUNG-CANCER; SUBSEQUENT NEOPLASMS; CONTRALATERAL BREAST AB Radiation has long been associated with carcinogenesis. Nevertheless, it is an important part of multimodality therapy for many malignancies. It is critical to assess the risk of secondary malignant neoplasms (SMNs) after radiation treatment. The authors reviewed the literature with a focus on radiation and associated SMNs for primary hematologic, breast, gynecologic, and pediatric tumors. Radiation appeared to increase the risk of SMN in all of these; however, this risk was found to be associated with age, hormonal influences, chemotherapy use, environmental influences, genetic predisposition, infection, and immunosuppression. The risk also appears to be altered with modern radiotherapy techniques. Practitioners of all specialties who treat cancer survivors in follow-up should be aware of this potential risk. Cancer 2016;122:1809-21. (c) 2016 American Cancer Society. Radiation appears to increase the risk of developing secondary neoplasms. This risk appears to be altered by multiple factors. C1 [Kamran, Sophia C.] Harvard Univ, Sch Med, Harvard Radiat Oncol Program, Boston, MA USA. [de Gonzalez, Amy Berrington] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ng, Andrea; Haas-Kogan, Daphne; Viswanathan, Akila N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02115 USA. RP Viswanathan, AN (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,ASB 1,L2, Boston, MA 02115 USA. EM aviswanathan@lroc.harvard.edu FU National Institutes of Health [R21 167800] FX Akila N. Viswanathan is supported by National Institutes of Health grant R21 167800. NR 54 TC 1 Z9 1 U1 3 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JUN 15 PY 2016 VL 122 IS 12 BP 1809 EP 1821 DI 10.1002/cncr.29841 PG 13 WC Oncology SC Oncology GA DP3NR UT WOS:000378402100007 PM 26950597 ER PT J AU Wills, AB Spaulding, AB Adjemian, J Prevots, DR Turk, SP Williams, C Marques, A AF Wills, Aprielle B. Spaulding, Alicen B. Adjemian, Jennifer Prevots, D. Rebecca Turk, Siu-Ping Williams, Carla Marques, Adriana TI Long-term Follow-up of Patients With Lyme Disease: Longitudinal Analysis of Clinical and Quality-of-life Measures SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE Borrelia burgdorferi; Lyme disease; epidemiology; quality of life; longitudinal analysis ID CONFIRMED ERYTHEMA MIGRANS; ACRODERMATITIS CHRONICA ATROPHICANS; PERIPHERAL NEUROPATHY; ANTIBIOTIC-TREATMENT; DOUBLE-BLIND; NEUROBORRELIOSIS; CEFTRIAXONE; BORRELIOSIS; OUTCOMES; MANIFESTATIONS AB Background. Lyme disease is the most common vector-borne disease in the United States. Some patients report persistent or intermittent subjective symptoms of mild to moderate intensity after antibiotic treatment for Lyme disease. We sought to evaluate trends in clinical and quality-of-life (QOL) measures in a cohort of patients with Lyme disease enrolled in a natural history study at the National Institutes of Health from 2001-2014. Methods. QOL was measured using the self-administered 36-item Short Form Health Survey (SF-36) during study follow-up. Primary outcomes included mean physical (PCS) and mental (MCS) health QOL composite scores and reporting long-term (>= 2 years) symptoms, adjusted for Lyme disease stage and severity at diagnosis. Results. Overall, 101 patients with an average follow-up time of 3.9 years (range, 0.5-11.3 years) were included. At first visit, overall mean QOL scores were below the US population mean for both PCS (45.6 +/- 10.4) andMCS (47.3 +/- 11.5) but increased to just above the national average after 3 years of follow-up for both PCS (50.7 +/- 9.6) and MCS (50.1 +/- 10.0). Baseline QOL scores were lowest in those with late disease (P < 0.01) but also increased by the end of follow-up to national averages. In multivariate analysis, the only factors significantly associated with long-term symptoms or lower QOL scores were other comorbidities unrelated to Lyme disease. Conclusions. Comorbid conditions can play a role in the reporting of long-term symptoms and overall QOL of Lyme disease patients and should be considered in the evaluation of these patients. C1 [Wills, Aprielle B.; Spaulding, Alicen B.; Adjemian, Jennifer; Prevots, D. Rebecca] NIAID, Epidemiol Unit, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Wills, Aprielle B.; Spaulding, Alicen B.; Adjemian, Jennifer; Prevots, D. Rebecca; Turk, Siu-Ping; Marques, Adriana] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Adjemian, Jennifer] US PHS, Commissioned Corps, Rockville, MD USA. [Williams, Carla] NCI, Clin Monitoring Res Program, Leidos Biomed Res Inc, Frederick, MD 21701 USA. RP Wills, AB (reprint author), NIAID, Epidemiol Unit, Lab Clin Infect Dis, NIH, 8 W Dr,Quarters 15B-1, Bethesda, MD 20892 USA. EM aprielle.wills@nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the NIH; National Cancer Institute, Center for Cancer Research, NIH [HHSN261200800001E] FX This work was supported, in part, by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the NIH. This project was funded, in part, with federal funds from the National Cancer Institute, Center for Cancer Research, NIH (contract number HHSN261200800001E). NR 37 TC 5 Z9 6 U1 10 U2 16 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 15 PY 2016 VL 62 IS 12 BP 1546 EP 1551 DI 10.1093/cid/ciw189 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DP3ZL UT WOS:000378434900012 PM 27025825 ER PT J AU Dropulic, LK Ali, MA Ombrello, AK Cohen, JI AF Dropulic, Lesia K. Ali, Mir A. Ombrello, Amanda K. Cohen, Jeffrey I. TI Periodic Illness Associated With Epstein-Barr Virus: A New Diagnosis After a 22-Year Follow-up SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID ENCODING MEVALONATE KINASE; HYPERIMMUNOGLOBULINEMIA-D; FEVER SYNDROME; PRIMARY IMMUNODEFICIENCIES; MUTATIONS; CHILD; IGD C1 [Dropulic, Lesia K.; Ali, Mir A.; Cohen, Jeffrey I.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Ombrello, Amanda K.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIH, Med Virol Sect, Infect Dis Lab, Bldg 50,Rm 6134, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov NR 7 TC 0 Z9 0 U1 4 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 15 PY 2016 VL 62 IS 12 BP 1613 EP U164 DI 10.1093/cid/ciw197 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DP3ZL UT WOS:000378434900024 PM 27025823 ER PT J AU Pepper, DJ Sun, JF Welsh, J Cui, XZ Suffredini, AF Eichacker, PQ AF Pepper, Dominique J. Sun, Junfeng Welsh, Judith Cui, Xizhong Suffredini, Anthony F. Eichacker, Peter Q. TI Increased body mass index and adjusted mortality in ICU patients with sepsis or septic shock: a systematic review and meta-analysis SO CRITICAL CARE LA English DT Review DE Sepsis; Obesity; Overweight; Body mass index; Mortality; Meta-analysis ID INTENSIVE-CARE-UNIT; INTERNATIONAL MULTICENTER COHORT; HIGH-DENSITY-LIPOPROTEINS; OBESITY PARADOX; CRITICALLY-ILL; DIFFICULT INTUBATION; RETROSPECTIVE COHORT; HEIGHT ESTIMATION; ADIPOSE-TISSUE; DEFINITIONS AB Background: At least 25 % of adults admitted to intensive care units (ICU) in the United States have an overweight, obese or morbidly obese body mass index (BMI). The effect of BMI on adjusted mortality in adults requiring ICU treatment for sepsis is unclear. We performed a systematic review of adjusted all-cause mortality for underweight, overweight, obese and morbidly obese BMIs relative to normal BMI for adults admitted to the ICU with sepsis, severe sepsis, and septic shock. Method: PubMed, the Cochrane Library, and EMBASE electronic databases were searched through November 18, 2015, without language restrictions. We included studies that reported multivariate regression analyses for all-cause mortality using standard BMI categories for adults admitted to the ICU for sepsis, severe sepsis, and septic shock. Articles were selected by consensus among multiple reviewers. Electronic database searches yielded 10,312 articles, of which six were eligible. Data were extracted by one reviewer and then reviewed by three independent reviewers. For the meta-analyses performed, the adjusted odds ratios (aOR) of mortality were combined using a random-effects model. Risk of bias was assessed using the Newcastle Ottawa quality assessment scale for cohort studies. Results: Four retrospective (n = 6609 patients) and two prospective (n = 556) studies met inclusion criteria. Compared to normal BMI, across five studies each, overweight or obese BMIs reduced the adjusted odds ratio (95 % CI) of mortality [aOR] [0.83 (0.75, 0.91) p < 0.001 and 0.82 (0.67, 0.99) p = 0.04, respectively] with low or moderate heterogeneity (I-2 = 15.7 %, p = 0.31 and I-2 = 53.0 %, p = 0.07, respectively). Across three studies each, morbidly obese BMI and underweight BMI did not alter aOR [0.90 (0.59, 1.39), p = 0.64; I-2 = 43.3 %, p = 0.17; and 1.24 (0.79, 1.95), p = 0.35; I-2 = 15.6 %, p = 0.31 respectively]. Only one study clearly defined how and when height and weight measurements were calculated. Site of underlying infection and illness severity may have favored overweight and obese BMIs. Conclusions: This is the first meta-analysis to show that overweight or obese BMIs reduce adjusted mortality in adults admitted to the ICU with sepsis, severe sepsis, or septic shock. More rigorous studies that address these limitations are needed to clarify the impact of BMI on sepsis ICU outcomes. C1 [Pepper, Dominique J.; Sun, Junfeng; Cui, Xizhong; Suffredini, Anthony F.; Eichacker, Peter Q.] NIH, Dept Crit Care Med, Ctr Clin, Clin Ctr Bldg 10,Room 2C145,10 Ctr Dr, Bethesda, MD 20892 USA. [Welsh, Judith] NIH, Natl Inst Hlth Lib, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Pepper, DJ (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Clin Ctr Bldg 10,Room 2C145,10 Ctr Dr, Bethesda, MD 20892 USA. EM dominique.pepper@nih.gov FU National Institutes of Health Clinical Center FX The National Institutes of Health Clinical Center supported this work. NR 62 TC 2 Z9 2 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1466-609X EI 1364-8535 J9 CRIT CARE JI Crit. Care PD JUN 15 PY 2016 VL 20 AR 181 DI 10.1186/s13054-016-1360-z PG 10 WC Critical Care Medicine SC General & Internal Medicine GA DP5VX UT WOS:000378567400001 PM 27306751 ER PT J AU Marzahn, MR Marada, S Lee, J Nourse, A Kenrick, S Zhao, HY Ben-Nissan, G Kolaitis, RM Peters, JL Pounds, S Errington, WJ Prive, GG Taylor, JP Sharon, M Schuck, P Ogden, SK Mittag, T AF Marzahn, Melissa R. Marada, Suresh Lee, Jihun Nourse, Amanda Kenrick, Sophia Zhao, Huaying Ben-Nissan, Gili Kolaitis, Regina-Maria Peters, Jennifer L. Pounds, Stanley Errington, Wesley J. Prive, Gilbert G. Taylor, J. Paul Sharon, Michal Schuck, Peter Ogden, Stacey K. Mittag, Tanja TI Higher-order oligomerization promotes localization of SPOP to liquid nuclear speckles SO EMBO JOURNAL LA English DT Article DE isodesmic self-association; membrane-less organelle; prostate cancer; speckle-type POZ protein; ubiquitin ligase ID STATIC LIGHT-SCATTERING; UBIQUITIN LIGASE COMPLEX; PROTEIN SELF-ASSOCIATION; PROSTATE-CANCER; QUANTITATIVE CHARACTERIZATION; SEDIMENTATION-VELOCITY; ENDOPLASMIC-RETICULUM; PHASE-TRANSITIONS; UNFOLDED PROTEIN; EQUILIBRIUM AB Membrane-less organelles in cells are large, dynamic protein/protein or protein/RNA assemblies that have been reported in some cases to have liquid droplet properties. However, the molecular interactions underlying the recruitment of components are not well understood. Herein, we study how the ability to form higher-order assemblies influences the recruitment of the speckle-type POZ protein (SPOP) to nuclear speckles. SPOP, a cullin-3-RING ubiquitin ligase (CRL3) substrate adaptor, self-associates into higher-order oligomers; that is, the number of monomers in an oligomer is broadly distributed and can be large. While wild-type SPOP localizes to liquid nuclear speckles, self-association-deficient SPOP mutants have a diffuse distribution in the nucleus. SPOP oligomerizes through its BTB and BACK domains. We show that BTB-mediated SPOP dimers form linear oligomers via BACK domain dimerization, and we determine the concentration-dependent populations of the resulting oligomeric species. Higher-order oligomerization of SPOP stimulates CRL3(SPOP) ubiquitination efficiency for its physiological substrate Gli3, suggesting that nuclear speckles are hotspots of ubiquitination. Dynamic, higher-order protein self-association may be a general mechanism to concentrate functional components in membrane-less cellular bodies. C1 [Marzahn, Melissa R.; Lee, Jihun; Mittag, Tanja] St Jude Childrens Res Hosp, Dept Biol Struct, 332 N Lauderdale St, Memphis, TN 38105 USA. [Marada, Suresh; Kolaitis, Regina-Maria; Ogden, Stacey K.] St Jude Childrens Res Hosp, Dept Cell & Mol Biol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Nourse, Amanda] St Jude Childrens Res Hosp, Mol Interact Anal Shared Resource, 332 N Lauderdale St, Memphis, TN 38105 USA. [Kenrick, Sophia] Wyatt Technol Corp, Santa Barbara, CA USA. [Zhao, Huaying; Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. [Ben-Nissan, Gili; Sharon, Michal] Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. [Peters, Jennifer L.] St Jude Childrens Res Hosp, Dept Cellular Imaging Shared Resource, 332 N Lauderdale St, Memphis, TN 38105 USA. [Pounds, Stanley] St Jude Childrens Res Hosp, Dept Biostat, 332 N Lauderdale St, Memphis, TN 38105 USA. [Errington, Wesley J.; Prive, Gilbert G.] Univ Toronto, Dept Biochem, Toronto, ON, Canada. [Prive, Gilbert G.] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Taylor, J. Paul] St Jude Childrens Res Hosp, Howard Hughes Med Inst, Dept Cell & Mol Biol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Errington, Wesley J.] Univ Minnesota, Dept Biomed Engn, Minneapolis, MN USA. RP Mittag, T (reprint author), St Jude Childrens Res Hosp, Dept Biol Struct, 332 N Lauderdale St, Memphis, TN 38105 USA.; Ogden, SK (reprint author), St Jude Childrens Res Hosp, Dept Cell & Mol Biol, 332 N Lauderdale St, Memphis, TN 38105 USA. EM stacey.ogden@stjude.org; tanja.mittag@stjude.org OI Sharon, Michal/0000-0003-3933-0595 FU V Foundation Scholar Grant [R01GM112846, R01GM101087]; National Cancer Institute Cancer Center Support Grant (St. Jude Children's Research Hospital) [P30CA21765]; American Lebanese Syrian Associated Charities; Intramural Program of the National Institute of Biomedical Imaging and Bioengineering FX We thank BA Schulman, WK Pierce, EW Martin, and CR Grace for valuable discussions and N Clark for preliminary data collection. We also thank H Haecker (St. Jude Children's Research Hospital). This work was funded by a V Foundation Scholar Grant (T.M.), R01GM112846 (T.M.), R01GM101087 (S.K.O.), the National Cancer Institute Cancer Center Support Grant P30CA21765 (at St. Jude Children's Research Hospital), the American Lebanese Syrian Associated Charities (to J.P.T., S.K.O., and T.M.), and the Intramural Program of the National Institute of Biomedical Imaging and Bioengineering (P.S.). Microscopy images were acquired at the Cell & Tissue Imaging Center at St. Jude Children's Research Hospital. NR 73 TC 1 Z9 1 U1 8 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD JUN 15 PY 2016 VL 35 IS 12 BP 1254 EP 1275 DI 10.15252/embj.201593169 PG 22 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DQ0ZC UT WOS:000378929300002 PM 27220849 ER PT J AU Espana, RA Schmeichel, BE Berridge, CW AF Espana, Rodrigo A. Schmeichel, Brooke E. Berridge, Craig W. TI Norepinephrine at the nexus of arousal, motivation and relapse SO BRAIN RESEARCH LA English DT Review DE Stimulants; Addiction; Amphetamine; Catecholamines; Noradrenergic; Locus coeruleus ID DOPAMINE-BETA-HYDROXYLASE; COCAINE-INDUCED REINSTATEMENT; STRESS-INDUCED REINSTATEMENT; MEDIAL PREOPTIC AREA; CORTICOTROPIN-RELEASING-FACTOR; CONDITIONED PLACE PREFERENCE; LOCUS-COERULEUS NEURONS; WAKE-PROMOTING ACTIONS; POSITIVE REINFORCING PROPERTIES; HALOTHANE-ANESTHETIZED RAT AB Arousal plays a critical role in cognitive, affective and motivational processes. Consistent with this, the dysregulation of arousal-related neural systems is implicated in a variety of psychiatric disorders, including addiction. Noradrenergic systems exert potent arousal enhancing actions that involve signaling at alpha(1)- and (beta-noradrenergic receptors within a distributed network of subcortical regions. The majority of research into noradrenergic modulation of arousal has focused on the nucleus locus coeruleus. Nevertheless, anatomical studies demonstrate that multiple noradrenergic nuclei innervate subcortical arousal-related regions, providing a substrate for differential regulation of arousal across these distinct noradrenergic nuclei. The arousal-promoting actions of psychostimulants and other drugs of abuse contribute to their widespread abuse. Moreover, relapse can be triggered by a variety of arousal-promoting events, including stress and re-exposure to drugs of abuse. Evidence has long-indicated that norepinephrine plays an important role in relapse. Recent observations suggest that noradrenergic signaling elicits affectively-neutral arousal that is sufficient to reinstate drug seeking. Collectively, these observations indicate that norepinephrine plays a key role in the interaction between arousal, motivation, and relapse. This article is part of a Special Issue entitled SI: Noradrenergic System. (C) 2016 Elsevier B.V. All rights reserved. C1 [Espana, Rodrigo A.] Drexel Univ, Coll Med, Dept Neurobiol & Anat, Philadelphia, PA 19104 USA. [Schmeichel, Brooke E.] NIDA, Intramural Res Program, Baltimore, MD USA. [Berridge, Craig W.] Univ Wisconsin, Dept Psychol, 1202 W Johnson St, Madison, WI 53706 USA. RP Espana, RA (reprint author), Drexel Univ, Coll Med, Dept Neurobiol & Anat, Philadelphia, PA 19104 USA. EM respana@drexelmed.edu; brooke.schmeichel@nih.gov; berridge@wisc.edu FU PHS [DA10681, DA00389, MH081843, DA031900]; University of Wisconsin Graduate School; National Institute on Drug Abuse FX This work was supported by PHS grants DA10681, DA00389, MH081843, DA031900, the University of Wisconsin Graduate School, and the National Institute on Drug Abuse, Intramural Research Program. The authors declare no conflict of interest. NR 106 TC 2 Z9 2 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD JUN 15 PY 2016 VL 1641 SI SI BP 207 EP 216 DI 10.1016/j.brainres.2016.01.002 PN B PG 10 WC Neurosciences SC Neurosciences & Neurology GA DP4ED UT WOS:000378448100006 PM 26773688 ER PT J AU Robertson, SD Plummer, NW Jensen, P AF Robertson, Sabrina D. Plummer, Nicholas W. Jensen, Patricia TI Uncovering diversity in the development of central noradrenergic neurons and their efferents SO BRAIN RESEARCH LA English DT Article DE Norepinephrine; Hoxb1; Fate map; Recombinase-based intersectional; genetic fate mapping; Efferents; Rhombomere ID ACID RESPONSE ELEMENT; HOXA2 MUTANT MICE; HINDBRAIN; SYSTEM; PROJECTIONS; EXPRESSION; HOXB-1; NOREPINEPHRINE; ORGANIZATION; CEREBELLUM AB Uncovering the mechanisms that underlie central noradrenergic neuron heterogeneity is essential to understanding selective subtype vulnerability to disease and environmental insult. Using recombinase-based intersectional genetic fate mapping we have previously demonstrated that molecularly distinct progenitor populations give rise to mature noradrenergic neurons differing in their anatomical location, axon morphology and efferent projection pattern. Here we review the findings from our previous study and extend our analysis of the noradrenergic subpopulation defined by transient developmental expression of Hoxb1. Using a combination of intersectional genetic fate mapping and analysis of a targeted loss of function mutation in Hoxb1, we have now uncovered additional heterogeneity based on the requirement of some noradrenergic neurons for Hoxb1 expression. By comparing the distribution of noradrenergic neurons derived from the Hoxb1 expression domain in wild-type and mutant mice, we demonstrate that Hoxb1 expression is required by a subset of neurons in the pons. Additional fate mapping, using a Hoxb1 enhancer element that drives Cre recombinase expression exclusively in rhombomere 4 of the hindbrain, reveals the existence of a subpopulation of noradrenergic neurons in the pons with more restricted axonal targets than the full Hoxb1-derived subpopulation. The unique projection profile of this newly defined subpopulation suggests that it may be functionally distinct. These analyses shed new light on the molecular determinants of noradrenergic identity in the pons and the overall complexity of the central noradrenergic system. This article is part of a Special Issue entitled SI: Noradrenergic System. Published by Elsevier B.V. C1 [Plummer, Nicholas W.; Jensen, Patricia] NIEHS, Neurobiol Lab, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Robertson, Sabrina D.] N Carolina State Univ, Biotechnol Program, Dept Mol & Biomed Sci, Raleigh, NC 27695 USA. RP Jensen, P (reprint author), NIEHS, Neurobiol Lab, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM Patricia.jensen@nih.gov OI Robertson, Sabrina/0000-0003-4598-6929 FU NIH, National Institute of Environmental Health Sciences [ZIA-ES-102805] FX We thank Dr. S. Dymecki for RC::FrePe mice. We thank T. Wolfgang, G. Keeley and NIEHS Fluorescence Microscopy, Vivarium, Knockout Mice, and Statistics services for assistance. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ZIA-ES-102805). NR 29 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD JUN 15 PY 2016 VL 1641 SI SI BP 234 EP 244 DI 10.1016/j.brainres.2015.11.023 PN B PG 11 WC Neurosciences SC Neurosciences & Neurology GA DP4ED UT WOS:000378448100008 PM 26612521 ER PT J AU Mejias-Aponte, CA AF Mejias-Aponte, Carlos A. TI Specificity and impact of adrenergic projections to the midbrain dopamine system SO BRAIN RESEARCH LA English DT Review DE Norepinephrine; Dopamine; Anatomy; Physiology; Addiction; Prefrontal cortex ID VENTRAL TEGMENTAL AREA; FREELY MOVING RATS; RECEPTOR MESSENGER-RNA; CURRENT I-H; PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS; EXTRACELLULAR DOPAMINE; LOCUS-COERULEUS; BETA-HYDROXYLASE; SUBSTANTIA-NIGRA AB Dopamine (DA) is a neuromodulator that regulates different brain circuits involved in cognitive functions, motor coordination, and emotions. Dysregulation of DA is associated with many neurological and psychiatric disorders such as Parkinson's disease and substance abuse. Several lines of research have shown that the midbrain DA system is regulated by the central adrenergic system. This review focuses on adrenergic interactions with midbrain DA neurons. It discusses the current neuroanatomy including source of adrenergic innervation, type of synapses, and adrenoceptors expression. It also discusses adrenergic regulation of DA cell activity and neurotransmitter release. Finally, it reviews several neurological and psychiatric disorders where changes in adrenergic system are associated with dysregulation of the midbrain DA system. This article is part of a Special Issue entitled SI: Noradrenergic System. (C) 2016 Elsevier B.V. All rights reserved. C1 [Mejias-Aponte, Carlos A.] NIDA, Histol Core, Neuronal Networks Sect, Integrat Neurosci Res Branch,Biomed Res Ctr, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. RP Mejias-Aponte, CA (reprint author), NIDA, Histol Core, Neuronal Networks Sect, Integrat Neurosci Res Branch,Biomed Res Ctr, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM mejiasca@mail.nih.gov FU National Institute on Drug Abuse FX Research is supported by the National Institute on Drug Abuse Intramural Research Program. My gratitude goes to Vadim Kashtelyan, Gustavo Mejias-Torres and David Barker for proofreading the manuscript and providing edits to improve its readability. NR 152 TC 1 Z9 1 U1 10 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD JUN 15 PY 2016 VL 1641 SI SI BP 258 EP 273 DI 10.1016/j.brainres.2016.01.036 PN B PG 16 WC Neurosciences SC Neurosciences & Neurology GA DP4ED UT WOS:000378448100010 PM 26820641 ER PT J AU Citrin, DE AF Citrin, Deborah E. TI Short-Term Screening Assays for the Identification of Therapeutics for Cancer SO CANCER RESEARCH LA English DT Editorial Material ID HELA CELLS; INHIBITOR; INVITRO C1 [Citrin, Deborah E.] NIH, Radiat Oncol Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. RP Citrin, DE (reprint author), NCI, Bldg 10,Hatfield CRC,B2-3500, Bethesda, MD 20892 USA. EM citrind@mail.nih.gov NR 13 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2016 VL 76 IS 12 BP 3443 EP 3445 DI 10.1158/0008-5472.CAN-16-1299 PG 3 WC Oncology SC Oncology GA DO8VN UT WOS:000378063200002 PM 27306870 ER PT J AU Basiorka, AA McGraw, KL De Ceuninck, L Griner, LN Zhang, L Clark, JA Caceres, G Sokol, L Komrokji, RS Reuther, GW Wei, S Tavernier, J List, AF AF Basiorka, Ashley A. McGraw, Kathy L. De Ceuninck, Leentje Griner, Lori N. Zhang, Ling Clark, Justine A. Caceres, Gisela Sokol, Lubomir Komrokji, Rami S. Reuther, Gary W. Wei, Sheng Tavernier, Jan List, Alan F. TI Lenalidomide Stabilizes the Erythropoietin Receptor by Inhibiting the E3 Ubiquitin Ligase RNF41 SO CANCER RESEARCH LA English DT Article ID MYELODYSPLASTIC SYNDROMES; THALIDOMIDE TERATOGENICITY; CELLS; DEGRADATION; CYTOKINE; DIFFERENTIATION AB In a subset of patients with non-del(5q) myelodysplastic syndrome (MDS), lenalidomide promotes erythroid lineage competence and effective erythropoiesis. To determine the mechanism by which lenalidomide promotes erythropoiesis, we investigated its action on erythropoietin receptor (EpoR) cellular dynamics. Lenalidomide upregulated expression and stability of JAK2-associated EpoR in UT7 erythroid cells and primary CD71+ erythroid progenitors. The effects of lenalidomide on receptor turnover were Type I cytokine receptor specific, as evidenced by coregulation of the IL3-R alpha receptor but not c-Kit. To elucidate this mechanism, we investigated the effects of lenalidomide on the E3 ubiquitin ligase RNF41. Lenalidomide promoted EpoR/RNF41 association and inhibited RNF41 auto-ubiquitination, accompanied by a reduction in EpoR ubiquitination. To confirm that RNF41 is the principal target responsible for EpoR stabilization, HEK293T cells were transfected with EpoR and/or RNF41 gene expression vectors. Steady-state EpoR expression was reduced in EpoR/RNF41 cells, whereas EpoR upregulation by lenalidomide was abrogated, indicating that cellular RNF41 is a critical determinant of drug-induced receptor modulation. Notably, shRNA suppression of CRBN gene expression failed to alter EpoR upregulation, indicating that drug-induced receptor modulation is independent of cereblon. Immunohistochemical staining showed that RNF41 expression decreased in primary erythroid cells of lenalidomide-responding patients, suggesting that cellular RNF41 expression merits investigation as a biomarker for lenalidomide response. Our findings indicate that lenalidomide has E3 ubiquitin ligase inhibitory effects that extend to RNF41 and that inhibition of RNF41 auto-ubiquitination promotes membrane accumulation of signaling competent JAK2/EpoR complexes that augment Epo responsiveness. (C) 2016 AACR. C1 [Basiorka, Ashley A.; McGraw, Kathy L.; Clark, Justine A.; Sokol, Lubomir; Komrokji, Rami S.; List, Alan F.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Malignant Hematol, Tampa, FL 33682 USA. [Basiorka, Ashley A.] Univ S Florida, Canc Biol PhD Program, Tampa, FL USA. [De Ceuninck, Leentje; Tavernier, Jan] Univ Ghent, VIB Dept Med Prot Res, Ghent, Belgium. [Griner, Lori N.] NICHHD, NIH, Bethesda, MD 20892 USA. [Zhang, Ling] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Hematopathol, Tampa, FL 33682 USA. [Caceres, Gisela] Univ S Florida, H Lee Moffitt Canc Ctr, Morsani Mol Diagnost Lab, Tampa, FL 33682 USA. [Reuther, Gary W.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Mol Oncol, Tampa, FL 33682 USA. [Wei, Sheng] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Immunol, Tampa, FL 33682 USA. RP List, AF (reprint author), SRB CEO, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM Alan.List@Moffitt.org FU National Cancer Institute/NIH [5 R01 CA131076-04]; Belgian government [IUAP P6/36]; Group-ID Multidisciplinary Research Partnership of Ghent University; ERC Advanced Grant [340941] FX Support for this work was provided by the National Cancer Institute/NIH (5 R01 CA131076-04) and by grants from the Belgian government (IUAP P6/36) and the Group-ID Multidisciplinary Research Partnership of Ghent University. J. Tavernier holds an ERC Advanced Grant (No 340941). NR 30 TC 2 Z9 2 U1 5 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2016 VL 76 IS 12 BP 3531 EP 3540 DI 10.1158/0008-5472.CAN-15-1756 PG 10 WC Oncology SC Oncology GA DO8VN UT WOS:000378063200011 PM 27197154 ER PT J AU Zhou, BY Wang, L Zhang, S Bennett, BD He, F Zhang, Y Xiong, CL Han, L Diao, LX Li, PS Fargo, DC Cox, AD Hu, G AF Zhou, Bingying Wang, Li Zhang, Shu Bennett, Brian D. He, Fan Zhang, Yan Xiong, Chengliang Han, Leng Diao, Lixia Li, Pishun Fargo, David C. Cox, Adrienne D. Hu, Guang TI INO80 governs superenhancer-mediated oncogenic transcription and tumor growth in melanoma SO GENES & DEVELOPMENT LA English DT Article DE INO80; chromatin remodeler; oncogenic transcription; superenhancer ID SUPER-ENHANCERS; REGULATORY REGIONS; CELL IDENTITY; CHROMATIN; CANCER; MUTATIONS; LANDSCAPE; DIFFERENTIATION; EPIGENETICS; INHIBITION AB Superenhancers (SEs) are large genomic regions with a high density of enhancer marks. In cancer, SEs are found near oncogenes and dictate cancer gene expression. However, how oncogenic SEs are regulated remains poorly understood. Here, we show that INO80, achromatin remodeling complex, is required for SE-mediated oncogenic transcription and tumor growth in melanoma. The expression of Ino80, the SWI/SNFATPase, is elevated in melanoma cells and patient melanomas compared with normal melanocytes and benign nevi. Furthermore, Ino80 silencing selectively inhibits melanoma cell proliferation, anchorage-independent growth, tumorigenesis, and tumor maintenance in mouse xenografts. Mechanistically, Ino80 occupies >90% of SEs, and its occupancy is dependent on transcription factors such as MITF and Sox9. Ino80 binding reduces nucleosome occupancy and facilitates Mediator recruitment, thus promoting oncogenic transcription. Consistently, genes co-occupied by Ino80 and Med1 are selectively expressed in melanomas compared with melanocytes. Together, our results reveal an essential role of INO80-dependent chromatin remodeling in SE function and suggest a novel strategy for disrupting SEs in cancer treatment. C1 [Zhou, Bingying; Wang, Li] Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing 100037, Peoples R China. [Zhou, Bingying; Wang, Li] Peking Union Med Coll, Beijing 100037, Peoples R China. [Zhou, Bingying; Cox, Adrienne D.] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Zhou, Bingying; Cox, Adrienne D.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Wang, Li; Li, Pishun; Hu, Guang] NIEHS, Epigenet & Stem Cell Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. [Zhang, Shu] Chinese Peoples Liberat Army Gen Hosp, Dept Pulm & Crit Care Med, Beijing 100853, Peoples R China. [Bennett, Brian D.; Fargo, David C.] NIEHS, Integrat Bioinformat, POB 12233, Res Triangle Pk, NC 27709 USA. [He, Fan] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Nephrol, Wuhan 430030, Hubei, Peoples R China. [Zhang, Yan; Xiong, Chengliang] Huazhong Univ Sci & Technol, Tongji Med Coll, Ctr Reprod Med, Family Planning Res Inst, Wuhan 430030, Hubei, Peoples R China. [Han, Leng] Univ Texas Hlth Sci Ctr Houston, Dept Biochem & Mol Biol, McGovern Med Sch, Houston, TX 77030 USA. [Diao, Lixia] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Cox, Adrienne D.] Univ N Carolina, Dept Radiat Oncol, Chapel Hill, NC 27599 USA. RP Wang, L (reprint author), Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing 100037, Peoples R China.; Wang, L (reprint author), Peking Union Med Coll, Beijing 100037, Peoples R China.; Cox, AD (reprint author), Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA.; Cox, AD (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA.; Wang, L; Hu, G (reprint author), NIEHS, Epigenet & Stem Cell Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA.; Cox, AD (reprint author), Univ N Carolina, Dept Radiat Oncol, Chapel Hill, NC 27599 USA. EM wangl@pumc.edu.cn; adrienne_cox@med.unc.edu; hug4@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health, the National Institute of Environmental Health Sciences [Z01ES102745]; National Institutes of Health [CA042978, CA161494] FX We thank the Epigenomics core facility at National Institute of Environmental Health Sciences for providing the Illumina sequencing services. This study was supported in part by the Intramural Research Program of the National Institutes of Health, the National Institute of Environmental Health Sciences (Z01ES102745 to G.H.) and National Institutes of Health grants CA042978 and CA161494 (to A.D.C.). B.Z., L.W., A.D.C., and G.H. designed the experiments. B.Z. and L.W. carried out the experiments in melanoma cell lines. L.W. and S.Z. carried out animal experiments. F.H., Y.Z., and C.X. carried out experiments in patient samples. L.W. and P.L. carried out genomic experiments. B.B., D.F., L.H., and L.D. carried out bioinformatics analysis. B.Z., L.W., A.D.C., and G.H. interpreted the data and wrote the manuscript. NR 41 TC 1 Z9 1 U1 6 U2 11 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD JUN 15 PY 2016 VL 30 IS 12 BP 1440 EP 1453 DI 10.1101/gad.277178.115 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA DP5JV UT WOS:000378533000007 PM 27340176 ER PT J AU Chao, FA Byrd, RA AF Chao, Fa-An Byrd, R. Andrew TI Geometric Approximation: A New Computational Approach To Characterize Protein Dynamics from NMR Adiabatic Relaxation Dispersion Experiments SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; CONFORMATIONAL DYNAMICS; R-1-RHO RELAXATION; FAST-EXCHANGE; UBIQUITINATION; ACTIVATION; RECOGNITION; CATALYSIS; MOTIONS; PULSES AB A new computational strategy is reported that provides a fast approximation of numerical solutions of differential equations in general. The method is demonstrated with the analysis of NMR adiabatic relaxation dispersion experiments to reveal biomolecular dynamics. When an analytical solution to the theoretical equations describing a physical process is not available, the new approach can significantly accelerate the computational speed of the conventional numerical integration up to 10(5) times. NMR adiabatic relaxation dispersion experiments enhanced with optimized proton-decoupled pulse sequences, although extremely powerful, have previously been refractory to quantitative analysis. Both simulations and experimental validation demonstrate detectable "slow" (microsecond to millisecond) conformational exchange rates from 10(2) to 10(5) s(-1). This greatly expanded time-scale range enables the characterization of a wide array of conformational fluctuations for individual residues, which correlate with biomolecular function and were previously inaccessible. Moreover, the new computational method can be potentially generalized for analysis of new types of relaxation dispersion experiments to characterize the various dynamics of biomolecular systems. C1 [Chao, Fa-An; Byrd, R. Andrew] NCI, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Chao, FA; Byrd, RA (reprint author), NCI, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM fa-an.chao@nih.gov; byrdra@mail.nih.gov OI Byrd, R. Andrew/0000-0003-3625-4232 FU Intramural Research Program of the National Cancer Institute FX This work was supported by the Intramural Research Program of the National Cancer Institute. We thank Prof. Gianluigi Veglia and Dr. Youlin Xia (University of Minnesota) for providing the original sequences of the adiabatic spin-lock experiments, Prof. Nathaniel J. Traaseth (New York University) for inspirational discussions, and Dr. Michelle L. Gill for technical support and discussions. The biological samples were provided by Ms. Jess Li. NR 34 TC 2 Z9 2 U1 5 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUN 15 PY 2016 VL 138 IS 23 BP 7337 EP 7345 DI 10.1021/jacs.6b02786 PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA DP0QC UT WOS:000378193300025 PM 27225523 ER PT J AU Singleton, A Hardy, J AF Singleton, Andrew Hardy, John TI The Evolution of Genetics: Alzheimer's and Parkinson's Diseases SO NEURON LA English DT Review ID GENOME-WIDE ASSOCIATION; COMMON VARIANTS; RISK LOCI; IDENTIFIES VARIANTS; MISSENSE MUTATIONS; SEQUENCE VARIANTS; SUSCEPTIBILITY; METAANALYSIS; PATHWAY; COMPLEX AB Genetic discoveries underlie the majority of the current thinking in neurodegenerative disease. This work has been driven by the significant gains made in identifying causal mutations; however, the translation of genetic causes of disease into pathobiological understanding remains a challenge. The application of a second generation of genetics methods allows the dissection of moderate and mild genetic risk factors for disease. This requires new thinking in two key areas: what constitutes proof of pathogenicity, and how do we translate these findings to biological understanding. Here we describe the progress and ongoing evolution in genetics. We describe a view that rejects the tradition that genetic proof has to be absolute before functional characterization and centers on a multi-dimensional approach integrating genetics, reference data, and functional work. We also argue that these challenges cannot be efficiently met by traditional hypothesis-driven methods but that high content system-wide efforts are required. C1 [Singleton, Andrew; Hardy, John] NIA, Lab Neurogenet, Bethesda, MD 20892 USA. RP Singleton, A (reprint author), NIA, Lab Neurogenet, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services [ZO1 AG000949] FX This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project ZO1 AG000949. NR 62 TC 5 Z9 5 U1 22 U2 40 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD JUN 15 PY 2016 VL 90 IS 6 BP 1154 EP 1163 DI 10.1016/j.neuron.2016.05.040 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DP5HT UT WOS:000378527600006 PM 27311081 ER PT J AU Gremel, CM Chancey, JH Atwood, BK Luo, GX Neve, R Ramakrishnan, C Deisseroth, K Lovinger, DM Costa, RM AF Gremel, Christina M. Chancey, Jessica H. Atwood, Brady K. Luo, Guoxiang Neve, Rachael Ramakrishnan, Charu Deisseroth, Karl Lovinger, David M. Costa, Rui M. TI Endocannabinoid Modulation of Orbitostriatal Circuits Gates Habit Formation SO NEURON LA English DT Article ID OBSESSIVE-COMPULSIVE DISORDER; GOAL-DIRECTED BEHAVIOR; ORBITOFRONTAL CORTEX; DORSAL STRIATUM; DORSOLATERAL STRIATUM; PREFRONTAL CORTEX; REINFORCER DEVALUATION; CANNABINOID RECEPTORS; DORSOMEDIAL STRIATUM; SYNAPTIC MODULATION AB Everyday function demands efficient and flexible decision-making that allows for habitual and goal-directed action control. An inability to shift has been implicated in disorders with impaired decision-making, including obsessive-compulsive disorder and addiction. Despite this, our understanding of the specific molecular mechanisms and circuitry involved in shifting action control remains limited. Here we identify an endogenous molecular mechanism in a specific cortical-striatal pathway that mediates the transition between goal-directed and habitual action strategies. Deletion of cannabinoid type 1 (CB1) receptors from cortical projections originating in the orbital frontal cortex (OFC) prevents mice from shifting from goal-directed to habitual instrumental lever pressing. Activity of OFC neurons projecting to dorsal striatum (OFC-DS) and, specifically, activity of OFC-DS terminals is necessary for goal-directed action control. Lastly, CB1 deletion from OFC-DS neurons prevents the shift from goal-directed to habitual action control. These data suggest that the emergence of habits depends on endocannabinoid-mediated attenuation of a competing circuit controlling goal-directed behaviors. C1 [Gremel, Christina M.; Chancey, Jessica H.; Atwood, Brady K.; Luo, Guoxiang; Lovinger, David M.] NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. [Gremel, Christina M.] Univ Calif San Diego, Dept Psychol, Neurosci Grad Program, La Jolla, CA 92093 USA. [Neve, Rachael] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. [Ramakrishnan, Charu; Deisseroth, Karl] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. [Costa, Rui M.] Champalimaud Inst Unknown, Champalimaud Neurosci Programme, P-1400038 Lisbon, Portugal. RP Lovinger, DM (reprint author), NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA.; Costa, RM (reprint author), Champalimaud Inst Unknown, Champalimaud Neurosci Programme, P-1400038 Lisbon, Portugal. EM lovindav@mail.nih.gov; rui.costa@neuro.fchampalimaud.org FU NIAAA Division of Intramural Clinical and Biological Research, ERA-NET; European Research Council [COG 617142]; HHMI [IEC 55007415]; Pathway to Independence Award [R00 AA021780]; NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation FX We thank Matthew Pava for assistance in the electrophysiological experiments and Emily Baltz for assistance with intracranial surgeries. We thank Drs. Beat Lutz and Giovanni Marsicano for providing the Cnr1loxP/loxP mice. The DREADD virus was provided by the Gene Therapy and Vector Core at the University of North Carolina. This research was supported by the NIAAA Division of Intramural Clinical and Biological Research, ERA-NET; European Research Council (COG 617142) and HHMI (IEC 55007415) grants to R.M.C.; and Pathway to Independence Award R00 AA021780 and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation to C.M.G. NR 56 TC 4 Z9 4 U1 5 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD JUN 15 PY 2016 VL 90 IS 6 BP 1312 EP 1324 DI 10.1016/j.neuron.2016.04.043 PG 13 WC Neurosciences SC Neurosciences & Neurology GA DP5HT UT WOS:000378527600018 PM 27238866 ER PT J AU Grimaldi, P Saleem, KS Tsao, D AF Grimaldi, Piercesare Saleem, Kadharbatcha S. Tsao, Doris TI Anatomical Connections of the Functionally Defined "Face Patches'' in the Macaque Monkey SO NEURON LA English DT Article ID INFERIOR TEMPORAL CORTEX; PRIMATE CEREBRAL-CORTEX; INFEROTEMPORAL AREA TE; CORTICAL CONNECTIONS; PREFRONTAL CORTEX; PROCESSING AREAS; LOBE; NEURONS; REPRESENTATIONS; ORGANIZATION AB The neural circuits underlying face recognition provide a model for understanding visual object representation, social cognition, and hierarchical information processing. A fundamental piece of information lacking to date is the detailed anatomical connections of the face patches. Here, we injected retrograde tracers into four different face patches (PL, ML, AL, AM) to characterize their anatomical connectivity. We found that the patches are strongly and specifically connected to each other, and individual patches receive inputs from extrastriate cortex, the medial temporal lobe, and three subcortical structures (the pulvinar, claustrum, and amygdala). Inputs from prefrontal cortex were surprisingly weak. Patches were densely interconnected to one another in both feedforward and feedback directions, inconsistent with a serial hierarchy. These results provide the first direct anatomical evidence that the face patches constitute a highly specialized system and suggest that subcortical regions may play a vital role in routing face-related information to subsequent processing stages. C1 [Grimaldi, Piercesare; Tsao, Doris] CALTECH, Howard Hughes Med Inst, Div Biol & Biol Engn, Pasadena, CA 91125 USA. [Saleem, Kadharbatcha S.] NIMH, Neuropsychol Lab, Bldg 9, Bethesda, MD 20892 USA. [Saleem, Kadharbatcha S.] NIMH, NIH, Bethesda, MD 20892 USA. [Grimaldi, Piercesare] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Fuster Lab Cognit Neurosci, Los Angeles, CA 90095 USA. RP Grimaldi, P; Tsao, D (reprint author), CALTECH, Howard Hughes Med Inst, Div Biol & Biol Engn, Pasadena, CA 91125 USA.; Grimaldi, P (reprint author), Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Fuster Lab Cognit Neurosci, Los Angeles, CA 90095 USA. EM pcgrimaldi@gmail.com; dortsao@caltech.edu FU Howard Hughes Medical Institute; NIH [1R01EY019702, P50 MH942581A] FX We thank members of the Tsao lab and the three anonymous reviewers for comments on the manuscript; N. Schweers for technical assistance; and S. Ohayon, P. Bao, and S. Moeller for assistance with data analysis. The work was supported by the Howard Hughes Medical Institute and by the NIH (1R01EY019702, P50 MH942581A). NR 64 TC 4 Z9 4 U1 4 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD JUN 15 PY 2016 VL 90 IS 6 BP 1325 EP 1342 DI 10.1016/j.neuron.2016.05.009 PG 18 WC Neurosciences SC Neurosciences & Neurology GA DP5HT UT WOS:000378527600019 PM 27263973 ER PT J AU Walter, KS Pepin, KM Webb, CT Gaff, HD Krause, PJ Pitzer, VE Diuk-Wasser, MA AF Walter, Katharine S. Pepin, Kim M. Webb, Colleen T. Gaff, Holly D. Krause, Peter J. Pitzer, Virginia E. Diuk-Wasser, Maria A. TI Invasion of two tick-borne diseases across New England: harnessing human surveillance data to capture underlying ecological invasion processes SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE invasion; Lyme disease; babesiosis; tick-borne disease; occupancy model ID VECTOR IXODES-SCAPULARIS; EASTERN UNITED-STATES; HUMAN LYME-DISEASE; BORRELIA-BURGDORFERI; HUMAN BABESIOSIS; RANGE EXPANSION; METAPOPULATION DYNAMICS; INFECTIOUS-DISEASE; NANTUCKET-ISLAND; DAMMINI AB Modelling the spatial spread of vector-borne zoonotic pathogens maintained in enzootic transmission cycles remains a major challenge. The best available spatio-temporal data on pathogen spread often take the form of human disease surveillance data. By applying a classic ecological approach-occupancy modelling-to an epidemiological question of disease spread, we used surveillance data to examine the latent ecological invasion of tick-borne pathogens. Over the last half-century, previously undescribed tick-borne pathogens including the agents of Lyme disease and human babesiosis have rapidly spread across the northeast United States. Despite their epidemiological importance, the mechanisms of tick-borne pathogen invasion and drivers underlying the distinct invasion trajectories of the co-vectored pathogens remain unresolved. Our approach allowed us to estimate the unobserved ecological processes underlying pathogen spread while accounting for imperfect detection of human cases. Our model predicts that tick-borne diseases spread in a diffusion-like manner with occasional long-distance dispersal and that babesiosis spread exhibits strong dependence on Lyme disease. C1 [Walter, Katharine S.; Krause, Peter J.; Pitzer, Virginia E.; Diuk-Wasser, Maria A.] Yale Univ, Sch Publ Hlth, Dept Epidemiol Microbial Dis, 60 Coll St, New Haven, CT 06520 USA. [Pepin, Kim M.] US Anim & Plant Hlth Inspect Serv, USDA, Natl Wildlife Res Ctr, 4101 LaPorte Ave, Ft Collins, CO 80521 USA. [Pepin, Kim M.; Webb, Colleen T.; Pitzer, Virginia E.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Webb, Colleen T.] Colorado State Univ, Dept Biol, Ft Collins, CO 80523 USA. [Gaff, Holly D.] Old Dominion Univ, Dept Biol Sci, 302a Mills Godwin Bldg, Norfolk, VA 23529 USA. [Diuk-Wasser, Maria A.] Columbia Univ, Dept Ecol Evolut & Environm Biol, 1200 Amsterdam Ave, New York, NY 10027 USA. RP Walter, KS (reprint author), Yale Univ, Sch Publ Hlth, Dept Epidemiol Microbial Dis, 60 Coll St, New Haven, CT 06520 USA. EM katharine.walter@yale.edu OI Pitzer, Virginia/0000-0003-1015-2289 FU NIH pre-doctoral training grant [5T32AI007404-23]; NIH Ruth L. Kirschstein National Research Service Award [F31 AI118233-01A1]; Research and Policy in Disease Dynamics (RAPIDD) programme, Fogarty International Center, NIH; Department of Homeland Security; USDA-APHIS-WS; RAPIDD; Gordon and Laura Gund Foundation; National Institutes of Health, Ecology and Evolution of Infectious Disease Programme [R01 GM105246] FX K.S.W. was supported by the NIH pre-doctoral training grant 5T32AI007404-23 and the NIH Ruth L. Kirschstein National Research Service Award F31 AI118233-01A1. K.M.P. was partly supported by the Research and Policy in Disease Dynamics (RAPIDD) programme, Fogarty International Center, NIH and Department of Homeland Security and partly by USDA-APHIS-WS. C.T.W. and V.E.P. were funded by RAPIDD. P.J.K. was supported by the Gordon and Laura Gund Foundation. M.D.W. was supported by the National Institutes of Health, Ecology and Evolution of Infectious Disease Programme (R01 GM105246). NR 62 TC 0 Z9 0 U1 10 U2 21 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 EI 1471-2954 J9 P ROY SOC B-BIOL SCI JI Proc. R. Soc. B-Biol. Sci. PD JUN 15 PY 2016 VL 283 IS 1832 AR 20160834 DI 10.1098/rspb.2016.0834 PG 10 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA DP2KZ UT WOS:000378318700023 ER PT J AU Kon, AA Davidson, JE Morrison, W Danis, M White, DB AF Kon, Alexander A. Davidson, Judy E. Morrison, Wynne Danis, Marion White, Douglas B. TI Shared Decision-Making in Intensive Care Units Executive Summary of the American College of Critical Care Medicine and American Thoracic Society Policy Statement SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID INTERNATIONAL CONSENSUS CONFERENCE; INFORMED NON-DISSENT; OF-LIFE CARE; APRIL 2003; ICU; CHALLENGES; DEPRESSION; BRUSSELS; BELGIUM; SUPPORT C1 [Kon, Alexander A.] Naval Med Ctr San Diego, San Diego, CA USA. [Kon, Alexander A.] Univ Calif San Diego, San Diego, CA 92103 USA. [Davidson, Judy E.] Univ Calif Hlth Syst, San Diego, CA USA. [Morrison, Wynne] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Danis, Marion] NIH, Bldg 10, Bethesda, MD 20892 USA. [White, Douglas B.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. RP Kon, AA (reprint author), Naval Med Ctr San Diego, San Diego, CA USA.; Kon, AA (reprint author), Univ Calif San Diego, San Diego, CA 92103 USA. NR 24 TC 2 Z9 2 U1 0 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUN 15 PY 2016 VL 193 IS 12 BP 1334 EP 1336 PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO8FF UT WOS:000378017300008 PM 27097019 ER PT J AU Jang, H Muratcioglu, S Gursoy, A Keskin, O Nussinov, R AF Jang, Hyunbum Muratcioglu, Serena Gursoy, Attila Keskin, Ozlem Nussinov, Ruth TI Membrane-associated Ras dimers are isoform-specific: K-Ras dimers differ from H-Ras dimers SO BIOCHEMICAL JOURNAL LA English DT Article DE HVR; K-Ras4B; nanoclusters; Raf activation; Raf dimerization; Ras interfaces; plasma membrane; signalling ID CONTINUUM ELECTROSTATICS CALCULATIONS; FREE-ENERGY DECOMPOSITION; AMYLOID ION CHANNELS; SMALL GTPASE K-RAS4B; MOLECULAR-DYNAMICS; PLASMA-MEMBRANE; HYPERVARIABLE REGION; PROTEIN INTERACTIONS; FORMS DIMERS; ATOMIC RADII AB Are the dimer structures of active Ras isoforms similar? This question is significant since Ras can activate its effectors as a monomer; however, as a dimer, it promotes Raf's activation and MAPK (mitogen-activated protein kinase) cell signalling. In the present study, we model possible catalytic domain dimer interfaces of membrane-anchored GTP-bound K-Ras4B and H-Ras, and compare their conformations. The active helical dimers formed by the allosteric lobe are isoform-specific: K-Ras4B-GTP favours the alpha 3 and alpha 4 interface; H-Ras-GTP favours alpha 4 and alpha 5. Both isoforms also populate a stable beta-sheet dimer interface formed by the effector lobe; a less stable beta-sandwich interface is sustained by salt bridges of the beta-sheet side chains. Raf's high-affinity beta-sheet interaction is promoted by the active helical interface. Collectively, Ras isoforms' dimer conformations are not uniform; instead, the isoform-specific dimers reflect the favoured interactions of the HVRs (hypervariable regions) with cell membrane microdomains, biasing the effector-binding site orientations, thus isoform binding selectivity. C1 [Jang, Hyunbum; Nussinov, Ruth] NCI, Canc & Inflammat Program, Basic Sci Program, Leidos Biomed Res Inc,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Muratcioglu, Serena; Keskin, Ozlem] Koc Univ, Dept Chem & Biol Engn, Istanbul, Turkey. [Gursoy, Attila] Koc Univ, Dept Comp Engn, Istanbul, Turkey. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Canc & Inflammat Program, Basic Sci Program, Leidos Biomed Res Inc,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA.; Nussinov, R (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. EM NussinoR@helix.nih.gov RI Gursoy, Attila/E-9565-2015 OI Gursoy, Attila/0000-0002-2297-2113 FU Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the National Institutes of Health, Frederick National Laboratory, Center for Cancer Research; Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) (Scientific and Technological Research Council of Turkey) [114M196] FX This project has been funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health [grant number HHSN261200800001E]. This research was supported in part by the Intramural Research Program of the National Institutes of Health, Frederick National Laboratory, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. This work has been partially supported by the Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) (Scientific and Technological Research Council of Turkey) [grant number 114M196]. NR 69 TC 5 Z9 5 U1 5 U2 12 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD JUN 15 PY 2016 VL 473 BP 1719 EP 1732 DI 10.1042/BCJ20160031 PN 12 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DO7WC UT WOS:000377992700006 PM 27057007 ER PT J AU Carlson, KSB Nguyen, L Schwartz, K Lawrence, DA Schwartz, BS AF Carlson, Karen-Sue B. Lan Nguyen Schwartz, Kat Lawrence, Daniel A. Schwartz, Bradford S. TI Neuroserpin Differentiates Between Forms of Tissue Type Plasminogen Activator via pH Dependent Deacylation SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Article DE neuroserpin; tissue plasminogen activator; serpin; serine protease; decacylation ID SERPIN-PROTEINASE COMPLEX; SERINE-PROTEASE INHIBITOR; RECEPTOR-RELATED PROTEIN; RAT HIPPOCAMPAL-NEURONS; LONG-TERM POTENTIATION; D-ASPARTATE RECEPTORS; REACTIVE CENTER LOOP; BLOOD-BRAIN-BARRIER; SINGLE-CHAIN FORM; FOREBRAIN ISCHEMIA AB Tissue-type plasminogen activator (t-PA), initially characterized for its critical role in fibrinolysis, also has key functions in both physiologic and pathologic processes in the CNS. Neuroserpin (NSF) is a t-PA specific serine protease inhibitor (serpin) found almost exclusively in the CNS that regulates t-PA's proteolytic activity and protects against t-PA mediated seizure propagation and blood brain barrier disruption. This report demonstrates that NSP inhibition of t-PA varies profoundly as a function of pH within the biologically relevant pH range for the CNS, and reflects the stability, rather than the formation of NSP: t-PA acyl-enzyme complexes. Moreover, NSP differentiates between the zymogen-like single chain form (single chain t-PA, sct-PA) and the mature protease form (two chain t-PA, tct-PA) of t-PA, demonstrating different pH profiles for protease inhibition, different pH ranges over which catalytic deacylation occurs, and different pH dependent profiles of deacylation rates for each form of t-PA. NSP's pH dependent inhibition of t-PA is not accounted for by differential acylation, and is specific for the NSP-t-PA serpin-protease pair. These results demonstrate a novel mechanism for the differential regulation of the two forms of t-PA in the CNS, and suggest a potential specific regulatory role for CNS pH in controlling t-PA proteolytic activity. C1 [Carlson, Karen-Sue B.; Schwartz, Bradford S.] Univ Wisconsin, Dept Biomol Chem, Madison, WI USA. [Carlson, Karen-Sue B.] Univ Wisconsin, Med Scientist Training Program, Madison, WI USA. [Lan Nguyen; Schwartz, Kat; Schwartz, Bradford S.] Univ Illinois, Dept Biochem, Urbana, IL 61801 USA. [Lan Nguyen; Schwartz, Kat; Schwartz, Bradford S.] Univ Illinois, Dept Med, Urbana, IL 61801 USA. [Lawrence, Daniel A.] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Lawrence, Daniel A.] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. [Carlson, Karen-Sue B.] Med Coll Wisconsin, Dept Internal Med, Milwaukee, WI 53226 USA. [Lan Nguyen] Indiana Univ, Dept Med & Pediat, Indianapolis, IN 46204 USA. [Schwartz, Kat] NIH, Natl Ctr Advancing Translat Sci, Bldg 10, Bethesda, MD 20892 USA. RP Schwartz, BS (reprint author), Univ Wisconsin, Dept Biomol Chem, Madison, WI USA.; Schwartz, BS (reprint author), Univ Illinois, Dept Biochem, Urbana, IL 61801 USA.; Schwartz, BS (reprint author), Univ Illinois, Dept Med, Urbana, IL 61801 USA. EM bschwartz@morgridge.org FU National Institutes of Health [PHS HL-43506, PHS HL055374, NS079639] FX This publication was made possible by National Institutes of Health grants to BS [PHS HL-43506; PHS HL055374] and to DL [PHS HL055374 and NS079639]; and also from the Carle Foundation, Urbana, IL to BS. NR 78 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 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD JUN 15 PY 2016 VL 10 AR 154 DI 10.3389/fncel/2016.00154 PG 11 WC Neurosciences SC Neurosciences & Neurology GA DO7LH UT WOS:000377963600001 PM 27378851 ER PT J AU Vacchio, MS Bosselut, R AF Vacchio, Melanie S. Bosselut, Remy TI What Happens in the Thymus Does Not Stay in the Thymus: How T Cells Recycle the CD4(+)-CD8(+) Lineage Commitment Transcriptional Circuitry To Control Their Function SO JOURNAL OF IMMUNOLOGY LA English DT Review ID INNATE LYMPHOID-CELLS; HELPER TYPE-1 CELLS; FINGER PROTEIN MAZR; CD4 EXPRESSION; NEGATIVE SELECTION; POSITIVE SELECTION; GENE-EXPRESSION; RUNX PROTEINS; THYMOCYTE DIFFERENTIATION; IMMUNODEFICIENCY-VIRUS AB MHC-restricted CD4(+) and CD8(+) T cells are at the core of most adaptive immune responses. Although these cells carry distinct functions, they arise from a common precursor during thymic differentiation, in a developmental sequence that matches CD4 and CD8 expression and functional potential with MHC restriction. Although the transcriptional control of CD4(+)-CD8(+) lineage choice in the thymus is now better understood, less was known about what maintains the CD4(+) and CD8(+) lineage integrity of mature T cells. In this review, we discuss the mechanisms that establish in the thymus, and maintain in postthymic cells, the separation of these lineages. We focus on recent studies that address the mechanisms of epigenetic control of Cd4 expression and emphasize how maintaining a transcriptional circuitry nucleated around Thpok and Runx proteins, the key architects of CD4(+)-CD8(+) lineage commitment in the thymus, is critical for CD4(+) T cell helper functions. C1 [Vacchio, Melanie S.; Bosselut, Remy] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bosselut, R (reprint author), NCI, Lab Immune Cell Biol, NIH, Bldg 37,Room 3032,37 Convent Dr, Bethesda, MD 20892 USA. EM remy@helix.nih.gov FU Intramural Research Program of the National Cancer Institute, Center for Cancer Research FX We thank P. Love and T. Ciucci for useful discussions and J.D. Ashwell, P. Love, and T. Ciucci for reading the manuscript. We apologize to colleagues whose work could not be discussed because of space limitations. Research work in the authors' laboratory is supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research. NR 110 TC 2 Z9 2 U1 5 U2 7 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2016 VL 196 IS 12 BP 4848 EP 4856 DI 10.4049/jimmunol.1600415 PG 9 WC Immunology SC Immunology GA DO7BP UT WOS:000377937500002 PM 27260768 ER PT J AU Martin-Avila, A Medina-Tamayo, J Ibarra-Sanchez, A Vazquez-Victorio, G Castillo-Arellano, JI Hernandez-Mondragon, AC Rivera, J Madera-Salcedo, IK Blank, U Macias-Silva, M Gonzalez-Espinosa, C AF Martin-Avila, Alejandro Medina-Tamayo, Jaciel Ibarra-Sanchez, Alfredo Vazquez-Victorio, Genaro Ivan Castillo-Arellano, Jorge Cristal Hernandez-Mondragon, Alma Rivera, Juan Madera-Salcedo, Iris K. Blank, Ulrich Macias-Silva, Marina Gonzalez-Espinosa, Claudia TI Protein Tyrosine Kinase Fyn Regulates TLR4-Elicited Responses on Mast Cells Controlling the Function of a PP2A-PKC alpha/beta Signaling Node Leading to TNF Secretion SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; PHOSPHATASE 2A; ENDOTOXIN TOLERANCE; CYTOKINE PRODUCTION; GENE-EXPRESSION; INNATE IMMUNITY; LYN KINASE; ACTIVATION; DEGRANULATION; PATHWAYS AB Mast cells produce proinflammatory cytokines in response to TLR4 ligands, but the signaling pathways involved are not fully described. In this study, the participation of the Src family kinase Fyn in the production of TNF after stimulation with LPS was evaluated using bone marrow-derived mast cells from wild-type and Fyn-deficient mice. Fyn(-/-) cells showed higher LPS-induced secretion of preformed and de novo-synthesized TNF. In both cell types, TNF colocalized with vesicle-associated membrane protein (VAMP) 3-positive compartments. Addition of LPS provoked coalescence of VAMP3 and its interaction with synaptosomal-associated protein 23; those events were increased in the absence of Fyn. Higher TNF mRNA levels were also observed in Fyn-deficient cells as a result of increased transcription and greater mRNA stability after LPS treatment. Fyn(-/-) cells also showed higher LPS-induced activation of TAK-1 and ERK1/2, whereas I kappa B kinase and I kappa B were phosphorylated, even in basal conditions. Increased responsiveness in Fyn(-/-) cells was associated with a lower activity of protein phosphatase 2A (PP2A) and augmented activity of protein kinase C (PKC)alpha/beta, which was dissociated from PP2A and increased its association with the adapter protein neuroblast differentiation-associated protein (AHNAK, desmoyokin). LPS-induced PKC alpha/beta activity was associated with VAMP3 coalescence in WT and Fyn-deficient cells. Reconstitution of MC-deficient Wsh mice with Fyn(-/-) MCs produced greater LPS-dependent production of TNF in the peritoneal cavity. Our data show that Fyn kinase is activated after TLR4 triggering and exerts an important negative control on LPS-dependent TNF production in MCs controlling the inactivation of PP2Ac and activation of PKC alpha/beta necessary for the secretion of TNF by VAMP3(+) carriers. C1 [Martin-Avila, Alejandro; Medina-Tamayo, Jaciel; Ibarra-Sanchez, Alfredo; Ivan Castillo-Arellano, Jorge; Cristal Hernandez-Mondragon, Alma; Gonzalez-Espinosa, Claudia] Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Dept Farmacobiol, Calzada Tenorios 235, Mexico City 14330, DF, Mexico. [Vazquez-Victorio, Genaro; Macias-Silva, Marina] Univ Nacl Autonoma Mexico, Dept Biol Celular & Desarrollo, Inst Fisiol Celular, Ciudad Univ, Mexico City 04510, DF, Mexico. [Rivera, Juan] NIAMSD, NIH, Bethesda, MD 20892 USA. [Madera-Salcedo, Iris K.; Blank, Ulrich] Univ Paris Diderot, INSERM, Fac Med, UMRS1149, Site 10, F-75018 Paris, France. RP Gonzalez-Espinosa, C (reprint author), Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Dept Farmacobiol, Calzada Tenorios 235, Mexico City 14330, DF, Mexico. EM cgonzal@cinvestav.mx FU Consejo Nacional de Ciencia y Tecnologia Mexico (Conacyt) [Conacyt-ANR188565]; Agence Nationale de la Recherche France [ANR-12-ISV3-0006-01]; Conacyt [404373] FX This work was supported by an international collaboration grant between Consejo Nacional de Ciencia y Tecnologia Mexico (Conacyt) (Conacyt-ANR188565) and Agence Nationale de la Recherche France (ANR-12-ISV3-0006-01) and scholarship 404373 from Conacyt (to J.I.C.-A.). NR 75 TC 1 Z9 1 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2016 VL 196 IS 12 BP 5075 EP 5088 DI 10.4049/jimmunol.1501823 PG 14 WC Immunology SC Immunology GA DO7BP UT WOS:000377937500025 PM 27183589 ER PT J AU Dodd, LE Proschan, MA Neuhaus, J Koopmeiners, JS Neaton, J Beigel, JD Barrett, K Lane, HC Davey, RT AF Dodd, Lori E. Proschan, Michael A. Neuhaus, Jacqueline Koopmeiners, Joseph S. Neaton, James Beigel, John D. Barrett, Kevin Lane, Henry Clifford Davey, Richard T., Jr. TI Design of a Randomized Controlled Trial for Ebola Virus Disease Medical Countermeasures: PREVAIL II, the Ebola MCM Study SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE emerging infectious diseases; Ebola virus disease; clinical trials; adaptive design; Bayesian design ID CLINICAL-TRIALS; OUTCOMES; CANCER AB Background. Unique challenges posed by emerging infectious diseases often expose inadequacies in the conventional phased investigational therapeutic development paradigm. The recent Ebola outbreak in West Africa presents a critical case-study highlighting barriers to faster development. During the outbreak, clinical trials were implemented with unprecedented speed. Yet, in most cases, this fast-tracked approach proved too slow for the rapidly evolving epidemic. Controversy abounded as to the most appropriate study designs to yield safety and efficacy data, potentially causing delays in pivotal studies. Preparation for research during future outbreaks may require acceptance of a paradigm that circumvents, accelerates, or reorders traditional phases, without losing sight of the traditional benchmarks by which drug candidates must be assessed for activity, safety and efficacy. Methods. We present the design of an adaptive, parent protocol, ongoing in West Africa until January 2016. The exigent circumstances of the outbreak and limited prior clinical experience with experimental treatments, led to more direct bridging from preclinical studies to human trials than the conventional paradigm would typically have sanctioned, and required considerable design flexibility. Results. Preliminary evaluation of the "barely Bayesian" design was provided through computer simulation studies. The understanding and public discussion of the study design will help its future implementation. C1 [Dodd, Lori E.; Proschan, Michael A.; Barrett, Kevin; Lane, Henry Clifford; Davey, Richard T., Jr.] NIAID, 6700 B Rockledge,5601 Fishers Lane,MSC 9820, Bethesda, MD 20892 USA. [Beigel, John D.] Frederick Natl Lab Canc Res, Leidos Biomed Res, Frederick, MD USA. [Neuhaus, Jacqueline; Koopmeiners, Joseph S.; Neaton, James] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. RP Dodd, LE (reprint author), NIAID, 6700 B Rockledge,5601 Fishers Lane,MSC 9820, Bethesda, MD 20892 USA. EM doddl@mail.nih.gov FU Division of Clinical Research, National Institute of Allergy and Infectious Diseases; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was partially funded by the Division of Clinical Research, National Institute of Allergy and Infectious Diseases. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health (contract HHSN261200800001E). NR 14 TC 8 Z9 8 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 15 PY 2016 VL 213 IS 12 BP 1906 EP 1913 DI 10.1093/infdis/jiw061 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DO0BL UT WOS:000377444300009 PM 26908739 ER PT J AU Clark, CE Fay, MP Chico, ME Sandoval, CA Vaca, MG Boyd, A Cooper, PJ Nutman, TB AF Clark, Carolyn E. Fay, Michael P. Chico, Martha E. Sandoval, Carlos A. Vaca, Maritza G. Boyd, Alexis Cooper, Philip J. Nutman, Thomas B. TI Maternal Helminth Infection Is Associated With Higher Infant Immunoglobulin A Titers to Antigen in Orally Administered Vaccines SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE maternal; helminth; vaccine; immunization; IgA ID MYCOBACTERIAL ANTIGENS; GEOHELMINTH INFECTIONS; DEVELOPING-COUNTRIES; ROTAVIRUS VACCINES; ANTIBODY-RESPONSE; IMMUNE-RESPONSES; CONTROLLED-TRIAL; CHOLERA VACCINE; BIRTH COHORT; CHILDREN AB Background. Many studies have documented lower vaccine efficacy among children in low-income countries, compared with their counterparts in high-income countries. This disparity is especially apparent with respect to oral vaccines such as rotavirus and oral polio vaccines. One potential contributing factor is the presence of maternal antenatal helminth infections, which can modulate the infant's developing immune system. Methods. Using a multiplex immunoassay, we tested plasma immunoglobulin A (IgA) or immunoglobulin G (IgG) levels specific for antigens in 9 routinely administered childhood vaccines among 1639 children aged approximately 13 months enrolled in the ECUAVIDA (Ecuador Life) birth cohort study in Ecuador. We compared vaccine responses in 712 children of mothers who tested positive for helminth infections in the last trimester of pregnancy to responses in 927 children of mothers without helminth infection. Results. Plasma IgA levels specific for antigens in rotavirus vaccine and oral polio vaccine containing poliovirus serotypes 1 and 3 were all significantly higher in children of helminth-infected mothers, compared with children of uninfected mothers. Plasma IgG levels specific for diphtheria, tetanus, pertussis, measles, rubella, and Haemophilus influenzae type b vaccine antigens were comparable between the 2 groups. Conclusions. Antenatal maternal helminth infections were not associated with reduced antibody responses to infant vaccines, but rather with modestly increased IgA responses to oral vaccines. C1 [Clark, Carolyn E.; Boyd, Alexis; Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. [Fay, Michael P.] NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Chico, Martha E.; Sandoval, Carlos A.; Vaca, Maritza G.; Cooper, Philip J.] Lab Invest FEPIS, Quininde, Ecuador. [Cooper, Philip J.] Pontificia Univ Catolica Ecuador, Fac Ciencias Exactas & Nat, Ctr Invest Enfermedades Infecciosas & Cron, Quito, Ecuador. [Cooper, Philip J.] St Georges Univ London, Inst Infect & Immun, London, England. [Clark, Carolyn E.] Norwegian Inst Publ Hlth, Domain Infect Control & Environm Hlth, Oslo, Norway. [Boyd, Alexis] Bill & Melinda Gates Fdn, Seattle, WA USA. RP Nutman, TB (reprint author), NIH, Parasit Dis Lab, Bldg 4,Rm B1-03,4 Ctr Dr, Bethesda, MD 20892 USA. EM tnutman@niaid.nih.gov FU Wellcome Trust [088862/Z/09/Z]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases FX This work was supported by the Wellcome Trust (grant 088862/Z/09/Z) and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases. NR 32 TC 3 Z9 3 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 15 PY 2016 VL 213 IS 12 BP 1996 EP 2004 DI 10.1093/infdis/jiw066 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DO0BL UT WOS:000377444300021 PM 26908751 ER PT J AU Wennberg, AMV Spira, AP Pettigrew, C Soldan, A Zipunnikov, V Rebok, GW Roses, AD Lutz, MW Miller, MM Thambisetty, M Albert, MS AF Wennberg, Alexandra M. V. Spira, Adam P. Pettigrew, Corinne Soldan, Anja Zipunnikov, Vadim Rebok, George W. Roses, Allen D. Lutz, Michael W. Miller, Michael M. Thambisetty, Madhav Albert, Marilyn S. TI Blood glucose levels and cortical thinning in cognitively normal, middle-aged adults SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE Cortical thinning; Alzheimer's disease; APOE; TOMM40; Blood glucose ID WHITE-MATTER INTEGRITY; SURFACE-BASED ANALYSIS; HUMAN CEREBRAL-CORTEX; ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; MITOCHONDRIAL DYSFUNCTION; HIPPOCAMPAL ATROPHY; INSULIN-RESISTANCE; DIABETES-MELLITUS; COORDINATE SYSTEM AB Type II diabetes mellitus (DM) increases risk for cognitive decline and is associated with brain atrophy in older demented and non-demented individuals. We investigated (1) the cross-sectional association between fasting blood glucose level and cortical thickness in a sample of largely middle-aged, cognitively normal adults, and (2) whether these associations were modified by genes associated with both lipid processing and dementia. To explore possible modifications by genetic status, we investigated the interaction between blood glucose levels and the apolipoprotein E (APOE) epsilon 4 allele and the translocase of the outer mitochondrial membrane (TOMM) 40 '523 genotype on cortical thickness. Cortical thickness measures were based on mean thickness in a subset of a priori-selected brain regions hypothesized to be vulnerable to atrophy in Alzheimer's disease (AD) (i.e., 'AD vulnerable regions'). Participants included 233 cognitively normal subjects in the BIOCARD study who had a measure of fasting blood glucose and cortical thickness measures, quantified by magnetic resonance imaging (MRI) scans. After adjustment for age, sex, race, education, depression, and medical conditions, higher blood glucose was associated with thinner parahippocampal gyri (B = -0.002; 95% CI -0.004, -0.0004) and temporal pole (B = -0.002; 95% CI -0.004, -0.0001), as well as reduced average thickness over AD vulnerable regions (B = -0.001; 95% CI -0.002, -0.0001). There was no evidence for greater cortical thinning in c4 carriers of the APOE gene or in APOE epsilon 3/3 individuals carrying the TOMM40 VL/VL genotypes. When individuals with glucose levels in the diabetic range (>= 126 mg/dL), were excluded from the analysis, the associations between glucose levels and cortical thickness were no longer significant. These findings suggest that glucose levels in the diabetic range are associated with reduced cortical thickness in AD vulnerable regions as early as middle age. (C) 2016 Elsevier B.V. All rights reserved. C1 [Wennberg, Alexandra M. V.; Spira, Adam P.; Rebok, George W.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, 615 N Wolfe St, Baltimore, MD 21205 USA. [Spira, Adam P.; Rebok, George W.] Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, 733 N Broadway, Baltimore, MD 21205 USA. [Spira, Adam P.; Zipunnikov, Vadim; Rebok, George W.] Johns Hopkins Ctr Aging & Hlth, 2024 E Monument St, Baltimore, MD 21205 USA. [Pettigrew, Corinne; Soldan, Anja; Albert, Marilyn S.] Johns Hopkins Sch Med, Dept Neurol, 733 N Broadway, Baltimore, MD 21205 USA. [Zipunnikov, Vadim] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, 615 N Wolfe St, Baltimore, MD 21205 USA. [Roses, Allen D.; Lutz, Michael W.] Duke Univ, Sch Med, Dept Neurol, 8 Searle Ctr Dr, Durham, NC 27703 USA. [Miller, Michael M.] Johns Hopkins Univ, Dept Biomed Engn, 3400 N Charles St, Baltimore, MD 21218 USA. [Thambisetty, Madhav] NIA, Unit Clin & Translat Neurosci, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Wennberg, AMV (reprint author), Mayo Clin, Dept Hlth Sci Res, 200 1st St SW, Rochester, MN 55905 USA. EM wennberg.alexandra@mayo.edu; aspira@jhu.edu; cpettigrew@jhmi.edu; asoldan1@jhmi.edu; vadim.zipunnikov@gmail.com; grebok1@jhu.edu; allen.roses@duke.edu; michael.lutz@duke.edu; mim@cis.jhu.edu; thambisettym@mail.nih.gov; malbert9@jhmi.edu RI Wennberg, Alexandra/O-9563-2016; OI Wennberg, Alexandra/0000-0003-4906-1165; Lutz, Michael/0000-0001-8809-5574 FU National Institute on Aging; Johns Hopkins University; William and Ella Owens Medical Research Foundation; National Institutes of Health [U19-AG03365, P50-AG005146, T32-AG027668] FX Drs. Wennberg, Pettigrew, Soldan, Zipunnikov, Rebok, Lutz, Miller, Thambisetty, and Albert report no conflicts of interest. Dr. Spira has received grants from the National Institute on Aging, Johns Hopkins University, and the William and Ella Owens Medical Research Foundation. Dr. Roses is the Jefferson-Pilot Professor of Neurosciences and Neurology at Duke University. Dr. Roses is the CEO and sole shareholder of Zinfandel Pharmaceuticals, Inc. (a NC S-Corp). Zinfandel is an alliance with Takeda Pharmaceuticals to manage the TOMMORROW study.; This study was supported in part by grants from the National Institutes of Health (U19-AG03365, P50-AG005146, and T32-AG027668). The BIOCARD Study consists of 7 Cores with the following members: (1) the Administrative Core (Marilyn Albert, Barbara Rodzon); (2) the Clinical Core (Ola Seines, Marilyn Albert, Anja Soldan, Rebecca Gottesman, Ned Sacktor, Guy McKhann, Scott Turner, Leonie Farrington, Maura Grega, Gay Rudow, Daniel D'Agostino, Scott Rudow); (3) the Imaging Core (Michael Miller, Susumu Mori, Tilak Ratnanather, Timothy Brown, Hayan Chi, Anthony Kolasny, Kenichi Oishi, Thomas Reigel, Laurent Younes); (4) the Biospecimen Core (Abhay Moghekar, Richard O'Brien, Abby Spangler); (5) the Informatics Core (Roberta Scherer, David Shade, Ann Ervin, Jennifer Jones, Matt Toepfner, Lauren Parlett, April Patterson, Aisha Mohammed); (6) the Biostatistics Core (Mei-Cheng Wang, Qing Cai, Daisy Lu); and (7) the Neuropathology Core (Juan Troncoso, Barbara Crain, Olga Pletnikova, Gay Rudow, and Karen Fisher). The authors are grateful to the members of the BIOCARD Scientific Advisory Board who provide continued oversight and guidance regarding the conduct of the study including: Drs John Cemansky, David Holtzman, David Knopman, Walter Kukull, and John McArdle, and Drs Neil Buckholtz, John Hsiao, Laurie Ryan, and Jovier Evans, who provide oversight on behalf of the National Institute on Aging and the National Institute of Mental Health (NIMH), respectively. The authors thank the members of the BIOCARD Resource Allocation Committee who provide ongoing guidance regarding the use of the biospecimens collected as part of the study, including: Drs Constantine Lyketsos, Carlos Pardo, Gerard Schellenberg, Leslie Shaw, Madhav Thambisetty, and John Trojanowski. NR 56 TC 1 Z9 1 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X EI 1878-5883 J9 J NEUROL SCI JI J. Neurol. Sci. PD JUN 15 PY 2016 VL 365 BP 89 EP 95 DI 10.1016/j.jns.2016.04.017 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DN8FC UT WOS:000377313600020 PM 27206882 ER PT J AU Climaco-Arvizu, S Dominguez-Acosta, O Cabanas-Cortes, MA Rodriguez-Sosa, M Gonzalez, FJ Vega, L Elizondo, G AF Climaco-Arvizu, Samantha Dominguez-Acosta, Omar Asuncion Cabanas-Cortes, Maria Rodriguez-Sosa, Miriam Gonzalez, Frank J. Vega, Libia Elizondo, Guillermo TI Aryl hydrocarbon receptor influences nitric oxide and arginine production and alters M1/M2 macrophage polarization SO LIFE SCIENCES LA English DT Article DE Arginase; Aryl hydrocarbon receptor; Leishmaniasis; Macrophage; Nitric oxide ID AHR-NULL MICE; SYNTHASE EXPRESSION; INFECTION; ARGINASE; INFLAMMATION; LEISHMANIA; METABOLISM; TOXICITY AB Aims: The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxicity of environmental pollutants. It is also implicated in the regulation of the immune system. Ahr-null macrophages overproduce several proinflammatory cytokines following LPS-mediated stimulation, suggesting that AHR affects the balance between the inflammatory M1 and anti-inflammatory M2 phenotypes. Therefore, the present study aimed to examine whether the loss of AHR modifies macrophage polarization. Materials and methods: Peritoneal macrophages fromwild-type and Ahr-null mice were differentiated into M1 or M2 phenotype by treatment with LPS/IFN gamma or IL-4, and several M1 and M2 markers were determined by qPCR and ELISA assays. Macrophage phagocytic capacity was determined through phagocytosis of yeast and Leishmania major infection assays. Nitric oxide (NO) and urea production, and arginase activity were also determined. Key findings: When macrophages were polarized to the M1 phenotype, Ahr-null cells presented a mixed response; higher levels of IL-1 beta, IL-6, IL-12, and TNF alpha were observed after IFN gamma- and LPS-mediated activation. However, Ahr-null cells also exhibited decreased NO production and phagocytic capacity. When macrophage was polarized to the M2 phenotype, Ahr-null cells exhibited lower levels of Fizz1, Ym1, and IL-10. In contrast, arginase activity was increased when compared to wild-type macrophages. In addition, macrophages from Ahrnull mice were more susceptible to L. major infection. Significance: Disruption of the Ahr gene alters macrophage polarization when compared to WT macrophage. These changes may affect the development and resolution of several diseases such as bacterial or parasitic infections. (C) 2016 Elsevier Inc. All rights reserved. C1 [Climaco-Arvizu, Samantha; Dominguez-Acosta, Omar; Asuncion Cabanas-Cortes, Maria; Elizondo, Guillermo] CINVESTAV IPN, Dept Biol Celular, Av IPN 2508, Mexico City 07360, DF, Mexico. [Rodriguez-Sosa, Miriam] UNAM, Fac Estudios Super Iztacala, Unidad Biomed, Tlalnepantla 54090, Estado De Mexic, Mexico. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Vega, Libia] CINVESTAV IPN, Dept Toxicol, Av IPN 2508, Mexico City 07360, DF, Mexico. RP Elizondo, G (reprint author), CINVESTAV IPN, Dept Biol Celular, Av IPN 2508, Mexico City 07360, DF, Mexico. EM gazuela@cinvestav.mx FU CONACYT [153377] FX We thank Dr. Leopoldo Flores for his helpful comments. This work was supported by CONACYT grant number 153377. NR 31 TC 0 Z9 0 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 EI 1879-0631 J9 LIFE SCI JI Life Sci. PD JUN 15 PY 2016 VL 155 BP 76 EP 84 DI 10.1016/j.lfs.2016.05.001 PG 9 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA DO1LW UT WOS:000377540700011 PM 27153778 ER PT J AU Barch, DM Gotlib, IH Bilder, RM Pine, DS Smoller, JW Brown, CH Huggins, W Hamilton, C Haim, A Farber, GK AF Barch, Deanna M. Gotlib, Ian H. Bilder, Robert M. Pine, Daniel S. Smoller, Jordan W. Brown, C. Hendricks Huggins, Wayne Hamilton, Carol Haim, Adam Farber, Gregory K. TI Common Measures for National Institute of Mental Health Funded Research SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID DIFFICULTIES QUESTIONNAIRE SDQ; LIFE EVENTS QUESTIONNAIRE; SELF-REPORT VERSION; PSYCHOMETRIC PROPERTIES; HIPPOCAMPAL VOLUMES; PHENX MEASURES; CDE PROJECT; HIGH-RISK; STRENGTHS; PSYCHOSIS C1 [Barch, Deanna M.] Washington Univ, Dept Psychol, Box 1125,One Brookings Dr, St Louis, MO 63130 USA. [Barch, Deanna M.] Washington Univ, Dept Psychiat, Box 1125,One Brookings Dr, St Louis, MO 63130 USA. [Barch, Deanna M.] Washington Univ, Dept Radiol, Box 1125,One Brookings Dr, St Louis, MO 63130 USA. [Gotlib, Ian H.] Stanford Univ, Dept Psychol, Stanford, CA USA. [Bilder, Robert M.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Bilder, Robert M.] Univ Calif Los Angeles, Dept Biobehav Sci & Psychol, Los Angeles, CA USA. [Pine, Daniel S.] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. [Smoller, Jordan W.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Smoller, Jordan W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Smoller, Jordan W.] Broad Inst, Stanley Ctr Psychiat Res, Boston, MA USA. [Brown, C. Hendricks] Northwestern Univ, Dept Psychiat, Chicago, IL 60611 USA. [Huggins, Wayne; Hamilton, Carol] RTI Int, Durham, NC USA. [Haim, Adam] NIMH, Off Clin Res, Bethesda, MD 20892 USA. [Farber, Gregory K.] NIMH, Off Technol Dev & Coordinat, Bethesda, MD 20892 USA. RP Barch, DM (reprint author), Washington Univ, Dept Psychol, Box 1125,One Brookings Dr, St Louis, MO 63130 USA.; Barch, DM (reprint author), Washington Univ, Dept Psychiat, Box 1125,One Brookings Dr, St Louis, MO 63130 USA.; Barch, DM (reprint author), Washington Univ, Dept Radiol, Box 1125,One Brookings Dr, St Louis, MO 63130 USA. EM dbarch@wustl.edu OI Brown, C Hendricks/0000-0002-0294-2419 FU NHGRI NIH HHS [U41 HG007050]; NICHD NIH HHS [U54 HD087011]; NIMH NIH HHS [K24 MH094614, R01 MH040859, R01 MH066031, R01 MH074849, R01 MH084840, R01 MH090786, R01 MH098454, R01 MH101478, R01 MH101495, U54 MH091657] NR 41 TC 0 Z9 0 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 15 PY 2016 VL 79 IS 12 BP E91 EP E96 DI 10.1016/j.biopsych.2015.07.006 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DN0ZV UT WOS:000376796500001 PM 26903402 ER PT J AU Patel, PR Sun, W Kim, M Huang, XL Sanderson, PE Tanaka, TQ Mckew, JC Simeonov, A Williamson, KC Zheng, W Huang, WW AF Patel, Paresma R. Sun, Wei Kim, Myunghoon Huang, Xiuli Sanderson, Philip E. Tanaka, Takeshi Q. McKew, John C. Simeonov, Anton Williamson, Kim C. Zheng, Wei Huang, Wenwei TI In vitro evaluation of imidazo[4,5-c]quinolin-2-ones as gametocytocidal antimalarial agents SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Antimalarial; Plasmodium falciparum; Gametocytes; Gametocytocidal; Imidazo[4,5-c]quinolin-2-one ID INHIBITOR; NVP-BEZ235 AB Novel imidazo[4,5-c] quinolin-2-ones were synthesized and evaluated in asexual blood stage and late stage gametocyte assays of Plasmodium falciparum, a major causative agent of malaria. The design of these compounds is based on a recently identified lead compound from a high throughput screen. A concise synthesis was developed that allowed for generation of analogues with substitution around both the quinoline and imidazolidinone rings. Through structure-activity relationship studies, a number of potent compounds were identified that possessed excellent antimalarial activity against both the asexual and sexual stages with minimal cytotoxicity in mammalian cells. This is the first Letter describing SAR and gametocytocidal activity of imidazo[4,5-c] quinolin-2-ones, a new lead series for malaria treatment and prevention. Published by Elsevier Ltd. C1 [Patel, Paresma R.; Sun, Wei; Kim, Myunghoon; Huang, Xiuli; Sanderson, Philip E.; McKew, John C.; Simeonov, Anton; Zheng, Wei; Huang, Wenwei] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Tanaka, Takeshi Q.; Williamson, Kim C.] Loyola Univ, Dept Biol, Chicago, IL 60660 USA. [Patel, Paresma R.] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Tanaka, Takeshi Q.] Obihiro Univ Agr & Vet Med, Natl Res Ctr Protozoan Dis, Obihiro, Hokkaido 0808555, Japan. [McKew, John C.] aTyr Pharma Inc, 3545 John Hopkins Court,Suite 250, San Diego, CA 92121 USA. [Williamson, Kim C.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. RP Huang, WW (reprint author), NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. EM huangwe@mail.nih.gov RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU National Center for Advancing Translational Sciences and Public Health Service Grant from the National Institute of Allergy and Infectious Diseases [AI101396] FX The authors would like to thank Paul Shinn, Danielle VanLeer, and Jennifer Bennison for assistance with compound management. This work was supported by the Intramural Research Programs of the National Center for Advancing Translational Sciences and Public Health Service Grant AI101396 from the National Institute of Allergy and Infectious Diseases. T.Q.T. is a JSPS Research Fellow in Biomedical and Behavioral Research at the NIH. NR 15 TC 2 Z9 2 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JUN 15 PY 2016 VL 26 IS 12 BP 2907 EP 2911 DI 10.1016/j.bmcl.2016.04.045 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA DN0BA UT WOS:000376728200033 PM 27156776 ER PT J AU Gail, MH Wu, JC Wang, ML Yaun, SS Cook, NR Eliassen, AH McCullough, ML Yu, K Zeleniuch-Jacquotte, A Smith-Warner, SA Ziegler, RG Carroll, RJ AF Gail, Mitchell H. Wu, Jincao Wang, Molin Yaun, Shiaw-Shyuan Cook, Nancy R. Eliassen, A. Heather McCullough, Marjorie L. Yu, Kai Zeleniuch-Jacquotte, Anne Smith-Warner, Stephanie A. Ziegler, Regina G. Carroll, Raymond J. TI Calibration and seasonal adjustment for matched case-control studies of vitamin D and cancer SO STATISTICS IN MEDICINE LA English DT Article DE calibration; seasonal adjustment; measurement error; matched case-control study; molecular epidemiology; biomarkers ID BREAST-CANCER; 25-HYDROXYVITAMIN D; D METABOLITES; SERUM-LEVELS; RISK AB Vitamin D measurements are influenced by seasonal variation and specific assay used. Motivated by multicenter studies of associations of vitamin D with cancer, we formulated an analytic framework for matched case-control data that accounts for seasonal variation and calibrates to a reference assay. Calibration data were obtained from controls sampled within decile strata of the uncalibrated vitamin D values. Seasonal sine-cosine series were fit to control data. Practical findings included the following: (1) failure to adjust for season and calibrate increased variance, bias, and mean square error and (2) analysis of continuous vitamin D requires a variance adjustment for variation in the calibration estimate. An advantage of the continuous linear risk model is that results are independent of the reference date for seasonal adjustment. (3) For categorical risk models, procedures based on categorizing the seasonally adjusted and calibrated vitamin D have near nominal operating characteristics; estimates of log odds ratios are not robust to choice of seasonal reference date, however. Thus, public health recommendations based on categories of vitamin D should also define the time of year to which they refer. This work supports the use of simple methods for calibration and seasonal adjustment and is informing analytic approaches for the multicenter Vitamin D Pooling Project for Breast and Colorectal Cancer. Published 2016. This article has been contributed to by US Government employees and their work is in the public domain in the USA. C1 [Gail, Mitchell H.; Yu, Kai; Ziegler, Regina G.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Wu, Jincao] Food & Drug Adm, Div Biostat, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Wang, Molin] Harvard Univ, Dept Biostat, TH Chan Sch Publ Hlth, Boston, MA USA. [Wang, Molin; Cook, Nancy R.; Eliassen, A. Heather; Smith-Warner, Stephanie A.] Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA USA. [Yaun, Shiaw-Shyuan; Smith-Warner, Stephanie A.] Harvard Univ, Dept Nutr, TH Chan Sch Publ Hlth, Boston, MA USA. [Cook, Nancy R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med, Boston, MA 02115 USA. [Eliassen, A. Heather] Brigham & Womens Hosp, Dept Med, Med Network, Channing Div, 75 Francis St, Boston, MA 02115 USA. [Eliassen, A. Heather] Harvard Univ, Sch Med, Boston, MA USA. [McCullough, Marjorie L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Dept Populat Hlth, New York, NY USA. [Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Perlmutter Canc Ctr, New York, NY USA. [Carroll, Raymond J.] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. [Carroll, Raymond J.] Univ Technol Sydney, Dept Math & Stat, Sydney, NSW 2007, Australia. RP Gail, MH (reprint author), NCI, Biostat Branch, 9609 Med Ctr Dr,Rm 7E-138, Rockville, MD 20850 USA. EM gailm@mail.nih.gov OI Cook, Nancy/0000-0002-9705-0842; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU Intramural Research Program of the National Cancer Institute, Division of Cancer Epidemiology and Genetics; National Cancer Institute [U01-CA057030, R01-CA098661, UM1-CA182934, P30-CA016087]; National Institute of Environmental Health Sciences [ES000260]; American Cancer Society; [R01-CA152071] FX This work was supported by the Intramural Research Program of the National Cancer Institute, Division of Cancer Epidemiology and Genetics. Carroll's research was supported by a grant from the National Cancer Institute (U01-CA057030). We thank Stephanie Weinstein, Demetrius Albanes, and Michal Freedman for the use of ATBC and PLCO data; the American Cancer Society for use of the CPSII data; Li Cheung for help with R programming; and Mattias Johansson and David Muller for assistance with the sine-cosine method for seasonal adjustment. The American Cancer Society funded the creation, maintenance, and update of the CPSII cohort. The NYUWHS is supported by the National Cancer Institute (grants R01-CA098661, UM1-CA182934, and P30-CA016087) and by the National Institute of Environmental Health Sciences (center grant ES000260). The main Vitamin D Pooling Project was supported by R01-CA152071. NR 10 TC 1 Z9 1 U1 2 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 15 PY 2016 VL 35 IS 13 BP 2133 EP 2148 DI 10.1002/sim.6856 PG 16 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 DL4LI UT WOS:000375607200002 PM 27133461 ER PT J AU Sun, ZJ Inskip, PD Wang, JX Kwon, D Zhao, YC Zhang, LA Wang, Q Fan, SJ AF Sun, Zhijuan Inskip, Peter D. Wang, Jixian Kwon, Deukwoo Zhao, Yongcheng Zhang, Liangan Wang, Qin Fan, Saijun TI Solid cancer incidence among Chinese medical diagnostic x-ray workers, 1950-1995: Estimation of radiation-related risks SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE medical X-ray workers; solid cancer; ionizing radiation; occupational exposure; epidemiology; China ID OCCUPATIONAL-EXPOSURE; DOSE RECONSTRUCTION; IONIZING-RADIATION; COHORT; MORTALITY AB The objective of this study was to estimate solid cancer risk attributable to long-term, fractionated occupational exposure to low doses of ionizing radiation. Based on cancer incidence for the period 1950-1995 in a cohort of 27,011 Chinese medical diagnostic X-ray workers and a comparison cohort of 25,782 Chinese physicians who did not use X-ray equipment in their work, we used Poisson regression to fit excess relative risk (ERR) and excess absolute risk (EAR) dose-response models for incidence of all solid cancers combined. Radiation dose reconstruction was based on a previously published method that relied on simulating measurements for multiple X-ray machines, workplaces and working conditions, information about protective measures, including use of lead aprons, and work histories. The resulting model was used to estimate calendar year-specific badge dose calibrated as personal dose equivalent (Sv). To obtain calendar year-specific colon doses (Gy), we applied a standard organ conversion factor. A total of 1,643 cases of solid cancer were identified in 1.45 million person-years of follow-up. In both ERR and EAR models, a statistically significant radiation dose-response relationship was observed for solid cancers as a group. Averaged over both sexes, and using colon dose as the dose metric, the estimated ERR/Gy was 0.87 (95% CI: 0.48, 1.45), and the EAR was 22 per 10(4)PY-Gy (95% CI: 14, 32) at age 50. We obtained estimates of the ERR and EAR of solid cancers per unit dose that are compatible with those derived from other populations chronically exposed to low dose-rate occupational or environmental radiation. C1 [Sun, Zhijuan; Wang, Jixian; Zhao, Yongcheng; Zhang, Liangan; Wang, Qin; Fan, Saijun] Chinese Acad Med Sci, Tianjin Key Lab Radiat Med & Mol Nucl Med, Inst Radiat Med, Tianjin 300192, Peoples R China. [Sun, Zhijuan; Wang, Jixian; Zhao, Yongcheng; Zhang, Liangan; Wang, Qin; Fan, Saijun] Peking Union Med Coll, Tianjin 300192, Peoples R China. [Sun, Zhijuan; Inskip, Peter D.; Kwon, Deukwoo] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Kwon, Deukwoo] Univ Miami, Sch Med, Silvestre Comprehens Canc Ctr, Miami, FL USA. RP Wang, JX (reprint author), Peking Union Med Coll, Tianjin 300192, Peoples R China.; Wang, JX (reprint author), Chinese Acad Med Sci, Inst Radiat Med, Tianjin 300192, Peoples R China. EM wangjixian@irm-cams.ac.cn FU National Natural Science Foundation of China [81502760]; Institute of Radiation Medicine, Peking Union Medical College (PUMC) & Chinese Academy of Medical Sciences [SF1210]; PUMC Youth Fund; Fundamental Research Funds for the Central Universities [33320140032]; Science Research Foundation for Doctor-Subject of High School of the National Education Department of China [20121106120041]; Intramural Research Program of the National Institutes of Health; National Cancer Institute, Department of Health and Human Services, USA, China Scholarship Council FX Grant sponsor: National Natural Science Foundation of China; Grant number: 81502760; Grant sponsor: Institute of Radiation Medicine, Peking Union Medical College (PUMC) & Chinese Academy of Medical Sciences; Grant number: SF1210; Grant sponsor: PUMC Youth Fund and the Fundamental Research Funds for the Central Universities; Grant number: 33320140032; Grant sponsor: Science Research Foundation for Doctor-Subject of High School of the National Education Department of China; Grant number: 20121106120041; Grant sponsors: Intramural Research Program of the National Institutes of Health and the National Cancer Institute, Department of Health and Human Services, USA, China Scholarship Council NR 28 TC 0 Z9 0 U1 3 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 JUN 15 PY 2016 VL 138 IS 12 BP 2875 EP 2883 DI 10.1002/ijc.30036 PG 9 WC Oncology SC Oncology GA DJ3XS UT WOS:000374140600011 PM 26860236 ER PT J AU Norman, AI Ivkov, R Forbes, JG Greer, SC AF Norman, Alexander I. Ivkov, Robert Forbes, Jeffrey G. Greer, Sandra C. TI The polymerization of actin: Structural changes from small-angle neutron scattering (vol 123, 154904, 2005) SO JOURNAL OF CHEMICAL PHYSICS LA English DT Correction ID FILAMENT C1 [Norman, Alexander I.; Greer, Sandra C.] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. [Norman, Alexander I.; Greer, Sandra C.] Univ Maryland, Dept Chem & Biomol Engn, College Pk, MD 20742 USA. [Ivkov, Robert] Triton BioSyst Inc, Chelmsford, MA 01824 USA. [Forbes, Jeffrey G.] Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Prote & Nanotechnol Sect, Muscle Biol Lab, NIH,DHHS, Bldg 50, Bethesda, MD 20892 USA. [Norman, Alexander I.] ExxonMobil Chem Co, Global Chem Res, 5200 Bayway Dr, Baytown, TX 77520 USA. [Ivkov, Robert] Johns Hopkins Univ, Dept Radiat Oncol & Mol Radiat Sci, Sch Med, Baltimore, MD 21231 USA. [Forbes, Jeffrey G.] TWIC Inc, 4423 Lehigh Rd,172, College Pk, MD 20740 USA. [Greer, Sandra C.] Mills Coll, Dept Chem, Oakland, CA 94613 USA. RP Greer, SC (reprint author), Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA.; Greer, SC (reprint author), Univ Maryland, Dept Chem & Biomol Engn, College Pk, MD 20742 USA. EM sgreer@umd.edu NR 11 TC 0 Z9 0 U1 0 U2 2 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD JUN 14 PY 2016 VL 144 IS 22 AR 229902 DI 10.1063/1.4953362 PG 2 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA DQ0XW UT WOS:000378926100040 PM 27306026 ER PT J AU Shoffner, J Trommer, B Thurm, A Farmer, C Langley, WA Soskey, L Rodriguez, AN D'Souza, P Spence, SJ Hyland, K Swedo, SE AF Shoffner, John Trommer, Barbara Thurm, Audrey Farmer, Cristan Langley, William A., III Soskey, Laura Rodriguez, Aldeboran N. D'Souza, Precilla Spence, Sarah J. Hyland, Keith Swedo, Susan E. TI CSF concentrations of 5-methyltetrahydrofolate in a cohort of young children with autism SO NEUROLOGY LA English DT Article ID CEREBRAL FOLATE-DEFICIENCY; KEARNS-SAYRE SYNDROME; CEREBROSPINAL-FLUID; AUTOANTIBODIES; POPULATION; DISORDERS; SPECTRUM; DISEASES; UTILITY; CNS AB Objective:To examine the association between cerebral folate deficiency and autism, this study examined CSF 5-methyltetrahydrofolate (5-MTHF) concentrations in a group of young children with autism, investigated the natural variation in CSF 5-MTHF over time, and assessed the relationship between CSF 5-MTHF and symptoms.Methods:CSF was collected from 67 children with a diagnosis of DSM-IV-TR autistic disorder (age, mean SD 43 11 months), with a second CSF sample obtained 1-3 years later on 31 of these subjects (time to follow-up, 30 +/- 8 months).Results:At time 1, 7% (5/67) of participants had 5-MTHF <40 nmol/L. At follow-up, 23% (7/31) of participants had 5-MTHF <40 nmol/L (only one of whom had been low at time 1). A moderate correlation with a very wide confidence interval (CI) was observed between time 1 and time 2 CSF 5-MTHF measurements (Pearson r[p] = 0.38 [0.04]; 95% CI 0.02-0.64). Neither the CSF 5-MTHF levels nor changes over time correlated with the clinical features of autism.Conclusions:CSF 5-MTHF levels vary significantly over time in an unpredictable fashion and do not show a significant relationship to typical clinical features of autism. Reduced CSF 5-MTHF levels are a nonspecific finding in autism. Our data do not support the use of lumbar puncture for assessment of CSF 5-MTHF in autism. C1 [Shoffner, John; Langley, William A., III; Hyland, Keith] Georgia State Univ, Med Neurogenet, Atlanta, GA 30303 USA. [Shoffner, John] Georgia State Univ, Atlanta, GA 30303 USA. [Trommer, Barbara; Thurm, Audrey; Farmer, Cristan; Soskey, Laura; Rodriguez, Aldeboran N.; D'Souza, Precilla; Spence, Sarah J.; Swedo, Susan E.] NIMH, Pediat & Dev Neurosci Branch, NIH, Bethesda, MD 20892 USA. [Trommer, Barbara] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Spence, Sarah J.] Boston Childrens Hosp, Dept Neurol, Boston, MA USA. RP Swedo, SE (reprint author), NIMH, Pediat & Dev Neurosci Branch, NIH, Bethesda, MD 20892 USA. EM swedos@mail.nih.gov FU National Institute of Mental Health of the National Institutes of Health [NCT00298246, 06-M-0102, ZIA MH002914]; Department of Defense [W81XWH-09-1-0367, W81XWH-10-1-0547] FX Supported by the Intramural Program of the National Institute of Mental Health of the National Institutes of Health, NCT00298246, 06-M-0102, and ZIA MH002914. John Shoffner, MD, William A. Langley, III, PhD, and Keith Hyland, PhD, were supported by the Department of Defense under award numbers W81XWH-09-1-0367 and W81XWH-10-1-0547. Views and opinions of and endorsements by the author(s) do not reflect those of the US Army, the Department of Defense, NIMH, NIH, HHS, or the United States Government. NR 29 TC 2 Z9 2 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUN 14 PY 2016 VL 86 IS 24 BP 2258 EP 2263 DI 10.1212/WNL.0000000000002766 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA DP8AT UT WOS:000378721000013 PM 27178705 ER PT J AU Sacchetti, B Funari, A Remoli, C Giannicola, G Kogler, G Liedtke, S Cossu, G Serafini, M Sampaolesi, M Tagliafico, E Tenedini, E Saggio, I Robey, PG Riminucci, M Bianco, P AF Sacchetti, Benedetto Funari, Alessia Remoli, Cristina Giannicola, Giuseppe Kogler, Gesine Liedtke, Stefanie Cossu, Giulio Serafini, Marta Sampaolesi, Maurilio Tagliafico, Enrico Tenedini, Elena Saggio, Isabella Robey, Pamela G. Riminucci, Mara Bianco, Paolo TI No Identical "Mesenchymal Stem Cells'' at Different Times and Sites: Human Committed Progenitors of Distinct Origin and Differentiation Potential Are Incorporated as Adventitial Cells in Microvessels SO STEM CELL REPORTS LA English DT Article ID SKELETAL-MUSCLE; STROMAL CELLS; CORD BLOOD; HEMATOPOIETIC NICHE; SATELLITE CELLS; SOURCES REVEALS; SMOOTH-MUSCLE; DORSAL AORTA; PDGF-B; PERICYTES AB A widely shared view reads that mesenchymal stem/stromal cells (''MSCs'') are ubiquitous in human connective tissues, can be defined by a common in vitro phenotype, share a skeletogenic potential as assessed by in vitro differentiation assays, and coincide with ubiquitous pericytes. Using stringent in vivo differentiation assays and transcriptome analysis, we show that human cell populations from different anatomical sources, regarded as ''MSCs'' based on these criteria and assumptions, actually differ widely in their transcriptomic signature and in vivo differentiation potential. In contrast, they share the capacity to guide the assembly of functional microvessels in vivo, regardless of their anatomical source, or in situ identity as perivascular or circulating cells. This analysis reveals that muscle pericytes, which are not spontaneously osteochondrogenic as previously claimed, may indeed coincide with an ectopic perivascular subset of committed myogenic cells similar to satellite cells. Cord blood-derived stromal cells, on the other hand, display the unique capacity to form cartilage in vivo spontaneously, in addition to an assayable osteogenic capacity. These data suggest the need to revise current misconceptions on the origin and function of so-called ''MSCs,'' with important applicative implications. The data also support the view that rather than a uniform class of ''MSCs,'' different mesoderm derivatives include distinct classes of tissue-specific committed progenitors, possibly of different developmental origin. C1 [Sacchetti, Benedetto; Funari, Alessia; Remoli, Cristina; Riminucci, Mara; Bianco, Paolo] Univ Roma La Sapienza, Stem Cell Lab, Dept Mol Med, I-00161 Rome, Italy. [Giannicola, Giuseppe] Univ Roma La Sapienza, Dept Anat Histol Forens Med & Orthoped Sci, I-00158 Rome, Italy. [Kogler, Gesine; Liedtke, Stefanie] Univ Dusseldorf, Inst Transplant Diagnost & Cellular Therapeut, Med Ctr, D-40225 Dusseldorf, Germany. [Cossu, Giulio] Univ Manchester, Inst Inflammat & Repair, Manchester M13 9PL, Lancs, England. [Serafini, Marta] Univ Milano Bicocca, San Gerardo Hosp, Tettamanti Res Ctr, Dept Pediat,Dulbecco Telethon Inst, I-20900 Monza, Italy. [Sampaolesi, Maurilio] Katholieke Univ Leuven, Dept Dev & Regenerat, B-3000 Leuven, Belgium. [Tagliafico, Enrico; Tenedini, Elena] Univ Modena & Reggio Emilia, Ctr Genome Res, I-41121 Modena, Italy. [Saggio, Isabella] Univ Roma La Sapienza, Dept Biol & Biotechnol C Darwin, IBPM CNR, I-00185 Rome, Italy. [Robey, Pamela G.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Riminucci, M (reprint author), Univ Roma La Sapienza, Stem Cell Lab, Dept Mol Med, I-00161 Rome, Italy.; Robey, PG (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM probey@dir.nidcr.nih.gov; mara.riminucci@uniroma1.it RI Robey, Pamela/H-1429-2011; Tagliafico, Enrico/C-9079-2009; OI Robey, Pamela/0000-0002-5316-5576; Tagliafico, Enrico/0000-0003-0981-2542; Cossu, Giulio/0000-0001-5863-9593; TENEDINI, Elena/0000-0003-0285-765X FU Telethon [GGP09227, TCP07004]; MIUR; Fondazione Cenci Bolognetti; Ministry of Health of Italy; EU (PluriMes consortium) [FP7-HEALTH-2013-INNOVATION-1-G.A. 602423]; Sapienza University of Rome; Fondazione Roma; Bilateral grant [DFG-KO2119/8-1]; DIR; NIDCR, of the IRP; NIH; DHHS FX Sadly, Prof. Paolo Bianco passed away while this manuscript was in revision. We dedicate this study to him, for all of his outstanding contributions throughout the years, and his complete dedication to bringing clarity to this area of research. This work was supported by Telethon (Grant GGP09227), MIUR, Fondazione Cenci Bolognetti, Ministry of Health of Italy, EU (PluriMes consortium, FP7-HEALTH-2013-INNOVATION-1-G.A. 602423), Sapienza University of Rome to P.B.; Fondazione Roma to P.B. and M.R.; Bilateral grant DFG-KO2119/8-1 to P.B. and G.K.; by Telethon (Grant TCP07004) to M.S.; and by DIR, NIDCR, of the IRP, NIH, DHHS to P.G.R. NR 43 TC 8 Z9 8 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD JUN 14 PY 2016 VL 6 IS 6 BP 897 EP 913 DI 10.1016/j.stemcr.2016.05.011 PG 17 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA DO8KQ UT WOS:000378032600012 PM 27304917 ER PT J AU Deschamps, JD Ogunsola, AF Jameson, JB Yasgar, A Flitter, BA Freedman, CJ Melvin, JA Nguyen, JVMH Maloney, DJ Jadhav, A Simeonov, A Bomberger, JM Holman, TR AF Deschamps, Joshua D. Ogunsola, Abiola F. Jameson, J. Brian, II Yasgar, Adam Flitter, Becca A. Freedman, Cody J. Melvin, Jeffrey A. Nguyen, Jason V. M. H. Maloney, David J. Jadhav, Ajit Simeonov, Anton Bomberger, Jennifer M. Holman, Theodore R. TI Biochemical and Cellular Characterization and Inhibitor Discovery of Pseudomonas aeruginosa 15-Lipoxygenase SO BIOCHEMISTRY LA English DT Article ID AIRWAY EPITHELIAL-CELLS; EARLY CYSTIC-FIBROSIS; SOYBEAN LIPOXYGENASE-1; SELECTIVE INHIBITORS; BIOFILM FORMATION; ARACHIDONATE 15-LIPOXYGENASE; STRUCTURAL INVESTIGATIONS; BRONCHOALVEOLAR LAVAGE; SUBSTRATE-SPECIFICITY; HUMAN RETICULOCYTE AB Pseudomonas aeruginosa is an opportunistic pathogen that can cause nosocomial and chronic infections in immunotompromised patients. P. aeruginosa secretes a lipoxygenase, LoxA, but the biological role of this enzyme is-currently unknown. LoxA is poorly similar in sequence to both soybean LOX-1 (s15-LOX-1) and human 15-LOX-1 (37 and, 39%, respectively) yet has kinetics comparably fast versus these of s15-LOX-1 (at pH 6.5, K-cat, = 181 +/- 6 s(-1) and K-cat/K-m.716 +/- 2 mu M-1 s(-1)). LoxA is capable of efficiently catalyzing the peroxidation of a broad range of free fatty acid (FA) substrates.(e.g., AA and LA) with high positional specificity, indicating a 15-LOX. Its mechanism includes hydrogen atom abstraction [a kinetic isotope effect (KIE) of >30], yet LoxA. is a poor catalyst against phosphoester FAs, suggesting that LoxA is not involved in membrane decomposition. LoxA also does not react with 5- or 15-HETEs, indicating poor involvement in lipoxin production. A LOX high-throughput screen of the LOPAC library yielded a variety of low-micromolar inhibitors; however, none selectively targeted Loth over the human LOX isozymes. With respect to cellular activity, the level of LoxA expression is increased when P. aeruginosa undergoes the transition to a biofilin mode of growth, but LoxA is not required for biofilm growth on abiotic surfaces. However, LoxA does appear to be required for biofilm growth in association with the-host airway epithelium, suggesting, a role for LoxA in mediating bacterium-host interactions during, colonization. C1 [Deschamps, Joshua D.; Jameson, J. Brian, II; Freedman, Cody J.; Nguyen, Jason V. M. H.; Holman, Theodore R.] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA. [Ogunsola, Abiola F.; Flitter, Becca A.; Melvin, Jeffrey A.; Bomberger, Jennifer M.] Univ Pittsburgh, Dept Microbiol & Mol Genet, Pittsburgh, PA 15219 USA. [Yasgar, Adam; Maloney, David J.; Jadhav, Ajit; Simeonov, Anton] NIH, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr,MSC 3370, Bethesda, MD 20892 USA. RP Holman, TR (reprint author), Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA.; Bomberger, JM (reprint author), Univ Pittsburgh, Dept Microbiol & Mol Genet, Pittsburgh, PA 15219 USA. EM jbomb@pitt.edu; tholman@chemistry.ucsc.edu FU National Institutes of Health [GM56062, S10-RR20939, R00HL098342, T32AI49820]; Gilead Research Scholars in Cystic Fibrosis Grant; Cystic Fibrosis Foundation (CFF) [MELVIN15F0]; National Center for Advancing Translational Sciences; National Science Foundation [CHE-1427922] FX This work was supported by the National Institutes of Health [GM56062 and S10-RR20939 (T.R.H.), R00HL098342 (J.M.B.), and T32AI49820 (J.A.M.)], a Gilead Research Scholars in Cystic Fibrosis Grant (J.M.B.), the Cystic Fibrosis Foundation (CFF, MELVIN15F0), the intramural research program of the National Center for Advancing Translational Sciences (A.Y., D.J.M., A.J., and A.S.), and the National Science Foundation (MS equipment grant CHE-1427922). NR 61 TC 2 Z9 2 U1 3 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 14 PY 2016 VL 55 IS 23 BP 3329 EP 3340 DI 10.1021/acs.biochem.6b00338 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DO8EX UT WOS:000378016500016 PM 27226387 ER PT J AU Davis, SK Xu, RH Riestra, P Gebreab, SY Khan, RJ Gaye, A Hickson, D Sims, M Bidulescu, A AF Davis, Sharon K. Xu, Ruihua Riestra, Pia Gebreab, Samson Y. Khan, Rumana J. Gaye, Amadou Hickson, DeMarc Sims, Mario Bidulescu, Aurelian TI Association of adiponectin and socioeconomic status in African American men and women: the Jackson heart study SO BMC PUBLIC HEALTH LA English DT Article DE Biomarkers; Cardiovascular disease; Socioeconomic status; Adiponectin; African Americans ID C-REACTIVE PROTEIN; CARDIOVASCULAR-DISEASE; RISK-FACTORS; EDUCATION; MARKERS; HYPERTENSION; INFLAMMATION; PREVALENCE; FIBRINOGEN; GLUCOSE AB Background: Recent emphasis has been placed on elucidating the biologic mechanism linking socioeconomic status (SES) to cardiovascular disease (CVD). Positive associations of inflammatory biomarkers provide evidence suggestive of a biologic pathway by which SES may predispose to CVD. African Americans have disproportionately lower SES and have a higher prevalence of CVD risk factors compared to most ethnic/racial groups. Adiponectin (an anti-inflammatory marker) is also lower. The objective of this study was to assess the association of adiponectin with SES among African American men and women using the Jackson Heart Study. Methods: Study sample included 4340 participants. Linear regression was performed separately by SES and stratified by sex. Annual household income and level of education was used as proxies for SES. Crude, age, health behavior and health status adjusted models were analyzed. The main outcome was log-transformed adiponectin. Results: Men in the lowest income group had significantly higher adiponectin than those in the highest income group in the fully adjusted model (beta/standard error [se], p value = .16/.08, p = .0008. Men with < high school level of education had significantly higher adiponectin in the crude and age adjusted models than those with = college degree (.25/.05, p < .0001; .14/.05/ p = .005, respectively). Women with some college or vocational training in the crude and age adjusted models had lower adiponectin compared to women with = college degree (-.09/.03, p = .004; -.06/.03, p = .04, respectively). Conclusion: Findings suggest a potential inverse biologic pathway between annual household income and adiponectin among African American men. There was no such finding among women. Findings suggest interventions should be targeted for higher SES African American men to improve adiponectin levels. C1 [Davis, Sharon K.; Xu, Ruihua; Riestra, Pia; Gebreab, Samson Y.; Khan, Rumana J.; Gaye, Amadou] NHGRI, Social Epidemiol Res Unit, NIH, 10 Ctr Dr,Room 7 N320,MSC 1644, Bethesda, MD 20892 USA. [Hickson, DeMarc; Sims, Mario] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Bidulescu, Aurelian] Indiana Univ, Sch Publ Hlth, Bloomington, IN 47405 USA. RP Davis, SK (reprint author), NHGRI, Social Epidemiol Res Unit, NIH, 10 Ctr Dr,Room 7 N320,MSC 1644, Bethesda, MD 20892 USA. EM sharon.davis@nih.gov OI Gaye, Amadou/0000-0002-1180-2792 FU National Heart, Lung and Blood Institute and the National Institute on Minority Health and Health Disparities [HHSN268201200046C, HHSN26820120047C, HHSM268201300048C, HHSN26820130049C, HHSN268201300050C]; PHS Award from the National Center for Research Resources [UL1RR025008]; National Heart, Lung and Blood Institute [UH1HL073461]; intramural program of the National Human Genome Research Institute, National Institutes of Health; National Human Genome Research Institute FX The authors would like to thank the staff and the participants of the Jackson Heart Study for their valuable contributions. Funding for the Jackson Heart Study was supported by contracts HHSN268201200046C, HHSN26820120047C, HHSM268201300048C, HHSN26820130049C, HHSN268201300050C from the National Heart, Lung and Blood Institute and the National Institute on Minority Health and Health Disparities. The adiponectin measurements were partially supported by PHS Award UL1RR025008 from the National Center for Research Resources and by grant UH1HL073461 from the National Heart, Lung and Blood Institute. Sharon K. Davis, Ruihua Xu, Pia Riestra, Samson Y. Gebreab, Rumana J. Khan and Amadou Gaye are supported by the intramural program of the National Human Genome Research Institute, National Institutes of Health. The National Human Genome Research Institute supported the design and conduct of the study, management of analyses, interpretation of the data, review and approval of the manuscript. Sharon K. Davis had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The authors have no disclosures to report. NR 31 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD JUN 14 PY 2016 VL 16 AR 511 DI 10.1186/s12889-016-3167-x PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DO3WX UT WOS:000377714300002 PM 27301295 ER PT J AU Mera, P Laue, K Ferron, M Confavreux, C Wei, JW Galan-Diez, M Lacampagne, A Mitchell, SJ Mattison, JA Chen, Y Bacchetta, J Szulc, P Kitsis, RN de Cabo, R Friedman, RA Torsitano, C McGraw, TE Puchowicz, M Kurland, I Karsenty, G AF Mera, Paula Laue, Kathrin Ferron, Mathieu Confavreux, Cyril Wei, Jianwen Galan-Diez, Marta Lacampagne, Alain Mitchell, Sarah J. Mattison, Julie A. Chen, Yun Bacchetta, Justine Szulc, Pawel Kitsis, Richard N. de Cabo, Rafael Friedman, Richard A. Torsitano, Christopher McGraw, Timothy E. Puchowicz, Michelle Kurland, Irwin Karsenty, Gerard TI Osteocalcin Signaling in Myofibers Is Necessary and Sufficient for Optimum Adaptation to Exercise SO CELL METABOLISM LA English DT Article ID SKELETAL-MUSCLE CONTRACTION; AMPK PHOSPHORYLATION; ENERGY-METABOLISM; INSULIN; GLUCOSE; INTERLEUKIN-6; DISTINCT; BONE; MECHANISMS; EXPRESSION AB Circulating levels of undercarboxylated and bioactive osteocalcin double during aerobic exercise at the time levels of insulin decrease. In contrast, circulating levels of osteocalcin plummet early during adulthood in mice, monkeys, and humans of both genders. Exploring these observations revealed that osteocalcin signaling in myofibers is necessary for adaptation to exercise by favoring uptake and catabolism of glucose and fatty acids, the main nutrients of myofibers. Osteocalcin signaling in myofibers also accounts for most of the exercise-induced release of interleukin-6, a myokine that promotes adaptation to exercise in part by driving the generation of bioactive osteocalcin. We further show that exogenous osteocalcin is sufficient to enhance the exercise capacity of young mice and to restore to 15-month-old mice the exercise capacity of 3-month-old mice. This study uncovers a bone-tomuscle feedforward endocrine axis that favors adaptation to exercise and can reverse the age-induced decline in exercise capacity. C1 [Mera, Paula; Laue, Kathrin; Ferron, Mathieu; Wei, Jianwen; Karsenty, Gerard] Columbia Univ, Med Ctr, Dept Genet & Dev, New York, NY 10032 USA. [Confavreux, Cyril; Bacchetta, Justine; Szulc, Pawel] Univ Lyon, Hosp Civils Lyon, INSERM, UMR1033, F-69003 Lyon, France. [Galan-Diez, Marta] Columbia Univ, Med Ctr, Dept Physiol & Cellular Biophys, New York, NY 10032 USA. [Lacampagne, Alain] Univ Montpellier, CHRU Montpellier, CNRS, INSERM,UMR 9214,U1046, F-34295 Montpellier 5, France. [Mitchell, Sarah J.; Mattison, Julie A.; de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Chen, Yun; Kitsis, Richard N.] Yeshiva Univ Albert Einstein Coll Med, Dept Cell Biol, Dept Med Cardiol, 1300 Morris Pk Ave, Bronx, NY 10461 USA. [Chen, Yun; Kitsis, Richard N.] Yeshiva Univ Albert Einstein Coll Med, Wilf Family Cardiovasc Res Inst, Bronx, NY 10461 USA. [Friedman, Richard A.] Columbia Univ, Med Ctr, Dept Biomed Informat, New York, NY 10032 USA. [Torsitano, Christopher; McGraw, Timothy E.] Cornell Univ, Weill Med Coll, Dept Biochem, New York, NY 10065 USA. [Puchowicz, Michelle] Case Western Reserve Univ, Sch Med, Dept Nutr, Cleveland, OH 44106 USA. [Kurland, Irwin] Yeshiva Univ Albert Einstein Coll Med, Dept Med, 1300 Morris Pk Ave, Bronx, NY 10461 USA. [Ferron, Mathieu] Inst Rech Clin Montreal, Integrat & Mol Physiol Res Unit, Montreal, PQ H2W 1R7, Canada. RP Karsenty, G (reprint author), Columbia Univ, Med Ctr, Dept Genet & Dev, New York, NY 10032 USA. EM gk2172@cumc.columbia.edu RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU NIH [5RO1AR045548, PO1AG032959, P60DK020541, RO1HL60665, U24DK76174]; Wilf Family Foundation; Ellison Senior Scholar Award; EMBO postdoctoral fellowship; National Institute on Aging FX We thank Drs. C. Cosentino, P. Ducy, L. Herrero, M. Hussain, R. Sellers, D. Serra, and E. Sornay-Rendu for advice or reagents, and Dr. M. McKee for electronic microscopy analyses. This work was supported by NIH grants 5RO1AR045548, PO1AG032959 (G.K.), P60DK020541 (I.K.), RO1HL60665 (R.N.K.), and U24DK76174 (M.P.); the Wilf Family Foundation (R.N.K.); an Ellison Senior Scholar Award (G.K.); an EMBO postdoctoral fellowship (K.L.); and the Intramural Research Program of the National Institute on Aging (R.dC., S.J.M., and J.A.M.). NR 47 TC 10 Z9 11 U1 2 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD JUN 14 PY 2016 VL 23 IS 6 BP 1078 EP 1092 DI 10.1016/j.cmet.2016.05.004 PG 15 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA DO7ZA UT WOS:000378000600020 PM 27304508 ER PT J AU Mitchell, SJ Madrigal-Matute, J Scheibye-Knudsen, M Fang, E Aon, M Gonzalez-Reyes, JA Cortassa, S Kaushik, S Gonzalez-Freire, M Patel, B Wahl, D Ali, A Calvo-Rubio, M Buron, MI Guiterrez, V Ward, TM Palacios, HH Cai, H Frederick, DW Hine, C Broeskamp, F Habering, L Dawson, J Beasley, TM Wan, JX Ikeno, Y Hubbard, G Becker, KG Zhang, YQ Bohr, VA Longo, DL Navas, P Ferrucci, L Sinclair, DA Cohen, P Egan, JM Mitchell, JR Baur, JA Allison, DB Anson, RM Villalba, JM Madeo, F Cuervo, AM Pearson, KJ Ingram, DK Bernier, M de Cabo, R AF Mitchell, Sarah J. Madrigal-Matute, Julio Scheibye-Knudsen, Morten Fang, Evandro Aon, Miguel Gonzalez-Reyes, Jose A. Cortassa, Sonia Kaushik, Susmita Gonzalez-Freire, Marta Patel, Bindi Wahl, Devin Ali, Ahmed Calvo-Rubio, Miguel Buron, Maria I. Guiterrez, Vincent Ward, Theresa M. Palacios, Hector H. Cai, Huan Frederick, David W. Hine, Christopher Broeskamp, Filomena Habering, Lukas Dawson, John Beasley, T. Mark Wan, Junxiang Ikeno, Yuji Hubbard, Gene Becker, Kevin G. Zhang, Yongqing Bohr, Vilhelm A. Longo, Dan L. Navas, Placido Ferrucci, Luigi Sinclair, David A. Cohen, Pinchas Egan, Josephine M. Mitchell, James R. Baur, Joseph A. Allison, David B. Anson, R. Michael Villalba, Jose M. Madeo, Frank Cuervo, Ana Maria Pearson, Kevin J. Ingram, Donald K. Bernier, Michel de Cabo, Rafael TI Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice SO CELL METABOLISM LA English DT Article ID GENETICALLY HETEROGENEOUS MICE; EXTENDS LIFE-SPAN; CHAPERONE-MEDIATED AUTOPHAGY; DIFFERENT DIETARY FATS; SHORT-TERM CALORIE; BODY-MASS INDEX; RHESUS-MONKEYS; NORDIHYDROGUAIARETIC ACID; MITOCHONDRIAL BIOGENESIS; CAENORHABDITIS-ELEGANS AB Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlate with lifespan extension, although it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented ageassociated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions. C1 [Mitchell, Sarah J.; Scheibye-Knudsen, Morten; Gonzalez-Freire, Marta; Wahl, Devin; Ali, Ahmed; Guiterrez, Vincent; Ward, Theresa M.; Palacios, Hector H.; Ferrucci, Luigi; Anson, R. Michael; Pearson, Kevin J.; Bernier, Michel; de Cabo, Rafael] NIA, Translat Gerontol Branch, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. [Madrigal-Matute, Julio; Kaushik, Susmita; Patel, Bindi; Cuervo, Ana Maria] Albert Einstein Coll Med, Inst Aging Studies, Dept Dev & Mol Biol, Bronx, NY 10461 USA. [Scheibye-Knudsen, Morten; Fang, Evandro; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. [Scheibye-Knudsen, Morten] Univ Copenhagen, Dept Cellular & Mol Med, Ctr Hlth Aging, DK-2200 Copenhagen, Denmark. [Aon, Miguel; Cortassa, Sonia] NIA, Lab Cardiovasc Sci, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. [Gonzalez-Reyes, Jose A.; Calvo-Rubio, Miguel; Buron, Maria I.; Villalba, Jose M.] Univ Cordoba, Dept Cell Biol Physiol & Immunol, Agrifood Campus Int Excellence,CeiA3, E-14071 Cordoba, Spain. [Cai, Huan; Egan, Josephine M.] NIA, Lab Clin Invest, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. [Frederick, David W.; Baur, Joseph A.] Univ Penn, Dept Physiol, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. [Hine, Christopher; Mitchell, James R.] Harvard Univ, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Broeskamp, Filomena; Habering, Lukas; Madeo, Frank] Graz Univ, NAWI Graz, Inst Mol Biosci, A-8010 Graz, Austria. [Broeskamp, Filomena; Habering, Lukas; Madeo, Frank] BioTechMed Graz, A-8010 Graz, Austria. [Dawson, John; Beasley, T. Mark; Allison, David B.] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Dawson, John; Beasley, T. Mark; Allison, David B.] Birmingham Atlanta Vet Adm Hosp, GRECC, Birmingham, AL 35294 USA. [Wan, Junxiang; Cohen, Pinchas] Univ So Calif, Leonard Davis Sch Gerontol, Los Angeles, CA 90089 USA. [Ikeno, Yuji; Hubbard, Gene] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78245 USA. [Becker, Kevin G.; Zhang, Yongqing; Longo, Dan L.] NIA, Lab Genet, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. [Navas, Placido] Univ Pablo de Olavide, CSIC, Ctr Andaluz Biol Desarrollo, Seville 41013, Spain. [Navas, Placido] Univ Pablo de Olavide, CIBERER, Inst Salud Carlos III, Seville 41013, Spain. [Sinclair, David A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Pearson, Kevin J.] Univ Kentucky, Grad Ctr Nutr Sci, CT Wethington Bldg,Room 591,900 South Limestone, Lexington, KY 40536 USA. [Ingram, Donald K.] Pennington Biomed Res Ctr, Baton Rouge, LA 70809 USA. RP de Cabo, R (reprint author), NIA, Translat Gerontol Branch, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM decabora@mail.nih.gov RI de Cabo, Rafael/J-5230-2016; Aon, Miguel/A-6564-2008; OI de Cabo, Rafael/0000-0002-3354-2442; Aon, Miguel/0000-0002-4355-5431; Scheibye-Knudsen, Morten/0000-0002-6637-1280; Gonzalez-Reyes, Jose A./0000-0003-1918-5490; , rafael/0000-0003-2830-5693 FU Intramural Research Program of the National Institute on Aging, NIH; NIH [R01 AG043483, R01 DK098656, AG031782, 1P01AG034906, 1R01GM090311, 1R01ES 020812]; Proteostasis of Aging Core [AG038072]; American Diabetes Association [1-15-MI-03]; FWF [I1000, P27893, P29203, P24381-B20]; BMWFW [80.109/0001-WF/V/3b/2015]; Spanish Ministerio de Economia y Competitividad [BFU2011-23578, BFU2015-64630-R] FX This work was supported in part by the Intramural Research Program of the National Institute on Aging, NIH, and by NIH grants R01 AG043483 and R01 DK098656 (J.A.B.), NIH grant AG031782 (A.M.C.), and the Proteostasis of Aging Core AG038072 (A.M.C.). J.M.M. was supported by a postdoctoral fellowship from the American Diabetes Association, grant 1-15-MI-03. P.C. was supported by NIH grants (1P01AG034906, 1R01GM090311, and 1R01ES 020812). F.M. is grateful to the FWF for grants LIPOTOX, I1000, P27893, P29203, and P24381-B20 and the BMWFW for grants "Unconventional Research" and "Flysleep" (80.109/0001-WF/V/3b/2015). J.M.V. was supported by the Spanish Ministerio de Economia y Competitividad (grants BFU2011-23578 and BFU2015-64630-R). The authors thank the personnel from the Servicio Centralizado de Apoyo a la Investigacion (SCAI; University of Cordoba) for technical support. Special thanks to the members of the Translational Gerontology Branch and the Comparative Medicine Section of the National Institute on Aging. In particular we acknowledge Paul Bastian, Elin Lehrmann, Frances Fan, Robin Minor, Dawn Nines, and Dawn Boyer. NR 115 TC 4 Z9 4 U1 4 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD JUN 14 PY 2016 VL 23 IS 6 BP 1093 EP 1112 DI 10.1016/j.cmet.2016.05.027 PG 20 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA DO7ZA UT WOS:000378000600021 PM 27304509 ER PT J AU Sciolino, NR Plummer, NW Chen, YW Alexander, GM Robertson, SD Dudek, SM McElligott, ZA Jensen, P AF Sciolino, Natale R. Plummer, Nicholas W. Chen, Yu-Wei Alexander, Georgia M. Robertson, Sabrina D. Dudek, Serena M. McElligott, Zoe A. Jensen, Patricia TI Recombinase-Dependent Mouse Lines for Chemogenetic Activation of Genetically Defined Cell Types SO CELL REPORTS LA English DT Article ID LOCUS-COERULEUS NEURONS; SITE-SPECIFIC RECOMBINATION; PROTEIN-COUPLED RECEPTORS; EMBRYONIC STEM-CELLS; MAMMALIAN-CELLS; MICE; CRE; TRANSGENES; MODULATION; EXPRESSION AB Chemogenetic technologies, including the mutated human Gq-coupled M3 muscarinic receptor (hM3Dq), have greatly facilitated our ability to directly link changes in cellular activity to altered physiology and behavior. Here, we extend the hM3Dq toolkit with recombinase-responsive mouse lines that permit hM3Dq expression in virtually any cell type. These alleles encode a fusion protein designed to increase effective expression levels by concentrating hM3Dq to the cell body and dendrites. To illustrate their broad utility, we targeted three different genetically defined cell populations: noradrenergic neurons of the compact, bilateral locus coeruleus and two dispersed populations, Camk2a+ neurons and GFAP+ glia. In all three populations, we observed reproducible expression and confirmed that activation of hM3Dq is sufficient to dose-dependently evoke phenotypic changes, without extreme phenotypes associated with hM3Dq overexpression. These alleles offer the ability to non-invasively control activity of diverse cell types to uncover their function and dysfunction at any developmental stage. C1 [Sciolino, Natale R.; Plummer, Nicholas W.; Chen, Yu-Wei; Alexander, Georgia M.; Dudek, Serena M.; Jensen, Patricia] NIEHS, Neurobiol Lab, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. [Robertson, Sabrina D.] N Carolina State Univ, Biotechnol Program, Dept Mol Biomed Sci, Raleigh, NC 27695 USA. [McElligott, Zoe A.] Univ N Carolina, Sch Med, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27514 USA. [McElligott, Zoe A.] Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC 27514 USA. RP Jensen, P (reprint author), NIEHS, Neurobiol Lab, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. EM patricia.jensen@nih.gov FU Intramural Research Program of the NIH, NIEHS [ES102805, ES100221] FX We thank D. D'Agostin, G. Jones, and K. Smith for technical assistance. We thank B. Roth (University of North Carolina) for providing the hM3Dq-mCherry-2ACT88 cDNA. We also thank J. Haam, C. Erxleben, C. Hull (Duke University), and D. Weinshenker (Emory University) for helpful advice. Valuable support was provided by the NIEHS Comparative Medicine Branch, Knockout Mouse Core, Biostatistics and Computational Biology Branch, and Fluorescence Microscopy and Imaging Core. We thank the NIDA Drug Supply Program for providing the CNO. This research was supported by the Intramural Research Program of the NIH, NIEHS (ES102805 to P.J. and ES100221 to S.M.D.). NR 30 TC 0 Z9 0 U1 1 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 14 PY 2016 VL 15 IS 11 BP 2563 EP 2573 DI 10.1016/j.celrep.2016.05.034 PG 11 WC Cell Biology SC Cell Biology GA DO4TG UT WOS:000377776400023 PM 27264177 ER PT J AU Mitter, SS Vedanthan, R Islami, F Pourshams, A Khademi, H Kamangar, F Abnet, CC Dawsey, SM Pharoah, PD Brennan, P Fuster, V Boffetta, P Malekzadeh, R AF Mitter, Sumeet S. Vedanthan, Rajesh Islami, Farhad Pourshams, Akram Khademi, Hooman Kamangar, Farin Abnet, Christian C. Dawsey, Sanford M. Pharoah, Paul D. Brennan, Paul Fuster, Valentin Boffetta, Paolo Malekzadeh, Reza TI Household Fuel Use and Cardiovascular Disease Mortality Golestan Cohort Study SO CIRCULATION LA English DT Article DE air pollution; epidemiology; heart diseases; mortality; stroke ID DIESEL-EXHAUST INHALATION; INDOOR AIR-POLLUTION; WOOD SMOKE EXPOSURE; LONG-TERM EXPOSURE; BLOOD-PRESSURE; ESOPHAGEAL CANCER; BIOMASS FUEL; WOMEN; INTERVENTION; COOKING AB Background-Household air pollution is the third largest risk factor for global disease burden, but direct links with cardiovascular disease mortality are limited. This study aimed to evaluate the relationship between household fuel use and cardiovascular disease mortality. Methods and Results-The Golestan Cohort Study in northeastern Iran enrolled 50 045 individuals 40 to 75 years of age between 2004 and 2008 and collected data on lifetime household fuel use and other baseline exposures. Participants were followed up through 2012 with a 99% successful follow-up rate. Cox proportional hazards models were fitted to calculate hazard ratios for associations between pehen (local dung), wood, kerosene/diesel, or natural gas burning for cooking and heating and all-cause and cause-specific mortality, with adjustment for lifetime exposure to each of these fuels and potential confounders. A total of 3073 participants (6%) died during follow-up; 78% of these deaths were attributable to noncommunicable diseases, including cardiovascular, oncological, and respiratory illnesses. Adjusted 10-year hazard ratios from kerosene/diesel burning were 1.06 (95% confidence interval, 1.02-1.10) and 1.11 (95% confidence interval, 1.06-1.17) for all-cause and cardiovascular mortality, respectively. Subtype-specific analyses revealed a significant increase in ischemic heart disease (10-year hazard ratio, 1.14; 95% confidence interval, 1.06-1.21) and a trend toward cerebrovascular accident (10-year hazard ratio, 1.08; 95% confidence interval, 0.99-1.17) mortality. Stratification by sex revealed a potential signal for increased risk for all-cause and cardiovascular disease mortality among women compared with men, with similar risk for ischemic heart disease mortality. Conclusions-Household exposure to high-pollution fuels was associated with increased risk for all-cause and cardiovascular disease mortality. Replicating these results worldwide would support efforts to reduce such exposures. C1 [Mitter, Sumeet S.] Northwestern Univ, Feinberg Sch Med, Dept Med, Div Cardiol, 676 N St Clair St,Ste 600, Chicago, IL 60611 USA. [Vedanthan, Rajesh; Fuster, Valentin] Icahn Sch Med Mt Sinai, Zena & Michael A Wiener Cardiovasc Inst, New York, NY 10029 USA. [Islami, Farhad; Brennan, Paul] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Islami, Farhad; Brennan, Paul] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA. [Islami, Farhad; Pourshams, Akram; Malekzadeh, Reza] Univ Tehran Med Sci, Digest Dis Res Inst, Digest Oncol Res Ctr, Tehran, Iran. [Islami, Farhad] Amer Canc Soc, Surveillance & Hlth Serv Res, Atlanta, GA 30329 USA. [Khademi, Hooman; Brennan, Paul] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Hlth Anal, Baltimore, MD 21239 USA. [Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Pharoah, Paul D.] Univ Cambridge, Dept Oncol, Cambridge CB2 1TN, England. [Pharoah, Paul D.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB2 1TN, England. [Fuster, Valentin] Ctr Nacl Invest Cardiovasc, Madrid, Spain. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. RP Mitter, SS (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Med, Div Cardiol, 676 N St Clair St,Ste 600, Chicago, IL 60611 USA. EM sumeet.mitter@northwestern.edu RI Abnet, Christian/C-4111-2015; Fuster, Valentin/H-4319-2015 OI Abnet, Christian/0000-0002-3008-7843; Fuster, Valentin/0000-0002-9043-9986 FU Tehran University of Medical Sciences (Tehran, Iran) [81/15]; Cancer Research UK (London, UK) [C20/A5860]; US National Cancer Institute (Bethesda, MD); International Agency for Research on Cancer (Lyon, France); Fogarty International Center of the National Institutes of Health (Bethesda, MD) [K01 TW 009218-05] FX The Golestan Cohort Study was funded by Tehran University of Medical Sciences (grant 81/15, Tehran, Iran), by Cancer Research UK (grant C20/A5860, London, UK), by the Intramural Research Program of the US National Cancer Institute (Bethesda, MD), and through various collaborative research agreements with the International Agency for Research on Cancer (Lyon, France). Dr Vedanthan receives grant funding from the Fogarty International Center of the National Institutes of Health (K01 TW 009218-05, Bethesda, MD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 39 TC 2 Z9 2 U1 5 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JUN 14 PY 2016 VL 133 IS 24 BP 2360 EP + DI 10.1161/CIRCULATIONAHA.115.020288 PG 23 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DO8PI UT WOS:000378045100009 PM 27297340 ER PT J AU McCracken, ML Gorini, G McCracken, LM Mayfield, RD Harris, RA Trudell, JR AF McCracken, Mandy L. Gorini, Giorgio McCracken, Lindsay M. Mayfield, R. Dayne Harris, R. Adron Trudell, James R. TI Inter- and Intra-Subunit Butanol/Isoflurane Sites of Action in the Human Glycine Receptor SO FRONTIERS IN MOLECULAR NEUROSCIENCE LA English DT Article DE GLRA1; alcohol; anesthetic; Xenopus oocytes; GluCl model; massspectrometry; immunoblotting; proteomics ID GATED ION CHANNELS; ACID TYPE-A; ANESTHETIC BINDING-SITE; GABA(A) RECEPTOR; CROSS-LINKING; TRANSMEMBRANE DOMAIN; GENERAL-ANESTHETICS; ACETYLCHOLINE-RECEPTOR; CHLORIDE CHANNEL; STRUCTURAL BASIS AB Glycine receptors (GlyRs) mediate inhibitory neurotransmission and are targets for alcohols and anesthetics in brain. GlyR transmembrane (TM) domains contain critical residues for alcohol/anesthetic action: amino acid A288 in TM3 forms crosslinks with TM1 (1229) in the adjacent subunit as well as TM2 (S267) and TM4 (Y406, W407, 1409, Y410) in the same subunit. We hypothesized that these residues may participate in intra-subunit and inter-subunit sites of alcohol/anesthetic action. The following double and triple mutants of GLRA1 cDNA (encoding human glycine receptor alpha 1 subunit) were injected into)Aenopus laevis oocytes: I229C/A288C, 1229C/A288C/C290S, A288C/Y406C, A288C/W407C, A288C/1409C, and A288C/Y410C along with the corresponding single mutants and wild-type GLRA1. Butanol (22 mM) or isoflurane (0.6 mM) potentiation of GlyR-mediated currents before and after application of the cysteine crosslinking agent HgCL2 (10 mu M) was measured using two-electrode voltage clamp electrophysiology. Crosslinking nearly abolished butanol and isoflurane potentiation in the I229C/A288C and 1229C/A288C/C290S mutants but had no effect in single mutants or wild-type. Crosslinking also inhibited butanol and isoflurane potentiation in the TM3-4 mutants (A288C/Y406C, A288C/W407C, A288C/1409C, A288C/Y410C) with no effect in single mutants or wild-type. We extracted proteins from oocytes expressing I229C/288C, A288C/Y410C, or wild-type GlyRs, used mass spectrometry to verify their expression and possible inter-subunit dimerization, plus immunoblotting to investigate the biochemical features of proposed crosslinks. Wild-type GlyR subunits measured about 50 kDa; after crosslinking, the dimeric/monomeric 100:50 kDa band ratio was significantly increased in I229C/288C but not A288C/Y410C mutants or wild-type, providing support for TM1-3 inter-subunit and TM3-4 intra-subunit crosslinking. A GlyR homology model based on the GluCl template provides further evidence for a multi-site model for alcohol/anesthetic interaction with human GLRA1. C1 [McCracken, Mandy L.; Gorini, Giorgio; McCracken, Lindsay M.; Mayfield, R. Dayne; Harris, R. Adron] Univ Texas Austin, Waggoner Ctr Alcohol & Addict Res, Austin, TX 78712 USA. [McCracken, Mandy L.] NIDA, Integrat Neurosci Res Branch, Neurobiol Addict Sect, NIH, Baltimore, MD USA. [Trudell, James R.] Stanford Sch Med, Dept Anesthesia, Stanford, CA USA. [Trudell, James R.] Stanford Sch Med, Beckman Program Mol & Genet Med, Stanford, CA USA. RP Harris, RA (reprint author), Univ Texas Austin, Waggoner Ctr Alcohol & Addict Res, Austin, TX 78712 USA. EM harris@austin.utexas.edu RI Gorini, Giorgio/D-7053-2014 OI Gorini, Giorgio/0000-0002-0893-5922 FU National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism [R01 AA013378, R37 AA006399, R01 AA020980, U01 AA016648, U01 AA0209260] FX This work was supported by the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism (grants R01 AA013378; R37 AA006399; R01 AA020980; U01 AA016648; U01 AA0209260). NR 63 TC 0 Z9 0 U1 3 U2 7 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5099 J9 FRONT MOL NEUROSCI JI Front. Molec. Neurosci. PD JUN 14 PY 2016 VL 9 AR 45 DI 10.3389/fnmol.2016.00045 PG 13 WC Neurosciences SC Neurosciences & Neurology GA DO3WT UT WOS:000377713900001 PM 27378846 ER PT J AU Lerner, ZF Browning, RC AF Lerner, Zachary F. Browning, Raymond C. TI Compressive and shear hip joint contact forces are affected by pediatric obesity during walking SO JOURNAL OF BIOMECHANICS LA English DT Article DE Obesity; Gait biomechanics; Musculoskeletal modeling; Personalized; Joint loading; OpenSim; Orthopedics ID MUSCULOSKELETAL PAIN; PHYSICAL-ACTIVITY; LOWER-EXTREMITY; MUSCLE FUNCTION; BONE GEOMETRY; CHILDREN; ADOLESCENTS; GAIT; OVERWEIGHT; KINEMATICS AB Obese children exhibit altered gait mechanics compared to healthy-weight children and have an increased prevalence of hip pain and pathology. This study sought to determine the relationships between body mass and compressive and shear hip joint contact forces during walking. Kinematic and kinetic data were collected during treadmill walking at 1 m s(-1) in 10 obese and 10 healthy-weight 8-12 year-olds. We estimated body composition, segment masses, lower-extremity alignment, and femoral neck angle via radiographic images, created personalized musculoskeletal models in OpenSim, and computed muscle forces and hip joint contact forces. Hip extension at mid-stance was 9 degrees less, on average, in the obese children (p < 0.001). Hip abduction, knee flexion, and body-weight normalized peak hip moments were similar between groups. Normalized to body-weight, peak contact forces were similar at the first peak and slightly lower at the second peak between the obese and healthy-weight participants. Total body mass explained a greater proportion of contact force variance compared to lean body mass in the compressive (r(2)=0.89) and vertical shear (perpendicular to the physic acting superior-to-inferior) (r(2)=0.84) directions; lean body mass explained a greater proportion in the posterior shear direction (r(2)=0.54). Stance-average contact forces in the compressive and vertical shear directions increased by 41 N and 48 N, respectively, for every kilogram of body mass. Age explained less than 27% of the hip loading variance. No effect of sex was found. The proportionality between hip loads and body-weight may be implicated in an obese child's increased risk of hip pain and pathology. Published by Elsevier Ltd. C1 [Lerner, Zachary F.] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bethesda, MD 20892 USA. [Lerner, Zachary F.; Browning, Raymond C.] Colorado State Univ, Sch Biomed Engn, Ft Collins, CO 80523 USA. [Browning, Raymond C.] Colorado State Univ, Dept Hlth & Exercise Sci, Ft Collins, CO 80523 USA. RP Lerner, ZF (reprint author), NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, CRC, Bldg 10,Room 1-1469,MSC 1604, Bethesda, MD 20892 USA. EM Zachary.Lerner@nih.gov FU Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health [F31HD080261]; ACSM Foundation Research Grant from the American College of Sports Medicine FX This research was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number F31HD080261 and by an ACSM Foundation Research Grant from the American College of Sports Medicine. We thank the Medical Center of the Rockies Healthy Hearts program for their assistance in participant recruitment. We also thank all of the researchers associated with Orthoload for making their valuable datasets publically available. NR 30 TC 0 Z9 0 U1 5 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 EI 1873-2380 J9 J BIOMECH JI J. Biomech. PD JUN 14 PY 2016 VL 49 IS 9 BP 1547 EP 1553 DI 10.1016/j.jbiomech.2016.03.033 PG 7 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA DO4DE UT WOS:000377731200020 PM 27040390 ER PT J AU Liu, HP Kurtoglu, M Leon-Annicchiarico, CL Munoz-Pinedo, C Barredo, J Leclerc, G Merchan, J Liu, XF Lampidis, TJ AF Liu, Huaping Kurtoglu, Metin Lucia Leon-Annicchiarico, Clara Munoz-Pinedo, Cristina Barredo, Julio Leclerc, Guy Merchan, Jaime Liu, Xiongfei Lampidis, Theodore J. TI Combining 2-deoxy-D-glucose with fenofibrate leads to tumor cell death mediated by simultaneous induction of energy and ER stress SO ONCOTARGET LA English DT Article DE 2-deoxy-D-glucose; fenofibrate; energy stress; mTOR; eIF2 alpha ID GLYCOLYTIC INHIBITOR 2-DEOXY-D-GLUCOSE; ENDOPLASMIC-RETICULUM; METABOLISM; GLYCOSYLATION; CYTOTOXICITY; INCREASES; APOPTOSIS; EFFICACY; CANCERS AB Unregulated growth and replication as well as an abnormal microenvironment, leads to elevated levels of stress which is a common trait of cancer. By inducing both energy and endoplasmic reticulum (ER) stress, 2-Deoxy-glucose (2-DG) is particularly well-suited to take advantage of the therapeutic window that heightened stress in tumors provides. Under hypoxia, blocking glycolysis with 2-DG leads to significant lowering of ATP resulting in energy stress and cell death in numerous carcinoma cell types. In contrast, under normoxia, 2-DG at a low-concentration is not toxic in most carcinomas tested, but induces growth inhibition, which is primarily due to ER stress. Here we find a synergistic toxic effect in several tumor cell lines in vitro combining 2-DG with fenofibrate (FF), a drug that has been safely used for over 40 years to lower cholesterol in patients. This combination induces much greater energy stress than either agent alone, as measured by ATP reduction, increased p-AMPK and downregulation of mTOR. Inhibition of mTOR results in blockage of GRP78 a critical component of the unfolded protein response which we speculate leads to greater ER stress as observed by increased p-eIF2 alpha. Moreover, to avoid an insulin response and adsorption by the liver, 2-DG is delivered by slow-release pump yielding significant anti-tumor control when combined with FF. Our results provide promise for developing this combination clinically and others that combine 2-DG with agents that act synergistically to selectively increase energy and ER stress to a level that is toxic to numerous tumor cell types. C1 [Liu, Huaping; Liu, Xiongfei; Lampidis, Theodore J.] Univ Miami, Miller Sch Med, Dept Cell Biol, Miami, FL 33136 USA. [Liu, Huaping; Barredo, Julio; Leclerc, Guy; Merchan, Jaime; Liu, Xiongfei; Lampidis, Theodore J.] Sylvester Comprehens Canc Ctr, Miami, FL USA. [Kurtoglu, Metin] NIH, Bldg 10, Bethesda, MD 20892 USA. [Lucia Leon-Annicchiarico, Clara; Munoz-Pinedo, Cristina] IDIBELL Bellvitage Biomed Res Inst, Cell Death Regulat Grp, Barcelona, Spain. [Barredo, Julio; Leclerc, Guy] Univ Miami, Miller Sch Med, Dept Pediat, Miami, FL 33136 USA. [Merchan, Jaime] Univ Miami, Miller Sch Med, Dept Med, Miami, FL 33136 USA. RP Lampidis, TJ (reprint author), Univ Miami, Miller Sch Med, Dept Cell Biol, Miami, FL 33136 USA.; Lampidis, TJ (reprint author), Sylvester Comprehens Canc Ctr, Miami, FL USA. EM tlampidi@miami.edu RI Munoz-Pinedo, Cristina/B-6118-2008 OI Munoz-Pinedo, Cristina/0000-0002-9120-664X NR 27 TC 1 Z9 1 U1 2 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 14 PY 2016 VL 7 IS 24 BP 36461 EP 36473 DI 10.18632/oncotarget.9263 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4MJ UT WOS:000377756800075 PM 27183907 ER PT J AU Kaye, DR Pinto, PA Cecchi, F Reilly, J Semerjian, A Rabe, DC Gupta, G Choyke, PL Bottaro, DP AF Kaye, Deborah R. Pinto, Peter A. Cecchi, Fabiola Reilly, Joseph Semerjian, Alice Rabe, Daniel C. Gupta, Gopal Choyke, Peter L. Bottaro, Donald P. TI Tumor and Plasma Met Levels in Non-Metastatic Prostate Cancer SO PLOS ONE LA English DT Article ID HEPATOCYTE GROWTH-FACTOR; C-MET; BONE METASTASES; ANTIGEN LEVEL; PROGRESSION; EXPRESSION; RECEPTOR; CABOZANTINIB; CARCINOMA; LOCATION AB Objective To measure Met protein content in prostate biopsies guided by fused magnetic resonance and ultrasound imaging, and to measure soluble Met (sMet) protein concentration in plasma samples from patients presenting evidence of prostate cancer. Patients and Methods 345 patients had plasma samples drawn prior to image-guided biopsy of the prostate. Of these, 32% had benign biopsies. Of the 236 that were positive for prostate adenocarcinoma (PCa), 132 treated by total prostatectomy had Gleason scores of 6 (17%), 7, (55%), 8 (16%), or 9-10 (12%). 23% had evidence of local invasion. Plasma samples were also obtained from 80 healthy volunteers. Tissue Met and plasma sMet were measured by two-site immunoassay; values were compared among clinically defined groups using non-parametric statistical tests to determine significant differences or correlations. Results PCa tumor Met correlated significantly with plasma sMet, but median values were similar among benign and malignant groups. Median plasma sMet values were also similar among those groups, although both medians were significantly above normal. Median Met content in primary PCa tumors and sMet concentrations were independent of Gleason score, final pathologic stage and age. Conclusion Plasma sMet is not predictive of PCa or its severity in patients with organ-confined or locally invasive disease. Quantitative analysis of Met protein content and activation state in PCa tumor biopsy samples was highly feasible and may have value in follow-up to genomic and/or transcriptomic-based screens that show evidence of oncogenically relevant MET gene features that occur at relatively low frequency in non-metastatic PCa. C1 [Kaye, Deborah R.; Pinto, Peter A.; Cecchi, Fabiola; Reilly, Joseph; Semerjian, Alice; Rabe, Daniel C.; Gupta, Gopal; Bottaro, Donald P.] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Choyke, Peter L.] NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Kaye, Deborah R.] Johns Hopkins Univ, James Buchanan Brady Urol Inst, 600 N Wolfe St, Baltimore, MD 21287 USA. [Cecchi, Fabiola; Reilly, Joseph] NantOmics, 9600 Med Ctr Dr,Suite 300, Rockville, MD 20850 USA. [Semerjian, Alice] George Washington Univ Med Fac Associates, 2150 Penn Ave NW, Washington, DC 20037 USA. [Rabe, Daniel C.] Univ Chicago, Div Biol Sci, BSLC, 924 E 57th St,Suite 104, Chicago, IL 60637 USA. [Gupta, Gopal] Loyola Univ, Med Ctr, Dept Urol, 2160 S First Ave,Bldg 54,Room 237A, Maywood, IL 60153 USA. RP Bottaro, DP (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM dbottaro@helix.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; National Institutes of Health Intramural Research Program, National Cancer Institute, Center for Cancer Research [ZIA BC011124] FX This work was funded by the National Institutes of Health Intramural Research Program, National Cancer Institute, Center for Cancer Research, awarded to DPB, ZIA BC011124: http://fundedresearch.cancer.gov/nciportfolio/search/detailsaction=abstr act&grantNum=ZIA%20BC%20011124&grantID=34045&grtSCDC=FY%202013&absID=340 45&absSCDC=PUB2013. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Alessio Giubellino for contributions to Met measurements reported here. NR 28 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 14 PY 2016 VL 11 IS 6 AR e0157130 DI 10.1371/journal.pone.0157130 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO5KO UT WOS:000377822200030 PM 27300295 ER PT J AU Lee, ES Vedanthan, R Jeemon, P Kamano, JH Kudesia, P Rajan, V Engelgau, M Moran, AE AF Lee, Edward S. Vedanthan, Rajesh Jeemon, Panniyammakal Kamano, Jemima H. Kudesia, Preeti Rajan, Vikram Engelgau, Michael Moran, Andrew E. TI Quality Improvement for Cardiovascular Disease Care in Low- and Middle-Income Countries: A Systematic Review SO PLOS ONE LA English DT Review ID CLUSTER-RANDOMIZED-TRIAL; ACUTE CORONARY SYNDROMES; RHEUMATIC HEART-DISEASE; HEALTH-INSURANCE; CLINICAL-TRIAL; BLOOD-PRESSURE; RISK-FACTORS; SECONDARY PREVENTION; POLYPILL POLYCAP; PEER SUPPORT AB Background The majority of global cardiovascular disease (CVD) burden falls on people living in low- and middle-income countries (LMICs). In order to reduce preventable CVD mortality and morbidity, LMIC health systems and health care providers need to improve the delivery and quality of CVD care. Objectives As part of the Disease Control Priorities Three (DCP3) Study efforts addressing quality improvement, we reviewed and summarized currently available evidence on interventions to improve quality of clinic-based CVD prevention and management in LMICs. Methods We conducted a narrative review of published comparative clinical trials that evaluated efficacy or effectiveness of clinic-based CVD prevention and management quality improvement interventions in LMICs. Conditions selected a priori included hypertension, diabetes, hyperlipidemia, coronary artery disease, stroke, rheumatic heart disease, and congestive heart failure. MEDLINE and EMBASE electronic databases were systematically searched. Studies were categorized as occurring at the system or patient/provider level and as treating the acute or chronic phase of CVD. Results From 847 articles identified in the electronic search, 49 met full inclusion criteria and were selected for review. Selected studies were performed in 19 different LMICs. There were 10 studies of system level quality improvement interventions, 38 studies of patient/provider interventions, and one study that fit both criteria. At the patient/provider level, regardless of the specific intervention, intensified, team-based care generally led to improved medication adherence and hypertension control. At the system level, studies provided evidence that introduction of universal health insurance coverage improved hypertension and diabetes control. Studies of system and patient/provider level acute coronary syndrome quality improvement interventions yielded inconclusive results. The duration of most studies was less than 12 months. Conclusions The results of this review suggest that CVD care quality improvement can be successfully implemented in LMICs. Most studies focused on chronic CVD conditions; more acute CVD care quality improvement studies are needed. Longer term interventions and follow-up will be needed in order to assess the sustainability of quality improvement efforts in LMICs. C1 [Lee, Edward S.] Univ So Calif, Keck Sch Med, Dept Med, Palliat & Gen Internal Med,Div Geriatr, Los Angeles, CA 90033 USA. [Vedanthan, Rajesh] Icahn Sch Med Mt Sinai, Div Cardiol, Dept Med, New York, NY 10029 USA. [Jeemon, Panniyammakal] Publ Hlth Fdn India, Ctr Control Chron Condit, Cochin, Kerala, India. [Kamano, Jemima H.] Moi Univ, Coll Hlth Sci, Eldoret, Kenya. [Kamano, Jemima H.] Acad Model Providing Access Healthcare, Eldoret, Kenya. [Kudesia, Preeti] World Bank, Hlth Nutr & Populat Global Practice, Kathmandu, Nepal. [Rajan, Vikram] World Bank, Jakarta, Indonesia. [Engelgau, Michael] NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Moran, Andrew E.] Columbia Univ, Div Gen Med, Dept Med, Med Ctr, New York, NY USA. RP Moran, AE (reprint author), Columbia Univ, Div Gen Med, Dept Med, Med Ctr, New York, NY USA. EM aem35@cumc.columbia.edu FU U.S. National Heart, Lung and Blood Institute career development award [K08 HL089675-01]; Fogarty International Center of the U.S. National Institutes of Health [K01 TW 009218-05]; Department of Biotechnology India Alliance clinical and public health intermediate career fellowship; Wellcome Trust FX AEM was supported by a grant from the U.S. National Heart, Lung and Blood Institute career development award (K08 HL089675-01; www.nhlbi.nih.gov). RV was supported by a grant from the Fogarty International Center of the U.S. National Institutes of Health (K01 TW 009218-05; www.flc.nih.gov). PJ is supported by a Wellcome Trust, Department of Biotechnology India Alliance clinical and public health intermediate career fellowship (www.wellcome.ac.uk). The views expressed in this article are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, National Institutes of Health, or the U.S. Department of Health and Human Services. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 3 Z9 3 U1 6 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 14 PY 2016 VL 11 IS 6 AR e0157036 DI 10.1371/journal.pone.0157036 PG 28 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO5KO UT WOS:000377822200025 PM 27299563 ER PT J AU Moscicki, AB Yao, TJ Ryder, MI Russell, JS Dominy, SS Patel, K McKenna, M Van Dyke, RB Seage, GR Hazra, R Shiboski AF Moscicki, Anna-Barbara Yao, Tzy-Jyun Ryder, Mark I. Russell, Jonathan S. Dominy, Stephen S. Patel, Kunjal McKenna, Matt Van Dyke, Russell B. Seage, George R., III Hazra, Rohan Shiboski TI The Burden of Oral Disease among Perinatally HIV-Infected and HIV-Exposed Uninfected Youth SO PLOS ONE LA English DT Article ID EARLY ENAMEL CARIES; DENTAL-CARIES; ANTIRETROVIRAL TREATMENT; US CHILDREN; PREVALENCE; PREDICTORS; BACTERIA; THERAPY; LESIONS; HUMANS AB Objective To compare oral health parameters in perinatally HIV-infected (PHIV) and perinatally HIV-exposed but uninfected youth (PHEU). Methods In a cross-sectional substudy within the Pediatric HIV/AIDS Cohort Study, participants were examined for number of decayed teeth (DT), Decayed, Missing, and Filled Teeth (DMFT), oral mucosal disease, and periodontal disease (PD). Covariates for oral health parameters were examined using zero-inflated negative binomial regression and ordinal logistic regression models. Results Eleven sites enrolled 209 PHIV and 126 PHEU. Higher DT scores were observed in participants who were PHIV [ Adjusted Mean Ratio (aMR) = 1.7 (95% CI 1.2-2.5)], female [ aMR = 1.4 (1.0-1.9)], had no source of regular dental care [aMR = 2.3 (1.5-3.4)], and had a high frequency of meals/snacks [>= 5 /day vs 0-3, aMR = 1.9 (1.1-3.1)] and juice/soda [>= 5 /day vs 0-3, aMR = 1.6 (1.1-2.4)]. Higher DMFT scores were observed in participants who were older [>= 19, aMR = 1.9 (1.2-2.9)], had biological parent as caregiver [ aMR = 1.2 (1.0-1.3)], had a high frequency of juice/soda [>= 5 /day vs 0-3, aMR = 1.4 (1.1-1.7)] and a low salivaflow rate [mL/min, aMR = 0.8 per unit higher (0.6-1.0)]. Eighty percent had PD; no differences were seen by HIV status using the patient-based classifications of health, gingivitis or mild, moderate, or severe periodontitis. No associations were observed of CD4 count and viral load with oral health outcomes after adjustment. Conclusions Oral health was poor in PHIV and PHEU youth. This was dismaying since most HIV infected children in the U.S. are carefully followed at medical health care clinics. This data underscore the need for regular dental care. As PHIV youth were at higher risk for cavities, it will be important to better understand this relationship in order to develop targeted interventions. C1 [Moscicki, Anna-Barbara] Univ Calif Los Angeles, Dept Pediat, Div Adolescent Med, Los Angeles, CA 90024 USA. [Yao, Tzy-Jyun; Russell, Jonathan S.; McKenna, Matt] Harvard Univ, TH Chan Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Ryder, Mark I.; Shiboski] Univ Calif San Francisco, Sch Dent, Dept Orofacial Sci, San Francisco, CA USA. [Dominy, Stephen S.] Univ Calif San Francisco, Sch Med, Dept Psychiat, San Francisco, CA 94143 USA. [Patel, Kunjal] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Van Dyke, Russell B.] Tulane Univ, Sch Med, Dept Pediat, New Orleans, LA 70112 USA. [Seage, George R., III] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, Bethesda, MD USA. RP Moscicki, AB (reprint author), Univ Calif Los Angeles, Dept Pediat, Div Adolescent Med, Los Angeles, CA 90024 USA. EM amoscicki@mednet.ucla.edu FU National Institute of Dental and Craniofacial Research; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Allergy and Infectious Diseases; Office of AIDS Research; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders; National Heart Lung and Blood Institute; National Institute on Alcohol Abuse and Alcoholism; Harvard T. H. Chan School of Public Health [HD052102, 3 U01 HD052102-05S1, 3 U01 HD052102-06S3]; Tulane University School of Medicine [HD052104, 3U01 HD052104-06S1] FX This study was supported by the National Institute of Dental and Craniofacial Research and Eunice Kennedy Shriver National Institute of Child Health and Human Development with cofunding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard T. H. Chan School of Public Health (HD052102, 3 U01 HD052102-05S1, and 3 U01 HD052102-06S3) (PI: George Seage; Project Director: Julie Alperen) and the Tulane University School of Medicine (HD052104, 3U01 HD052104-06S1) (PI: Russell Van Dyke; Co-PI: Kenneth Rich; Project Director: Patrick Davis). Data management services were provided by Frontier Science and Technology Research Foundation (PI: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc (PI: Julie Davidson). The funders NICHD have a significant role in study design, data collection, decision to publish and preparation of manuscript. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. Westat, Inc. provided regulatory services, protocol development support and logistical support but had no additional role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 2 Z9 2 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 14 PY 2016 VL 11 IS 6 AR e0156459 DI 10.1371/journal.pone.0156459 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO5KO UT WOS:000377822200008 PM 27299992 ER PT J AU Soto, C Ofek, G Joyce, MG Zhang, BS Mckee, K Longo, NS Yang, YP Huang, JH Parks, R Eudailey, J Lloyd, KE Alam, SM Haynes, BF Mullikin, JC Connors, M Mascola, JR Shapiro, L Kwong, PD AF Soto, Cinque Ofek, Gilad Joyce, M. Gordon Zhang, Baoshan Mckee, Krisha Longo, Nancy S. Yang, Yongping Huang, Jinghe Parks, Robert Eudailey, Joshua Lloyd, Krissey E. Alam, S. Munir Haynes, Barton F. Mullikin, James C. Connors, Mark Mascola, John R. Shapiro, Lawrence Kwong, Peter D. CA NISC Comparative Sequencing TI Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8 SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; BROADLY NEUTRALIZING ANTIBODIES; POTENT NEUTRALIZATION; HIV-1 NEUTRALIZATION; 2F5-LIKE ANTIBODIES; IMMUNOGEN DESIGN; STRUCTURAL BASIS; GP41; EPITOPE; AUTOREACTIVITY AB Antibody 10E8 targets the membrane-proximal external region (MPER) of HIV-1 gp41, neutralizes >97% of HIV-1 isolates, and lacks the auto-reactivity often associated with MPER-directed antibodies. The developmental pathway of 10E8 might therefore serve as a promising template for vaccine design, but samples from time-of-infection-often used to infer the B cell record-are unavailable. In this study, we used crystallography, next-generation sequencing (NGS), and functional assessments to infer the 10E8 developmental pathway from a single time point. Mutational analysis indicated somatic hypermutation of the 2nd-heavy chain-complementarity determining region (CDR H2) to be critical for neutralization, and structures of 10E8 variants with V-gene regions reverted to genomic origin for heavy- nd-light chains or heavy chain-only showed structural differences > 2 angstrom relative to mature 10E8 in the CDR H2 and H3. To understand these developmental changes, we used bioinformatic sieving, maximum likelihood, and parsimony analyses of immunoglobulin transcripts to identify 10E8-lineage members, to infer the 10E8-unmutated common ancestor (UCA), and to calculate 10E8-developmental intermediates. We were assisted in this analysis by the preservation of a critical D-gene segment, which was unmutated in most 10E8-lineage sequences. UCA and early intermediates weakly bound a 26-residue-MPER peptide, whereas HIV-1 neutralization and epitope recognition in liposomes were only observed with late intermediates. Antibody 10E8 thus develops from a UCA with weak MPER affinity and substantial differences in CDR H2 and H3 from the mature 10E8; only after extensive somatic hypermutation do 10E8-lineage members gain recognition in the context of membrane and HIV-1 neutralization. C1 [Soto, Cinque; Ofek, Gilad; Joyce, M. Gordon; Zhang, Baoshan; Mckee, Krisha; Longo, Nancy S.; Yang, Yongping; Mascola, John R.; Shapiro, Lawrence; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Huang, Jinghe; Connors, Mark] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Parks, Robert; Eudailey, Joshua; Lloyd, Krissey E.; Alam, S. Munir; Haynes, Barton F.] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC USA. [Mullikin, James C.; NISC Comparative Sequencing] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY USA. RP Mascola, JR; Shapiro, L; Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Shapiro, L (reprint author), Columbia Univ, Dept Biochem & Mol Biophys, New York, NY USA. EM jmascola@nih.gov; shapiro@convex.hhmi.columbia.edu; pdkwong@nih.gov FU Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Human Genome Research Institute, National Institutes of Health; Center for HIV/AIDS Vaccine Immunology-Immunogen Design grant from the Division of AIDS National Institutes of Infectious Disease, NIH [UM1 AI100645] FX Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases and the National Human Genome Research Institute, National Institutes of Health, and by the Center for HIV/AIDS Vaccine Immunology-Immunogen Design grant UM1 AI100645 to BFH from the Division of AIDS National Institutes of Infectious Disease, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 6 Z9 6 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 14 PY 2016 VL 11 IS 6 AR e0157409 DI 10.1371/journal.pone.0157409 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO5KO UT WOS:000377822200046 PM 27299673 ER PT J AU Zainabadi, K AF Zainabadi, Kayvan TI Malaria Parasite CLAG3, a Protein Linked to Nutrient Channels, Participates in High Molecular Weight Membrane-Associated Complexes in the Infected Erythrocyte SO PLOS ONE LA English DT Article ID RED-BLOOD-CELLS; SURFACE ANION CHANNEL; PLASMODIUM-FALCIPARUM; HOST ERYTHROCYTE; PERMEATION PATHWAYS; MULTIGENE FAMILY; RHOPH COMPLEX; RESISTANCE; PERMEABILITY; COMPONENT AB Malaria infected erythrocytes show increased permeability to a number of solutes important for parasite growth as mediated by the Plasmodial Surface Anion Channel (PSAC). The P. falciparum clag3 genes have recently been identified as key determinants of PSAC, though exactly how they contribute to channel function and whether additional host/ parasite proteins are required remain unknown. To begin to answer these questions, I have taken a biochemical approach. Here I have used an epitope-tagged CLAG3 parasite to perform coimmunoprecipitation experiments using membrane fractions of infected erythrocytes. Native PAGE and mass spectrometry studies reveal that CLAG3 participate in at least three different high molecular weight complexes: a similar to 720kDa complex consisting of CLAG3, RHOPH2 and RHOPH3; a similar to 620kDa complex consisting of CLAG3 and RHOPH2; and a similar to 480kDa complex composed solely of CLAG3. Importantly, these complexes can be found throughout the parasite lifecycle but are absent in untransfected controls. Extracellular biotin labeling and protease susceptibility studies localize the 480kDa complex to the erythrocyte membrane. This complex, likely composed of a homo-oligomer of 160kDa CLAG3, may represent a functional subunit, possibly the pore, of PSAC. C1 [Zainabadi, Kayvan] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Zainabadi, Kayvan] Univ Maryland, Sch Med, Inst Global Hlth, Div Malaria Res, Baltimore, MD 21201 USA. RP Zainabadi, K (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA.; Zainabadi, K (reprint author), Univ Maryland, Sch Med, Inst Global Hlth, Div Malaria Res, Baltimore, MD 21201 USA. EM kzainabadi@medicine.umaryland.edu FU Malaria Infection Biology Research Fellowship (NIAID); Intramural Research Program of NIAID, National Institutes of Health FX This research was supported by a Malaria Infection Biology Research Fellowship (NIAID) and by the Intramural Research Program of NIAID, National Institutes of Health.; I would like to thank Susan Pierce for her encouragement, Louis Miller and Tom Wellems for their support and critical reading of the manuscript, Sanjay Desai for helpful discussions and feedback on experiments, and the Research Technologies Branch of the National Institutes of Allergy and Infectious Diseases (NIAD), particularly Renee Olano, for their help with mass spectrometry experiments. This research was supported by a Malaria Infection Biology Research Fellowship (NIAID) and by the Intramural Research Program of NIAID, National Institutes of Health. NR 35 TC 1 Z9 1 U1 0 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 14 PY 2016 VL 11 IS 6 AR e0157390 DI 10.1371/journal.pone.0157390 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO5KO UT WOS:000377822200045 PM 27299521 ER PT J AU Grace, PM Strand, KA Galer, EL Urban, DJ Wang, XH Baratta, MV Fabisiak, TJ Anderson, ND Cheng, KJ Greene, LI Berkelhammer, D Zhang, YN Ellis, AL Yin, HH Campeau, S Rice, KC Roth, BL Maier, SF Watkins, LR AF Grace, Peter M. Strand, Keith A. Galer, Erika L. Urban, Daniel J. Wang, Xiaohui Baratta, Michael V. Fabisiak, Timothy J. Anderson, Nathan D. Cheng, Kejun Greene, Lisa I. Berkelhammer, Debra Zhang, Yingning Ellis, Amanda L. Yin, Hang Hubert Campeau, Serge Rice, Kenner C. Roth, Bryan L. Maier, Steven F. Watkins, Linda R. TI Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE TLR4; P2X7R; danger signals; DAMP; opioid-induced hyperalgesia ID OPIOID-INDUCED HYPERALGESIA; HIV-1 ENVELOPE GLYCOPROTEIN; PROINFLAMMATORY CYTOKINES; PERIPHERAL INFECTION; POSTOPERATIVE PAIN; IMMUNE ACTIVATION; P2X(7) RECEPTORS; CONTROLLED-TRIAL; UNITED-STATES; MURINE MODEL AB Opioid use for pain management has dramatically increased, with little assessment of potential pathophysiological consequences for the primary pain condition. Here, a short course of morphine, starting 10 d after injury in male rats, paradoxically and remarkably doubled the duration of chronic constriction injury (CCI)-allodynia, months after morphine ceased. No such effect of opioids on neuropathic pain has previously been reported. Using pharmacologic and genetic approaches, we discovered that the initiation and maintenance of this multimonth prolongation of neuropathic pain was mediated by a previously unidentified mechanism for spinal cord and pain-namely, morphine-induced spinal NOD-like receptor protein 3 (NLRP3) inflammasomes and associated release of interleukin-1 beta (IL-1 beta). As spinal dorsal horn microglia expressed this signaling platform, these cells were selectively inhibited in vivo after transfection with a novel Designer Receptor Exclusively Activated by Designer Drugs (DREADD). Multiday treatment with the DREADD-specific ligand clozapine-N-oxide prevented and enduringly reversed morphine-induced persistent sensitization for weeks to months after cessation of clozapine-N-oxide. These data demonstrate both the critical importance of microglia and that maintenance of chronic pain created by early exposure to opioids can be disrupted, resetting pain to normal. These data also provide strong support for the recent "two-hit hypothesis" of microglial priming, leading to exaggerated reactivity after the second challenge, documented here in the context of nerve injury followed by morphine. This study predicts that prolonged pain is an unrealized and clinically concerning consequence of the abundant use of opioids in chronic pain. C1 [Grace, Peter M.; Strand, Keith A.; Galer, Erika L.; Wang, Xiaohui; Baratta, Michael V.; Fabisiak, Timothy J.; Anderson, Nathan D.; Greene, Lisa I.; Berkelhammer, Debra; Zhang, Yingning; Ellis, Amanda L.; Campeau, Serge; Maier, Steven F.; Watkins, Linda R.] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. [Grace, Peter M.; Strand, Keith A.; Galer, Erika L.; Wang, Xiaohui; Baratta, Michael V.; Fabisiak, Timothy J.; Anderson, Nathan D.; Greene, Lisa I.; Berkelhammer, Debra; Zhang, Yingning; Ellis, Amanda L.; Yin, Hang Hubert; Campeau, Serge; Maier, Steven F.; Watkins, Linda R.] Univ Colorado, Ctr Neurosci, Boulder, CO 80309 USA. [Grace, Peter M.] Univ Adelaide, Sch Med, Discipline Pharmacol, Adelaide, SA 5005, Australia. [Urban, Daniel J.; Roth, Bryan L.] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Wang, Xiaohui] Chinese Acad Sci, Changchun Inst Appl Chem, Chem Biol Lab, Changchun 130022, Jilin, Peoples R China. [Wang, Xiaohui; Yin, Hang Hubert] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA. [Wang, Xiaohui; Yin, Hang Hubert] Univ Colorado, BioFrontiers Inst, Boulder, CO 80309 USA. [Cheng, Kejun; Rice, Kenner C.] NIAAA, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Yin, Hang Hubert] Tsinghua Univ, Dept Chem, Ctr Basic Mol Sci, Beijing 100082, Peoples R China. RP Grace, PM (reprint author), Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA.; Grace, PM (reprint author), Univ Colorado, Ctr Neurosci, Boulder, CO 80309 USA.; Grace, PM (reprint author), Univ Adelaide, Sch Med, Discipline Pharmacol, Adelaide, SA 5005, Australia. EM peter.grace@colorado.edu OI Grace, Peter/0000-0002-8999-1220 FU American Pain Society Future Leaders in Pain Research Grants Program; National Health and Medical Research Council CJ Martin Fellowship [1054091]; American Australian Association Sir Keith Murdoch Fellowship; National Natural Science Foundation of China [21543013]; Natural Science Foundation of Jilin Province [20160101211JC]; NIH [DE021966, DA023132, DA017204, U01MH105892, GM101279]; NIH Intramural Research Programs of the National Institute on Drug Abuse; National Institute of Alcohol Abuse and Alcoholism FX This work was supported by the American Pain Society Future Leaders in Pain Research Grants Program (P.M.G.); National Health and Medical Research Council CJ Martin Fellowship ID 1054091 (to P.M.G.); American Australian Association Sir Keith Murdoch Fellowship (P.M.G.); National Natural Science Foundation of China Grant 21543013 (to X.W.); Natural Science Foundation of Jilin Province Grant 20160101211JC (to X.W.); and NIH Grants DE021966, DA023132 (to L.R.W.), DA017204 (to D.J.U. and B.L.R.), U01MH105892 (to B.L.R.), and GM101279 (to H.H.Y.). The work of the Chemical Biology Research Branch was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse and the National Institute of Alcohol Abuse and Alcoholism. NR 85 TC 11 Z9 11 U1 7 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 14 PY 2016 VL 113 IS 24 BP E3441 EP E3450 DI 10.1073/pnas.1602070113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO7FW UT WOS:000377948800018 PM 27247388 ER PT J AU Li, H Wang, SY Kong, R Ding, WG Lee, FH Parker, Z Kim, E Learn, GH Hahn, P Policicchio, B Brocca-Cofano, E Deleage, C Hao, XP Chuang, GY Gorman, J Gardner, M Lewis, MG Hatziioannou, T Santra, S Apetrei, C Pandrea, I Alam, SM Liao, HX Shen, XY Tomaras, GD Farzan, M Chertova, E Keele, BF Estes, JD Lifson, JD Doms, RW Montefiori, DC Haynes, BF Sodroski, JG Kwong, PD Hahn, BH Shaw, GM AF Li, Hui Wang, Shuyi Kong, Rui Ding, Wenge Lee, Fang-Hua Parker, Zahra Kim, Eunlim Learn, Gerald H. Hahn, Paul Policicchio, Ben Brocca-Cofano, Egidio Deleage, Claire Hao, Xingpei Chuang, Gwo-Yu Gorman, Jason Gardner, Matthew Lewis, Mark G. Hatziioannou, Theodora Santra, Sampa Apetrei, Cristian Pandrea, Ivona Alam, S. Munir Liao, Hua-Xin Shen, Xiaoying Tomaras, Georgia D. Farzan, Michael Chertova, Elena Keele, Brandon F. Estes, Jacob D. Lifson, Jeffrey D. Doms, Robert W. Montefiori, David C. Haynes, Barton F. Sodroski, Joseph G. Kwong, Peter D. Hahn, Beatrice H. Shaw, George M. TI Envelope residue 375 substitutions in simian-human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE HIV/AIDS; SHIV; CD4; HIV-1 envelope ID BROADLY NEUTRALIZING ANTIBODIES; GP120 INNER DOMAIN; INFECTIOUS MOLECULAR CLONES; HIV-1 ENVELOPE; IN-VIVO; CONFORMATIONAL TRANSITIONS; QUATERNARY INTERACTIONS; CD4-BOUND CONFORMATION; SUBOPTIMAL NUCLEOTIDES; CHALLENGE STOCKS AB Most simian-human immunodeficiency viruses (SHIVs) bearing envelope (Env) glycoproteins from primary HIV-1 strains fail to infect rhesus macaques (RMs). We hypothesized that inefficient Env binding to rhesus CD4 (rhCD4) limits virus entry and replication and could be enhanced by substituting naturally occurring simian immunodeficiency virus Env residues at position 375, which resides at a critical location in the CD4-binding pocket and is under strong positive evolutionary pressure across the broad spectrum of primate lentiviruses. SHIVs containing primary or transmitted/founder HIV-1 subtype A, B, C, or D Envs with genotypic variants at residue 375 were constructed and analyzed in vitro and in vivo. Bulky hydrophobic or basic amino acids substituted for serine-375 enhanced Env affinity for rhCD4, virus entry into cells bearing rhCD4, and virus replication in primary rhCD4 T cells without appreciably affecting antigenicity or antibody-mediated neutralization sensitivity. Twenty-four RMs inoculated with subtype A, B, C, or D SHIVs all became productively infected with different Env375 variants-S, M, Y, H, W, or F-that were differentially selected in different Env backbones. Notably, SHIVs replicated persistently at titers comparable to HIV-1 in humans and elicited autologous neutralizing antibody responses typical of HIV-1. Seven animals succumbed to AIDS. These findings identify Env-rhCD4 binding as a critical determinant for productive SHIV infection in RMs and validate a novel and generalizable strategy for constructing SHIVs with Env glycoproteins of interest, including those that in humans elicit broadly neutralizing antibodies or bind particular Ig germ-line B-cell receptors. C1 [Li, Hui; Wang, Shuyi; Kong, Rui; Ding, Wenge; Lee, Fang-Hua; Parker, Zahra; Kim, Eunlim; Learn, Gerald H.; Hahn, Paul; Hahn, Beatrice H.; Shaw, George M.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Policicchio, Ben; Brocca-Cofano, Egidio; Apetrei, Cristian; Pandrea, Ivona] Univ Pittsburgh, Ctr Vaccine Res, Pittsburgh, PA 15261 USA. [Deleage, Claire; Hao, Xingpei; Chertova, Elena; Keele, Brandon F.; Estes, Jacob D.; Lifson, Jeffrey D.; Kwong, Peter D.] Frederick Natl Lab, Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick, MD 21702 USA. [Chuang, Gwo-Yu; Gorman, Jason] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Gardner, Matthew; Farzan, Michael] Scripps Res Inst, Dept Infect Dis, Jupiter, FL 33458 USA. [Lewis, Mark G.] Bioqual Inc, Rockville, MD 20852 USA. [Hatziioannou, Theodora] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10016 USA. [Santra, Sampa] Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. [Alam, S. Munir; Liao, Hua-Xin; Shen, Xiaoying; Tomaras, Georgia D.; Montefiori, David C.; Haynes, Barton F.] Duke Univ, Dept Med, Durham, NC 27710 USA. [Doms, Robert W.] Childrens Hosp Philadelphia, Dept Pathol, Philadelphia, PA 19104 USA. [Sodroski, Joseph G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02215 USA. RP Hahn, BH; Shaw, GM (reprint author), Univ Penn, Dept Med, Philadelphia, PA 19104 USA. EM bhahn@upenn.edu; shawg@upenn.edu FU Bill & Melinda Gates Foundation [OPP37874, OPP1145046]; NIH Grants [AI100645, AI088564, AI094604, AI087383, AI078788, AI045008, HHSN261200800001E] FX We thank C. Xu, T. He, T. Dunsmore, G. H. Richter, K. Raehtz, J. Roser, R. Fast, K. Oswald, R. Shoemaker, J. Bess, and A. Meyer for technical assistance. This project was funded in part by Bill & Melinda Gates Foundation Grants OPP37874 and OPP1145046; and NIH Grants AI100645, AI088564, AI094604, AI087383, AI078788, AI045008, and HHSN261200800001E. NR 117 TC 12 Z9 12 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 14 PY 2016 VL 113 IS 24 BP E3413 EP E3422 DI 10.1073/pnas.1606636113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO7FW UT WOS:000377948800015 PM 27247400 ER PT J AU Burnham, P Kim, MS Agbor-Enoh, S Luikart, H Valantine, HA Khush, KK De Vlaminck, I AF Burnham, Philip Kim, Min Seong Agbor-Enoh, Sean Luikart, Helen Valantine, Hannah A. Khush, Kiran K. De Vlaminck, Iwijn TI Single-stranded DNA library preparation uncovers the origin and diversity of ultrashort cell-free DNA in plasma SO SCIENTIFIC REPORTS LA English DT Article ID NONINVASIVE DIAGNOSIS; TRANSPLANT RECIPIENTS; READ ALIGNMENT; SEQUENCE; REJECTION; INJURY; PCR AB Circulating cell-free DNA (cfDNA) is emerging as a powerful monitoring tool in cancer, pregnancy and organ transplantation. Nucleosomal DNA, the predominant form of plasma cfDNA, can be adapted for sequencing via ligation of double-stranded DNA (dsDNA) adapters. dsDNA library preparations, however, are insensitive to ultrashort, degraded cfDNA. Drawing inspiration from advances in paleogenomics, we have applied a single-stranded DNA (ssDNA) library preparation method to sequencing of cfDNA in the plasma of lung transplant recipients (40 samples, six patients). We found that ssDNA library preparation yields a greater portion of sub-100 bp nuclear genomic cfDNA (p << 10(-5), Mann-Whitney U Test), and an increased relative abundance of mitochondrial (10.7x, p << 10(-5)) and microbial cfDNA (71.3x, p << 10(-5)). The higher yield of microbial sequences from this method increases the sensitivity of cfDNA-based monitoring for infections following transplantation. We detail the fragmentation pattern of mitochondrial, nuclear genomic and microbial cfDNA over a broad fragment length range. We report the observation of donor-specific mitochondrial cfDNA in the circulation of lung transplant recipients. A ssDNA library preparation method provides a more informative window into understudied forms of cfDNA, including mitochondrial and microbial derived cfDNA and short nuclear genomic cfDNA, while retaining information provided by standard dsDNA library preparation methods. C1 [Burnham, Philip; Kim, Min Seong; De Vlaminck, Iwijn] Cornell Univ, Meinig Sch Biomed Engn, Ithaca, NY 14853 USA. [Agbor-Enoh, Sean; Valantine, Hannah A.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Luikart, Helen; Khush, Kiran K.] Stanford Univ, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA. RP De Vlaminck, I (reprint author), Cornell Univ, Meinig Sch Biomed Engn, Ithaca, NY 14853 USA. EM id93@cornell.edu OI De Vlaminck, Iwijn/0000-0001-6085-7311 FU Noyce Foundation; National Science Foundation GRFP [DGE-1144153] FX We thank Fanny Chen and Peter Schweitzer for assistance with library preparation and sequencing assays. We thank Erin Berthelsen, Robert Goggs, Elizabeth Wilcox and Rory James Todhunter (Cornell University College of Veterinary Medicine), for providing animal blood samples for assay testing and development. This work is supported by the Noyce Foundation (IDV), and the National Science Foundation GRFP (PB, DGE-1144153). NR 41 TC 2 Z9 2 U1 4 U2 10 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 14 PY 2016 VL 6 AR 27859 DI 10.1038/srep27859 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO5MR UT WOS:000377827700001 PM 27297799 ER PT J AU Li, M Dai, YX Zhu, YJ Fu, CL Tan, VY Wang, YA Wang, X Hong, XF Liu, Q Li, TM Qin, JX Ma, XW Fang, JY Otto, M AF Li, Min Dai, Yingxin Zhu, Yuanjun Fu, Chih-Lung Tan, Vee Y. Wang, Yanan Wang, Xing Hong, Xufen Liu, Qian Li, Tianming Qin, Juanxiu Ma, Xiaowei Fang, Jingyuan Otto, Michael TI Virulence determinants associated with the Asian community-associated methicillin-resistant Staphylococcus aureus lineage ST59 SO SCIENTIFIC REPORTS LA English DT Article ID PHENOL-SOLUBLE MODULINS; MONOCLONAL-ANTIBODY; GENE-EXPRESSION; ALPHA-TOXIN; INFECTIONS; EVOLUTION; USA300; TISSUE; AGR; STRAINS AB Understanding virulence is vital for the development of novel therapeutics to target infections with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), which cause an ongoing epidemic in the United States and are on a global rise. However, what defines virulence particularly of global CA-MRSA lineages is poorly understood. Threatening a vast population, the predominant Asian CA-MRSA lineage ST59 is of major epidemiological importance. However, there have been no molecular analyses using defined virulence gene deletion mutants in that lineage as of yet. Here, we compared virulence in skin, lung, and blood infection models of ST59 CA-MRSA isolates with geographically matched hospital-associated MRSA isolates. We selected a representative ST59 CA-MRSA isolate based on toxin expression and virulence characteristics, and produced isogenic gene deletion mutants of important CA-MRSA virulence determinants (alpha-toxin, PSM alpha, Agr) in that isolate for in-vitro and in-vivo analyses. Our results demonstrate strongly enhanced virulence of ST59 CA-MRSA over hospital-associated lineages, supporting the notion that enhanced virulence is characteristic for CA-MRSA. Furthermore, they show strong and significant contribution of Agr, alpha-toxin, and PSM alpha to pathogenesis of ST59 CA-MRSA skin, lung, and blood infection, emphasizing the value of drug development efforts targeted toward those virulence determinants. C1 [Li, Min; Dai, Yingxin; Zhu, Yuanjun; Wang, Yanan; Hong, Xufen; Liu, Qian; Li, Tianming; Qin, Juanxiu; Ma, Xiaowei] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Dept Lab Med, Shanghai, Peoples R China. [Zhu, Yuanjun; Fu, Chih-Lung; Tan, Vee Y.; Otto, Michael] NIAID, Pathogen Mol Genet Sect, Bacteriol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Wang, Xing] Shanghai Jiao Tong Univ, Sch Med, Shanghai Childrens Med Ctr, Dept Lab Med, Shanghai, Peoples R China. [Fang, Jingyuan] Shanghai Jiao Tong Univ, Shanghai Inst Digest Dis, Sch Med, Dept Gastroenterol & Hepatol,Renji Hosp, Shanghai, Peoples R China. RP Li, M (reprint author), Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Dept Lab Med, Shanghai, Peoples R China.; Otto, M (reprint author), NIAID, Pathogen Mol Genet Sect, Bacteriol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ruth_limin@126.com; motto@niaid.nih.gov FU Intramural Research Program of NIAID at NIH [ZIA AI000904]; National Natural Science Foundation of China [81322025, 81371875]; Shanghai Shuguang Talent Project [12SG03]; Shanghai Committee of Science and Technology, China [14140901000, 15411960500]; Foundation for Innovative Research Groups of the National Natural Science Foundation of China [81421001] FX The authors thank Binh An Diep for ST59 isolates from San Francisco. This work was supported by the Intramural Research Program of NIAID at NIH (grant ZIA AI000904 to M.O.), the National Natural Science Foundation of China (grants 81322025 and 81371875, to M.L.), the Shanghai Shuguang Talent Project (grant 12SG03, to M.L.), the Shanghai Committee of Science and Technology, China (grants 14140901000, 15411960500, to M.L.) and the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (grant 81421001, to M.L.). NR 42 TC 1 Z9 1 U1 2 U2 6 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 14 PY 2016 VL 6 AR 27899 DI 10.1038/srep27899 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO5MF UT WOS:000377826500001 PM 27296890 ER PT J AU Biesecker, LG AF Biesecker, Leslie G. TI Long QT Syndrome and Potentially Pathogenic Genetic Variants SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID EXOME C1 [Biesecker, Leslie G.] NHGRI, NIH, Bldg 49 4A56, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, NIH, Bldg 49 4A56, Bethesda, MD 20892 USA. EM lesb@mail.nih.gov NR 3 TC 2 Z9 2 U1 1 U2 1 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 14 PY 2016 VL 315 IS 22 BP 2467 EP 2467 DI 10.1001/jama.2016.2918 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DO3CE UT WOS:000377656900026 PM 27299623 ER PT J AU Weinsaft, JW Devereux, RB Preiss, LR Feher, A Roman, MJ Basson, CT Geevarghese, A Ravekes, W Dietz, HC Holmes, K Habashi, J Pyeritz, RE Bavaria, J Milewski, K LeMaire, SA Morris, S Milewicz, DM Prakash, S Maslen, C Song, HK Silberbach, GM Shohet, RV McDonnell, N Hendershot, T Eagle, KA Asch, FM AF Weinsaft, Jonathan W. Devereux, Richard B. Preiss, Liliana R. Feher, Attila Roman, Mary J. Basson, Craig T. Geevarghese, Alexi Ravekes, William Dietz, Harry C. Holmes, Kathryn Habashi, Jennifer Pyeritz, Reed E. Bavaria, Joseph Milewski, Karianna LeMaire, Scott A. Morris, Shaine Milewicz, Dianna M. Prakash, Siddharth Maslen, Cheryl Song, Howard K. Silberbach, G. Michael Shohet, Ralph V. McDonnell, Nazli Hendershot, Tabitha Eagle, Kim A. Asch, Federico M. CA GENTAC Registry Investigators TI Aortic Dissection in Patients With Genetically Mediated Aneurysms Incidence and Predictors in the GenTAC Registry SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE aortic aneurysm; aortic dissection; bicuspid aortic valve; Marfan syndrome ID MARFAN-SYNDROME; INTERNATIONAL REGISTRY; HEART-DISEASE; VALVE; COMPLICATIONS; ELASTICITY; GUIDELINES; MANAGEMENT; DILATION; PATTERNS AB BACKGROUND Aortic dissection (AoD) is a serious complication of thoracic aortic aneurysm (TAA). Relative risk for AoD in relation to TAA etiology, incidence, and pattern after prophylactic TAA surgery are poorly understood. OBJECTIVES This study sought to determine the incidence, pattern, and relative risk for AoD among patients with genetically associated TAA. METHODS The population included adult GenTAC participants without AoD at baseline. Standardized core laboratory tests classified TAA etiology and measured aortic size. Follow-up was performed for AoD. RESULTS Bicuspid aortic valve (BAV) (39%) and Marfan syndrome (MFS) (22%) were the leading diagnoses in the studied GenTAC participants (n = 1,991). AoD occurred in 1.6% over 3.6 +/- 2.0 years; 61% of AoD occurred in patients with MFS. Cumulative AoD incidence was 6-fold higher among patients with MFS (4.5%) versus others (0.7%; p < 0.001). MFS event rates were similarly elevated versus those in patients with BAV (0.3%; p < 0.001). AoD originated in the distal arch or descending aorta in 71%; 52% of affected patients, including 68% with MFS, had previously undergone aortic grafting. In patients with proximal aortic surgery, distal aortic size (descending thoracic, abdominal aorta) was larger among patients with AoD versus those without AoD (both p < 0.05), whereas the ascending aorta size was similar. Conversely, in patients without previous surgery, aortic root size was greater in patients with subsequent AoD (p < 0.05), whereas distal aortic segments were of similar size. MFS (odds ratio: 7.42; 95% confidence interval: 3.43 to 16.82; p < 0.001) and maximal aortic size (1.86 per cm; 95% confidence interval: 1.26 to 2.67; p = 0.001) were independently associated with AoD. Only 4 of 31 (13%) patients with AoD had pre-dissection images that fulfilled size criteria for prophylactic TAA surgery at a subsequent AoD site. CONCLUSIONS Among patients with genetically associated TAA, MFS augments risk for AoD even after TAA grafting. Although increased aortic size is a risk factor for subsequent AoD, events typically occur below established thresholds for prophylactic TAA repair. (C) 2016 by the American College of Cardiology Foundation. C1 [Weinsaft, Jonathan W.; Devereux, Richard B.; Feher, Attila; Roman, Mary J.; Basson, Craig T.; Geevarghese, Alexi] Weill Cornell Med Coll, 525 East 68th St, New York, NY 10021 USA. [Preiss, Liliana R.; Hendershot, Tabitha] RTI Int, Biostat & Epidemiol Div, Rockville, MD USA. [Ravekes, William; Holmes, Kathryn; Habashi, Jennifer] Johns Hopkins Univ, Dept Pediat Cardiol, Baltimore, MD USA. [Dietz, Harry C.] Johns Hopkins Univ, Inst Med Genet, Baltimore, MD USA. [Pyeritz, Reed E.] Univ Penn, Div Med Genet, Philadelphia, PA 19104 USA. [Bavaria, Joseph; Milewski, Karianna] Univ Penn, Div Cardiovasc Surg, Philadelphia, PA 19104 USA. [LeMaire, Scott A.] Baylor Coll Med, Div Cardiothorac Surg, Houston, TX 77030 USA. [LeMaire, Scott A.] Texas Heart Inst, Houston, TX 77025 USA. [Morris, Shaine] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Milewicz, Dianna M.; Prakash, Siddharth] Univ Texas Hlth Sci Ctr Houston, Div Med Genet, Houston, TX 77030 USA. [Maslen, Cheryl] Oregon Hlth & Sci Univ, Heart Res Ctr, Portland, OR 97201 USA. [Song, Howard K.] Oregon Hlth & Sci Univ, Div Cardiothorac Surg, Portland, OR 97201 USA. [Silberbach, G. Michael] Oregon Hlth & Sci Univ, Dept Pediat Cardiol, Portland, OR 97201 USA. [Shohet, Ralph V.] Queens Med Ctr, Div Cardiovasc Res, Honolulu, HI USA. [McDonnell, Nazli] NIA, NIH, Baltimore, MD 21224 USA. [Eagle, Kim A.] Univ Michigan Hlth Syst, Dept Cardiol, Ann Arbor, MI USA. [Asch, Federico M.] Washington Hosp Ctr, MedStar Hlth Res Inst, Cardiovasc Core Lab, Washington, DC 20010 USA. RP Weinsaft, JW (reprint author), Weill Cornell Med Coll, Dept Med, Greenberg Div Cardiol, 525 East 68th St, New York, NY 10021 USA. EM jww2001@med.cornell.edu FU National Heart, Lung, and Blood Institute; National Institute of Arthritis, Musculoskeletal and Skin Diseases [HHSN268200648199C, HHSN268201000048C] FX GenTAC supported by National Heart, Lung, and Blood Institute and National Institute of Arthritis, Musculoskeletal and Skin Diseases (HHSN268200648199C, HHSN268201000048C). Dr. LeMaire is a member of the Advisory Board for Baxter Healthcare; the clinical study principal investigator for Vascutek Terumo and Baxter Healthcare; and a clinical trial co-investigator for Medtronic, W.L. Gore & Associates, and GlaxoSmithKline. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 24 TC 3 Z9 3 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 14 PY 2016 VL 67 IS 23 BP 2744 EP 2754 DI 10.1016/j.jacc.2016.03.570 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DN7RF UT WOS:000377274300007 PM 27282895 ER PT J AU Moreno, H Morfini, G Buitrago, L Ujlaki, G Choi, S Yu, E Moreira, JE Avila, J Brady, ST Pant, H Sugimori, M Llinas, RR AF Moreno, H. Morfini, G. Buitrago, L. Ujlaki, G. Choi, S. Yu, E. Moreira, J. E. Avila, J. Brady, S. T. Pant, H. Sugimori, M. Llinas, R. R. TI TAU PATHOLOGY-MEDIATED PRESYNAPTIC DYSFUNCTION SO NEUROSCIENCE LA English DT Article DE tauopathy; IP3 receptor; ryanodine receptor; phosphatase-activating domain of tau; GSK3; Cdk5 ID INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; DEPENDENT AXONAL-TRANSPORT; AMYLOID PRECURSOR PROTEIN; EARLY ALZHEIMERS-DISEASE; SQUID GIANT SYNAPSE; IN-VIVO; 2-AMINOETHOXYDIPHENYL BORATE; NEUROTRANSMITTER RELEASE; FRONTOTEMPORAL DEMENTIA; INTRACELLULAR CA2+ AB Brain tauopathies are characterized by abnormal processing of tau protein. While somatodendritic tau mislocalization has attracted considerable attention in tauopathies, the role of tau pathology in axonal transport, connectivity and related dysfunctions remains obscure. We have previously shown using the squid giant synapse that presynaptic microinjection of recombinant human tau protein (htau42) results in failure of synaptic transmission. Here, we evaluated molecular mechanisms mediating this effect. Thus, the initial event, observed after htau42 presynaptic injection, was an increase in transmitter release. This event was mediated by calcium release from intracellular stores and was followed by a reduction in evoked transmitter release. The effect of htau42 on synaptic transmission was recapitulated by a peptide comprising the phosphatase-activating domain of tau, suggesting activation of phosphotransferases. Accordingly, findings indicated that htau42-mediated toxicity involves the activities of both GSK3 and Cdk5 kinases. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Moreno, H.; Buitrago, L.] Suny Downstate Med Ctr, Robert F Furchgott Ctr Neural & Behav Sci, Dept Neurol, Brooklyn, NY 11203 USA. [Moreno, H.; Buitrago, L.] Suny Downstate Med Ctr, Robert F Furchgott Ctr Neural & Behav Sci, Dept Physiol Pharmacol, Brooklyn, NY 11203 USA. [Moreno, H.; Morfini, G.; Buitrago, L.; Ujlaki, G.; Choi, S.; Yu, E.; Moreira, J. E.; Brady, S. T.; Pant, H.; Sugimori, M.; Llinas, R. R.] Marine Biol Lab, Woods Hole, MA 02543 USA. [Morfini, G.; Brady, S. T.] Univ Illinois, Dept Anat & Cell Biol, Chicago, IL 60607 USA. [Moreira, J. E.] Univ Sao Paulo, Riberao Preto Sch Med, Pathol & Forens Med, BR-14000000 Ribeirao Preto, SP, Brazil. [Avila, J.] Univ Autonoma Madrid, Ctr Biol Mol Severo Ochoa, E-28049 Madrid, Spain. [Pant, H.] NINDS, Lab Neurochem, Bethesda, MD 20824 USA. [Choi, S.; Yu, E.; Sugimori, M.; Llinas, R. R.] NYU, Sch Med, Dept Physiol & Neurosci, New York, NY 10016 USA. RP Moreno, H (reprint author), Marine Biol Lab, Woods Hole, MA 02543 USA. EM Herman.Moreno@downstate.edu; Rodolfo.Llinas@nyumc.org RI Avila, Jesus/I-2610-2015; OI Avila, Jesus/0000-0002-6288-0571; Sugimori, Mutsuyuki/0000-0002-2908-3167 FU NIH [AG027476, NS066942, NS23868, NS23320, NS41170, NS082730]; Alzheimer's Association; FAPESP (Science Foundation for the Sao Paulo State, Brasil) [19011-0] FX Supported by NIH AG027476 to H. Moreno; a donation from ToyamaPharmaceuticals to RL and MS. NIH NS066942 (to GM), NS23868, NS23320, NS41170, NS082730 (to STB) and a Zenith Award from the Alzheimer's Association grants to STB and grant from FAPESP (Science Foundation for the Sao Paulo State, Brasil; 19011-0) to JEM. NR 42 TC 3 Z9 3 U1 2 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD JUN 14 PY 2016 VL 325 BP 30 EP 38 DI 10.1016/j.neuroscience.2016.03.044 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DJ8ZK UT WOS:000374503200004 PM 27012611 ER PT J AU Machiela, MJ Zhou, WY Karlins, E Sampson, JN Freedman, ND Yang, Q Hicks, B Dagnall, C Hautman, C Jacobs, KB Abnet, CC Aldrich, MC Amos, C Amundadottir, LT Arslan, AA Beane-Freeman, LE Berndt, SI Black, A Blot, WJ Bock, CH Bracci, PM Brinton, LA Bueno-De-Mesquita, HB Burdett, L Buring, JE Butler, MA Canzian, F Carreon, T Chaffee, KG Chang, IS Chatterjee, N Chen, C Chen, C Chen, KX Chung, CC Cook, LS Bou, MC Cullen, M Davis, FG De Vivo, I Ding, T Doherty, J Duell, EJ Epstein, CG Fan, JH Figueroa, JD Fraumeni, JF Friedenreich, CM Fuchs, CS Gallinger, S Gao, YT Gapstur, SM Garcia-Closas, M Gaudet, MM Gaziano, JM Giles, GG Gillanders, EM Giovannucci, EL Goldin, L Goldstein, AM Haiman, CA Hallmans, G Hankinson, SE Harris, CC Henriksson, R Holly, EA Hong, YC Hoover, RN Hsiung, CA Hu, N Hu, W Hunter, DJ Hutchinson, A Jenab, M Johansen, C Khaw, KT Kim, HN Kim, YH Kim, YT Klein, AP Klein, R Koh, WP Kolonel, LN Kooperberg, C Kraft, P Krogh, V Kurtz, RC LaCroix, A Lan, Q Landi, MT Le Marchand, L Li, DH Liang, XL Liao, LM Lin, DX Liu, JJ Lissowska, J Lu, LG Magliocco, AM Malats, N Matsuo, K McNeill, LH McWilliams, RR Melin, BS Mirabello, L Moore, L Olson, SH Orlow, I Park, JY Patino-Garcia, A Peplonska, B Peters, U Petersen, GM Pooler, L Prescott, J Prokunina-Olsson, L Purdue, MP Qiao, YL Rajaraman, P Real, FX Riboli, E Risch, HA Rodriguez-Santiago, B Ruder, AM Savage, SA Schumacher, F Schwartz, AG Schwartz, KL Seow, A Setiawan, VW Severi, G Shen, H Sheng, X Shin, MH Shu, XO Silverman, DT Spitz, MR Stevens, VL Stolzenberg-Solomon, R Stram, D Tang, ZZ Taylor, PR Teras, LR Tobias, GS Van den Berg, D Visvanathan, K Wacholder, S Wang, JC Wang, ZM Wentzensen, N Wheeler, W White, E Wiencke, JK Wolpin, BM Wong, MP Wu, C Wu, TC Wu, XF Wu, YL Wunder, JS Xia, L Yang, HP Yang, PC Yu, K Zanetti, KA Zeleniuch-Jacquotte, A Zheng, W Zhou, B Ziegler, RG Perez-Jurado, LA Caporaso, NE Rothman, N Tucker, M Dean, MC Yeager, M Chanock, SJ AF Machiela, Mitchell J. Zhou, Weiyin Karlins, Eric Sampson, Joshua N. Freedman, Neal D. Yang, Qi Hicks, Belynda Dagnall, Casey Hautman, Christopher Jacobs, Kevin B. Abnet, Christian C. Aldrich, Melinda C. Amos, Christopher Amundadottir, Laufey T. Arslan, Alan A. Beane-Freeman, Laura E. Berndt, Sonja I. Black, Amanda Blot, William J. Bock, Cathryn H. Bracci, Paige M. Brinton, Louise A. Bueno-de-Mesquita, H. Bas Burdett, Laurie Buring, Julie E. Butler, Mary A. Canzian, Federico Carreon, Tania Chaffee, Kari G. Chang, I-Shou Chatterjee, Nilanjan Chen, Chu Chen, Constance Chen, Kexin Chung, Charles C. Cook, Linda S. Bou, Marta Crous Cullen, Michael Davis, Faith G. De Vivo, Immaculata Ding, Ti Doherty, Jennifer Duell, Eric J. Epstein, Caroline G. Fan, Jin-Hu Figueroa, Jonine D. Fraumeni, Joseph F. Friedenreich, Christine M. Fuchs, Charles S. Gallinger, Steven Gao, Yu-Tang Gapstur, Susan M. Garcia-Closas, Montserrat Gaudet, Mia M. Gaziano, J. Michael Giles, Graham G. Gillanders, Elizabeth M. Giovannucci, Edward L. Goldin, Lynn Goldstein, Alisa M. Haiman, Christopher A. Hallmans, Goran Hankinson, Susan E. Harris, Curtis C. Henriksson, Roger Holly, Elizabeth A. Hong, Yun-Chul Hoover, Robert N. Hsiung, Chao A. Hu, Nan Hu, Wei Hunter, David J. Hutchinson, Amy Jenab, Mazda Johansen, Christoffer Khaw, Kay-Tee Kim, Hee Nam Kim, Yeul Hong Kim, Young Tae Klein, Alison P. Klein, Robert Koh, Woon-Puay Kolonel, Laurence N. Kooperberg, Charles Kraft, Peter Krogh, Vittorio Kurtz, Robert C. LaCroix, Andrea Lan, Qing Landi, Maria Teresa Le Marchand, Loic Li, Donghui Liang, Xiaolin Liao, Linda M. Lin, Dongxin Liu, Jianjun Lissowska, Jolanta Lu, Lingeng Magliocco, Anthony M. Malats, Nuria Matsuo, Keitaro McNeill, Lorna H. McWilliams, Robert R. Melin, Beatrice S. Mirabello, Lisa Moore, Lee Olson, Sara H. Orlow, Irene Park, Jae Yong Patino-Garcia, Ana Peplonska, Beata Peters, Ulrike Petersen, Gloria M. Pooler, Loreall Prescott, Jennifer Prokunina-Olsson, Ludmila Purdue, Mark P. Qiao, You-Lin Rajaraman, Preetha Real, Francisco X. Riboli, Elio Risch, Harvey A. Rodriguez-Santiago, Benjamin Ruder, Avima M. Savage, Sharon A. Schumacher, Fredrick Schwartz, Ann G. Schwartz, Kendra L. Seow, Adeline Setiawan, Veronica Wendy Severi, Gianluca Shen, Hongbing Sheng, Xin Shin, Min-Ho Shu, Xiao-Ou Silverman, Debra T. Spitz, Margaret R. Stevens, Victoria L. Stolzenberg-Solomon, Rachael Stram, Daniel Tang, Ze-Zhong Taylor, Philip R. Teras, Lauren R. Tobias, Geoffrey S. Van den Berg, David Visvanathan, Kala Wacholder, Sholom Wang, Jiu-Cun Wang, Zhaoming Wentzensen, Nicolas Wheeler, William White, Emily Wiencke, John K. Wolpin, Brian M. Wong, Maria Pik Wu, Chen Wu, Tangchun Wu, Xifeng Wu, Yi-Long Wunder, Jay S. Xia, Lucy Yang, Hannah P. Yang, Pan-Chyr Yu, Kai Zanetti, Krista A. Zeleniuch-Jacquotte, Anne Zheng, Wei Zhou, Baosen Ziegler, Regina G. Perez-Jurado, Luis A. Caporaso, Neil E. Rothman, Nathaniel Tucker, Margaret Dean, Michael C. Yeager, Meredith Chanock, Stephen J. TI Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome SO NATURE COMMUNICATIONS LA English DT Article ID DETECTABLE CLONAL MOSAICISM; SOMATIC MOSAICISM; HUMAN GENOME; CANCER; BLOOD; METHYLATION; CELLS; HEMATOPOIESIS; ANEUPLOIDIES; MUTATION AB To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases. C1 [Machiela, Mitchell J.; Zhou, Weiyin; Karlins, Eric; Sampson, Joshua N.; Freedman, Neal D.; Yang, Qi; Hicks, Belynda; Dagnall, Casey; Hautman, Christopher; Abnet, Christian C.; Amundadottir, Laufey T.; Beane-Freeman, Laura E.; Berndt, Sonja I.; Black, Amanda; Brinton, Louise A.; Burdett, Laurie; Chatterjee, Nilanjan; Chung, Charles C.; Cullen, Michael; Epstein, Caroline G.; Figueroa, Jonine D.; Fraumeni, Joseph F.; Goldin, Lynn; Goldstein, Alisa M.; Hoover, Robert N.; Hu, Nan; Hu, Wei; Hutchinson, Amy; Lan, Qing; Landi, Maria Teresa; Liao, Linda M.; Mirabello, Lisa; Moore, Lee; Prokunina-Olsson, Ludmila; Purdue, Mark P.; Rajaraman, Preetha; Savage, Sharon A.; Seow, Adeline; Silverman, Debra T.; Stolzenberg-Solomon, Rachael; Taylor, Philip R.; Tobias, Geoffrey S.; Wacholder, Sholom; Wang, Zhaoming; Wentzensen, Nicolas; Yang, Hannah P.; Yu, Kai; Ziegler, Regina G.; Caporaso, Neil E.; Rothman, Nathaniel; Tucker, Margaret; Dean, Michael C.; Yeager, Meredith; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Zhou, Weiyin; Karlins, Eric; Yang, Qi; Hicks, Belynda; Dagnall, Casey; Hautman, Christopher; Jacobs, Kevin B.; Burdett, Laurie; Chung, Charles C.; Cullen, Michael; Hutchinson, Amy; Wang, Zhaoming; Yeager, Meredith] Leidos Biomed Res Inc, Div Canc Epidemiol & Genet, Natl Canc Inst, Canc Genom Res Lab, Bethesda, MD 20892 USA. [Jacobs, Kevin B.] Bioinformed LLC, Gaithersburg, MD 20877 USA. [Aldrich, Melinda C.] Vanderbilt Univ, Sch Med, Dept Thorac Surg, Nashville, TN 37232 USA. [Aldrich, Melinda C.; Blot, William J.; Zheng, Wei] Vanderbilt Univ, Med Ctr, Vanderbilt Epidemiol Ctr, Dept Med,Div Epidemiol, Nashville, TN 37232 USA. [Amos, Christopher] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Div Canc Prevent & Populat Sci, Houston, TX 77030 USA. [Arslan, Alan A.] NYU, Sch Med, Dept Obstet & Gynecol, New York, NY 10016 USA. [Arslan, Alan A.] NYU, Sch Med, Dept Environm Med, New York, NY 10016 USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Inst Canc, New York, NY 10016 USA. [Blot, William J.] Int Epidemiol Inst, Rockville, MD 20850 USA. [Bock, Cathryn H.; Schwartz, Ann G.] Wayne State Univ, Sch Med, Karmanos Canc Inst, Detroit, MI 48201 USA. [Bock, Cathryn H.; Schwartz, Ann G.] Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI 48201 USA. [Bracci, Paige M.; Holly, Elizabeth A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Dept Determinants Chron Dis DCD, Bilthoven 3721, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr, Dept Gastroenterol & Hepatol, NL-3584 CX Utrecht, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London SW7 2AZ, England. [Bueno-de-Mesquita, H. Bas] Univ Malaya, Fac Med, Dept Social & Prevent Med, Kuala Lumpur 50603, Malaysia. [Buring, Julie E.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Butler, Mary A.; Carreon, Tania; Ruder, Avima M.] NIOSH, Ctr Dis Control & Prevent, Cincinnati, OH 45226 USA. [Canzian, Federico] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. [Chaffee, Kari G.; Petersen, Gloria M.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Chang, I-Shou] Natl Hlth Res Inst, Natl Inst Canc Res, Zhunan 35053, Taiwan. [Chen, Chu; Kooperberg, Charles; LaCroix, Andrea; Peters, Ulrike; White, Emily] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Chen, Constance; Bou, Marta Crous; De Vivo, Immaculata; Hunter, David J.; Kraft, Peter; Prescott, Jennifer] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. [Chen, Kexin] Tianjin Med Univ, Canc Inst & Hosp, Dept Epidemiol & Biostat, Tianjin 300040, Peoples R China. [Cook, Linda S.] Univ New Mexico, Albuquerque, NM 87131 USA. [Bou, Marta Crous; De Vivo, Immaculata; Fuchs, Charles S.; Giovannucci, Edward L.; Hankinson, Susan E.; Hunter, David J.; Prescott, Jennifer; Wolpin, Brian M.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Bou, Marta Crous; De Vivo, Immaculata; Fuchs, Charles S.; Giovannucci, Edward L.; Hankinson, Susan E.; Hunter, David J.; Prescott, Jennifer; Wolpin, Brian M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Davis, Faith G.] Univ Alberta, Sch Publ Hlth, Dept Publ Hlth Sci, Edmonton, AB T6G 2R3, Canada. [Ding, Ti; Tang, Ze-Zhong] Shanxi Canc Hosp, Taiyuan 030013, Shanxi, Peoples R China. [Doherty, Jennifer] Dartmouth Coll, Geisel Sch Med, Lebanon, NH 03755 USA. [Duell, Eric J.] Catalan Inst Oncol ICO IDIBELL, Bellvitge Biomed Res Inst, Canc Epidemiol Res Program, Unit Nutr & Canc, Barcelona 08908, Spain. Shanghai Canc Inst, Shanghai 200032, Peoples R China. [Friedenreich, Christine M.] Alberta Hlth Serv, Canc Control Alberta, Dept Populat Hlth Res, Calgary, AB T2N 2T9, Canada. [Fuchs, Charles S.; Wolpin, Brian M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Gallinger, Steven] Samuel Lunenfeld Res Inst, Fred A Litwin Ctr Canc Genet, Toronto, ON M5G 1X5, Canada. [Gao, Yu-Tang] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Shanghai Canc Inst,Dept Epidemiol, Shanghai 200032, Peoples R China. [Gapstur, Susan M.; Gaudet, Mia M.; Stevens, Victoria L.; Teras, Lauren R.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England. [Garcia-Closas, Montserrat] Inst Canc Res, Breakthrough Breast Canc Ctr, Sutton SM2 5NG, Surrey, England. [Gaziano, J. Michael] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. [Gaziano, J. Michael] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Gaziano, J. Michael] Vet Affairs Boston Healthcare Syst, VA Cooperat Studies Programs, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA 02130 USA. [Giles, Graham G.; Severi, Gianluca] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Canc Epidemiol Ctr, Canc Council Victoria, Melbourne, Vic 3010, Australia. [Giles, Graham G.; Severi, Gianluca] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia. [Gillanders, Elizabeth M.; Zanetti, Krista A.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Haiman, Christopher A.; Schumacher, Fredrick; Setiawan, Veronica Wendy; Stram, Daniel; Van den Berg, David] Univ So Calif, Keck Sch Med, Dept Prevent Med, Div Biostat, Los Angeles, CA 90033 USA. [Hallmans, Goran] Umea Univ, Dept Publ Hlth & Clin Med Nutr Res, S-90187 Umea, Sweden. [Hankinson, Susan E.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Harris, Curtis C.] NCI, Ctr Canc Res, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. [Henriksson, Roger; Melin, Beatrice S.] Umea Univ, Dept Radiat Sci Oncol, S-90187 Umea, Sweden. [Hong, Yun-Chul] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul 151742, South Korea. [Hsiung, Chao A.] Natl Hlth Res Inst, Inst Populat Hlth Sci, Zhunan 35053, Taiwan. [Hunter, David J.] Harvard & MIT, Broad Inst, Cambridge, MA 02142 USA. [Jenab, Mazda] WHO, IARC, F-69372 Lyon, France. [Johansen, Christoffer] Rigshosp, Finsen Ctr, Oncol, DK-2100 Copenhagen, Denmark. [Johansen, Christoffer] Danish Canc Soc, Res Ctr, Unit Survivorship Res, DK-2100 Copenhagen, Denmark. [Khaw, Kay-Tee] Univ Cambridge, Sch Clin Med, Cambridge CB2 1TN, England. [Kim, Hee Nam] Chonnam Natl Univ, Ctr Creat Biomed Scientists, Gwangju 500757, South Korea. [Kim, Yeul Hong] Korea Univ, Anam Hosp, Coll Med, Dept Internal Med,Div Oncol Hematol, Seoul 151742, South Korea. [Kim, Young Tae] Seoul Natl Univ, Coll Med, Canc Res Inst, Dept Thorac & Cardiovasc Surg, Seoul 03080, South Korea. [Klein, Alison P.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21287 USA. [Klein, Robert] Mem Sloan Kettering Canc Ctr, Program Canc Biol & Genet, New York, NY 10065 USA. [Koh, Woon-Puay] Duke NUS Grad Med Sch, Singapore 169857, Singapore. [Koh, Woon-Puay; Seow, Adeline] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 119077, Singapore. [Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96813 USA. [Krogh, Vittorio] Fdn IRCCS Ist Nazl Tumori, I-20133 Milan, Italy. [Kurtz, Robert C.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Li, Donghui] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Liang, Xiaolin; Olson, Sara H.; Orlow, Irene] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Lin, Dongxin; Wu, Chen] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Etiol & Carcinogenesis, Beijing 100730, Peoples R China. [Lin, Dongxin; Wu, Chen] Peking Union Med Coll, Beijing 100730, Peoples R China. [Lin, Dongxin; Wu, Chen] Chinese Acad Med Sci, Canc Inst & Hosp, State Key Lab Mol Oncol, Beijing 100730, Peoples R China. [Liu, Jianjun] Genome Inst Singapore, Dept Human Genet, Singapore 138672, Singapore. [Liu, Jianjun] Anhui Med Univ, Sch Life Sci, Hefei 230032, Peoples R China. [Lissowska, Jolanta] Maria Sklodowska Curie Canc Ctr & Inst Oncol, Dept Canc Epidemiol & Prevent, PL-02781 Warsaw, Poland. [Lu, Lingeng; Risch, Harvey A.] Yale Univ, Sch Publ Hlth, New Haven, CT 06510 USA. [Magliocco, Anthony M.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Malats, Nuria; Real, Francisco X.] Spanish Natl Canc Res Ctr CNIO, Madrid 28029, Spain. [Matsuo, Keitaro] Aichi Canc Ctr, Res Inst, Div Mol Med, Nagoya, Aichi 4648681, Japan. [McNeill, Lorna H.] Univ Texas MD Anderson Canc Ctr, Duncan Family Inst, Dept Hlth Dispar Res, Div OVP Canc Prevent & Populat Sci, Houston, TX 77030 USA. [McNeill, Lorna H.] Univ Texas MD Anderson Canc Ctr, Duncan Family Inst, Ctr Community Engaged Translat Res, Houston, TX 77030 USA. [McWilliams, Robert R.] Mayo Clin, Dept Oncol, Rochester, MN 55905 USA. [Park, Jae Yong] Kyungpook Natl Univ, Med Ctr, Lung Canc Ctr, Daegu 101, South Korea. [Patino-Garcia, Ana] Univ Navarra, Univ Navarra Clin, Navarra Inst Hlth Res, IdiSNA,Dept Pediat, E-31080 Pamplona, Spain. [Peplonska, Beata] Nofer Inst Occupat Med, PL-91348 Lodz, Poland. [Pooler, Loreall; Sheng, Xin; Xia, Lucy] Univ So Calif, Los Angeles, CA 90007 USA. [Qiao, You-Lin] Chinese Acad Med Sci, Canc Inst Hosp, Dept Epidemiol, Beijing 100730, Peoples R China. [Real, Francisco X.; Rodriguez-Santiago, Benjamin; Perez-Jurado, Luis A.] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona 08002, Spain. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Div Epidemiol & Biostat, London SW7 2AZ, England. [Rodriguez-Santiago, Benjamin; Perez-Jurado, Luis A.] Ctr Invest Biomed Red Enfermedades Raras CIBERER, Barcelona 28029, Spain. [Rodriguez-Santiago, Benjamin] QGenomics, Quantitat Genom Med Lab, Barcelona 08003, Spain. [Schwartz, Kendra L.] Wayne State Univ, Sch Med, Karmanos Canc Inst, Detroit, MI 48201 USA. [Schwartz, Kendra L.] Wayne State Univ, Sch Med, Dept Family Med & Publ Hlth Sci, Detroit, MI 48201 USA. [Severi, Gianluca] Human Genet Fdn HuGeF, I-10126 Turin, Italy. [Shen, Hongbing] Nanjing Med Univ, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Nanjing 210029, Jiangsu, Peoples R China. [Shen, Hongbing] Nanjing Med Univ, Sch Publ Hlth, Dept Epidemiol, Nanjing 210029, Jiangsu, Peoples R China. [Shin, Min-Ho] Chonnam Natl Univ, Sch Med, Dept Prevent Med, Gwanju 501746, South Korea. [Shu, Xiao-Ou] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr,Dept Med, Nashville, TN 37232 USA. [Spitz, Margaret R.] Baylor Coll Med, Houston, TX 77030 USA. [Visvanathan, Kala] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21218 USA. [Wang, Jiu-Cun] Fudan Univ, Sch Life Sci, Key Lab Contemporary Anthropol, Minist Educ, Shanghai 200433, Peoples R China. [Wang, Jiu-Cun] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200433, Peoples R China. [Wheeler, William] Informat Management Serv Inc, Calverton, MD 20904 USA. [Wiencke, John K.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Wong, Maria Pik] Univ Hong Kong, Li Ka Shing Fac Med, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. [Wu, Tangchun] Huazhong Univ Sci & Technol, Sch Publ Hlth, Inst Occupat Med, Wuhan 430400, Peoples R China. [Wu, Tangchun] Huazhong Univ Sci & Technol, Sch Publ Hlth, Key Lab Environm & Hlth, Minist Educ, Wuhan 430400, Peoples R China. [Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Wu, Yi-Long] Guangdong Gen Hosp, Guangdong Lung Canc Inst, Guangzhou 515200, Guangdong, Peoples R China. [Wu, Yi-Long] Guangdong Acad Med Sci, Guangzhou 515200, Guangdong, Peoples R China. [Wunder, Jay S.] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Yang, Pan-Chyr] Natl Taiwan Univ, Coll Med, Dept Internal Med, Taipei 10617, Taiwan. [Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Dept Populat Hlth, New York, NY 10016 USA. [Zhou, Baosen] China Med Univ, Sch Publ Hlth, Dept Epidemiol, Shenyang 110001, Peoples R China. RP Chanock, SJ (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM chanocks@mail.nih.gov RI Krogh, Vittorio/K-2628-2016; Abnet, Christian/C-4111-2015; Tobias, Geoffrey/M-4135-2016; Qiao, You-Lin/B-4139-2012; Zheng, Wei/O-3351-2013; Beane Freeman, Laura/C-4468-2015 OI Krogh, Vittorio/0000-0003-0122-8624; Abnet, Christian/0000-0002-3008-7843; Tobias, Geoffrey/0000-0002-2878-8253; Qiao, You-Lin/0000-0001-6380-0871; Zheng, Wei/0000-0003-1226-070X; Beane Freeman, Laura/0000-0003-1294-4124 FU Broad Center for Genotyping and Analysis [U01HG04424]; Cancer Prevention Study-II (American Cancer Society); Center for Inherited Disease Research [U01HG004438, HHSN268200782096C]; Endometrial cancer [ROl CA 134958]; Fred Hutchinson Cancer Research Center (funds from the Fred Hutchinson Cancer Research Center and National Institute of Health) [R35 CA 39779, RO1 CA 75977, R03 CA 80636, NO1 HD 2 3166, KO5 CA 92002, CA 105212, RO1 CA87538]; Fudan Lung Cancer Study Ministry of Health [201002007]; Ministry of Science and Technology [2011BAIO9B00]; National S&T Major Special Project [2011ZX09102-010-01]; China National High-Tech Research and Development Program [2012AA02A517, 2012AA02A518]; National Science Foundation of China [30890034]; National Basic Research Program [2012CB944600]; Scientific and Technological Support Plans from Jiangsu Province [BE2010715]; Genes and Environment in Lung Cancer, Singapore Study (National Medical Research Council Singapore) [NMRC/0897/2004, NMRC/1075/2006]; Agency for Science, Technology and Research (A*STAR) of Singapore; National Research Program on Genomic Medicine in Taiwan [DOH98-TD-G-111-015]; National Research Program for Biopharmaceuticals in Taiwan [DOH 100-TD-PB-111TM013]; National Science Council, Taiwan [NSC 100-2319-B-400-001]; Guangdong Study (Foundation of Guangdong Science and Technology Department [2006B60101010, 2007A032000002, 2011A030400010]; Guangzhou Science and Information Technology Bureau [2011Y2-00014]; Chinese Lung Cancer Research Foundation; National Natural Science Foundation of China [81101549]; Natural Science Foundation of Guangdong Province [S2011010000792]; Hong Kong Study (General Research Fund of Research Grant Council, Hong Kong) [781511M]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH; Intramural Research Program of the NIH, National Library of Medicine; Intramural Research Program of the National Institute for Occupational Safety and Health; Ministry of Health, Labor, and Welfare for Research on Applying Health Technology; National Cancer Center Research and Development Fund; NCI [R01-CA121210]; Korea Health Technology R&D Project (Korea Health Industry Development Institute (KHIDI); Ministry of Health & Welfare, Republic of Korea [HI14C0066]; Ministry of Health [201002007]; Melanoma [NCI R29CA70334, R01CA100264, P50CA093459]; National Research Foundation of Korea (NRF); Korea government (MSIP) [NRF-2014R1A2A2A05003665]; NLCS (China National High-Tech Research and Development Program Grant [2009AA022705]; Priority Academic Program Development of Jiangsu Higher Education Institution; National Key Basic Research Program Grant [2011CB503805]; Nurses' Health Study [P01 CA87969, ROl CA49449]; Yunnan Lung Cancer Study (Intramural program of U.S. National Institutes of Health; National Cancer Institute; NIH/NCI [K07 CA 172294]; Women's Health Initiative (National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services) [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; Tianjin Cancer Institute and Hospital, National Foundation for Cancer Research US; [U01 CA164973]; [U01 CA098758] FX Some individuals, studies, and centers received individual support as follows: Broad Center for Genotyping and Analysis (U01HG04424); Cancer Prevention Study-II (American Cancer Society); Center for Inherited Disease Research (U01HG004438, HHSN268200782096C); Endometrial cancer (ROl CA 134958); Fred Hutchinson Cancer Research Center (funds from the Fred Hutchinson Cancer Research Center and National Institute of Health grants (R35 CA 39779, RO1 CA 75977, R03 CA 80636, NO1 HD 2 3166, KO5 CA 92002, CA 105212 and RO1 CA87538)); Fudan Lung Cancer Study (Ministry of Health (201002007); Ministry of Science and Technology (2011BAIO9B00); National S&T Major Special Project (2011ZX09102-010-01); China National High-Tech Research and Development Program (2012AA02A517, 2012AA02A518); National Science Foundation of China (30890034); National Basic Research Program (2012CB944600); Scientific and Technological Support Plans from Jiangsu Province (BE2010715)); Gene-Environment Association Studies (Coordinating Center:U01 HG004446, Manuscript preparation: P01-GM099568); Genes and Environment in Lung Cancer, Singapore Study (National Medical Research Council Singapore grant (NMRC/0897/2004, NMRC/1075/2006); Agency for Science, Technology and Research (A*STAR) of Singapore); Genetic Epidemiological Study of Lung Adenocarcinoma (National Research Program on Genomic Medicine in Taiwan (DOH98-TD-G-111-015); National Research Program for Biopharmaceuticals in Taiwan (DOH 100-TD-PB-111TM013); National Science Council, Taiwan (NSC 100-2319-B-400-001)); Guangdong Study (Foundation of Guangdong Science and Technology Department (2006B60101010, 2007A032000002, 2011A030400010); Guangzhou Science and Information Technology Bureau (2011Y2-00014); Chinese Lung Cancer Research Foundation; National Natural Science Foundation of China (81101549); Natural Science Foundation of Guangdong Province (S2011010000792)); Hong Kong Study (General Research Fund of Research Grant Council, Hong Kong (781511M)); Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH; Intramural Research Program of the NIH, National Library of Medicine; Intramural Research Program of the National Institute for Occupational Safety and Health; Japanese Female Lung Cancer Collaborative Study (Grants-in-Aid from the Ministry of Health, Labor, and Welfare for Research on Applying Health Technology and for the 3rd-term Comprehensive 10-year Strategy for Cancer Control; National Cancer Center Research and Development Fund; Grant-in-Aid for Scientific Research on Priority Areas and on Innovative Area from the Ministry of Education, Science, Sports, Culture and Technology of Japan; NCI (R01-CA121210)); Korea Health Technology R&D Project (Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C0066)); Lung cancer (ZO1CP010200); Lung health (U01HG004738); Ministry of Health (201002007); Ministry of Science and Technology (2011BAIO9B00); Melanoma (NCI R29CA70334, R01CA100264, P50CA093459); Multiethnic Cohort Study (Infrastructure grant (U01 CA164973) and U01 CA098758); National Research Foundation of Korea (NRF) (funded by the Korea government (MSIP) (NRF-2014R1A2A2A05003665)); NLCS (China National High-Tech Research and Development Program Grant (2009AA022705); Priority Academic Program Development of Jiangsu Higher Education Institution; National Key Basic Research Program Grant (2011CB503805)); Nurses' Health Study (P01 CA87969, ROl CA49449); Nurses' Health Study II (UM1 CA176726, ROl 6; 7262); OpPancreatic cancer (Mayo Clinic SPORE in Pancreatic Cancer: P50CA102701); Prostate cancer (U01HG004726, NCI: CA63464, CA54281, CA1326792, RC2 CA148085); Shanghai Women's Health Cohort Study (National Institutes of Health (R37 CA70867); National Cancer Institute intramural research program; NCI Intramural Research Program contract (NO2 CP1101066)); Shenyang Lung Cancer Study (National Nature Science Foundation of China (81102194); Liaoning Provincial Department of Education (LS2010168); China Medical Board (00726)); Singapore Chinese Health Study (NIH grants: NCI ROl CA55069, R35 CA53890, ROl CA80205, and ROl CA144034); South Korea Multi-Center Lung Cancer Study (National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2011-0016106); National R&D Program for Cancer Control, Ministry of Health &Welfare, Republic of Korea (0720550-2); (A010250)); Tianjin Lung Cancer Study (Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT); China (IRT1076), Tianjin Cancer Institute and Hospital, National Foundation for Cancer Research US); University of Texas MD Anderson Cancer Center (institutional support for the Center for Translational and Public Health Genomics (NIH grant P50 CA 91846)); Women's Health Initiative (National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C); Wuhan lung cancer study (National Key Basic Research and Development Program (2011CB503800)) and Yunnan Lung Cancer Study (Intramural program of U.S. National Institutes of Health; National Cancer Institute). Melinda C. Aldrich was supported by NIH/NCI grant K07 CA 172294. We would like to thank the participants and staff of the NHS and NHSII cohorts for their valuable contributions as well as the following state 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. This study was approved by the Connecticut Department of Public Health (DPH) Human Investigations Committee. Certain data used in this publication were obtained from the DPH. The authors assume full responsibility for the analyses and interpretation of these data. The Women's Health Initiative would like to acknowledge the following individuals for their participation: Program Office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford, and Nancy Geller; Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg; Investigators and Academic Centers: (Brigham and Women's Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA). Marcia L. Stefanick; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Arizona, Tucson/Phoenix, AZ) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker.; Women's Health Initiative Memory Study: (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker. NR 40 TC 0 Z9 0 U1 13 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUN 13 PY 2016 VL 7 AR 118431 DI 10.1038/ncomms118431 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP3IY UT WOS:000378387800001 ER PT J AU Xu, WP Neckers, L AF Xu, Wanping Neckers, Len TI Gr(i)p the ER to Stress Out Melanoma SO CANCER CELL LA English DT Editorial Material ID CANCER AB Because of their elevated steady-state stress level, cancer cells are particularly sensitive to perturbation of mechanisms regulating protein homeostasis. In this issue, Cerezo and colleagues show that pharmacologic modulation of GRP78, master regulator of the unfolded protein response in the endoplasmic reticulum, can be exploited for cancer treatment. C1 [Xu, Wanping; Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM neckers@nih.gov NR 10 TC 1 Z9 2 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD JUN 13 PY 2016 VL 29 IS 6 BP 769 EP 771 DI 10.1016/j.ccell.2016.05.006 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO7AB UT WOS:000377933500001 PM 27300428 ER PT J AU Enewold, L Thomas, A AF Enewold, Lindsey Thomas, Anish TI Real-World Patterns of EGFR Testing and Treatment with Erlotinib for Non-Small Cell Lung Cancer in the United States SO PLOS ONE LA English DT Article ID GROWTH-FACTOR RECEPTOR; RANDOMIZED PHASE-3 TRIAL; HISPANIC WHITE PATIENTS; 1ST-LINE TREATMENT; OPEN-LABEL; AMERICAN SOCIETY; MUTATIONS; CHEMOTHERAPY; GEFITINIB; ADENOCARCINOMA AB Despite being the basis of one of the most effective interventions in lung cancer, little is known about the patterns of epidermal growth factor receptor (EGFR) mutation testing in the general population. We assessed the frequencies and determinants of EGFR testing and erlotinib treatment among a population-based sample. A random sample (n = 1,358) of patients diagnosed in 2010 with histologically-confirmed NSCLC, as reported to the Surveillance Epidemiology and End Results (SEER) program, had their medical records abstracted and treating physicians queried. Logistic regression was used to identify factors associated with EGFR testing and erlotinib treatment. Survival was examined using Cox proportional hazards regression. The frequency of EGFR testing was 16.8% overall and 22.6% for stage IV adenocarcinoma patients. Given an EGFR mutation, 33.6% of all patients and 48.3% of stage IV patients received erlotinib. Among stage IV patients, increased age, Medicaid/no/unknown insurance status, death within 2 months of diagnosis and comorbidity were inversely associated with EGFR testing; erlotinib treatment was less likely among smokers and patients with non-adenocarcinomas. EGFR-mutation was associated with improved survival, albeit only among stage IV adenocarcinomas. Less than a quarter of NSCLC patients diagnosed in 2010 received EGFR testing and less than half of the patients with EGFR-mutant stage IV tumors received erlotinib. Significant disparities were observed in EGFR mutation testing by health insurance status, comorbidity and age. A national strategy is imperative to ensure that resources and processes are in place to efficiently implement molecular testing of cancer. C1 [Enewold, Lindsey] NCI, Healthcare Assessment Res Branch, Healthcare Delivery Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Thomas, Anish] NCI, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Enewold, L (reprint author), NCI, Healthcare Assessment Res Branch, Healthcare Delivery Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM lindsey.enewold@nih.gov FU National Cancer Institute [HHSN261201000024C, HHSN261201000025C, HHSN261201000032C, HHSN261201000027C, HHSN261201000026C, HHSN261201000140C, HHSN261201000037C, HHSN261201000033C, HHSN261201000034C, HHSN261201000035C, HHSN261201000029C, HHSN261201000031C, HHSN261201000028C, HHSN261201000030C] FX This work was supported by the Intramural Research Program of the National Cancer Institute and National Cancer Institute contracts: HHSN261201000024C; HHSN261201000025C, HHSN261201000032C, HHSN261201000027C, HHSN261201000026C, HHSN261201000140C, HHSN261201000037C, HHSN261201000033C, HHSN261201000034C, HHSN261201000035C, HHSN261201000029C, HHSN261201000031C, HHSN261201000028C, and HHSN261201000030C. NR 33 TC 2 Z9 2 U1 3 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 13 PY 2016 VL 11 IS 6 AR e0156728 DI 10.1371/journal.pone.0156728 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO5KF UT WOS:000377821300011 PM 27294665 ER PT J AU Semba, RD Shardell, M Trehan, I Moaddel, R Maleta, KM Ordiz, MI Kraemer, K Khadeer, M Ferrucci, L Manary, MJ AF Semba, Richard D. Shardell, Michelle Trehan, Indi Moaddel, Ruin Maleta, Kenneth M. Ordiz, M. Isabel Kraemer, Klaus Khadeer, Mohammed Ferrucci, Luigi Manary, Mark J. TI Metabolic alterations in children with environmental enteric dysfunction SO SCIENTIFIC REPORTS LA English DT Article ID FALSE DISCOVERY RATES; INTESTINAL PERMEABILITY; PHOSPHATIDYLCHOLINE; ENTEROPATHY; TRYPTOPHAN; SEROTONIN; SPHINGOMYELINS; CITRULLINE; DISORDERS; TAURINE AB Environmental enteric dysfunction, an asymptomatic condition characterized by inflammation of the small bowel mucosa, villous atrophy, malabsorption, and increased intestinal permeability, is a major contributor to childhood stunting in low-income countries. Here we report the relationship of increased intestinal permeability with serum metabolites in 315 children without acute malnutrition, aged 12-59 months, in rural Malawi. Increased gut permeability was associated with significant differences in circulating metabolites that included lower serum phosphatidylcholines, sphingomyelins, tryptophan, ornithine, and citrulline, and elevated serum glutamate, taurine, and serotonin. Our findings suggest that environmental enteric dysfunction is characterized by alterations in important metabolites involved in growth and differentiation and gut function and integrity. C1 [Semba, Richard D.] Johns Hopkins Univ, Wilmer Eye Inst, Sch Med, Baltimore, MD 21287 USA. [Shardell, Michelle; Moaddel, Ruin; Khadeer, Mohammed; Ferrucci, Luigi] NIA, NIH, Baltimore, MD 21224 USA. [Trehan, Indi; Ordiz, M. Isabel; Manary, Mark J.] Washington Univ, Dept Pediat, St Louis, MO 63110 USA. [Trehan, Indi; Maleta, Kenneth M.; Manary, Mark J.] Univ Malawi, Sch Publ Hlth & Family Med, Coll Med, Blantyre, Malawi. [Kraemer, Klaus] Sight & Life, CH-4002 Basel, Switzerland. [Kraemer, Klaus] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. RP Semba, RD (reprint author), Johns Hopkins Univ, Wilmer Eye Inst, Sch Med, Baltimore, MD 21287 USA. EM rdsemba@jhmi.edu OI Maleta, Ken/0000-0002-2536-3938 FU Children's Discovery Institute; Hickey Family Foundation; National Institutes of Health [R01 AG27012]; Intramural Branch of the National Institute on Aging, Baltimore, Maryland FX This work was supported by the Children's Discovery Institute, the Hickey Family Foundation, the National Institutes of Health R01 AG27012 and the Intramural Branch of the National Institute on Aging, Baltimore, Maryland. NR 44 TC 4 Z9 4 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 13 PY 2016 VL 6 AR 28009 DI 10.1038/srep28009 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO8MW UT WOS:000378038700001 PM 27294788 ER PT J AU Guay, MD Czaja, W Aronova, MA Leapman, RD AF Guay, Matthew D. Czaja, Wojciech Aronova, Maria A. Leapman, Richard D. TI Compressed Sensing Electron Tomography for Determining Biological Structure SO SCIENTIFIC REPORTS LA English DT Article ID CRYOELECTRON TOMOGRAPHY; RECONSTRUCTION; REGULARIZATION; TRANSFORMS; MRI AB There has been growing interest in applying compressed sensing (CS) theory and practice to reconstruct 3D volumes at the nanoscale from electron tomography datasets of inorganic materials, based on known sparsity in the structure of interest. Here we explore the application of CS for visualizing the 3D structure of biological specimens from tomographic tilt series acquired in the scanning transmission electron microscope (STEM). CS-ET reconstructions match or outperform commonly used alternative methods in full and undersampled tomogram recovery, but with less significant performance gains than observed for the imaging of inorganic materials. We propose that this disparity stems from the increased structural complexity of biological systems, as supported by theoretical CS sampling considerations and numerical results in simulated phantom datasets. A detailed analysis of the efficacy of CS-ET for undersampled recovery is therefore complicated by the structure of the object being imaged. The numerical nonlinear decoding process of CS shares strong connections with popular regularized least-squares methods, and the use of such numerical recovery techniques for mitigating artifacts and denoising in reconstructions of fully sampled datasets remains advantageous. This article provides a link to the software that has been developed for CS-ET reconstruction of electron tomographic data sets. C1 [Guay, Matthew D.] Univ Maryland, Dept Appl Math & Sci Computat, College Pk, MD 20742 USA. [Czaja, Wojciech] Univ Maryland, Dept Math, College Pk, MD 20742 USA. [Aronova, Maria A.; Leapman, Richard D.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. RP Guay, MD (reprint author), Univ Maryland, Dept Appl Math & Sci Computat, College Pk, MD 20742 USA.; Leapman, RD (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. EM mguay@math.umd.edu; leapmanr@mail.nih.gov FU National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health; Defense Threat Reduction Agency [HDTRA1-13-1-0015] FX This research was partially supported by the intramural program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, and partially supported by Defense Threat Reduction Agency grant HDTRA1-13-1-0015 to the University of Maryland. NR 45 TC 2 Z9 2 U1 6 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 13 PY 2016 VL 6 AR 27614 DI 10.1038/srep27614 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO3AP UT WOS:000377652800001 PM 27291259 ER PT J AU Wu, HE Baumgardt, SL Fang, J Paterson, M Liu, YA Du, JH Shi, Y Qiao, SG Bosnjak, ZJ Warltier, DC Kersten, JR Ge, ZD AF Wu, Hsiang-En Baumgardt, Shelley L. Fang, Juan Paterson, Mark Liu, Yanan Du, Jianhai Shi, Yang Qiao, Shigang Bosnjak, Zeljko J. Warltier, David C. Kersten, Judy R. Ge, Zhi-Dong TI Cardiomyocyte GTP Cyclohydrolase 1 Protects the Heart Against Diabetic Cardiomyopathy SO SCIENTIFIC REPORTS LA English DT Article ID NITRIC-OXIDE SYNTHASE; POPULATION-BASED COHORT; REPERFUSION INJURY; MORTALITY TRENDS; INDUCED CARDIOPROTECTION; PERMEABILITY TRANSITION; ISCHEMIA-REPERFUSION; CARDIAC DYSFUNCTION; MYOCARDIAL-ISCHEMIA; 26S PROTEASOME AB Diabetic cardiomyopathy increases the risk of heart failure and death. At present, there are no effective approaches to preventing its development in the clinic. Here we report that reduction of cardiac GTP cyclohydrolase 1 (GCH1) degradation by genetic and pharmacological approaches protects the heart against diabetic cardiomyopathy. Diabetic cardiomyopathy was induced in C57BL/6 wild-type mice and transgenic mice with cardiomyocyte-specific overexpression of GCH1 with streptozotocin, and control animals were given citrate buffer. We found that diabetes-induced degradation of cardiac GCH1 proteins contributed to adverse cardiac remodeling and dysfunction in C57BL/6 mice, concomitant with decreases in tetrahydrobiopterin, dimeric and phosphorylated neuronal nitric oxide synthase, sarcoplasmic reticulum Ca2+ handling proteins, intracellular [Ca2+] i, and sarcoplasmic reticulum Ca2+ content and increases in phosphorylated p-38 mitogen-activated protein kinase and superoxide production. Interestingly, GCH-1 overexpression abrogated these detrimental effects of diabetes. Furthermore, we found that MG 132, an inhibitor for 26S proteasome, preserved cardiac GCH1 proteins and ameliorated cardiac remodeling and dysfunction during diabetes. This study deepens our understanding of impaired cardiac function in diabetes, identifies GCH1 as a modulator of cardiac remodeling and function, and reveals a new therapeutic target for diabetic cardiomyopathy. C1 [Wu, Hsiang-En; Baumgardt, Shelley L.; Paterson, Mark; Qiao, Shigang; Bosnjak, Zeljko J.; Warltier, David C.; Kersten, Judy R.; Ge, Zhi-Dong] Med Coll Wisconsin, Dept Anesthesiol, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [Wu, Hsiang-En] NIDA, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Fang, Juan] Med Coll Wisconsin, Dept Pediat, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [Liu, Yanan] Columbia Univ, Dept Med, 630 W 168th St, New York, NY 10032 USA. [Du, Jianhai] Univ Washington, Dept Biochem, 1705 NE Pacific St, Seattle, WA 98195 USA. [Shi, Yang] Aurora Hlth Care, Aurora Res Inst, 750 W Virginia St, Milwaukee, WI 53234 USA. [Bosnjak, Zeljko J.] Med Coll Wisconsin, Dept Physiol, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [Warltier, David C.; Kersten, Judy R.] Med Coll Wisconsin, Dept Pharmacol & Toxicol, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. RP Ge, ZD (reprint author), Med Coll Wisconsin, Dept Anesthesiol, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM Wilson.ge99@gmail.com FU National Institutes of Health [GM 066730]; United States Public Health Services, Bethesda, Maryland [HL 063705]; Pilot Grant from Research Affairs Committee, Medical College of Wisconsin FX We are grateful to Drs. John A. Auchampach, Ph.D. and Tina C. Wan, Ph.D. (Department of Pharmacology and Toxicology, Medical College of Wisconsin) for their equipment. This work was supported in part by the National Institutes of Health research grant GM 066730 and HL 063705 from the United States Public Health Services, Bethesda, Maryland and the Pilot Grant from Research Affairs Committee, Medical College of Wisconsin. NR 72 TC 1 Z9 1 U1 1 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 13 PY 2016 VL 6 AR 27925 DI 10.1038/srep27925 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO3DS UT WOS:000377661200002 PM 27295516 ER PT J AU Baty, H Nishikawa, H AF Baty, Hubert Nishikawa, Hiroaki TI Hyperbolic method for magnetic reconnection process in steady state magnetohydrodynamics SO MONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY LA English DT Article DE magnetic reconnection; MHD-methods: numerical; Sun: flares ID FINITE-VOLUME; 2 DIMENSIONS; DIFFUSION; SCHEMES; ANNIHILATION; ADVECTION AB A recent numerical approach for solving the advection-diffusion and Navier-Stokes equations is extended for the first time to a magnetohydrodynamic (MHD) model, aiming in particular consistent improvements over classical methods for investigating the magnetic reconnection process. In this study, we mainly focus on a two-dimensional incompressible set of resistive MHD equations written in flux-vorticity scalar variables. The originality of the method is based on hyperbolic reformulation of the dissipative terms, leading to the construction of an equivalent hyperbolic first-order (spatial derivatives) system. This enables the use of approximate Riemann solvers for handling dissipative and advective flux in the same way. A simple second-order finite-volume discretization on rectangular grids using an upwind flux is employed. The advantages of this method are illustrated by a comparison to two particular analytical steady state solutions of the inviscid magnetic reconnection mechanism, namely the magnetic annihilation and the reconnective diffusion problems. In particular, the numerical solution is obtained with the same order of accuracy for the solution and gradient for a wide range of magnetic Reynolds numbers, without any deterioration characteristic of more conventional schemes. The amelioration of the hyperbolic method and its extension to time-dependent MHD problems related to solar flares mechanisms is also discussed. C1 [Baty, Hubert] Univ Strasbourg, Observ Astronom Strasbourg, CNRS, UMR 7550, F-67000 Strasbourg, France. [Nishikawa, Hiroaki] NIA, Hampton, VA 23666 USA. RP Baty, H (reprint author), Univ Strasbourg, Observ Astronom Strasbourg, CNRS, UMR 7550, F-67000 Strasbourg, France. EM hubert.baty@unistra.fr RI Nishikawa, Hiroaki/M-1247-2016 OI Nishikawa, Hiroaki/0000-0003-4472-5313 FU French National Research Agency (ANR) [ANR-13-JS05-0003-01] FX The authors thank P. Helluy, J. Petri, and P. Ackerer for fruitful discussions. HB acknowledges support by French National Research Agency (ANR) through Grant ANR-13-JS05-0003-01 (Project EMPERE). We also acknowledge computational facilities available at Equip@Meso of the Universite de Strasbourg. We sincerely thank the anonymous referee for useful suggestions that helped improve the content of the paper. NR 25 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0035-8711 EI 1365-2966 J9 MON NOT R ASTRON SOC JI Mon. Not. Roy. Astron. Soc. PD JUN 11 PY 2016 VL 459 IS 1 BP 624 EP 637 DI 10.1093/mnras/stw654 PG 14 WC Astronomy & Astrophysics SC Astronomy & Astrophysics GA DM5KB UT WOS:000376386600049 ER PT J AU Blauwendraat, C Francescatto, M Gibbs, JR Jansen, IE Simon-Sanchez, J Hernandez, DG Dillman, AA Singleton, AB Cookson, MR Rizzu, P Heutink, P AF Blauwendraat, Cornelis Francescatto, Margherita Gibbs, J. Raphael Jansen, Iris E. Simon-Sanchez, Javier Hernandez, Dena G. Dillman, Allissa A. Singleton, Andrew B. Cookson, Mark R. Rizzu, Patrizia Heutink, Peter TI Comprehensive promoter level expression quantitative trait loci analysis of the human frontal lobe SO GENOME MEDICINE LA English DT Article DE Expression quantitative trait loci (eQTL); frontal lobe cortex; NRGN; Cap analysis gene expression sequencing (CAGEseq); PARK16 ID GENOME-WIDE ASSOCIATION; 17Q21.31 MICRODELETION SYNDROME; ANALYSIS GENE-EXPRESSION; LONG NONCODING RNAS; DNA-SEQUENCING DATA; PARKINSONS-DISEASE; CAP-ANALYSIS; TISSUE EXPRESSION; COMMON VARIANTS; KANSL1 CAUSE AB Background: Expression quantitative trait loci (eQTL) analysis is a powerful method to detect correlations between gene expression and genomic variants and is widely used to interpret the biological mechanism underlying identified genome wide association studies (GWAS) risk loci. Numerous eQTL studies have been performed on different cell types and tissues of which the majority has been based on microarray technology. Methods: We present here an eQTL analysis based on cap analysis gene expression sequencing (CAGEseq) data created from human postmortem frontal lobe tissue combined with genotypes obtained through genotyping arrays, exome sequencing, and CAGEseq. Using CAGEseq as an expression profiling technique combined with these different genotyping techniques allows measurement of the molecular effect of variants on individual transcription start sites and increases the resolution of eQTL analysis by also including the non-annotated parts of the genome. Results: We identified 2410 eQTLs and show that non-coding transcripts are more likely to contain an eQTL than coding transcripts, in particular antisense transcripts. We provide evidence for how previously identified GWAS loci for schizophrenia (NRGN), Parkinson's disease, and Alzheimer's disease (PARK16 and MAPT loci) could increase the risk for disease at a molecular level. Furthermore, we demonstrate that CAGEseq improves eQTL analysis because variants obtained from CAGEseq are highly enriched for having a functional effect and thus are an efficient method towards the identification of causal variants. Conclusion: Our data contain both coding and non-coding transcripts and has the added value that we have identified eQTLs for variants directly adjacent to TSS. Future eQTL studies would benefit from combining CAGEseq with RNA sequencing for a more complete interpretation of the transcriptome and increased understanding of eQTL signals. C1 [Blauwendraat, Cornelis; Rizzu, Patrizia] German Ctr Neurodegenerat Dis DZNE, Appl Genom Neurodegenerat Dis, Tubingen, Germany. [Francescatto, Margherita; Jansen, Iris E.; Simon-Sanchez, Javier; Heutink, Peter] German Ctr Neurodegenerat Dis DZNE, Genome Biol Neurodegenerat Dis, Tubingen, Germany. [Gibbs, J. Raphael; Hernandez, Dena G.; Dillman, Allissa A.; Singleton, Andrew B.; Cookson, Mark R.] NIA, Lab Neurogenet, Bethesda, MD 20892 USA. [Gibbs, J. Raphael] UCL, Inst Neurol, Dept Mol Neurosci, London, England. [Jansen, Iris E.; Heutink, Peter] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Amsterdam, Netherlands. [Simon-Sanchez, Javier; Heutink, Peter] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany. RP Blauwendraat, C (reprint author), German Ctr Neurodegenerat Dis DZNE, Appl Genom Neurodegenerat Dis, Tubingen, Germany. EM cornelis.blauwendraat@gmail.com FU European Union Seventh Framework Program [FP7-People-ITN-2008-238055]; EU Joint Program-Neurodegenerative Diseases (JPND); RiMod-FTD; Intramural Research Program of the NIH, National Institute on Aging [AG000932, AG000947] FX The research leading to these results has received funding from the European Union Seventh Framework Program under grant agreement FP7-People-ITN-2008-238055 ("BrainTrain" project) and the EU Joint Program-Neurodegenerative Diseases (JPND); RiMod-FTD. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (Project numbers AG000932 and AG000947). NR 90 TC 0 Z9 0 U1 8 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD JUN 10 PY 2016 VL 8 AR 65 DI 10.1186/s13073-016-0320-1 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA DP6FM UT WOS:000378592300002 PM 27287230 ER PT J AU Kim, S Thiessen, PA Cheng, T Yu, B Shoemaker, BA Wang, JY Bolton, EE Wang, YL Bryant, SH AF Kim, Sunghwan Thiessen, Paul A. Cheng, Tiejun Yu, Bo Shoemaker, Benjamin A. Wang, Jiyao Bolton, Evan E. Wang, Yanli Bryant, Stephen H. TI Literature information in PubChem: associations between PubChem records and scientific articles SO JOURNAL OF CHEMINFORMATICS LA English DT Article ID SMALL MOLECULES; DATABASE; UPDATE; COLLECTION; ACCESS; SYSTEM; ENTREZ AB Background: PubChem is an open archive consisting of a set of three primary public databases (BioAssay, Compound, and Substance). It contains information on a broad range of chemical entities, including small molecules, lipids, carbohydrates, and (chemically modified) amino acid and nucleic acid sequences (including siRNA and miRNA). Currently (as of Nov. 2015), PubChem contains more than 150 million depositor-provided chemical substance descriptions, 60 million unique chemical structures, and 225 million biological activity test results provided from over 1 million biological assay records. Description: Many PubChem records (substances, compounds, and assays) include depositor-provided cross-references to scientific articles in PubMed. Some PubChem contributors provide bioactivity data extracted from scientific articles. Literature-derived bioactivity data complement high-throughput screening (HTS) data from the concluded NIH Molecular Libraries Program and other HTS projects. Some journals provide PubChem with information on chemicals that appear in their newly published articles, enabling concurrent publication of scientific articles in journals and associated data in public databases. In addition, PubChem links records to PubMed articles indexed with the Medical Subject Heading (MeSH) controlled vocabulary thesaurus. Conclusion: Literature information, both provided by depositors and derived from MeSH annotations, can be accessed using PubChem's web interfaces, enabling users to explore information available in literature related to PubChem records beyond typical web search results. C1 [Kim, Sunghwan; Thiessen, Paul A.; Cheng, Tiejun; Yu, Bo; Shoemaker, Benjamin A.; Wang, Jiyao; Bolton, Evan E.; Wang, Yanli; Bryant, Stephen H.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Dept Hlth & Human Serv, 8600 Rockville Pike, Bethesda, MD 20894 USA. RP Kim, S (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Dept Hlth & Human Serv, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM kimsungh@ncbi.nlm.nih.gov RI Kim, Sunghwan/A-6738-2008 OI Kim, Sunghwan/0000-0001-9828-2074 FU Intramural Research Program of the National Library of Medicine, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health. Special thanks to PubChem team members (present and past), the Entrez infrastructure group, the MeSH group, and all PubChem data contributors without which this work would not be possible. We also thank Nancy Terry, NIH Library Editing Service, for reviewing the manuscript. NR 26 TC 1 Z9 1 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-2946 J9 J CHEMINFORMATICS JI J. Cheminformatics PD JUN 10 PY 2016 VL 8 AR 32 DI 10.1186/s13321-016-0142-6 PG 15 WC Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Chemistry; Computer Science GA DP0UH UT WOS:000378204900001 PM 27293485 ER PT J AU Loell, I Raouf, J Chen, YW Shi, RY Nennesmo, I Alexanderson, H Dastmalchi, M Nagaraju, K Korotkova, M Lundberg, IE AF Loell, Ingela Raouf, Joan Chen, Yi-Wen Shi, Rongye Nennesmo, Inger Alexanderson, Helene Dastmalchi, Maryam Nagaraju, Kanneboyina Korotkova, Marina Lundberg, Ingrid E. TI Effects on muscle tissue remodeling and lipid metabolism in muscle tissue from adult patients with polymyositis or dermatomyositis treated with immunosuppressive agents SO ARTHRITIS RESEARCH & THERAPY LA English DT Article DE Glucocorticoids; Treatment; Muscle biopsies; Polymyositis; Dermatomyositis; Gene expression profiling ID IDIOPATHIC INFLAMMATORY MYOPATHIES; INDUCIBLE GENE-EXPRESSION; I INTERFERON; MUSCULAR-DYSTROPHIES; INSULIN-RESISTANCE; DISEASE-ACTIVITY; RECEPTOR; FIBERS; GLUCOCORTICOIDS; LIPODYSTROPHY AB Background: Polymyositis (PM) and dermatomyositis (DM) are autoimmune muscle diseases, conventionally treated with high doses of glucocorticoids in combination with immunosuppressive drugs. Treatment is often dissatisfying, with persisting muscle impairment. We aimed to investigate molecular mechanisms that might contribute to the persisting muscle impairment despite immunosuppressive treatment in adult patients with PM or DM using gene expression profiling of repeated muscle biopsies. Methods: Paired skeletal muscle biopsies from six newly diagnosed adult patients with DM or PM taken before and after conventional immunosuppressive treatment were examined by gene expression microarray analysis. Selected genes that displayed changes in expression were analyzed by Western blot. Muscle biopsy sections were evaluated for inflammation, T lymphocytes (CD3), macrophages (CD68), major histocompatibility complex (MHC) class I expression and fiber type composition. Results: After treatment, genes related to immune response and inflammation, including inflammasome pathways and interferon, were downregulated. This was confirmed at the protein level for AIM-2 and caspase-1 in the inflammasome pathway. Changes in genes involved in muscle tissue remodeling suggested a negative effect on muscle regeneration and growth. Gene markers for fast type II fibers were upregulated and fiber composition was switched towards type II fibers in response to treatment. The expression of genes involved in lipid metabolism was altered, suggesting a potential lipotoxic effect on muscles of the immunosuppressive treatment. Conclusion: The anti-inflammatory effect of immunosuppressive treatment was combined with negative effects on genes involved in muscle tissue remodeling and lipid metabolism, suggesting a negative effect on recovery of muscle performance which may contribute to persisting muscle impairment in adult patients with DM and PM. C1 [Loell, Ingela; Raouf, Joan; Dastmalchi, Maryam; Korotkova, Marina; Lundberg, Ingrid E.] Karolinska Univ Hosp Solna, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden. [Chen, Yi-Wen; Nagaraju, Kanneboyina] Med Genet Res Ctr, Childrens Natl Med Ctr, Washington, DC USA. [Shi, Rongye] NHLBI, Ctr Human Immunol Autoimmun & Inflammat, NIH, Bldg 10, Bethesda, MD 20892 USA. [Nennesmo, Inger] Karolinska Univ Hosp Huddinge, Inst Lab Med LABMED, Stockholm, Sweden. [Alexanderson, Helene] Karolinska Inst, Dept NVS, Div Phys Therapy, Stockholm, Sweden. [Alexanderson, Helene] Karolinska Univ Hosp Solna, Phys Therapy Clin, Stockholm, Sweden. RP Lundberg, IE (reprint author), Karolinska Univ Hosp Solna, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden. EM Ingrid.Lundberg@ki.se FU Swedish Research Council; Swedish Rheumatism Association; King Gustaf V 80 Year Foundation; Karolinska Institutet; Stockholm County Council; National Institutes of Health [K26OD011171, R24HD050846-02, P50AR060836]; United States Department of Defense [W81XWH-05-1-0659, W81XWH-11-1-0782, W81XWH-11-1-0330, W81XWH 10-1-0767] FX This study was supported by grants from the Swedish Research Council, the Swedish Rheumatism Association, King Gustaf V 80 Year Foundation, Funds at the Karolinska Institutet and through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet. KN was supported by National Institutes of Health grantss K26OD011171, R24HD050846-02, and P50AR060836, and United States Department of Defense grants W81XWH-05-1-0659, W81XWH-11-1-0782, W81XWH-11-1-0330, and W81XWH 10-1-0767. NR 44 TC 1 Z9 1 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 EI 1478-6362 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PD JUN 10 PY 2016 VL 18 AR 136 DI 10.1186/s13075-016-1033-y PG 13 WC Rheumatology SC Rheumatology GA DO7QK UT WOS:000377976900002 PM 27287443 ER PT J AU Gillies, CE Otto, EA Vega-Warner, V Robertson, CC Sanna-Cherchi, S Gharavi, A Crawford, B Bhimma, R Winkler, C Kang, HM Sampson, MG AF Gillies, Christopher E. Otto, Edgar A. Vega-Warner, Virginia Robertson, Catherine C. Sanna-Cherchi, Simone Gharavi, Ali Crawford, Brendan Bhimma, Rajendra Winkler, Cheryl Kang, Hyun Min Sampson, Matthew G. CA Nephrotic Syndrome Study Network Michigan Kidney Translational Core TI tarSVM: Improving the accuracy of variant calls derived from microfluidic PCR-based targeted next generation sequencing using a support vector machine SO BMC BIOINFORMATICS LA English DT Article DE Microfluidic; PCR; Next-generation sequencing; Variant calling; Accuracy; Support vector machine; Nephrotic ID NEPHROTIC SYNDROME; NEPHROPATHY; CILIOPATHY; MUTATIONS; FRAMEWORK; GENOMES AB Background: Targeted sequencing of discrete gene sets is a cost effective strategy to screen subjects for monogenic forms of disease. One method to achieve this pairs microfluidic PCR with next generation sequencing. The PCR step of this pipeline creates challenges in accurate variant calling. This includes that most reads targeting a specific exon are duplicates that have been amplified from the PCR step. To reduce false positive variant calls from these experiments, previous studies have used threshold-based filtering of alternative allele depth ratio and manual inspection of the alignments. However even after manual inspection and filtering, many variants fail to be validated via Sanger sequencing. To improve the accuracy of variant calling from these experiments, we are challenged to design a variant filtering strategy that sufficiently models microfluidic PCR-specific issues. Results: We developed an open source variant filtering pipeline, targeted sequencing support vector machine ("tarSVM"), that uses a Support Vector Machine (SVM) and a new score the normalized allele dosage test to identify high quality variants from microfluidic PCR data. tarSVM maximizes training knowledge by selecting variants that are likely true and likely false variants by incorporating knowledge from the 1000 Genomes and the Exome Aggregation Consortium projects. tarSVM improves on previous approaches by synthesizing variant features from the Genome Analysis Toolkit and allele dosage information. We compared the accuracy of tarSVM versus existing variant quality filtering strategies on two cohorts (n = 474 and n = 1152), and validated our method on a third cohort (n = 75). In the first cohort, our method achieved 84.5 % accuracy of predicting whether or not a variant would be validated with Sanger sequencing versus 78.8 % for the second most accurate method. In the second cohort, our method had an accuracy of 73.3 %, versus 61.5 % for the second best method. Finally, our method had a false discovery rate of 5 % for the validation cohort. Conclusions: tarSVM increases the accuracy of variant calling when using microfluidic PCR based targeted sequencing approaches. This results in higher confidence downstream analyses, and ultimately reduces the costs Sanger validation. Our approach is less labor intensive than existing approaches, and is available as an open source pipeline for read trimming, aligning, variant calling, and variant quality filtering on GitHub at https://github.com/christopher-gillies/TargetSpecificGATKSequencingPipeline. C1 [Gillies, Christopher E.; Vega-Warner, Virginia; Robertson, Catherine C.; Crawford, Brendan; Sampson, Matthew G.] Univ Michigan, Sch Med, Dept Pediat Nephrol, Ann Arbor, MI USA. [Otto, Edgar A.] Univ Michigan, Sch Med, Dept Internal Med Nephrol, Ann Arbor, MI USA. [Sanna-Cherchi, Simone; Gharavi, Ali] Columbia Univ, Dept Med, Coll Phys & Surg, New York, NY USA. [Bhimma, Rajendra] Univ KwaZulu Natal, Dept Paediat & Child Hlth, Durban, South Africa. [Winkler, Cheryl] NCI, Frederick Natl Lab Canc Res, Mol Genet Epidemiol Sect, Frederick, MD 21701 USA. [Kang, Hyun Min] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Sampson, Matthew G.] 3560B MSRB2,1150 West Med Ctr Dr, Ann Arbor, MI 48109 USA. RP Sampson, MG (reprint author), Univ Michigan, Sch Med, Dept Pediat Nephrol, Ann Arbor, MI USA.; Sampson, MG (reprint author), 3560B MSRB2,1150 West Med Ctr Dr, Ann Arbor, MI 48109 USA. EM mgsamps@med.umich.edu OI Otto, Edgar/0000-0002-2387-9973 FU University of Michigan; NephCure Kidney International; Halpin Foundation; National Cancer Institute, National Institutes of Health [HHSN26120080001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; NIDDK [1 K08-DK100662-01]; Office of Rare Diseases Research (ORDR), NCATS [U54-DK-083912]; National Institute of Diabetes, Digestive, and Kidney Diseases [U54-DK-083912] FX The Nephrotic Syndrome Study Network Consortium (NEPTUNE); U54-DK-083912, is a part of the National Center for Advancing Translational Sciences (NCATS) Rare Disease Clinical Research Network (RDCRN), supported through a collaboration between the Office of Rare Diseases Research (ORDR), NCATS, and the National Institute of Diabetes, Digestive, and Kidney Diseases. RDCRN is an initiative of ORDR, NCATS. Additional funding and/or programmatic support for this project has also been provided by the University of Michigan, NephCure Kidney International, and the Halpin Foundation.; This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This Research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.; M.G.S. is a Carl Gottschalk Research Scholar of the American Society of Nephrology and is supported by the NIDDK Grant 1 K08-DK100662-01. NR 22 TC 0 Z9 0 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD JUN 10 PY 2016 VL 17 AR 233 DI 10.1186/s12859-016-1108-4 PG 13 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA DO5XU UT WOS:000377857200001 PM 27287006 ER PT J AU Godfrey, C Tauscher, G Hunsberger, S Austin, M Scott, L Schouten, JT Luetkemeyer, AF Benson, C Coombs, R Swindells, S AF Godfrey, Catherine Tauscher, Gail Hunsberger, Sally Austin, Melissa Scott, Lesley Schouten, Jeffrey T. Luetkemeyer, Anne F. Benson, Constance Coombs, Robert Swindells, Susan CA HIV Network Coordinating HANC TB D Natl Inst Allergy Infect Dis TI A survey of tuberculosis infection control practices at the NIH/NIAID/DAIDS-supported clinical trial sites in low and middle income countries SO BMC INFECTIOUS DISEASES LA English DT Article DE Infection prevention; HIV; AIDS; Resource limited; IC; Tuberculosis; Tuberculosis prevention; Low and middle income countries ID HEALTH-CARE WORKERS; DRUG-RESISTANT TUBERCULOSIS; SOUTH-AFRICA; HOSPITALS; SETTINGS; NIGERIA; RISK AB Background: Health care associated transmission of Mycobacterium tuberculosis (TB) is well described. A previous survey of infection control (IC) practices at clinical research sites in low and middle income countries (LMIC) funded by the National Institute of Allergy and Infectious Diseases (NIAID) conducting HIV research identified issues with respiratory IC practices. A guideline for TB IC based on international recommendations was developed and promulgated. This paper reports on adherence to the guideline at sites conducting or planning to conduct TB studies with the intention of supporting improvement. Methods: A survey was developed that assessed IC activities in three domains: facility level measures, administrative control measures and environmental measures. An external site monitor visited each site in 2013-2014, to complete the audit. A central review committee evaluated the site-level survey and results were tabulated. Fisher's exact test was performed to determine whether there were significant differences in practices at sites that had IC officers versus sites that did not have IC officers. Significance was assessed at pA (p.I263Nfs8*), a 2 bp duplication in exon 2: c.551_552dupTA (p.Q185Yfs4*) and an 11,117 bp deletion that removes all three coding exons of RP1. These variations segregated with the disease phenotype within the respective families and were not present in ethnically matched control samples. Conclusions: These results strongly suggest that these mutations in RP1 are responsible for the retinal phenotype in affected individuals of all four consanguineous families. C1 [Kabir, Firoz; Gottsch, Alexander D. H.; Riazuddin, S. Amer] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21287 USA. [Ullah, Inayat; Ali, Shahbaz; Naeem, Muhammad Asif; Khan, Shaheen N.; Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Assir, Muhammad Zaman; Akram, Javed; Riazuddin, Sheikh] Univ Hlth Sci, Allama Iqbal Med Coll, Lahore, Pakistan. [Assir, Muhammad Zaman; Akram, Javed; Riazuddin, Sheikh] Shaheed Zulfiqar Ali Bhutto Med Univ, Natl Ctr Genet Dis, Islamabad, Pakistan. [Ayyagari, Radha] Univ Calif San Diego, Shiley Eye Inst, San Diego, CA 92103 USA. [Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP Riazuddin, SA (reprint author), Johns Hopkins Univ, Sch Med, 600 N Wolfe St,Maumenee 840, Baltimore, MD 21287 USA. EM riazuddin@jhmi.edu FU Higher Education Commission, Islamabad, Pakistan; National Eye Institute [R01EY021237] FX We are thankful to all family members for their participation in this study. This study was supported in part by Higher Education Commission, Islamabad, Pakistan, and by the National Eye Institute Grant R01EY021237 (RA and SAR). NR 113 TC 0 Z9 0 U1 2 U2 2 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JUN 10 PY 2016 VL 22 BP 610 EP 625 PG 16 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA DO6YX UT WOS:000377930500001 PM 27307693 ER PT J AU Lemley, KV Bagnasco, SM Nast, CC Barisoni, L Conway, CM Hewitt, SM Song, PXK AF Lemley, Kevin V. Bagnasco, Serena M. Nast, Cynthia C. Barisoni, Laura Conway, Catherine M. Hewitt, Stephen M. Song, Peter X. K. TI Morphometry Predicts Early GFR Change in Primary Proteinuric Glomerulopathies: A Longitudinal Cohort Study Using Generalized Estimating Equations SO PLOS ONE LA English DT Article ID CHRONIC KIDNEY-DISEASE; INTERSTITIAL FIBROSIS; GLOMERULAR DENSITY; NEPHROTIC SYNDROME; NETWORK NEPTUNE; IGA NEPHROPATHY; PROGRESSION; BIOPSIES; NUMBER AB Objective Most predictive models of kidney disease progression have not incorporated structural data. If structural variables have been used in models, they have generally been only semi-quantitative. Methods We examined the predictive utility of quantitative structural parameters measured on the digital images of baseline kidney biopsies from the NEPTUNE study of primary proteinuric glomerulopathies. These variables were included in longitudinal statistical models predicting the change in estimated glomerular filtration rate (eGFR) over up to 55 months of follow-up. Results The participants were fifty-six pediatric and adult subjects from the NEPTUNE longitudinal cohort study who had measurements made on their digital biopsy images; 25% were African-American, 70% were male and 39% were children; 25 had focal segmental glomerular sclerosis, 19 had minimal change disease, and 12 had membranous nephropathy. We considered four different sets of candidate predictors, each including four quantitative structural variables (for example, mean glomerular tuft area, cortical density of patent glomeruli and two of the principal components from the correlation matrix of six fractional cortical areas-interstitium, atrophic tubule, intact tubule, blood vessel, sclerotic glomerulus, and patent glomerulus) along with 13 potentially confounding demographic and clinical variables (such as race, age, diagnosis, and baseline eGFR, quantitative proteinuria and BMI). We used longitudinal linear models based on these 17 variables to predict the change in eGFR over up to 55 months. All 4 models had a leave-one-out cross-validated R-2 of about 62%. Conclusions Several combinations of quantitative structural variables were significantly and strongly associated with changes in eGFR. The structural variables were generally stronger than any of the confounding variables, other than baseline eGFR. Our findings suggest that quantitative assessment of diagnostic renal biopsies may play a role in estimating the baseline risk of succeeding loss of renal function in future clinical studies, and possibly in clinical practice. C1 [Lemley, Kevin V.] Univ So Calif, Keck Sch Med, Div Pediat Nephrol, Dept Pediat, Los Angeles, CA 90033 USA. [Bagnasco, Serena M.] Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD USA. [Nast, Cynthia C.] Cedars Sinai Med Ctr, Dept Pathol, Los Angeles, CA 90048 USA. [Barisoni, Laura] Univ Miami, Dept Pathol, Miami, FL USA. [Conway, Catherine M.; Hewitt, Stephen M.] NCI, NIH, Bethesda, MD 20892 USA. [Song, Peter X. K.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Conway, Catherine M.] Leica Biosyst Ltd, Dublin, Ireland. RP Lemley, KV (reprint author), Univ So Calif, Keck Sch Med, Div Pediat Nephrol, Dept Pediat, Los Angeles, CA 90033 USA. EM klemley@chla.usc.edu FU NIH/ORDR [U-54DK083912]; NephCure Kidney International; National Cancer Institute (NIH): Intramural Research FX This work was supported by NIH/ORDR U-54DK083912; NephCure: nephcure.org (now NephCure Kidney International); and National Cancer Institute (NIH): Intramural Research. None of the funders had any role in study design, data collection or analysis, decision to publish, or preparation of the manuscript. NR 20 TC 0 Z9 0 U1 5 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 10 PY 2016 VL 11 IS 6 AR e0157148 DI 10.1371/journal.pone.0157148 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO1UG UT WOS:000377564000040 PM 27285824 ER PT J AU Gao, Y Yang, W AF Gao, Yang Yang, Wei TI Capture of a third Mg2+ is essential for catalyzing DNA synthesis SO SCIENCE LA English DT Article ID POLYMERASE-ETA; COMPUTATIONAL DESIGN; ENZYME CATALYSIS; INDUCED-FIT; MECHANISM; NUCLEOTIDE; FIDELITY; POLYMERIZATION; REPLICATION; SPECIFICITY AB It is generally assumed that an enzyme-substrate (ES) complex contains all components necessary for catalysis and that conversion to products occurs by rearrangement of atoms, protons, and electrons. However, we find that DNA synthesis does not occur in a fully assembled DNA polymerase-DNA-deoxynucleoside triphosphate complex with two canonical metal ions bound. Using time -resolved x-ray crystallography, we show that the phosphoryltransfer reaction takes place only after the ES complex captures a third divalent cation that is not coordinated by the enzyme. Binding of the third cation is incompatible with the basal ES complex and requires thermal activation of the ES for entry. It is likely that the third cation provides the ultimate boost over the energy barrier to catalysis of DNA synthesis. C1 [Gao, Yang; Yang, Wei] NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. RP Yang, W (reprint author), NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. EM wei.yang@nih.gov RI Gao, Yang/O-3445-2016 FU NIH [DK036146-08] FX Y.G. carried out all experiments; W.Y. conceived and designed the project, and both authors interpreted data and prepared the manuscript. We thank D. J. Leahy and M. Gellert for critical reading and editing the manuscript. This work is funded by NIH intramural program (DK036146-08, W.Y.). NR 32 TC 8 Z9 8 U1 12 U2 22 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JUN 10 PY 2016 VL 352 IS 6291 BP 1334 EP 1337 DI 10.1126/science.aad9633 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO7ON UT WOS:000377972000045 PM 27284197 ER PT J AU Wang, JJ Sun, LG Chen, LQ Xu, LB Wang, YH Wang, XM AF Wang, Jianjun Sun, Liguang Chen, Liqi Xu, Libin Wang, Yuhong Wang, Xinming TI The abrupt climate change near 4,400 yr BP on the cultural transition in Yuchisi, China and its global linkage SO SCIENTIFIC REPORTS LA English DT Article ID LATE HOLOCENE; FATTY-ACIDS; COLLAPSE; DROUGHT; AFRICAN; RECORD; CIVILIZATION; VARIABILITY; AMERICA; HISTORY AB Extreme climatic events have profound impacts on human society. Here we present the results of a study of organic biomarkers within a sedimentary section at the archaeological site of Yuchisi, eastern China, in order to reconstruct climatic variability during the Dawenkou (5,050-4,400 yr BP) and Longshan (4,400-4,000 yr BP) cultures. At similar to 4,400 yr BP, within the cultural transition horizon, abrupt changes in biomarkers, such as the fatty acid ratio C-18:2/C-18:0, 2C(31)/(C-27 + C-29), n-C-18-ol and n-C-30-ol, indicate the occurrence of local climate changes over the course of a few decades. These changes occurred during the transition from the Holocene warm period to a subsequent cold period which lasted for the following 600 years. This climatic shift has been recorded at numerous sites worldwide, and it is likely to have been the main cause of the widespread collapse of many isolated cultures at that time. The palaeoclimatic and archaeological data from the Yuchisi sediments may provide new insights into the relationship between climate change and prehistoric cultural transitions. C1 [Wang, Jianjun; Chen, Liqi] State Ocean Adm, Inst Oceanog 3, Key Lab Global Change & Marine Atmospher Chem, Xiamen, Peoples R China. [Wang, Jianjun; Sun, Liguang; Xu, Libin] Univ Sci & Technol China, Inst Polar Environm, Hefei 230026, Peoples R China. [Xu, Libin] Zhangjiagang Water Supply & Drainage Co, Zhangjiagang, Peoples R China. [Wang, Yuhong] NIH, Bldg 10, Bethesda, MD 20892 USA. [Wang, Xinming] Chinese Acad Sci, Guangzhou Inst Geochem, Guangzhou, Guangdong, Peoples R China. RP Wang, JJ (reprint author), State Ocean Adm, Inst Oceanog 3, Key Lab Global Change & Marine Atmospher Chem, Xiamen, Peoples R China.; Wang, JJ; Sun, LG (reprint author), Univ Sci & Technol China, Inst Polar Environm, Hefei 230026, Peoples R China. EM wangjianjun@tio.org.cn; slg@ustc.edu.cn FU Scientific Research Foundation of the Third Institute of Oceanography [2014031]; Ecological Environment Protection Division; State Oceanic Administration (SOA); Chinese Projects for Investigations and Assessments of the Arctic and Antarctic [CHINARE 04-03-07]; China Scholarship Council [201404180008] FX We thank Prof. Jan Bloemendal, Mr. Iain MacRae and Ms. Mary McPherson for their language editing of this work. This work was supported by the Scientific Research Foundation of the Third Institute of Oceanography (Grant No. 2014031), the Ecological Environment Protection Division, the State Oceanic Administration (SOA), Chinese Projects for Investigations and Assessments of the Arctic and Antarctic (CHINARE 04-03-07) and by the China Scholarship Council (201404180008). NR 56 TC 0 Z9 0 U1 6 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 10 PY 2016 VL 6 AR 27723 DI 10.1038/srep27723 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO3PN UT WOS:000377693600001 PM 27283832 ER PT J AU Ma, HS Greenblatt, SM Shirley, CM Duffield, AS Bruner, JK Li, L Bao, NY Jung, E Aplan, PD Ghiaur, G Jones, RJ Small, D AF Ma, Hayley S. Greenblatt, Sarah M. Shirley, Courtney M. Duffield, Amy S. Bruner, J. Kyle Li, Li Bao Nguyen Jung, Eric Aplan, Peter D. Ghiaur, Gabriel Jones, Richard J. Small, Donald TI All-trans retinoic acid synergizes with FLT3 inhibition to eliminate FLT3/ITD+ leukemia stem cells in vitro and in vivo SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; INTERNAL TANDEM DUPLICATION; ACUTE PROMYELOCYTIC LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; PROGNOSTIC-SIGNIFICANCE; KINASE INHIBITION; MUTATIONS; AML; ATRA; GENE AB FMS-like tyrosine kinase 3 (FLT3)-mutant acute myeloid leukemia (AML) portends a poor prognosis, and ineffective targeting of the leukemic stem cell (LSC) population remains one of several obstacles in treating this disease. All-trans retinoic acid (ATRA) has been used in several clinical trials for the treatment of nonpromyelocytic AML with limited clinical activity observed. FLT3 tyrosine kinase inhibitors (TKIs) used as monotherapy also achieve limited clinical responses and are thus far unable to affect cure rates in AML patients. We explored the efficacy of combining ATRA and FLT3 TKIs to eliminate FLT3/internal tandem duplication (ITD) 1 LSCs. Our studies reveal highly synergistic drug activity, preferentially inducing apoptosis in FLT3/ITD+ cell lines and patient samples. Colony-forming unit assays further demonstrate decreased clonogenicity of FLT3/ITD+ cells upon treatment with ATRA and TKI. Most importantly, the drug combination depletes FLT3/ITD+ LSCs in a genetic mouse model of AML, and prolongs survival of leukemic mice. Furthermore, engraftment of primary FLT3/ITD+ patient samples is reduced in mice following treatment with FLT3 TKI and ATRA in combination, with evidence of cellular differentiation occurring in vivo. Mechanistically, we provide evidence that the synergism of ATRA and FLT3 TKIs is at least in part due to the observation that FLT3 TKI treatment upregulates the antiapoptotic protein BcI6, limiting the drug's apoptotic effect. However, cotreatment with ATRA reduces BcI6 expression to baseline levels through suppression of interleukin-6 receptor signaling. These studies provide evidence of the potential of this drug combination to eliminate FLT3/ITD+ LSCs and reduce the rate of relapse in AML patients with FLT3 mutations. C1 [Ma, Hayley S.; Greenblatt, Sarah M.; Shirley, Courtney M.; Bruner, J. Kyle; Li, Li; Bao Nguyen; Ghiaur, Gabriel; Jones, Richard J.; Small, Donald] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Duffield, Amy S.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Jung, Eric] Penn State Hershey Coll Med, MD Program, Hershey, PA USA. [Aplan, Peter D.] NCI, Lab Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Small, Donald] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. RP Small, D (reprint author), Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, CRB1,1650 Orleans St, Baltimore, MD 21231 USA. EM donsmall@jhmi.edu RI Aplan, Peter/K-9064-2016 FU National Institutes of Health National Cancer Institute [CA90668, CA006973]; Giant Food Pediatric Cancer Research Fund; Kyle Haydock Professorship; Rally Foundation (The Truth 365 grant) FX This work was supported by grants from the National Institutes of Health National Cancer Institute (CA90668, CA006973), the Rally Foundation (The Truth 365 grant), and the Giant Food Pediatric Cancer Research Fund. D.S. is also supported by the Kyle Haydock Professorship. NR 42 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUN 9 PY 2016 VL 127 IS 23 BP 2867 EP 2878 DI 10.1182/blood-2015-05-646786 PG 12 WC Hematology SC Hematology GA EC1HV UT WOS:000387856400001 PM 27103744 ER PT J AU Pratt, D Uldrick, TS AF Pratt, Drew Uldrick, Thomas S. TI Primary effusion lymphoma and concurrent progressive Kaposi sarcoma associated with elevated interleukin-6 SO BLOOD LA English DT Editorial Material C1 [Pratt, Drew; Uldrick, Thomas S.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Pratt, D (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUN 9 PY 2016 VL 127 IS 23 BP 2940 EP 2940 DI 10.1182/blood-2016-02-700575 PG 1 WC Hematology SC Hematology GA DP2QW UT WOS:000378335900027 PM 28092896 ER PT J AU Solomon, A Fahey, JL Malmoren, RA AF Solomon, Alan Fahey, John L. Malmoren, Richard A. TI Immunohistologic Localization of Gamma-1-Macroglobulins, Beta-2A-Myeloma Proteins, 6.6 S Gamma-Myeloma Proteins and Bence Jones Proteins. SO BLOOD LA English DT Editorial Material C1 [Solomon, Alan] NCI, Metab Serv, NIH, Bethesda, MD 20892 USA. NCI, Pathol Anat Branch, NIH, Bethesda, MD 20892 USA. RP Solomon, A (reprint author), NCI, Metab Serv, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUN 9 PY 2016 VL 127 IS 23 DI 10.1182/blood-2016-04-709774 PG 1 WC Hematology SC Hematology GA DP2QW UT WOS:000378335900002 ER PT J AU Sridhar, S Steele-Mortimer, O AF Sridhar, Sushmita Steele-Mortimer, Olivia TI Inherent Variability of Growth Media Impacts the Ability of Salmonella Typhimurium to Interact with Host Cells SO PLOS ONE LA English DT Article ID ENTERICA SEROVAR TYPHIMURIUM; ORGANIC-ACID PRODUCTION; PATHOGENICITY ISLAND 1; III SECRETION SYSTEMS; D-GLUCARIC ACID; IN-VITRO; GASTROINTESTINAL-TRACT; EPITHELIAL-CELLS; MAMMALIAN-CELLS; HELA-CELLS AB Efficient invasion of non-phagocytic cells, such as intestinal epithelial cells, by Salmonella Typhimurium is dependent on the Salmonella Pathogenicity Island 1 (SPI-1)-encoded Type Three Secretion System. The environmental cues involved in SPI-1 induction are not well understood. In vitro, various conditions are used to induce SPI-1 and the invasive phenotype. Although lysogeny broth (LB) is widely used, multiple formulations exist, and variation can arise due to intrinsic differences in complex components. Minimal media are also susceptible to variation. Still, the impact of these inconsistencies on Salmonella virulence gene expression has not been well studied. The goal of this project is to identify growth conditions in LB and minimal mediumthat affect SPI-1 induction in vitro using both whole population and single cell analysis. Here we show, using a fluorescent reporter of the SPI-1 gene prgH, that growth of Salmonella in LB yields variable induction. Deliberate modification of media components can influence the invasive profile. Finally, we demonstrate that changes in SPI-1 inducing conditions can affect the ability of Salmonella to replicate intracellularly. These data indicate that the specific media growth conditions impact how the bacteria interact with host cells. C1 [Sridhar, Sushmita; Steele-Mortimer, Olivia] NIAID, Bacteriol Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Steele-Mortimer, O (reprint author), NIAID, Bacteriol Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM omortimer@niaid.nih.gov FU Intramural Research Program of the NIH, NIAID FX This work is supported by the Intramural Research Program of the NIH, NIAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; This research was supported by the Intramural Research Program of the NIH, NIAID. We would like to thank Aaron Carmody for expert flow cytometry support, Anita Mora for figures, and members of the lab for helpful comments throughout the process. NR 42 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 9 PY 2016 VL 11 IS 6 AR e0157043 DI 10.1371/journal.pone.0157043 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO1TW UT WOS:000377563000074 PM 27280414 ER PT J AU Brubaker, L Brown, MB Weber, AM AF Brubaker, Linda Brown, Morton B. Weber, Anne M. CA NICHD Pelvic Floor Disorders TI Corrections to Report of a Trial of Burch Colposuspension SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Brubaker, Linda] Loyola Univ, Stritch Sch Med, Chicago, IL 60611 USA. [Brown, Morton B.] Univ Michigan, Ann Arbor, MI 48109 USA. [Weber, Anne M.] NIH, Baltimore, MD USA. RP Brubaker, L (reprint author), Loyola Univ, Stritch Sch Med, Chicago, IL 60611 USA. EM lbrubaker@luc.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 9 PY 2016 VL 374 IS 23 BP 2295 EP 2295 DI 10.1056/NEJMc1605817 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DO6VB UT WOS:000377920500026 PM 27276578 ER PT J AU Dai, B Chen, AY Corkum, CP Peroutka, RJ Landon, A Houng, S Muniandy, PA Zhang, Y Lehrmann, E Mazan-Mamczarz, K Steinhardt, J Shlyak, M Chen, QC Becker, KG Livak, F Michalak, TI Talwani, R Gartenhaus, RB AF Dai, B. Chen, A. Y. Corkum, C. P. Peroutka, R. J. Landon, A. Houng, S. Muniandy, P. A. Zhang, Y. Lehrmann, E. Mazan-Mamczarz, K. Steinhardt, J. Shlyak, M. Chen, Q. C. Becker, K. G. Livak, F. Michalak, T. I. Talwani, R. Gartenhaus, R. B. TI Hepatitis C virus upregulates B-cell receptor signaling: a novel mechanism for HCV-associated B-cell lymphoproliferative disorders SO ONCOGENE LA English DT Article ID BLOOD MONONUCLEAR-CELLS; IN-VIVO; DNA-REPAIR; IONIZING-RADIATION; OCCULT INFECTION; LOW-LEVEL; EXPRESSION; LYMPHOMA; CHK2; REPLICATION AB B-cell receptor (BCR) signaling is essential for the development of B cells and has a critical role in B-cell neoplasia. Increasing evidence indicates an association between chronic hepatitis C virus (HCV) infection and B-cell lymphoma, however, the mechanisms by which HCV causes B-cell lymphoproliferative disorder are still unclear. Herein, we demonstrate the expression of HCV viral proteins in B cells of HCV-infected patients and show that HCV upregulates BCR signaling in human primary B cells. HCV nonstructural protein NS3/4A interacts with CHK2 and downregulates its activity, modulating HuR posttranscriptional regulation of a network of target mRNAs associated with B-cell lymphoproliferative disorders. Interestingly, the BCR signaling pathway was found to have the largest number of transcripts with increased association with HuR and was upregulated by NS3/4A. Our study reveals a previously unidentified role of NS3/4A in regulation of host BCR signaling during HCV infection, contributing to a better understanding of the molecular mechanisms underlying HCV-associated B-cell lymphoproliferative disorders. C1 [Dai, B.; Peroutka, R. J.; Landon, A.; Houng, S.; Muniandy, P. A.; Mazan-Mamczarz, K.; Steinhardt, J.; Livak, F.; Gartenhaus, R. B.] Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, Dept Med, Baltimore, MD 21201 USA. [Chen, A. Y.; Corkum, C. P.; Michalak, T. I.] Mem Univ Newfoundland, Fac Med, Div Biomed Sci, Mol Virol & Hepatol Res Grp, St John, NF, Canada. [Zhang, Y.; Lehrmann, E.; Becker, K. G.] NIA, Gene Express & Genom Unit, Genet Lab, NIH, Baltimore, MD 21224 USA. [Shlyak, M.; Talwani, R.] Univ Maryland, Sch Med, Inst Human Virol, Dept Infect Dis, Baltimore, MD 21201 USA. [Chen, Q. C.] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Gartenhaus, R. B.] Vet Adm Med Ctr, Baltimore, MD 21218 USA. RP Gartenhaus, RB (reprint author), Univ Maryland, Med Ctr, Marlene & Stewart Greenebaum Canc Ctr, Dept Med, 655 West Baltimore St,BRB 9-011, Baltimore, MD 21201 USA. EM rgartenhaus@som.umaryland.edu FU Department of Veterans Affairs; National Institutes of Health [R01AA017972, R01CA164311]; Canadian Institutes of Health Research [MOP-126056]; Canada Research Chair Program in Viral Hepatitis/Immunology; Intramural Research Program of the NIH, National Institute on Aging FX We are grateful to Dr El Mustapha Bahassi for the gift of CHK2 and its truncated constructs. We thank Dr Michael MC Lai from the Institute of Molecular Biology, Academia Sinica, Taiwan for generously sharing NS3/4A constructs. We are thankful to Dr Michael Gale Jr (University of Washington, WA, USA) for generously sharing a series of FLAG epitope-tagged NS3/4A truncation and deletion mutant plasmids. We are very grateful to Dr Eric Campeau for the use of pLenti-CMVTRE3G and pLenti-CMV-rtTA3-Blast plasmids. We thank Dr Shyamasundaran Kottilil and Dr Patricia M Mulrooney-Cousins for helpful discussions. Flow cytometry analyses were performed at the University of Maryland Marlene and Stewart Greenebaum Cancer Center Flow Cytometry Shared Service. This work was supported in part by a Merit Review Award from the Department of Veterans Affairs (RBG), R01AA017972 (RBG) and R01CA164311 (RBG) from the National Institutes of Health, as well as MOP-126056 (TIM) from the Canadian Institutes of Health Research and the Canada Research Chair Program in Viral Hepatitis/Immunology (TIM). This research was also supported in part by the Intramural Research Program of the NIH, National Institute on Aging (YZ, EL and KGB). NR 37 TC 2 Z9 3 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD JUN 9 PY 2016 VL 35 IS 23 BP 2979 EP 2990 DI 10.1038/onc.2015.364 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DO0NB UT WOS:000377474500004 PM 26434584 ER PT J AU Hoang, DT Venkatesh, BP Han, S Jo, J Watanabe, G Choi, MS AF Danh-Tai Hoang Venkatesh, B. Prasanna Han, Seungju Jo, Junghyo Watanabe, Gentaro Choi, Mahn-Soo TI Scaling Law for Irreversible Entropy Production in Critical Systems SO SCIENTIFIC REPORTS LA English DT Article ID FREE-ENERGY DIFFERENCES; NONEQUILIBRIUM MEASUREMENTS; EXPERIMENTAL-VERIFICATION; COSMOLOGICAL EXPERIMENTS; STATISTICAL-MECHANICS; EQUALITY; THERMODYNAMICS; INFORMATION; PHYSICS AB We examine the Jarzynski equality for a quenching process across the critical point of second-order phase transitions, where absolute irreversibility and the effect of finite-sampling of the initial equilibrium distribution arise in a single setup with equal significance. We consider the Ising model as a prototypical example for spontaneous symmetry breaking and take into account the finite sampling issue by introducing a tolerance parameter. The initially ordered spins become disordered by quenching the ferromagnetic coupling constant. For a sudden quench, the deviation from the Jarzynski equality evaluated from the ideal ensemble average could, in principle, depend on the reduced coupling constant epsilon(0) of the initial state and the system size L. We find that, instead of depending on epsilon(0) and L separately, this deviation exhibits a scaling behavior through a universal combination of epsilon(0) and L for a given tolerance parameter, inherited from the critical scaling laws of second-order phase transitions. A similar scaling law can be obtained for the finite-speed quench as well within the Kibble-Zurek mechanism. C1 [Danh-Tai Hoang; Venkatesh, B. Prasanna; Jo, Junghyo; Watanabe, Gentaro] Asia Pacific Ctr Theoret Phys, Pohang 37673, Gyeongbuk, South Korea. [Danh-Tai Hoang] NIDDK, NIH, Bethesda, MD 20892 USA. [Danh-Tai Hoang] Quang Binh Univ, Dept Nat Sci, Dong Hoi 510000, Quang Binh, Vietnam. [Venkatesh, B. Prasanna] Austrian Acad Sci, Inst Quantum Opt & Quantum Informat, Technikerstr 21a, A-6020 Innsbruck, Austria. [Venkatesh, B. Prasanna] Univ Innsbruck, Inst Theoret Phys, A-6020 Innsbruck, Austria. [Han, Seungju; Choi, Mahn-Soo] Korea Univ, Dept Phys, Seoul 02841, South Korea. [Jo, Junghyo] Pohang Univ Sci & Technol POSTECH, Dept Phys, Pohang 37673, Gyeongbuk, South Korea. [Watanabe, Gentaro] Inst for Basic Sci Korea, Ctr Theoret Phys Complex Syst, Daejeon 34051, South Korea. [Watanabe, Gentaro] Univ Sci & Technol, 217 Gajeong Ro, Daejeon 34113, South Korea. [Watanabe, Gentaro] Zhejiang Univ, Dept Phys, Hangzhou 310027, Zhejiang, Peoples R China. RP Choi, MS (reprint author), Korea Univ, Dept Phys, Seoul 02841, South Korea. EM choims@korea.ac.kr RI Watanabe, Gentaro/N-9456-2014; Prasanna Venkatesh, B/D-8289-2017 FU National Research Foundation (NRF) [2015-003689]; Ministry of Education of Korea through the BK21 Plus Initiative; Max Planck Society; MSIP of Korea; Gyeongsangbuk-Do; Pohang City through the JRG at APCTP; NRF [2012R1A1A2008028]; IBS [IBS-R024-D1]; Zhejiang University 100 Plan; Junior 1000 Talents Plan of China FX We thank Oscar Dahlsten and Carlo Danieli for helpful comments. S.H. and M.-S.C. are supported by the National Research Foundation (NRF; Grant No. 2015-003689) and by the Ministry of Education of Korea through the BK21 Plus Initiative. D.-T.H., J.J., B.P.V. and G.W. are supported jointly by the Max Planck Society, the MSIP of Korea, Gyeongsangbuk-Do and Pohang City through the JRG at APCTP. BPV thanks Prof. Oriol Romero-Isart for his support. GW also acknowledges support by the NRF (Grant No. 2012R1A1A2008028), by the IBS (Grant No. IBS-R024-D1), by the Zhejiang University 100 Plan, and by the Junior 1000 Talents Plan of China. NR 52 TC 0 Z9 0 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 9 PY 2016 VL 6 AR 27603 DI 10.1038/srep27603 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN8RQ UT WOS:000377347500001 PM 27277558 ER PT J AU Shinden, Y Ueo, H Tobo, T Gamachi, A Utou, M Komatsu, H Nambara, S Saito, T Ueda, M Hirata, H Sakimura, S Takano, Y Uchi, R Kurashige, J Akiyoshi, S Iguchi, T Eguchi, H Sugimachi, K Kubota, Y Kai, Y Shibuta, K Kijima, Y Yoshinaka, H Natsugoe, S Mori, M Maehara, Y Sakabe, M Kamiya, M Kakareka, JW Pohida, TJ Choyke, PL Kobayashi, H Ueo, H Urano, Y Mimori, K AF Shinden, Yoshiaki Ueo, Hiroki Tobo, Taro Gamachi, Ayako Utou, Mitsuaki Komatsu, Hisateru Nambara, Sho Saito, Tomoko Ueda, Masami Hirata, Hidenari Sakimura, Shotaro Takano, Yuki Uchi, Ryutaro Kurashige, Junji Akiyoshi, Sayuri Iguchi, Tomohiro Eguchi, Hidetoshi Sugimachi, Keishi Kubota, Yoko Kai, Yuichiro Shibuta, Kenji Kijima, Yuko Yoshinaka, Heiji Natsugoe, Shoji Mori, Masaki Maehara, Yoshihiko Sakabe, Masayo Kamiya, Mako Kakareka, John W. Pohida, Thomas J. Choyke, Peter L. Kobayashi, Hisataka Ueo, Hiroaki Urano, Yasuteru Mimori, Koshi TI Rapid diagnosis of lymph node metastasis in breast cancer using a new fluorescent method with gamma-glutamyl hydroxymethyl rhodamine green SO SCIENTIFIC REPORTS LA English DT Article ID NUCLEIC-ACID AMPLIFICATION; RECOMMENDATIONS AB Sentinel lymph node biopsy is performed as a standard procedure in breast cancer surgery, and the development of quick and simple methods to detect metastatic lesions is in high demand. Here, we validated a new fluorescent method using gamma-glutamyl hydroxymethyl rhodamine green to diagnose metastatic lymph nodes in breast cancer. One hundred and forty-nine lymph nodes from 38 breast cancer patients were evaluated in this study. Comparison of fluorescent and pathological images showed that this fluorescent method was successful for visualizing breast cancer cells in lymph nodes. This method had a sufficiently high sensitivity (97%), specificity (79%) and negative predictive value (99%) to render it useful for an intraoperative diagnosis of cancer. These preliminary findings suggest that this novel method is useful for distinguishing non-cancerous specimens from those in need of careful examination and could help save time and cost for surgeons and pathologists. C1 [Shinden, Yoshiaki; Ueo, Hiroki; Komatsu, Hisateru; Nambara, Sho; Saito, Tomoko; Ueda, Masami; Hirata, Hidenari; Sakimura, Shotaro; Takano, Yuki; Uchi, Ryutaro; Kurashige, Junji; Akiyoshi, Sayuri; Iguchi, Tomohiro; Eguchi, Hidetoshi; Sugimachi, Keishi; Mimori, Koshi] Kagoshima Univ, Grad Sch Med & Dent Sci, Dept Surg Breast & Thyroid Surg, Kagoshima, Kagoshima 8908520, Japan. [Shinden, Yoshiaki; Kijima, Yuko; Yoshinaka, Heiji; Natsugoe, Shoji] Kagoshima Univ, Grad Sch Med & Dent Sci, Dept Digest Surg Breast & Thyroid Surg, Kagoshima, Kagoshima 8908520, Japan. [Ueo, Hiroki; Maehara, Yoshihiko] Kyushu Univ, Grad Sch Med Sci, Dept Surg & Sci, Fukuoka 8128582, Japan. [Tobo, Taro; Utou, Mitsuaki] Kyushu Univ, Beppu Hosp, Dept Pathol, 4546 Tsurumihara, Beppu, Oita 8740838, Japan. [Gamachi, Ayako] Oita Univ, Dept Pathol, Yufu 8795593, Japan. [Kubota, Yoko; Kai, Yuichiro; Shibuta, Kenji; Ueo, Hiroaki] Ueo Breast Surg Hosp, Oita 8700854, Japan. [Mori, Masaki] Osaka Univ, Dept Surg Gastroenterol, Grad Sch Med, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan. [Sakabe, Masayo; Kamiya, Mako; Urano, Yasuteru] Univ Tokyo, Grad Sch Med, Tokyo 1130033, Japan. [Kakareka, John W.; Pohida, Thomas J.] NIH, Signal Proc & Instrumentat Sect, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. [Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Urano, Yasuteru] CREST, AMED, Tokyo 1000004, Japan. RP Mimori, K (reprint author), Kagoshima Univ, Grad Sch Med & Dent Sci, Dept Surg Breast & Thyroid Surg, Kagoshima, Kagoshima 8908520, Japan.; Urano, Y (reprint author), Univ Tokyo, Grad Sch Med, Tokyo 1130033, Japan.; Urano, Y (reprint author), CREST, AMED, Tokyo 1000004, Japan. EM uranokun@m.u-tokyo.ac.jp; kmimori@beppu.kyushu-u.ac.jp FU [25430111]; [25461953]; [25861199]; [25861200]; [24592005]; [21229015] FX The following grants and foundations supported this work: Grants-in-Aid for Scientific Research, grant numbers 25430111, 25461953, 25861199, 25861200, 24592005, and 21229015. We would like to thank Ms. M. Kasagi, Ms. S. Kohno, Ms. K. Oda, Ms. M. Aoyagi, Ms. T. Kawano, Mr. Y. Komatsu and Ms. Y. Abe for their assistance with the molecular biological and pathological procedures. NR 20 TC 1 Z9 1 U1 9 U2 15 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 9 PY 2016 VL 6 AR 27525 DI 10.1038/srep27525 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN8PP UT WOS:000377341800002 PM 27277343 ER PT J AU McFarland, JM Cumming, BG Butts, DA AF McFarland, James M. Cumming, Bruce G. Butts, Daniel A. TI Variability and Correlations in Primary Visual Cortical Neurons Driven by Fixational Eye Movements SO JOURNAL OF NEUROSCIENCE LA English DT Article DE fixational eye movements; noise correlations; V1; variability ID RESPONSE VARIABILITY; SPIKE TRAINS; CORTEX V1; RECEPTIVE-FIELDS; ONGOING ACTIVITY; AUDITORY-CORTEX; MACAQUE V1; ATTENTION; MONKEYS; STATE AB The ability to distinguish between elements of a sensory neuron's activity that are stimulus independent versus driven by the stimulus is critical for addressing many questions in systems neuroscience. This is typically accomplished by measuring neural responses to repeated presentations of identical stimuli and identifying the trial-variable components of the response as noise. In awake primates, however, small "fixational" eye movements (FEMs) introduce uncontrolled trial-to-trial differences in the visual stimulus itself, potentially confounding this distinction. Here, we describe novel analytical methods that directly quantify the stimulus-driven and stimulus-independent components of visual neuron responses in the presence of FEMs. We apply this approach, combined with precise model-based eye tracking, to recordings from primary visual cortex (V1), finding that standard approaches that ignore FEMs typically miss more than half of the stimulus-driven neural response variance, creating substantial biases in measures of response reliability. We show that these effects are likely not isolated to the particular experimental conditions used here, such as the choice of visual stimulus or spike measurement time window, and thus will be a more general problem for V1 recordings in awake primates. We also demonstrate that measurements of the stimulus-driven and stimulus-independent correlations among pairs of V1 neurons can be greatly biased by FEMs. These results thus illustrate the potentially dramatic impact of FEMs on measures of signal and noise in visual neuron activity and also demonstrate a novel approach for controlling for these eye-movement-induced effects. C1 [McFarland, James M.; Butts, Daniel A.] Univ Maryland, Dept Biol, 1210 Biol Psychol Bldg 144, College Pk, MD 20815 USA. [McFarland, James M.; Butts, Daniel A.] Univ Maryland, Program Neurosci & Cognit Sci, College Pk, MD 20815 USA. [Cumming, Bruce G.] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Butts, DA (reprint author), Univ Maryland, Dept Biol, 1210 Biol Psychol Bldg 144, College Pk, MD 20815 USA. EM dab@umd.edu OI Butts, Daniel/0000-0002-0158-5317 FU National Science Foundation [IIS-1350990]; National Institutes of Health [F32-EY-023921]; National Eye Institute Intramural Research Program Grant FX This work was supported by the National Science Foundation Grant IIS-1350990 (D.A.B.) and the National Institutes of Health Grant F32-EY-023921 (J.M.M) and National Eye Institute Intramural Research Program Grant (B.G.C.). We thank D. Parker and I. Bunea for providing excellent animal care and to M. Whiteway for helpful comments on the manuscript. NR 64 TC 0 Z9 0 U1 1 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 8 PY 2016 VL 36 IS 23 BP 6225 EP 6241 DI 10.1523/JNEUROSCI.4660-15.2016 PG 17 WC Neurosciences SC Neurosciences & Neurology GA DQ2CE UT WOS:000379007700011 PM 27277801 ER PT J AU Stalnaker, TA Berg, B Aujla, N Schoenbaum, G AF Stalnaker, Thomas A. Berg, Ben Aujla, Navkiran Schoenbaum, Geoffrey TI Cholinergic Interneurons Use Orbitofrontal Input to Track Beliefs about Current State SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cholinergic; orbitofrontal; rat; single unit; striatum ID TONICALLY ACTIVE NEURONS; DORSOLATERAL STRIATUM; PREFRONTAL CORTEX; DORSOMEDIAL STRIATUM; PRIMATE CAUDATE; INSULAR CORTEX; RAT STRIATUM; IN-VIVO; MONKEY; ACETYLCHOLINE AB When conditions change, organisms need to learn about the changed conditions without interfering with what they already know. To do so, they can assign the new learning to a new "state" and the old learning to a previous state. This state assignment is fundamental to behavioral flexibility. Cholinergic interneurons (CINs) in the dorsomedial striatum (DMS) are necessary for associative information to be compartmentalized in this way, but the mechanism by which they do so is unknown. Here we addressed this question by recording putative CINs from the DMS in rats performing a task consisting of a series of trial blocks, or states, that required the recall and application of contradictory associative information. We found that individual CINs in the DMS represented the current state throughout each trial. These state correlates were not observed in dorsolateral striatal CINs recorded in the same rats. Notably, DMS CIN ensembles tracked rats' beliefs about the current state such that, when states were miscoded, rats tended to make suboptimal choices reflecting the miscoding. State information held by the DMS CINs also depended completely on the orbitofrontal cortex, an area that has been proposed to signal environmental states. These results suggest that CINs set the stage for recalling associative information relevant to the current environment by maintaining a real-time representation of the current state. Such a role has novel implications for understanding the neural basis of a variety of psychiatric diseases, such as addiction or anxiety disorders, in which patients generalize inappropriately (or fail to generalize) between different environments. C1 [Stalnaker, Thomas A.; Berg, Ben; Aujla, Navkiran; Schoenbaum, Geoffrey] NIDA, Intramural Res Program, Cellular Neurobiol Res Branch, Behav Neurophysiol Res Sect, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Schoenbaum, Geoffrey] Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD 21218 USA. RP Stalnaker, TA; Schoenbaum, G (reprint author), NIDA, Intramural Res Program, Cellular Neurobiol Res Branch, Behav Neurophysiol Res Sect, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM thomas.stalnaker@nih.gov; geoffrey.schoenbaum@nih.gov FU Intramural Research Program at the National Institute on Drug Abuse (NIDA-IRP) FX This work was supported by the Intramural Research Program at the National Institute on Drug Abuse (NIDA-IRP). We acknowledge the assistance of Brandon Harvey, Director of the Optogenetics and Transgenic Technology Core at the NIDA-IRP. NR 59 TC 4 Z9 4 U1 2 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 8 PY 2016 VL 36 IS 23 BP 6242 EP 6257 DI 10.1523/JNEUROSCI.0157-16.2016 PG 16 WC Neurosciences SC Neurosciences & Neurology GA DQ2CE UT WOS:000379007700012 PM 27277802 ER PT J AU Knoll, AT Halladay, LR Holmes, AJ Levitt, P AF Knoll, Allison T. Halladay, Lindsay R. Holmes, Andrew J. Levitt, Pat TI Quantitative Trait Loci and a Novel Genetic Candidate for Fear Learning SO JOURNAL OF NEUROSCIENCE LA English DT Article DE anxiety; associative learning; HCN1; individual differences; quantitative trait gene; threat detection ID POSTTRAUMATIC-STRESS-DISORDER; ACTIVATED CATION CHANNELS; NUCLEOTIDE-GATED CHANNELS; AUXILIARY SUBUNIT TRIP8B; CA1 PYRAMIDAL NEURONS; HCN CHANNELS; BASOLATERAL AMYGDALA; ANXIETY DISORDERS; I-H; CONDITIONED FEAR AB Trauma- and stress-related disorders are clinically heterogeneous and associated with substantial genetic risk. Understanding the biological origins of heterogeneity of key intermediate phenotypes such as cognition and emotion can provide novel mechanistic insights into disorder pathogenesis. Performing quantitative genetics in animal models is a tractable strategy for examining both the genetic basis of intermediate phenotypes and functional testing of candidate quantitative traits genes (QTGs). Here, existing and newly collected data were used for collaborative genome-wide mapping of cued fear acquisition and expression in 65 mouse strains from the BXD genetic reference panel. For fear acquisition, we identified a significant locus on chromosome (Chr) 10 and eight suggestive loci on Chr 2, 4, 5, 11, 13, and 15. For fear expression, we identified one significant and another highly suggestive locus on Chr 13, as well as four suggestive loci on Chr 10, 11, and X. Across these loci, 60 putative QTGs were identified. The quantitative trait locus on distal Chr 13 contained a single, highly promising gene at the location of the peak likelihood ratio statistic score. The gene, hyperpolarization-activated cyclic nucleotide-gated channel 1 (Hcn1), regulates neuronal excitability. Validation experiments using behavioral pharmacology revealed that functional Hcn channels in the basolateral amygdala are necessary for conditioned fear acquisition and expression. Hcn1, together with the other candidate QTGs, thus provide new targets for neurobiological and treatment studies of fear learning and trauma-and stress-related disorders. C1 [Knoll, Allison T.; Levitt, Pat] Childrens Hosp Los Angeles, Program Dev Neurogenet, Inst Developing Mind, Saban Res Inst, Los Angeles, CA 90027 USA. [Levitt, Pat] Univ So Calif, Keck Sch Med, Dept Pediat, Los Angeles, CA 90089 USA. [Halladay, Lindsay R.; Holmes, Andrew J.] NIAAA, NIH, Lab Behav & Genom Neurosci, Bethesda, MD 20814 USA. RP Levitt, P (reprint author), Childrens Hosp Los Angeles, Mail Stop 135,4650 Sunset Blvd, Los Angeles, CA 90027 USA. EM plevitt@med.usc.edu FU Simms/Mann Chair in Developmental Neurogenetics and National Institute of Mental Health, National Institutes of Health [R01 MH080759]; National Institute on Alcohol Abuse and Alcoholism Intramural Program; Autism Speaks (Translational Postdoctoral Fellowship) [7595] FX This work was supported by the Simms/Mann Chair in Developmental Neurogenetics and National Institute of Mental Health, National Institutes of Health (Grant R01 MH080759 to P.L.), the National Institute on Alcohol Abuse and Alcoholism Intramural Program (A.J.H.), and Autism Speaks (Translational Postdoctoral Fellowship 7595 to A.T.K.). We thank Dr. Megan Mulligan and Dr. Robert Williams for helpful comments on this manuscript. NR 77 TC 1 Z9 1 U1 2 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 8 PY 2016 VL 36 IS 23 BP 6258 EP 6268 DI 10.1523/JNEUROSCI.0177-16.2016 PG 11 WC Neurosciences SC Neurosciences & Neurology GA DQ2CE UT WOS:000379007700013 PM 27277803 ER PT J AU Carstens, KE Phillips, ML Pozzo-Miller, L Weinberg, RJ Dudek, SM AF Carstens, Kelly E. Phillips, Mary L. Pozzo-Miller, Lucas Weinberg, Richard J. Dudek, Serena M. TI Perineuronal Nets Suppress Plasticity of Excitatory Synapses on CA2 Pyramidal Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE critical period; extracellular matrix; hippocampus; long-term potentiation ID LATERAL GENICULATE-NUCLEUS; CHONDROITIN SULFATE PROTEOGLYCANS; HIPPOCAMPAL AREA CA2; SYNAPTIC PLASTICITY; EXTRACELLULAR-MATRIX; VISUAL-CORTEX; ENVIRONMENTAL ENRICHMENT; TYROSINE-PHOSPHATASE; OXIDATIVE STRESS; HYALURONIC-ACID AB Long-term potentiation of excitatory synapses on pyramidal neurons in the stratum radiatum rarely occurs in hippocampal area CA2. Here, we present evidence that perineuronal nets (PNNs), a specialized extracellular matrix typically localized around inhibitory neurons, also surround mouse CA2 pyramidal neurons and envelop their excitatory synapses. CA2 pyramidal neurons express mRNA transcripts for the major PNN component aggrecan, identifying these neurons as a novel source for PNNs in the hippocampus. We also found that disruption of PNNs allows synaptic potentiation of normally plasticity-resistant excitatory CA2 synapses; thus, PNNs play a role in restricting synaptic plasticity in area CA2. Finally, we found that postnatal development of PNNs on CA2 pyramidal neurons is modified by early-life enrichment, suggesting that the development of circuits containing CA2 excitatory synapses are sensitive to manipulations of the rearing environment. C1 [Carstens, Kelly E.; Dudek, Serena M.] NIEHS, Neurobiol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Carstens, Kelly E.; Weinberg, Richard J.] Univ N Carolina, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 USA. [Phillips, Mary L.; Pozzo-Miller, Lucas] Univ Alabama Birmingham, Civitan Int Res Ctr, Dept Neurobiol, Birmingham, AL 35294 USA. RP Dudek, SM (reprint author), NIEHS, Neurobiol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM dudek@niehs.nih.gov OI Weinberg, Richard/0000-0001-9689-7278 FU Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health [Z01 ES100221]; National Institute of Neurological Disorders and Stroke [R01 NS039444]; National Institutes of Health Grant [NS-065027] FX This work was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health (Z01 ES100221); by National Institute of Neurological Disorders and Stroke Award R01 NS039444 (to R.J.W.); and by National Institutes of Health Grant NS-065027 (to L.P.-M.). We thank Susan Burette for technical assistance with electron microscopy, the National Institute of Environmental Health Sciences Fluorescence Microscopy and Imaging Center and the animal care staff for support, and David Armstrong and Georgia Alexander for input on this manuscript. NR 52 TC 5 Z9 5 U1 2 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 8 PY 2016 VL 36 IS 23 BP 6312 EP 6320 DI 10.1523/JNEUROSCI.0245-16.2016 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DQ2CE UT WOS:000379007700017 PM 27277807 ER PT J AU Fan, J He, QJ Liu, Y Zhang, FW Yang, XY Wang, Z Lu, N Fan, WP Lin, LS Niu, G He, NY Song, JB Chen, XY AF Fan, Jing He, Qianjun Liu, Yi Zhang, Fuwu Yang, Xiangyu Wang, Zhe Lu, Nan Fan, Wenpei Lin, Lisen Niu, Gang He, Nongyue Song, Jibin Chen, Xiaoyuan TI Light-Responsive Biodegradable Nanomedicine Overcomes Multidrug Resistance via NO-Enhanced Chemosensitization SO ACS APPLIED MATERIALS & INTERFACES LA English DT Article DE nitric oxide (NO); light-responsive; mPEG-PLGA; chemotherapy; multidrug resistance (MDR) ID NITRIC-OXIDE; TUMOR HYPOXIA; CANCER-CELLS; GENE-EXPRESSION; MDR1 GENE; PROTEIN; DOXORUBICIN; CARCINOMA; ANGIOGENESIS; CISPLATIN AB Multidrug resistance (MDR) is responsible for the relatively low effectiveness of chemotherapeutics. Herein, a nitric oxide (NO) gas-enhanced chemosensitization strategy is proposed to overcome MDR by construction of a biodegradable nanomedicine formula based on BNN6/DOX coloaded monomethoxy(polyethylene glycol)-poly(lactic-co-glycolic acid) (mPEG-PLGA). On one hand, the nanomedicine features high biocompatibility due to the high density of PEG and biodegradable PLGA. On the other hand, the nanoformula exhibits excellent stability under physiological conditions but exhibits stimuli-responsive decomposition of BNN6 for NO gas release upon ultraviolet-visible irradiation. More importantly, after NO release is triggered, gas molecules are generated that break the nanoparticle shell and lead to the release of doxorubicin. Furthermore, NO was demonstrated to reverse the MDR of tumor cells and enhance the chemosensitization for doxorubicin therapy. C1 [Fan, Jing; Yang, Xiangyu; He, Nongyue] Southeast Univ, State Key Lab Bioelect, Nanjing 210096, Jiangsu, Peoples R China. [Fan, Jing; Liu, Yi; Zhang, Fuwu; Yang, Xiangyu; Wang, Zhe; Lu, Nan; Fan, Wenpei; Lin, Lisen; Niu, Gang; Song, Jibin; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [He, Qianjun; Fan, Wenpei] Shenzhen Univ, Sch Med, Dept Biomed Engn, Guangdong Key Lab Biomed Measurements & Ultrasoun, Shenzhen 518060, Guangdong, Peoples R China. [Fan, Jing] Guangxi Med Univ, Biol Target Diag & Treatment Ctr, Nanning 530021, Guangxi, Peoples R China. RP He, NY (reprint author), Southeast Univ, State Key Lab Bioelect, Nanjing 210096, Jiangsu, Peoples R China.; Song, JB; Chen, XY (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. EM nyhe1958@163.com; jibin.song@nih.gov; shawn.chen@nih.gov RI HE, QIANJUN/M-2642-2013 OI HE, QIANJUN/0000-0003-0689-8838 FU National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health; National Key Program for Developing Basic Research of China [2014CB744501]; NSFC [61271056, 61471168, 61527806]; Shenzhen Basic Research Program [JCYJ20160226110137243]; China Scholarship Council FX We thank the financial support from the Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, the National Key Program for Developing Basic Research of China (Grant 2014CB744501), the NSFC (Grants 61271056, 61471168, and 61527806), the Shenzhen Basic Research Program (Grant JCYJ20160226110137243), and the State Scholarship Fund from the China Scholarship Council. NR 32 TC 13 Z9 13 U1 33 U2 57 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1944-8244 J9 ACS APPL MATER INTER JI ACS Appl. Mater. Interfaces PD JUN 8 PY 2016 VL 8 IS 22 BP 13804 EP 13811 DI 10.1021/acsami.6b03737 PG 8 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA DO2WQ UT WOS:000377642100017 PM 27213922 ER PT J AU Zholdybayeva, EV Talzhanov, YA Aitkulova, AM Tarlykov, PV Kulmambetova, GN Iskakova, AN Dzholdasbekova, AU Visternichan, OA Taizhanova, DZ Ramanculov, YM AF Zholdybayeva, Elena V. Talzhanov, Yerkebulan A. Aitkulova, Akbota M. Tarlykov, Pavel V. Kulmambetova, Gulmira N. Iskakova, Aisha N. Dzholdasbekova, Aliya U. Visternichan, Olga A. Taizhanova, Dana Zh Ramanculov, Yerlan M. TI Genetic risk factors for restenosis after percutaneous coronary intervention in Kazakh population SO HUMAN GENOMICS LA English DT Article DE Coronary heart disease; Restenosis; SNP; Genotyping ID NITRIC-OXIDE SYNTHASE; IN-STENT RESTENOSIS; ARTERY-DISEASE; MYOCARDIAL-INFARCTION; G894T POLYMORPHISM; HEART-DISEASE; ASSOCIATION; ANGIOPLASTY; PLACEMENT; RECEPTOR AB Background: After coronary stenting, the risk of developing restenosis is from 20 to 35 %. The aim of the present study is to investigate the association of genetic variation in candidate genes in patients diagnosed with restenosis in the Kazakh population. Methods: Four hundred fifty-nine patients were recruited to the study; 91 patients were also diagnosed with diabetes and were excluded from the sampling. DNA was extracted with the salting-out method. The patients were genotyped for 53 single-nucleotide polymorphisms. Genotyping was performed on the QuantStudio 12K Flex (Life Technologies). Differences in distribution of BMI score among different genotype groups were compared by analysis of variance (ANOVA). Also, statistical analysis was performed using R and PLINK v.1.07. Haplotype frequencies and LD measures were estimated by using the software Haploview 4.2. Results: A logistic regression analysis found a significant difference in restenosis rates for different genotypes. FGB (rs1800790) is significantly associated with restenosis after stenting (OR = 2.924, P = 2.3E-06, additive model) in the Kazakh population. CD14 (rs2569190) showed a significant association in the additive (OR = 0.08033, P = 2.11E-09) and dominant models (OR = 0.05359, P = 4.15E-11). NOS3 (rs1799983) was also highly associated with development of restenosis after stenting in additive (OR = 20.05, P = 2.74 E-12) and recessive models (OR = 22.24, P = 6.811E-10). Conclusions: Our results indicate that FGB (rs1800790), CD14 (rs2569190), and NOS3 (rs1799983) SNPs could be genetic markers for development of restenosis in Kazakh population. Adjustment for potential confounder factor BMI gave almost the same results. C1 [Zholdybayeva, Elena V.; Talzhanov, Yerkebulan A.; Aitkulova, Akbota M.; Tarlykov, Pavel V.; Kulmambetova, Gulmira N.; Iskakova, Aisha N.; Ramanculov, Yerlan M.] Natl Biotechnol Ctr, 13-5 KorgalzhinskoeHighway, Astana, Kazakhstan. [Dzholdasbekova, Aliya U.] Natl Sci Med Res Ctr, 42 Abylai Khan Ave, Astana, Kazakhstan. [Visternichan, Olga A.; Taizhanova, Dana Zh] Karaganda State Med Univ, 40 Gogol St, Karaganda, Kazakhstan. [Ramanculov, Yerlan M.] Nazarbayev Univ, Sch Sci & Technol, 53 Kabanbay Batyr Ave, Astana, Kazakhstan. [Iskakova, Aisha N.] Al Farabi Kazakh Natl Univ, Alma Ata, Kazakhstan. RP Zholdybayeva, EV (reprint author), Natl Biotechnol Ctr, 13-5 KorgalzhinskoeHighway, Astana, Kazakhstan. EM lenazhol@gmail.com RI Akhmadyarova, Bota/R-4730-2016; Tarlykov, Pavel/C-2587-2012; OI Tarlykov, Pavel/0000-0003-2075-307X; Iskakova, Aisha/0000-0002-0631-062X FU Ministry of Education and Science of the Republic of Kazakhstan [0112PK00361] FX This work was supported by a grant #0112PK00361 from the Ministry of Education and Science of the Republic of Kazakhstan. NR 46 TC 0 Z9 0 U1 5 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1473-9542 EI 1479-7364 J9 HUM GENOMICS JI Hum. Genomics PD JUN 8 PY 2016 VL 10 AR 15 DI 10.1186/s40246-016-0077-z PG 8 WC Genetics & Heredity SC Genetics & Heredity GA DO4XP UT WOS:000377788500001 PM 27277665 ER PT J AU Song, JB Wang, F Yang, XY Ning, B Harp, MG Culp, SH Hu, S Huang, P Nie, LM Chen, JY Chen, XY AF Song, Jibin Wang, Feng Yang, Xiangyu Ning, Bo Harp, Mary G. Culp, Stephen H. Hu, Song Huang, Peng Nie, Liming Chen, Jingyi Chen, Xiaoyuan TI Gold Nanoparticle Coated Carbon Nanotube Ring with Enhanced Raman Scattering and Photothermal Conversion Property for Theranostic Applications SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID IN-VIVO; PLASMONIC VESICLES; GRAPHENE OXIDE; CANCER-THERAPY; DRUG-DELIVERY; SERS; NANOSTRUCTURES; MOLECULES; SURFACE; PHOTODETECTION AB We report a new type of carbon nanotube ring (CNTR) coated with gold nanoparticles (CNTR@AuNPs) using CNTR as a template and surface attached redox-active polymer as a reducing agent. This nanostructure of CNTR bundle embedded in the gap of closely attached AuNPs can play multiple roles as a Raman probe to detect cancer cells and a photoacoustic (PA) contrast agent for imaging-guided cancer therapy. The CNTR@AuNP exhibits substantially higher Raman and optical signals than CNTR coated with a complete Au shell (CNTR@AuNS) and straight CNT@AuNP. The extinction intensity of CNTR@AuNP is about 120-fold higher than that of CNTR at 808 rim, and the surface enhanced Raman scattering (SERS) signal of CNTR@AuNP is about 110 times stronger than that of CNTR, presumably due to the combined effects of enhanced coupling between the embedded CNTR and the plasmon mode of the closely attached AuNPs, and the strong electromagnetic field in the cavity of the AuNP shell originated from the intercoupling of AuNPs. The greatly enhanced PA signal and photothermal conversion property of CNTR@AuNP were successfully employed for imaging and imaging-guided cancer therapy in two tumor xenograft models. Experimental observations were further supported by numerical simulations and perturbation theory analysis. C1 [Song, Jibin; Yang, Xiangyu; Huang, Peng; Nie, Liming; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Wang, Feng; Chen, Jingyi] Univ Arkansas, Dept Chem & Biochem, Fayetteville, AR 72701 USA. [Ning, Bo; Hu, Song] Univ Virginia, Dept Biomed Engn, Charlottesville, VA 22903 USA. [Harp, Mary G.; Culp, Stephen H.] Univ Virginia, Dept Urol, Charlottesville, VA 22903 USA. RP Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov RI Huang, Peng/R-2480-2016; Chen, Jingyi/E-7168-2010; OI Huang, Peng/0000-0003-3651-7813; Chen, Jingyi/0000-0003-0012-9640; Ning, Bo/0000-0002-6006-5696 FU Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH); Arkansas Breast Cancer Research Program; Arkansas Bioscience Institute FX This work was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), and the Arkansas Breast Cancer Research Program and the Arkansas Bioscience Institute. NR 47 TC 9 Z9 9 U1 119 U2 246 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUN 8 PY 2016 VL 138 IS 22 BP 7005 EP 7015 DI 10.1021/jacs.5b13475 PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA DO2XC UT WOS:000377643300021 PM 27193381 ER PT J AU Thanos, PK Kim, R Delis, F Ananth, M Chachati, G Rocco, MJ Masad, I Muniz, JA Grant, SC Gold, MS Cadet, JL Volkow, ND AF Thanos, Panayotis K. Kim, Ronald Delis, Foteini Ananth, Mala Chachati, George Rocco, Mark J. Masad, Ihssan Muniz, Jose A. Grant, Samuel C. Gold, Mark S. Cadet, Jean Lud Volkow, Nora D. TI Chronic Methamphetamine Effects on Brain Structure and Function in Rats SO PLOS ONE LA English DT Article ID PONTINE RETICULAR-FORMATION; HIGH-DOSE METHAMPHETAMINE; DEFAULT MODE NETWORK; CEREBRAL-BLOOD-FLOW; MICROGLIAL ACTIVATION; DOPAMINE TRANSPORTERS; PROTRACTED ABSTINENCE; INDUCED NEUROTOXICITY; NEUROTROPHIC FACTOR; IN-VITRO AB Methamphetamine (MA) addiction is a growing epidemic worldwide. Chronic MA use has been shown to lead to neurotoxicity in rodents and humans. Magnetic resonance imaging (MRI) studies in MA users have shown enlarged striatal volumes and positron emission tomography (PET) studies have shown decreased brain glucose metabolism (BGluM) in the striatum of detoxified MA users. The present study examines structural changes of the brain, observes microglial activation, and assesses changes in brain function, in response to chronic MA treatment. Rats were randomly split into three distinct treatment groups and treated daily for four months, via i.p. injection, with saline (controls), or low dose (LD) MA (4 mg/kg), or high dose (HD) MA (8 mg/kg). Sixteen weeks into the treatment period, rats were injected with a glucose analog, [F-18] fluorodeoxyglucose (FDG), and their brains were scanned with micro-PET to assess regional BGluM. At the end of MA treatment, magnetic resonance imaging at 21T was performed on perfused rats to determine regional brain volume and in vitro [H-3]PK 11195 autoradiography was performed on fresh-frozen brain tissue to measure microglia activation. When compared with controls, chronic HD MA-treated rats had enlarged striatal volumes and increases in [H-3]PK 11195 binding in striatum, the nucleus accumbens, frontal cortical areas, the rhinal cortices, and the cerebellar nuclei. FDG microPET imaging showed that LD MA-treated rats had higher BGluM in insular and somatosensory cortices, face sensory nucleus of the thalamus, and brainstem reticular formation, while HD MA-treated rats had higher BGluM in primary and higher order somatosensory and the retrosplenial cortices, compared with controls. HD and LD MA-treated rats had lower BGluM in the tail of the striatum, rhinal cortex, and subiculum and HD MA also had lower BGluM in hippocampus than controls. These results corroborate clinical findings and help further examine the mechanisms behind MA-induced neurotoxicity. C1 [Thanos, Panayotis K.; Chachati, George; Rocco, Mark J.] Univ Buffalo, Behav Neuropharmacol & Neuroimaging Lab Addict, Res Inst Addict, Buffalo, NY USA. [Kim, Ronald] Univ N Carolina, Dept Psychol, Chapel Hill, NC USA. [Delis, Foteini] Univ Ioannina, Sch Med, Dept Pharmacol, GR-45110 Ioannina, Greece. [Ananth, Mala] SUNY Stony Brook, Dept Neurosci, Stony Brook, NY 11794 USA. [Masad, Ihssan; Muniz, Jose A.; Grant, Samuel C.] Natl High Magnet Field Lab, Tallahassee, FL USA. [Gold, Mark S.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Cadet, Jean Lud] NIDA, Mol Neuropsychiat Res Branch, NIH, Dept Hlth & Human Serv, Baltimore, MD USA. [Volkow, Nora D.] NIAAA, Lab Neuroimaging, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RP Thanos, PK (reprint author), Univ Buffalo, Behav Neuropharmacol & Neuroimaging Lab Addict, Res Inst Addict, Buffalo, NY USA. EM pthanos@ria.buffalo.edu OI Grant, Samuel/0000-0001-7738-168X FU National Institutes of Health; National Institute on Alcohol and Alcoholism [AA11034]; Research Foundation of New York [RIAQ094] FX Funding was provided by National Institutes of Health; National Institute on Alcohol and Alcoholism, AA11034; and Research Foundation of New York, RIAQ094. NR 75 TC 5 Z9 5 U1 8 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 8 PY 2016 VL 11 IS 6 AR e0155457 DI 10.1371/journal.pone.0155457 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO1TJ UT WOS:000377561700005 PM 27275601 ER PT J AU Wooddell, LJ Kaburu, SSK Rosenberg, KL Meyer, JS Suomi, SJ Dettmer, AM AF Wooddell, Lauren J. Kaburu, Stefano S. K. Rosenberg, Kendra L. Meyer, Jerrold S. Suomi, Stephen J. Dettmer, Amanda M. TI Matrilineal Behavioral and Physiological Changes following the Death of a Non-Alpha Matriarch in Rhesus Macaques (Macaca mulatta) SO PLOS ONE LA English DT Article ID PITUITARY-ADRENOCORTICAL ACTIVITY; PAPIO-HAMADRYAS-URSINUS; CORTISOL CONCENTRATIONS; CHACMA BABOONS; HAIR CORTISOL; KILLER WHALES; WILD BABOONS; SOCIAL RANK; MONKEYS; DOMINANCE AB In many species, the loss of alpha matriarchs is associated with a number of negative outcomes such as troop fission, eviction, wounding, and reduced vitality. However, whether the dramatic consequences of their loss are due to their role as an old experienced figure or to their alpha status remains unclear. We tested the hypothesis that in a semi-free ranging colony of rhesus macaques (Macaca mulatta), the death of a non-alpha matriarch, who had a large set of kin, would lead to changes in behavior and physiological stress within her matriline. Following her death, her matriline increased in aggression, vigilance, and social grooming. Additionally, hierarchical stability, measured by levels of rank changes, decreased within her matriline, and levels of intense aggression by high-ranking animals were more frequent, as well as matrilineal wounding. Although ordinal rank was positively associated with higher chronic hair cortisol concentrations (HCCs) in the months before the matriarch's death, following her death, only those who experienced large increases in rank within her matriline displayed higher HCCs. Changes in matrilineal stability, aggression, behavior, and HCCs within the other two matrilines in the troop were not evident, although caution is needed due to the small sample sizes. We conclude that the death of the non-alpha matriarch led to matrilineal instability, characterized by higher levels of aggression and subsequent vigilance, rank changes, physiological stress, and grooming. We suggest that non-alpha matriarchs with a large number of kin and social support can be integral to the stability of matrilines. C1 [Wooddell, Lauren J.; Suomi, Stephen J.; Dettmer, Amanda M.] NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Poolesville, MD USA. [Kaburu, Stefano S. K.] Univ Calif Davis, Sch Vet Med, Dept Populat Hlth & Reprod, Davis, CA 95616 USA. [Rosenberg, Kendra L.; Meyer, Jerrold S.] Univ Massachusetts, Dept Psychol & Brain Sci, Amherst, MA 01003 USA. RP Wooddell, LJ (reprint author), NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Poolesville, MD USA. EM lauren.wooddell@nih.gov FU Division of Intramural Research, National Institute of Child Health and Human Development [1ZIAHD001107-32] FX This work was supported by the Division of Intramural Research, National Institute of Child Health and Human Development, 1ZIAHD001107-32, awarded to SJS, https://www.nichd.nih.gov/about/org/dir/Pages/index.aspx. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 72 TC 1 Z9 1 U1 7 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 8 PY 2016 VL 11 IS 6 AR e0157108 DI 10.1371/journal.pone.0157108 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO1TJ UT WOS:000377561700069 PM 27275743 ER PT J AU Schoch, CL Karsch-Mizrachi, I Ostell, JM AF Schoch, Conrad L. Karsch-Mizrachi, Ilene Ostell, James M. TI In memoriam -Scott Federhen (October 21, 1952-May 5, 2016) SO STANDARDS IN GENOMIC SCIENCES LA English DT Biographical-Item C1 [Schoch, Conrad L.; Karsch-Mizrachi, Ilene; Ostell, James M.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bldg 45,8600 Rockville Pike, Bethesda, MD 20894 USA. RP Schoch, CL (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bldg 45,8600 Rockville Pike, Bethesda, MD 20894 USA. EM schoch2@ncbi.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1944-3277 J9 STAND GENOMIC SCI JI Stand. Genomic Sci. PD JUN 8 PY 2016 VL 11 AR 41 DI 10.1186/s40793-016-0160-z PG 2 WC Genetics & Heredity; Microbiology SC Genetics & Heredity; Microbiology GA DO7HL UT WOS:000377953100001 ER PT J AU Nussinov, R AF Nussinov, Ruth TI Introduction to Protein Ensembles and Allostery SO CHEMICAL REVIEWS LA English DT Editorial Material ID HEMOGLOBIN; MODEL C1 [Nussinov, Ruth] NCI, Computat Struct Biol Sect, Bethesda, MD 20892 USA. [Nussinov, Ruth] Tel Aviv Univ, Sch Med, Dept Human Genet, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Computat Struct Biol Sect, Bethesda, MD 20892 USA.; Nussinov, R (reprint author), Tel Aviv Univ, Sch Med, Dept Human Genet, IL-69978 Tel Aviv, Israel. EM NussinoR@helix.nih.gov NR 8 TC 1 Z9 1 U1 4 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2665 EI 1520-6890 J9 CHEM REV JI Chem. Rev. PD JUN 8 PY 2016 VL 116 IS 11 SI SI BP 6263 EP 6266 DI 10.1021/acs.chemrev.6b00283 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA DO2WK UT WOS:000377641500001 PM 27268255 ER PT J AU Venditti, V Egner, TK Clore, GM AF Venditti, Vincenzo Egner, Timothy K. Clore, G. Marius TI Hybrid Approaches to Structural Characterization of Conformational Ensembles of Complex Macromolecular Systems Combining NMR Residual Dipolar Couplings and Solution X-ray Scattering SO CHEMICAL REVIEWS LA English DT Review ID PARAMAGNETIC RELAXATION ENHANCEMENT; SUGAR PHOSPHOTRANSFERASE SYSTEM; SMALL-ANGLE SCATTERING; PROTEIN-PROTEIN COMPLEXES; MOLECULAR-WEIGHT PROTEINS; LIQUID-CRYSTALLINE MEDIUM; RIGID-BODY MINIMIZATION; BACTERIAL ENZYME I; TENSOR-FREE METHOD; N-TERMINAL DOMAIN AB Solving structures or structural ensembles of large macromolecular systems in solution poses a challenging problem. While NMR provides structural information at atomic resolution, increased spectral complexity, chemical shift overlap, and short transverse relaxation times (associated with slow tumbling) render application of the usual techniques that have been so successful for medium sized systems (<50 kDa) difficult. Solution X-ray scattering, on the other hand, is not limited by molecular weight but only provides low resolution structural information related to the overall shape and size of the system under investigation. Here we review how combining atomic resolution structures of smaller domains with sparse experimental data afforded by NMR residual dipolar couplings (which yield both orientational and shape information) and solution X-ray scattering data in rigid-body simulated annealing calculations provides a powerful approach for investigating the structural aspects of conformational dynamics in large multidomain proteins. The application of this hybrid methodology is illustrated for the 128 kDa diner of bacterial Enzyme I which exists in a variety of open and closed states that are sampled at various points in the catalytic cycles, and for the capsid protein of the human immunodeficiency virus. C1 [Venditti, Vincenzo; Egner, Timothy K.] Iowa State Univ, Dept Chem, Ames, IA 50011 USA. [Venditti, Vincenzo] Iowa State Univ, Roy J Carver Dept Biochem Biophys & Mol Biol, Ames, IA 50011 USA. [Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Venditti, V (reprint author), Iowa State Univ, Dept Chem, Ames, IA 50011 USA.; Venditti, V (reprint author), Iowa State Univ, Roy J Carver Dept Biochem Biophys & Mol Biol, Ames, IA 50011 USA.; Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM venditti@iastate.edu; mariusc@mail.nih.gov FU Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH; Iowa State University FX We thank Charles Schwieters for helpful discussions. This work was supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH (G.M.C.) and by startup funding from Iowa State University (v.v.). NR 176 TC 3 Z9 3 U1 9 U2 25 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2665 EI 1520-6890 J9 CHEM REV JI Chem. Rev. PD JUN 8 PY 2016 VL 116 IS 11 SI SI BP 6305 EP 6322 DI 10.1021/acs.chemrev.5b00592 PG 18 WC Chemistry, Multidisciplinary SC Chemistry GA DO2WK UT WOS:000377641500003 PM 26739383 ER PT J AU Papaleo, E Saladino, G Lambrughi, M Lindorff-Larsen, K Gervasio, FL Nussinov, R AF Papaleo, Elena Saladino, Giorgio Lambrughi, Matteo Lindorff-Larsen, Kresten Gervasio, Francesco Luigi Nussinov, Ruth TI The Role of Protein Loops and Linkers in Conformational Dynamics and Allostery SO CHEMICAL REVIEWS LA English DT Review ID ELASTIC-NETWORK MODEL; FREE-ENERGY LANDSCAPE; UBIQUITIN-CONJUGATING ENZYMES; EXCHANGE MOLECULAR-DYNAMICS; X-RAY SCATTERING; YARROWIA-LIPOLYTICA LIPASE; CELL-REGULATORY SYSTEMS; MALTOSE-BINDING PROTEIN; MECHANICS FORCE-FIELDS; GROWTH-FACTOR RECEPTOR AB Proteins are dynamic entities that undergo a plethora of conformational changes that may take place on a wide range of time scales. These changes can be as small as the rotation of one or a few side-chain dihedral angles or involve concerted motions in larger portions of the three-dimensional structure; both kinds of motions can be important for biological function and allostery. It is becoming increasingly evident that "connector regions" are important components of the dynamic personality of protein structures. These regions may be either disordered loops, i.e., poorly structured regions connecting secondary structural elements, or linkers that connect entire protein domains. Experimental and computational studies have, however, revealed that these regions are not mere connectors, and their role in allostery and conformational changes has been emerging in the last few decades. Here we provide a detailed overview of the structural properties and classification of loops and linkers, as well as a discussion of the main computational methods employed to investigate their function and dynamical properties. We also describe their importance for protein dynamics and allostery using as examples key proteins in cellular biology and human diseases such as kinases, ubiquitinating enzymes, and transcription factors. C1 [Papaleo, Elena] Danish Canc Soc Res Ctr, Unit Stat Bioinformat & Registry, Computat Biol Lab, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. [Papaleo, Elena; Lindorff-Larsen, Kresten] Univ Copenhagen, Dept Biol, Struct Biol & NMR Lab, DK-2200 Copenhagen, Denmark. [Saladino, Giorgio; Gervasio, Francesco Luigi] UCL, Dept Chem, Mortimer St, London WC1E 6BT, England. [Lambrughi, Matteo] Univ Milano Bicocca, Dept Biotechnol & Biosci, Piazza Sci 2, I-20126 Milan, Italy. [Nussinov, Ruth] NCI, Canc & Inflammat Program, Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Papaleo, E (reprint author), Danish Canc Soc Res Ctr, Unit Stat Bioinformat & Registry, Computat Biol Lab, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.; Papaleo, E (reprint author), Univ Copenhagen, Dept Biol, Struct Biol & NMR Lab, DK-2200 Copenhagen, Denmark. EM elenap@cancer.dk RI Lindorff-Larsen, Kresten/K-6469-2014; OI Lindorff-Larsen, Kresten/0000-0002-4750-6039; Saladino, Giorgio/0000-0002-3234-5762 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Hallas-Moller grant from the Novo Nordisk Foundation; PRACE; Danish Council for Independent Research; Carlsberg Foundation; Velux Foundations; Lundbeck Foundation; EPSRC [EP/M013898/1]; DyNet PRACE-3IP Project [DECI-11]; ISCRA CINECA HPC Grants FX This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract no. HHSN261200800001E to RN. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research to RN. K.L.-L. was supported by a Hallas-Moller grant from the Novo Nordisk Foundation, and K.L.-L. acknowledges further support from PRACE, the Danish Council for Independent Research, the Carlsberg Foundation, Velux Foundations, and Lundbeck Foundation. F.L.G. and G.S. acknowledge support from EPSRC [Grant EP/M013898/1]. E.P. has been supported by DECI-11 DyNet PRACE-3IP Project and several ISCRA CINECA HPC Grants. NR 377 TC 12 Z9 12 U1 24 U2 46 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2665 EI 1520-6890 J9 CHEM REV JI Chem. Rev. PD JUN 8 PY 2016 VL 116 IS 11 SI SI BP 6391 EP 6423 DI 10.1021/acs.chemrev.5b00623 PG 33 WC Chemistry, Multidisciplinary SC Chemistry GA DO2WK UT WOS:000377641500006 PM 26889708 ER PT J AU Wei, GH Xi, WH Nussinov, R Ma, BY AF Wei, Guanghong Xi, Wenhui Nussinov, Ruth Ma, Buyong TI Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell SO CHEMICAL REVIEWS LA English DT Review ID INTRINSICALLY DISORDERED PROTEINS; FREE-ENERGY LANDSCAPE; MOLECULAR-DYNAMICS SIMULATIONS; ALPHA-B-CRYSTALLIN; X-RAY-SCATTERING; NUCLEAR-MAGNETIC-RESONANCE; ELONGATION-FACTOR G; STRUCTURALLY CONSERVED RESIDUES; PURINE NUCLEOSIDE PHOSPHORYLASE; ENTHALPY-ENTROPY COMPENSATION AB All soluble proteins populate conformational ensembles that together constitute the native state. Their fluctuations in water are intrinsic thermodynamic phenomena, and the distributions of the states on the energy landscape are determined by statistical thermodynamics; however, they are optimized to perform their biological functions. In this review we briefly describe advances in free energy landscape studies of protein conformational ensembles. Experimental (nuclear magnetic resonance; small angle X-ray scattering, single-molecule spectroscopy, and cryo-electron microscopy) and computational (replica-exchange molecular dynamics, metadynamics; and Markov state models) approaches have made great progress in recent years. These address the challenging characterization of the highly flexible and heterogeneous protein ensembles. We focus on structural aspects of protein conformational distributions, from collective motions of single- and multi-domain proteins, intrinsically disordered proteins, to multiprotein complexes. Importantly, we highlight recent studies that illustrate functional adjustment of protein conformational ensembles in the crowded cellular environment. We center on the role of the ensemble in recognition of small- and macro-molecules (protein and RNA/DNA) and emphasize emerging concepts of protein dynamics in enzyme catalysis. Overall, protein ensembles link fundamental physicochemical principles and protein behavior and the cellular network and its regulation. C1 [Wei, Guanghong; Xi, Wenhui] Fudan Univ, Key Lab Computat Phys Sci MOE, State Key Lab Surface Phys, Shanghai 200433, Peoples R China. [Wei, Guanghong; Xi, Wenhui] Fudan Univ, Dept Phys, Shanghai 200433, Peoples R China. [Nussinov, Ruth; Ma, Buyong] NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Wei, GH (reprint author), Fudan Univ, Key Lab Computat Phys Sci MOE, State Key Lab Surface Phys, Shanghai 200433, Peoples R China.; Wei, GH (reprint author), Fudan Univ, Dept Phys, Shanghai 200433, Peoples R China.; Ma, BY (reprint author), NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. EM ghwei@fudan.edu.cn; mabuyong@mail.nih.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU Federal funds from the National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; NSF of China [91227102, 11274075] 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 (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. G.W. acknowledges the financial support from the NSF of China (Grant Nos. 91227102 and 11274075). We thank Wengjie Chen for her help with the TOC figure. NR 574 TC 18 Z9 18 U1 39 U2 76 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2665 EI 1520-6890 J9 CHEM REV JI Chem. Rev. PD JUN 8 PY 2016 VL 116 IS 11 SI SI BP 6516 EP 6551 DI 10.1021/acs.chemrev.5b00562 PG 36 WC Chemistry, Multidisciplinary SC Chemistry GA DO2WK UT WOS:000377641500011 PM 26807783 ER PT J AU Lu, SY Jang, H Muratcioglu, S Gursoy, A Keskin, O Nussinov, R Zhang, J AF Lu, Shaoyong Jang, Hyunbum Muratcioglu, Serena Gursoy, Attila Keskin, Ozlem Nussinov, Ruth Zhang, Jian TI Ras Conformational Ensembles, Allostery, and Signaling SO CHEMICAL REVIEWS LA English DT Review ID PHOSPHOLIPASE-C-EPSILON; GUANINE-NUCLEOTIDE EXCHANGE; GTPASE-ACTIVATING PROTEIN; ONCOGENIC K-RAS; QUANTUM MECHANICS/MOLECULAR MECHANICS; PHOSPHOINOSITIDE 3-KINASE PATHWAY; GAP-CATALYZED-HYDROLYSIS; P-31 NMR-SPECTROSCOPY; FREE-ENERGY LANDSCAPE; H-RAS AB Ras proteins are classical members of small GTPases that function as molecular switches by alternating between inactive GDP-bound and active GTP-bound states. Ras activation is regulated by guanine nucleotide exchange factors that catalyze the exchange of GDP by GTP, and inactivation is terminated by GTPase-activating proteins that accelerate the intrinsic GTP hydrolysis rate by orders of magnitude. In this review, we focus on data that have accumulated over the past few years pertaining to the conformational ensembles and the allosteric regulation of Ras proteins and their interpretation from our conformational landscape standpoint. The Ras ensemble embodies all states, including the ligand-bound conformations, the activated (or inactivated) allosteric modulated states, post-translationally modified states, mutational states, transition states, and nonfunctional states serving as a reservoir for emerging functions. The ensemble is shifted by distinct mutational events, cofactors, post-translational modifications, and different membrane compositions. A better understanding of Ras biology can contribute to therapeutic strategies. C1 [Lu, Shaoyong; Zhang, Jian] Shanghai Jiao Tong Univ, Sch Med, Dept Pathophysiol,Chinese Minist Educ, Shanghai Univ E Inst Chem Biol,Key Lab Cell Diffe, Shanghai 200025, Peoples R China. [Lu, Shaoyong; Jang, Hyunbum; Nussinov, Ruth] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab, Frederick, MD 21702 USA. [Muratcioglu, Serena; Keskin, Ozlem] Koc Univ, Dept Chem & Biol Engn, Rumelifeneri Yolu, TR-34450 Sariyer, Turkey. [Gursoy, Attila] Koc Univ, Dept Comp Engn, Rumelifeneri Yolu, TR-34450 Sariyer, Turkey. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Zhang, J (reprint author), Shanghai Jiao Tong Univ, Sch Med, Dept Pathophysiol,Chinese Minist Educ, Shanghai Univ E Inst Chem Biol,Key Lab Cell Diffe, Shanghai 200025, Peoples R China.; Nussinov, R (reprint author), NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab, Frederick, MD 21702 USA.; Nussinov, R (reprint author), Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. EM NussinoR@helix.nih.gov; jian.zhang@sjtu.edu.cn RI Gursoy, Attila/E-9565-2015 OI Gursoy, Attila/0000-0002-2297-2113 FU National Basic Research Program of China (973 Program) [2015CB910403]; National Natural Science Foundation of China [81322046, 81302698, 81473137]; Shanghai Rising-Star Program [13QA1402300]; Program for New Century Excellent Talents in University [NCET-12-0355]; Shanghai Health and Family Planning Commission [20154Y0058]; Collaborative Innovation Center of Systems Biomedicine; TUBITAK Research Grant [114M196]; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research FX We thank Dr. Chung-Jung Tsai for discussions. This work was supported by National Basic Research Program of China (973 Program) (2015CB910403), National Natural Science Foundation of China (81322046, 81302698, 81473137), Shanghai Rising-Star Program (13QA1402300), Program for New Century Excellent Talents in University (NCET-12-0355), Shanghai Health and Family Planning Commission (20154Y0058), and Collaborative Innovation Center of Systems Biomedicine. This work has been partially supported by TUBITAK Research Grant No: 114M196. This project has also been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. This research was supported (in part) by the Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 456 TC 15 Z9 15 U1 11 U2 24 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2665 EI 1520-6890 J9 CHEM REV JI Chem. Rev. PD JUN 8 PY 2016 VL 116 IS 11 SI SI BP 6607 EP 6665 DI 10.1021/acs.chemrev.5b00542 PG 59 WC Chemistry, Multidisciplinary SC Chemistry GA DO2WK UT WOS:000377641500014 PM 26815308 ER PT J AU Liu, W Yang, RF Payne, AS Schowalter, RM Spurgeon, ME Lambert, PF Xu, XW Buck, CB You, JX AF Liu, Wei Yang, Ruifeng Payne, Aimee S. Schowalter, Rachel M. Spurgeon, Megan E. Lambert, Paul F. Xu, Xiaowei Buck, Christopher B. You, Jianxin TI Identifying the Target Cells and Mechanisms of Merkel Cell Polyomavirus Infection SO CELL HOST & MICROBE LA English DT Article ID EMBRYONIC STEM-CELLS; GROWTH-FACTOR; T-ANTIGENS; HUMAN SKIN; CARCINOMA; EXPRESSION; CANCER; METALLOPROTEINASES; PROLIFERATION; INTEGRATION AB Infection with Merkel cell polyomavirus (MCPyV) can lead to Merkel cell carcinoma (MCC), a lethal form of skin cancer. However, the skin cell type productively infected by MCPyV remains a central question. We combined cell culture and ex vivo approaches to identify human dermal fibroblasts as natural host cells that support productive MCPyV infection. Based on this, we established a cell culture model for MCPyV infection, which will facilitate investigation of the oncogenic mechanisms for this DNA virus. Using this model, we discovered that induction of matrix metalloproteinase (MMP) genes by the WNT/beta-catenin signaling pathway and other growth factors stimulates MCPyV infection. This suggests that MCC risk factors such as UV radiation and aging, which are known to stimulate WNT signaling and MMP expression, may promote viral infection and thus drive MCC. Our study also introduces the FDA-approved MEK antagonist trametinib as an effective inhibitor for controlling MCPyV infection. C1 [Liu, Wei; You, Jianxin] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Yang, Ruifeng; Xu, Xiaowei] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Payne, Aimee S.] Univ Penn, Dept Dermatol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Schowalter, Rachel M.; Buck, Christopher B.] NCI, Tumor Virus Mol Biol Sect, Cellular Oncol Lab, Bethesda, MD 20892 USA. [Spurgeon, Megan E.; Lambert, Paul F.] Univ Wisconsin, McArdle Lab Canc Res, Dept Oncol, Sch Med & Publ Hlth, 1400 Univ Ave, Madison, WI 53706 USA. RP You, JX (reprint author), Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. EM jianyou@mail.med.upenn.edu FU National Institutes of Health (NIH) [R01CA148768, R01CA142723, R01CA187718]; NIAMS [AR064220, R01AR054593, P50CA174523]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX The authors would like to thank Dr. Meenhard Herlyn (Wistar Institute) for skin cell marker antibodies, Dr. M. Celeste Simon (University of Pennsylvania) for providing TOF-flash and FOP-flash plasmids, Dr. Ling Li for technical support, and Margo MacDonald for editing the manuscript. We also thank the members of our laboratories for helpful discussion. This work was supported by the National Institutes of Health (NIH) grants R01CA148768, R01CA142723, R01CA187718, NIAMS AR064220, R01AR054593, and P50CA174523 and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 45 TC 5 Z9 5 U1 3 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD JUN 8 PY 2016 VL 19 IS 6 BP 775 EP 787 DI 10.1016/j.chom.2016.04.024 PG 13 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DO0CM UT WOS:000377447000009 PM 27212661 ER PT J AU Dunand, CJH Leon, PE Huang, M Choi, A Chromikova, V Ho, IY Tan, GS Cruz, J Hirsh, A Zheng, NY Mullarkey, CE Ennis, FA Terajima, M Treanor, JJ Topham, DJ Subbarao, K Palese, P Krammer, F Wilson, PC AF Dunand, Carole J. Henry Leon, Paul E. Huang, Min Choi, Angela Chromikova, Veronika Ho, Irvin Y. Tan, Gene S. Cruz, John Hirsh, Ariana Zheng, Nai-Ying Mullarkey, Caitlin E. Ennis, Francis A. Terajima, Masanori Treanor, John J. Topham, David J. Subbarao, Kanta Palese, Peter Krammer, Florian Wilson, Patrick C. TI Both Neutralizing and Non-Neutralizing Human H7N9 Influenza Vaccine-Induced Monoclonal Antibodies Confer Protection SO CELL HOST & MICROBE LA English DT Article ID DEPENDENT CELLULAR CYTOTOXICITY; VIRUS-VACCINE; A VIRUSES; IN-VIVO; HEALTHY-ADULTS; CLINICAL-TRIAL; HEMAGGLUTININ; RESPONSES; INFECTION; DOMAIN AB Pathogenic H7N9 avian influenza viruses continue to represent a public health concern, and several candidate vaccines are currently being developed. It is vital to assess if protective antibodies are induced following vaccination and to characterize the diversity of epitopes targeted. Here we characterized the binding and functional properties of twelve H7-reactive human antibodies induced by a candidate A/Anhui/1/2013 (H7N9) vaccine. Both neutralizing and non-neutralizing antibodies protected mice in vivo during passive transfer challenge experiments. Mapping the H7 hemagglutinin antigenic sites by generating escape mutant variants against the neutralizing antibodies identified unique epitopes on the head and stalk domains. Further, the broadly cross-reactive non-neutralizing antibodies generated in this study were protective through Fc-mediated effector cell recruitment. These findings reveal important properties of vaccine-induced antibodies and provide a better understanding of the human monoclonal antibody response to influenza in the context of vaccines. C1 [Dunand, Carole J. Henry; Huang, Min; Ho, Irvin Y.; Zheng, Nai-Ying; Wilson, Patrick C.] Univ Chicago, Dept Med, Rheumatol Sect, Knapp Ctr Lupus & Immunol Res, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Leon, Paul E.; Choi, Angela; Chromikova, Veronika; Tan, Gene S.; Hirsh, Ariana; Mullarkey, Caitlin E.; Palese, Peter; Krammer, Florian] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA. [Leon, Paul E.; Choi, Angela] Icahn Sch Med Mt Sinai, Grad Sch Biomed Sci, New York, NY 10029 USA. [Cruz, John] Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01655 USA. [Ennis, Francis A.; Terajima, Masanori] Univ Massachusetts, Sch Med, Dept Med, Div Infect Dis & Immunol, Worcester, MA 01655 USA. [Treanor, John J.] Univ Rochester, Sch Med & Dent, Dept Med, Div Infect Dis, Rochester, NY 14642 USA. [Topham, David J.] Univ Rochester, Sch Med & Dent, Dept Microbiol & Immunol, Ctr Vaccine Biol & Immunol, Rochester, NY 14642 USA. [Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Rockville, MD 20852 USA. [Palese, Peter] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. RP Wilson, PC (reprint author), Univ Chicago, Dept Med, Rheumatol Sect, Knapp Ctr Lupus & Immunol Res, 5841 S Maryland Ave, Chicago, IL 60637 USA.; Krammer, F (reprint author), Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA. EM florian.krammer@mssm.edu; wilsonp@uchicago.edu OI Palese, Peter/0000-0002-0337-5823; Krammer, Florian/0000-0003-4121-776X FU National Institute of Allergy and Infectious Diseases, NIH, Department of Health and Human Services, under CEIRS contracts [HHSN272201400006C, HHSN272201400008C]; NIH [U19AI109946-01, P01AI097092-03, P01AI097092-04S1, U19AI057266-11]; Division of Intramural Research, NIAID, NIH; Biomedical Advanced Research and Development Authority, HHS [HHSN272200900026C] FX This project has been funded in part with federal funds from the National Institute of Allergy and Infectious Diseases, NIH, Department of Health and Human Services, under CEIRS contracts No HHSN272201400006C (P.C.W., J.J.T., and D.J.T.) and HHSN272201400008C (P.P. and F.K.); NIH U19AI109946-01 (P.C.W., P.P., and F.K.), P01AI097092-03 (P.C.W. and P.P.), P01AI097092-04S1 (P.E.L.), and U19AI057266-11 (P.C.W.). Clinical trial NCT01995695 was supported by the Division of Intramural Research, NIAID, NIH and by the Biomedical Advanced Research and Development Authority, HHS, under contract #HHSN272200900026C. We thank Donna Neu, Mary Dawn T. Co, the Center for Therapeutic Antibody Development, the Flow Cytometry Center of Research Excellence, and the Microscopy Core at the Icahn School of Medicine at Mount Sinai and the University of Chicago Flow Cytometry Core. NR 54 TC 12 Z9 12 U1 2 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD JUN 8 PY 2016 VL 19 IS 6 BP 800 EP 813 DI 10.1016/j.chom.2016.05.014 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DO0CM UT WOS:000377447000011 ER PT J AU Grant, A Ponia, SS Tripathi, S Balasubramaniam, V Miorin, L Sourisseau, M Schwarz, MC Sanchez-Seco, MP Evans, MJ Best, SM Garcia-Sastre, A AF Grant, Alesha Ponia, Sanket S. Tripathi, Shashank Balasubramaniam, Vinod Miorin, Lisa Sourisseau, Marion Schwarz, Megan C. Paz Sanchez-Seco, Mari Evans, Matthew J. Best, Sonja M. Garcia-Sastre, Adolfo TI Zika Virus Targets Human STAT2 to Inhibit Type I Interferon Signaling SO CELL HOST & MICROBE LA English DT Article ID WEST-NILE-VIRUS; DENGUE VIRUS; NS5 PROTEIN; ANTAGONIST; FLAVIVIRUS; IDENTIFICATION; ACTIVATION; MECHANISMS; HEMISPHERE; EMERGENCE AB The ongoing epidemic of Zika virus (ZIKV) illustrates the importance of flaviviruses as emerging human pathogens. All vector-borne flaviviruses studied thus far have to overcome type I interferon (IFN) to replicate and cause disease in vertebrates. The mechanism(s) by which ZIKV antagonizes IFN signaling is unknown. Here, we report that the nonstructural protein NS5 of ZIKV and other flaviviruses examined could suppress IFN signaling, but through different mechanisms. ZIKV NS5 expression resulted in proteasomal degradation of the IFN-regulated transcriptional activator STAT2 from humans, but not mice, which may explain the requirement for IFN deficiency to observe ZIKV-induced disease in mice. The mechanism of ZIKV NS5 resembles dengue virus (DENV) NS5 and not its closer relative, Spondweni virus (SPOV). However, unlike DENV, ZIKV did not require the E3 ubiquitin ligase UBR4 to induce STAT2 degradation. Hence, flavivirus NS5 proteins exhibit a remarkable functional convergence in IFN antagonism, albeit by virus-specific mechanisms. C1 [Grant, Alesha; Tripathi, Shashank; Balasubramaniam, Vinod; Miorin, Lisa; Sourisseau, Marion; Schwarz, Megan C.; Evans, Matthew J.; Garcia-Sastre, Adolfo] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA. [Grant, Alesha; Tripathi, Shashank; Balasubramaniam, Vinod; Miorin, Lisa; Garcia-Sastre, Adolfo] Icahn Sch Med Mt Sinai, Global Hlth & Emerging Pathogens Inst, New York, NY 10029 USA. [Ponia, Sanket S.; Best, Sonja M.] NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Paz Sanchez-Seco, Mari] Inst Hlth Carlos III, Natl Ctr Microbiol, Lab Arbovirus & Imported Viral Dis, Madrid 28029, Spain. [Garcia-Sastre, Adolfo] Icahn Sch Med Mt Sinai, Dept Med, Div Infect Dis, 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, Dept Med, Div Infect Dis, New York, NY 10029 USA. EM adolfo.garcia-sastre@mssm.edu RI RMT Balasubramaniam, Vinod/B-6957-2017; OI RMT Balasubramaniam, Vinod/0000-0001-9583-307X; Evans, Matthew/0000-0002-4991-3877; Garcia-Sastre, Adolfo/0000-0002-6551-1827 FU Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases; [U19AI118610] FX We thank Barbara W. Johnson, Ana Fernandez-Sesma, and Steve Whitehead for kindly providing the 2015 PR ZIKV, 16881 DENV2, and 2015 Fortaleza ZIKV strains, respectively. We thank Genhong Cheng for IFNAR1-/- MEFs. We thank the microscopy and FACS SRF at Icahn School of Medicine for their support and Richard Cadagan for excellent technical assistance. This work was supported in part by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. These studies were also partly supported by a supplement to NIAID grant U19AI118610. NR 44 TC 32 Z9 32 U1 21 U2 45 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD JUN 8 PY 2016 VL 19 IS 6 BP 882 EP 890 DI 10.1016/j.chom.2016.05.009 PG 9 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DO0CM UT WOS:000377447000018 PM 27212660 ER PT J AU Guzman, DA Pellegrini, S Flesia, AG Aon, MA Marin, RH Kembro, JM AF Guzman, Diego A. Pellegrini, Stefania Flesia, Ana G. Aon, Miguel A. Marin, Raul H. Kembro, Jackelyn M. TI High resolution, week-long, locomotion time series from Japanese quail in a home-box environment SO SCIENTIFIC DATA LA English DT Article; Data Paper ID BEHAVIORAL RHYTHMS; HUMAN GAIT; DYNAMICS; FLUCTUATIONS; WALKING; HENS AB Temporal and spatial patterns of locomotion reflect both resting periods and the movement from one place to another to satisfy physiological and behavioural needs. Locomotion is studied in diverse areas of biology such as chronobiology and physiology, as well as in biomathematics. Herein, the locomotion of 24 visually-isolated Japanese quails in their home-box environment was recorded continuously over a 6.5 days at a 0.5 s sampling rate. Three time series are presented for each bird: (1) locomotor activity, (2) distance ambulated, and (3) zone of the box where the bird is located. These high resolution, week-long, time series consisting of 1.07 x 10(6) data points represent, to our knowledge, a unique data set in animal behavior, and are publically available on FigShare. The data obtained can be used for analyzing dynamic changes of daily or several day locomotion patterns, or for comparison with existing or future data sets or mathematical models across different taxa. C1 [Guzman, Diego A.; Pellegrini, Stefania; Marin, Raul H.; Kembro, Jackelyn M.] Univ Nacl Cordoba, Fac Ciencias Exactas Fis & Nat, CONICET, IIByT, Catedra Quim Biol,1611 Velez Sarsfield,X5016GCA, Cordoba, Argentina. [Guzman, Diego A.; Pellegrini, Stefania; Marin, Raul H.; Kembro, Jackelyn M.] Univ Nacl Cordoba, Fac Ciencias Exactas Fis & Nat, Inst Ciencia & Tecnol Alimentos, Catedra Quim Biol,1611 Velez Sarsfield,X5016GCA, Cordoba, Argentina. [Guzman, Diego A.] Aarhus Univ, Dept Anim Sci, 20 Blichers Alle,Post Box 50, DK-8830 Tjele, Denmark. [Flesia, Ana G.] Univ Nacl Cordoba, CONICET, CIEM, Ingn Medina Allende S-N Ciudad Univ,CP X5000HUA, Cordoba, Argentina. [Flesia, Ana G.] Univ Nacl Cordoba, Fac Matemat Astron & Fis FAMAF, Ingn Medina Allende S-N Ciudad Univ,CP X5000HUA, Cordoba, Argentina. [Aon, Miguel A.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. [Aon, Miguel A.] NIA, NIH, BRC BG Rm 09B119,251 Bayview Blvd, Baltimore, MD 21224 USA. RP Kembro, JM (reprint author), Univ Nacl Cordoba, Fac Ciencias Exactas Fis & Nat, CONICET, IIByT, Catedra Quim Biol,1611 Velez Sarsfield,X5016GCA, Cordoba, Argentina.; Kembro, JM (reprint author), Univ Nacl Cordoba, Fac Ciencias Exactas Fis & Nat, Inst Ciencia & Tecnol Alimentos, Catedra Quim Biol,1611 Velez Sarsfield,X5016GCA, Cordoba, Argentina. EM jkembro@efn.uncor.edu RI Aon, Miguel/A-6564-2008; OI Aon, Miguel/0000-0002-4355-5431; Flesia, Ana Georgina/0000-0001-6936-3764 NR 30 TC 1 Z9 1 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 7 PY 2016 VL 3 AR UNSP 160036 DI 10.1038/sdata.2016.36 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF3IK UT WOS:000390217800001 PM 27271772 ER PT J AU Zook, JM Catoe, D McDaniel, J Vang, L Spies, N Sidow, A Weng, ZM Liu, YL Mason, CE Alexander, N Henaff, E McIntyre, ABR Chandramohan, D Chen, F Jaeger, E Moshrefi, A Pham, K Stedman, W Liang, T Saghbini, M Dzakula, Z Hastie, A Cao, H Deikus, G Schadt, E Sebra, R Bashir, A Truty, RM Chang, CC Gulbahce, N Zhao, KY Ghosh, S Hyland, F Fu, YT Chaisson, M Xiao, CL Trow, J Sherry, ST Zaranek, AW Ball, M Bobe, J Estep, P Church, GM Marks, P Kyriazopoulou-Panagiotopoulou, S Zheng, GXY Schnall-Levin, M Ordonez, HS Mudivarti, PA Giorda, K Sheng, Y Rypdal, KB Salit, M AF Zook, Justin M. Catoe, David McDaniel, Jennifer Vang, Lindsay Spies, Noah Sidow, Arend Weng, Ziming Liu, Yuling Mason, Christopher E. Alexander, Noah Henaff, Elizabeth McIntyre, Alexa B. R. Chandramohan, Dhruva Chen, Feng Jaeger, Erich Moshrefi, Ali Khoa Pham Stedman, William Liang, Tiffany Saghbini, Michael Dzakula, Zeljko Hastie, Alex Cao, Han Deikus, Gintaras Schadt, Eric Sebra, Robert Bashir, Ali Truty, Rebecca M. Chang, Christopher C. Gulbahce, Natali Zhao, Keyan Ghosh, Srinka Hyland, Fiona Fu, Yutao Chaisson, Mark Xiao, Chunlin Trow, Jonathan Sherry, Stephen T. Zaranek, Alexander W. Ball, Madeleine Bobe, Jason Estep, Preston Church, George M. Marks, Patrick Kyriazopoulou-Panagiotopoulou, Sofia Zheng, Grace X. Y. Schnall-Levin, Michael Ordonez, Heather S. Mudivarti, Patrice A. Giorda, Kristina Sheng, Ying Rypdal, Karoline Bjarnesdatter Salit, Marc TI Extensive sequencing of seven human genomes to characterize benchmark reference materials SO SCIENTIFIC DATA LA English DT Article ID FRAMEWORK; READS AB The Genome in a Bottle Consortium, hosted by the National Institute of Standards and Technology (NIST) is creating reference materials and data for human genome sequencing, as well as methods for genome comparison and benchmarking. Here, we describe a large, diverse set of sequencing data for seven human genomes; five are current or candidate NIST Reference Materials. The pilot genome, NA12878, has been released as NIST RM 8398. We also describe data from two Personal Genome Project trios, one of Ashkenazim Jewish ancestry and one of Chinese ancestry. The data come from 12 technologies: BioNano Genomics, Complete Genomics paired-end and LFR, Ion Proton exome, Oxford Nanopore, Pacific Biosciences, SOLiD, 10X Genomics GemCode WGS, and Illumina exome and WGS paired-end, mate-pair, and synthetic long reads. Cell lines, DNA, and data from these individuals are publicly available. Therefore, we expect these data to be useful for revealing novel information about the human genome and improving sequencing technologies, SNP, indel, and structural variant calling, and de novo assembly. C1 [Zook, Justin M.; Catoe, David; McDaniel, Jennifer; Vang, Lindsay; Spies, Noah; Salit, Marc] NIST, Gaithersburg, MD 20899 USA. [Spies, Noah; Sidow, Arend; Weng, Ziming; Liu, Yuling; Salit, Marc] Stanford Univ, Stanford, CA 94305 USA. [Mason, Christopher E.; Alexander, Noah; Henaff, Elizabeth; McIntyre, Alexa B. R.; Chandramohan, Dhruva] Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, Feil Family Brain & Mind Res Inst, New York, NY 10065 USA. [Mason, Christopher E.; Alexander, Noah; Henaff, Elizabeth; McIntyre, Alexa B. R.; Chandramohan, Dhruva] Cornell Univ, Weill Med Coll, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10065 USA. [Chen, Feng; Jaeger, Erich; Moshrefi, Ali] Illumina Mission Bay, San Francisco, CA 94158 USA. [Khoa Pham; Stedman, William; Liang, Tiffany; Saghbini, Michael; Dzakula, Zeljko; Hastie, Alex; Cao, Han] BioNano Genom, San Diego, CA 92121 USA. [Deikus, Gintaras; Schadt, Eric; Sebra, Robert; Bashir, Ali; Bobe, Jason] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Truty, Rebecca M.; Chang, Christopher C.; Gulbahce, Natali] Complete Genom Inc, Mountain View, CA 94043 USA. [Zhao, Keyan; Ghosh, Srinka; Hyland, Fiona; Fu, Yutao] Thermo Fisher Sci, San Francisco, CA 94080 USA. [Chaisson, Mark] Univ Washington, Genome Sci, Seattle, WA 98105 USA. [Xiao, Chunlin; Trow, Jonathan] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 45 Ctr Dr, Bethesda, MD 20892 USA. [Zaranek, Alexander W.; Ball, Madeleine; Bobe, Jason; Estep, Preston; Church, George M.] PersonalGenomes Org, Boston, MA 02115 USA. [Estep, Preston; Church, George M.] Harvard Med Sch, Boston, MA 02115 USA. [Marks, Patrick; Kyriazopoulou-Panagiotopoulou, Sofia; Zheng, Grace X. Y.; Schnall-Levin, Michael; Ordonez, Heather S.; Mudivarti, Patrice A.; Giorda, Kristina] 10X Genom, Pleasanton, CA 94566 USA. [Sheng, Ying; Rypdal, Karoline Bjarnesdatter] Oslo Univ Hosp, Dept Med Genet, Kirkeveien 166,Bygg 25, N-0450 Oslo, Norway. RP Zook, JM (reprint author), NIST, Gaithersburg, MD 20899 USA. EM jzook@nist.gov FU Starr Cancer Consortium [I4-A442, I7-A765, I9-A9-071]; Irma T. Hirschl Trust; Monique Weill-Caulier Charitable Trust; Bert L and N Kuggie Vallee Foundation; WorldQuant Foundation; Pershing Square Sohn Cancer Research Alliance; NASA [NNX14AH50G]; National Institutes of Health [R25EB020393, R01NS076465] FX We thank members of the Genome in a Bottle Consortium for their feedback before and during this study. C.E.M. acknowledges funding from the Starr Cancer Consortium grant I4-A442, I7-A765, I9-A9-071), the Irma T. Hirschl and Monique Weill-Caulier Charitable Trusts, Bert L and N Kuggie Vallee Foundation and the WorldQuant Foundation (CEM), The Pershing Square Sohn Cancer Research Alliance, NASA (NNX14AH50G), and the National Institutes of Health (R25EB020393, R01NS076465). Certain commercial equipment, instruments, or materials are identified in this paper only to specify the experimental procedure adequately. Such identification is not intended to imply recommendation or endorsement by the NIST, nor is it intended to imply that the materials or equipment identified are necessarily the best available for the purpose. NR 30 TC 2 Z9 2 U1 2 U2 2 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 7 PY 2016 VL 3 AR UNSP 160025 DI 10.1038/sdata.2016.25 PG 26 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF3IE UT WOS:000390217200001 PM 27271295 ER PT J AU Robinson, OJ Krimsky, M Lieberman, L Vytal, K Ernst, M Grillon, C AF Robinson, O. J. Krimsky, M. Lieberman, L. Vytal, K. Ernst, M. Grillon, C. TI Anxiety-potentiated amygdala-medial frontal coupling and attentional control SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID AVERSIVE AMPLIFICATION CIRCUIT; DORSOMEDIAL PREFRONTAL CORTEX; COGNITIVE-BEHAVIORAL THERAPY; ANTERIOR CINGULATE; EMOTION REGULATION; THREAT; DISORDERS; MODULATION; CONTEXT; BIAS AB Anxiety disorders can be treated both pharmacologically and psychologically, but many individuals either fail to respond to treatment or relapse. Improving outcomes is difficult, in part because we have incomplete understanding of the neurobiological mechanisms underlying current treatments. In a sequence of studies, we have identified 'affective bias-related' amygdala-medial cortical coupling as a candidate substrate underlying adaptive anxiety (that is, anxiety elicited by threat of shock in healthy individuals) and shown that it is also chronically engaged in maladaptive anxiety disorders. We have provided evidence that this circuit can be modulated pharmacologically, but whether this mechanism can be shifted by simple psychological instruction is unknown. In this functional magnetic resonance imaging study, we extend a previously used translational anxiety induction (threat of shock) in healthy subjects (N = 43) and cognitive task to include an element of instructed attentional control. Replicating our previous findings, we show that induced anxiety engages 'affective bias-related' amygdala-dorsal medial frontal coupling during the processing of emotional faces. By contrast, instructing subjects to attend to neutral shapes (and ignore faces) disengages this circuitry and increases putative 'attentional control-related' coupling between the amygdala and a more rostral prefrontal region. These neural coupling changes are accompanied by corresponding modulation of behavioural performance. Taken together, these findings serve to further highlight the potential role of amygdala-medial frontal coupling in the pathogenesis of anxiety and highlight a mechanism by which it can be modulated via psychological instructions. This, in turn, generates hypotheses for future work exploring the mechanisms underlying psychological therapeutic interventions for anxiety. C1 [Robinson, O. J.] UCL, Inst Cognit Neurosci, Alexandra House,Queen Sq, London WC1N 3AR, England. [Robinson, O. J.; Krimsky, M.; Lieberman, L.; Vytal, K.; Ernst, M.; Grillon, C.] NIMH, Sect Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. RP Robinson, OJ (reprint author), UCL, Inst Cognit Neurosci, Alexandra House,Queen Sq, London WC1N 3AR, England. EM oliver.j.robinson@gmail.com FU National Institutes of Health; Medical Research Council [MR/K024280/1] FX This work was funded by the intramural programme of the National Institutes of Health and an individual Medical Research Council Career Development Award Fellowship to OJR (MR/K024280/1). NR 39 TC 3 Z9 3 U1 4 U2 6 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 7 PY 2016 VL 6 AR e833 DI 10.1038/tp.2016.105 PG 6 WC Psychiatry SC Psychiatry GA DW1QE UT WOS:000383416900005 PM 27271859 ER PT J AU Li, SX Ren, LQ Huang, PH Yao, XL Cuento, RA McCoy, JP Cameron, CE Levine, SJ Huang, TJ AF Li, Sixing Ren, Liqian Huang, Po-Hsun Yao, Xianglan Cuento, Rosemarie A. McCoy, J. Philip Cameron, Craig E. Levine, Stewart J. Huang, Tony Jun TI Acoustofluidic Transfer of Inflammatory Cells from Human Sputum Samples SO ANALYTICAL CHEMISTRY LA English DT Article ID SURFACE ACOUSTIC-WAVES; CARRIER-MEDIUM EXCHANGE; CONTINUOUS-FLOW; STANDING-WAVE; SEPARATION; PARTICLES; STREAMS; CHIP; DITHIOTHREITOL; MANIPULATION AB For sputum analysis, the transfer of inflammatory cells from liquefied sputum samples to a culture medium or buffer solution is a critical step because it removes the inflammatory cells from the presence of residual dithiothreitol (DTT), a reagent that reduces cell viability and interferes with further sputum analyses. In this work, we report an acoustofluidic platform for transferring inflammatory cells using standing surface acoustic waves (SSAW). In particular, we exploit the acoustic radiation force generated from a SSAW field to actively transfer inflammatory cells from a solution containing residual DTT to a buffer solution. The viability and integrity of the inflammatory cells are maintained during the acoustofluidic-based cell transfer process. Our acoustofluidic technique removes residual DTT generated in sputum liquefaction and facilitates immunophenotyping of major inflammatory cells from sputum samples. It enables cell transfer in a continuous flow, which aids the development of an automated, integrated system for on-chip sputum processing and analysis. C1 [Li, Sixing; Ren, Liqian; Huang, Po-Hsun; Huang, Tony Jun] Penn State Univ, Dept Engn Sci & Mech, 227 Hammond Bldg, University Pk, PA 16802 USA. [Li, Sixing; Cameron, Craig E.; Huang, Tony Jun] Penn State Univ, Mol Cellular & Integrat Biosci MCIBS Grad Program, Huck Inst Life Sci, University Pk, PA 16802 USA. [Cameron, Craig E.] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Yao, Xianglan; Cuento, Rosemarie A.; McCoy, J. Philip; Levine, Stewart J.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Huang, TJ (reprint author), Penn State Univ, Dept Engn Sci & Mech, 227 Hammond Bldg, University Pk, PA 16802 USA.; Huang, TJ (reprint author), Penn State Univ, Mol Cellular & Integrat Biosci MCIBS Grad Program, Huck Inst Life Sci, University Pk, PA 16802 USA.; Levine, SJ (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM levines@nhlbi.nih.gov; junhuang@psu.edu RI Huang, Po-Hsun/A-2713-2015; Li, Sixing/F-2383-2013; Huang, Tony/A-1546-2009; Ren, Liqiang/E-8953-2015 OI Huang, Po-Hsun/0000-0001-9600-0141; Ren, Liqiang/0000-0003-0863-4609 FU American Asthma Foundation (AAF) Scholar Award; National Institutes of Health [1R01AI120560-01]; NHLBI Division of Intramural Research; NIAID, NIH [AI45818]; NSF FX We thank Dr. Zhiwei Xie from Prof. Jiang Yang's group for microplate fluorescence measurements. This research was supported by the American Asthma Foundation (AAF) Scholar Award, National Institutes of Health (1R01AI120560-01), and the NHLBI Division of Intramural Research. S.L. and C.E.C. were funded in part by Grant AI45818 from NIAID, NIH. Components of this work were conducted at the Penn State node of the NSF-funded National Nanotechnology Infrastructure Network (NNIN). NR 49 TC 3 Z9 3 U1 6 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD JUN 7 PY 2016 VL 88 IS 11 BP 5655 EP 5661 DI 10.1021/acs.analchem.5b03383 PG 7 WC Chemistry, Analytical SC Chemistry GA DO2ST UT WOS:000377631000018 PM 27183317 ER PT J AU Fujii, R Friedman, ER Richards, J Tsang, KY Heery, CR Schlom, J Hodge, JW AF Fujii, Rika Friedman, Eitan R. Richards, Jacob Tsang, Kwong Y. Heery, Christopher R. Schlom, Jeffrey Hodge, James W. TI Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab SO ONCOTARGET LA English DT Article DE chordoma; programmed death-ligand 1 (PD-L1); antibody-dependent cell-mediated cytotoxicity (ADCC); cancer stem cells; immunotherapy ID TRANSCRIPTION FACTOR BRACHYURY; CANCER STEM-CELLS; EPITHELIAL-MESENCHYMAL TRANSITION; DEATH-LIGAND 1; PROGRAMMED DEATH-1; BREAST-CANCER; TUMOR-CELLS; PD-L1 EXPRESSION; NK CELLS; PHASE-I AB Chordoma, a rare bone tumor derived from the notochord, has been shown to be resistant to conventional therapies. Checkpoint inhibition has shown great promise in immune-mediated therapy of diverse cancers. The anti-PD-L1 mAb avelumab is unique among checkpoint inhibitors in that it is a fully human IgG1 capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC) of PD-L1-expressing tumor cells. Here, we investigated avelumab as a potential therapy for chordoma. We examined 4 chordoma cell lines, first for expression of PD-L1, and in vitro for ADCC killing using NK cells and avelumab. PD-L1 expression was markedly upregulated by IFN-gamma in all 4 chordoma cell lines, which significantly increased sensitivity to ADCC. Brachyury is a transcription factor that is uniformly expressed in chordoma. Clinical trials are ongoing in which chordoma patients are treated with brachyury-specific vaccines. Co-incubating chordoma cells with brachyury-specific CD8(+) T cells resulted in significant upregulation of PD-L1 on the tumor cells, mediated by the CD8(+) T cells' IFN-gamma production, and increased sensitivity of chordoma cells to avelumab-mediated ADCC. Residential cancer stem cell subpopulations of chordoma cells were also killed by avelumab-mediated ADCC to the same degree as non-cancer stem cell populations. These findings suggest that as a monotherapy for chordoma, avelumab may enable endogenous NK cells, while in combination with T-cell immunotherapy, such as a vaccine, avelumab may enhance NK-cell killing of chordoma cells via ADCC. C1 [Fujii, Rika; Friedman, Eitan R.; Richards, Jacob; Tsang, Kwong Y.; Heery, Christopher R.; Schlom, Jeffrey; Hodge, James W.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hodge, JW (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM jh241d@nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 FU Intramural Research Program of the Center for Cancer Research; National Cancer Institute; National Institutes of Health; Emd Sereno; NCI 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 aggrement (CRADA) betwwen Emd Sereno and the NCI. NR 55 TC 3 Z9 3 U1 5 U2 8 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 7 PY 2016 VL 7 IS 23 BP 33498 EP 33511 DI 10.18632/oncotarget.9256 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4KS UT WOS:000377752100002 PM 27172898 ER PT J AU Lefebvre, JS Lorenzo, EC Masters, AR Hopkins, JW Eaton, SM Smiley, ST Haynes, L AF Lefebvre, Julie S. Lorenzo, Erica C. Masters, April R. Hopkins, Jacob W. Eaton, Sheri M. Smiley, Stephen T. Haynes, Laura TI Vaccine efficacy and T helper cell differentiation change with aging SO ONCOTARGET LA English DT Article DE aging; influenza; Th subsets; influenza vaccination; antibody; Gerotarget ID INFLUENZA-VIRUS INFECTION; PLATELET-ACTIVATING-FACTOR; AGED MICE; STREPTOCOCCUS-PNEUMONIAE; SEASONAL INFLUENZA; IMMUNE-RESPONSES; LETHAL INFLUENZA; INNATE IMMUNITY; PROTECTION; DEFECTS AB Influenza and pneumonia are leading causes of death in elderly populations. With age, there is an increased inflammatory response and slower viral clearance during influenza infection which increases the risk of extended illness and mortality. Here we employ a preclinical murine model of influenza infection to examine the protective capacity of vaccination with influenza nucleoprotein (NP). While NP vaccination reduces influenza-induced lung inflammation in young mice, aged mice do not show this reduction, but are protected from influenza-induced mortality. Aged mice do make a significant amount of NP-specific IgG and adoptive transfer experiments show that NP antibody can protect from death but cannot reduce lung inflammation. Furthermore, young but not aged vaccinated mice generate significant numbers of NP-specific T cells following subsequent infection and few of these T cells are found in aged lungs early during infection. Importantly, aged CD4 T cells have a propensity to differentiate towards a T follicular helper (Tfh) phenotype rather than a T helper 1 (Th1) phenotype that predominates in the young. Since Th1 cells are important in viral clearance, reduced Th1 differentiation in the aged is critical and could account for some or all of the age-related differences in vaccine responses and infection resolution. C1 [Lefebvre, Julie S.; Eaton, Sheri M.; Smiley, Stephen T.] Trudeau Inst, Saranac Lake, NY USA. [Lorenzo, Erica C.; Masters, April R.; Hopkins, Jacob W.; Haynes, Laura] Univ Connecticut, Ctr Hlth, Dept Immunol, Farmington, CT USA. [Lorenzo, Erica C.; Masters, April R.; Hopkins, Jacob W.; Haynes, Laura] Univ Connecticut, Ctr Hlth, Ctr Aging, Farmington, CT USA. [Lefebvre, Julie S.] CHU Laval, Ctr Rech, Inst Univ Cardiol & Pneumol Quebec, Dept Pneumol, 2705 Blvd Laurier, Quebec City, PQ G1V 4G2, Canada. [Smiley, Stephen T.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Haynes, L (reprint author), Univ Connecticut, Ctr Hlth, Dept Immunol, Farmington, CT USA.; Haynes, L (reprint author), Univ Connecticut, Ctr Hlth, Ctr Aging, Farmington, CT USA. EM lhaynes@uchc.edu FU NIH/NIA grant [AG02160]; Trudeau Institute; UConn Center on Aging; Fonds de recherche du Quebec-Sante/Reseau quebecois de recherche sur le vieillissement/NIA FX This study was supported by NIH/NIA grant AG02160 to L.H. and funding from the Trudeau Institute and the UConn Center on Aging. J.S.L. is the recipient of a postdoctoral fellowship awarded jointly by the Fonds de recherche du Quebec-Sante/Reseau quebecois de recherche sur le vieillissement/NIA. NR 50 TC 0 Z9 0 U1 3 U2 4 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 7 PY 2016 VL 7 IS 23 BP 33581 EP 33594 DI 10.18632/oncotarget.9254 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4KS UT WOS:000377752100008 PM 27177221 ER PT J AU Park, J Kim, WG Zhao, L Enomoto, K Willingham, M Cheng, SY AF Park, Jeongwon Kim, Won Gu Zhao, Li Enomoto, Keisuke Willingham, Mark Cheng, Sheue-Yann TI Metformin blocks progression of obesity-activated thyroid cancer in a mouse model SO ONCOTARGET LA English DT Article DE thyroid carcinogenesis; obesity; metformin; mouse models ID HIGH-FAT DIET; INHIBITS GROWTH; DIABETIC-PATIENTS; BREAST-CANCER; CARCINOMA; MICE; RISK; RAPAMYCIN; KINASE; CELLS AB Compelling epidemiologic evidence indicates that obesity is associated with a high risk of human malignancies, including thyroid cancer. We previously demonstrated that a high fat diet (HFD) effectively induces the obese phenotype in a mouse model of aggressive follicular thyroid cancer (Thrb(PV/PV)Pten(+/-)mice). We showed that HFD promotes cancer progression through aberrant activation of the leptin-JAK2-STAT3 signaling pathway. HFD-promoted thyroid cancer progression allowed us to test other molecular targets for therapeutic opportunity for obesity-induced thyroid cancer. Metformin is a widely used drug to treat patients with type II diabetes. It has been shown to reduce incidences of neoplastic diseases and cancer mortality in type II diabetes patients. The present study aimed to test whether metformin could be a therapeutic for obesity-activated thyroid cancer. Thrb(PV/PV)Pten(+/-)mice were fed HFD together with metformin or vehicle-only, as controls, for 20 weeks. While HFD-Thrb(PV/PV)Pten(+/-)mice had shorter survival than LFD-treated mice, metformin had no effects on the survival of HFD-Thrb(PV/PV)Pten(+/-)mice. Remarkably, metformin markedly decreased occurrence of capsular invasion and completely blocked vascular invasion and anaplasia in HFD-ThrbPV/PVPten(+/-)mice without affecting thyroid tumor growth. The impeded cancer progression was due to the inhibitory effect of metformin on STAT3-ERK-vimentin and fibronectin-integrin signaling to decrease tumor cell invasion and de-differentiation. The present studies provide additional molecular evidence to support the link between obesity and thyroid cancer risk. Importantly, our findings suggest that metformin could be used as an adjuvant in combination with antiproliferative modalities to improve the outcome of patients with obesity-activated thyroid cancer. C1 [Park, Jeongwon; Kim, Won Gu; Zhao, Li; Enomoto, Keisuke; Willingham, Mark; Cheng, Sheue-Yann] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Kim, Won Gu] Univ Ulsan, Coll Med, Dept Internal Med, Div Endocrinol,Asan Med Ctr, Seoul 138736, South Korea. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov OI Kim, Won Gu/0000-0002-8404-7759 FU Intramural Research Program at the Center for Cancer Research; National Cancer Institute,; National Institutes of Health FX The present research was supported by the Intramural Research Program at the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 55 TC 0 Z9 0 U1 3 U2 8 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 7 PY 2016 VL 7 IS 23 BP 34832 EP 34844 DI 10.18632/oncotarget.8989 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4KS UT WOS:000377752100096 PM 27145454 ER PT J AU Vassilev, A Lee, CY Vassilev, B Zhu, WG Ormanoglu, P Martin, SE DePamphilis, ML AF Vassilev, Alex Lee, Chrissie Y. Vassilev, Boris Zhu, Wenge Ormanoglu, Pinar Martin, Scott E. DePamphilis, Melvin L. TI Identification of genes that are essential to restrict genome duplication to once per cell division SO ONCOTARGET LA English DT Article DE DNA re-replication; endoreplication; cell cycle regulation; aneuploidy; polyploidy ID DNA-DAMAGE RESPONSE; SPINDLE ASSEMBLY CHECKPOINT; EARLY EMBRYONIC-DEVELOPMENT; SCALE RNAI SCREENS; CYCLE PROGRESSION; CANCER-CELLS; CHROMOSOMAL INSTABILITY; TUMOR SUPPRESSION; MAMMALIAN-CELLS; RE-REPLICATION AB Nuclear genome duplication is normally restricted to once per cell division, but aberrant events that allow excess DNA replication (EDR) promote genomic instability and aneuploidy, both of which are characteristics of cancer development. Here we provide the first comprehensive identification of genes that are essential to restrict genome duplication to once per cell division. An siRNA library of 21,584 human genes was screened for those that prevent EDR in cancer cells with undetectable chromosomal instability. Candidates were validated by testing multiple siRNAs and chemical inhibitors on both TP53+ and TP53-cells to reveal the relevance of this ubiquitous tumor suppressor to preventing EDR, and in the presence of an apoptosis inhibitor to reveal the full extent of EDR. The results revealed 42 genes that prevented either DNA re-replication or unscheduled endoreplication. All of them participate in one or more of eight cell cycle events. Seventeen of them have not been identified previously in this capacity. Remarkably, 14 of the 42 genes have been shown to prevent aneuploidy in mice. Moreover, suppressing a gene that prevents EDR increased the ability of the chemotherapeutic drug Paclitaxel to induce EDR, suggesting new opportunities for synthetic lethalities in the treatment of human cancers. C1 [Vassilev, Alex; Lee, Chrissie Y.; Vassilev, Boris; DePamphilis, Melvin L.] NICHHD, NIH, Bethesda, MD 20892 USA. [Lee, Chrissie Y.] NantBioscience, Culver City, CA 90232 USA. [Zhu, Wenge] George Washington Univ, Dept Biochem & Mol Biol, Washington, DC 20037 USA. [Ormanoglu, Pinar; Martin, Scott E.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Martin, Scott E.] Genentech Inc, San Francisco, CA 94080 USA. RP DePamphilis, ML (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. EM depamphm@mail.nih.gov FU National Institutes of Health (NIH) Roadmap for Medical Research; NIH Molecular Libraries Program; intramural research programs of the National Human Genome Research Institute; National Institute of Child Health and Human Development; NIH grants [CA177898, CA184717] FX This work was supported by the National Institutes of Health (NIH) Roadmap for Medical Research, the NIH Molecular Libraries Program, the intramural research programs of the National Human Genome Research Institute and the National Institute of Child Health and Human Development, a Director's Challenge grant awarded to M.L.D, and NIH grants CA177898 and CA184717 awarded to W.Z. NR 84 TC 2 Z9 2 U1 1 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUN 7 PY 2016 VL 7 IS 23 BP 34956 EP 34976 DI 10.18632/oncotarget.9008 PG 21 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4KS UT WOS:000377752100105 PM 27144335 ER PT J AU Kang, HS Takeda, Y Jeon, K Jetten, AM AF Kang, Hong Soon Takeda, Yukimasa Jeon, Kilsoo Jetten, Anton M. TI The Spatiotemporal Pattern of Glis3 Expression Indicates a Regulatory Function in Bipotent and Endocrine Progenitors during Early Pancreatic Development and in Beta, PP and Ductal Cells SO PLOS ONE LA English DT Article ID POLYCYSTIC KIDNEY-DISEASE; NEONATAL DIABETES-MELLITUS; ZINC-FINGER PROTEINS; PHYSIOLOGICAL FUNCTIONS; LINEAGE DETERMINANTS; ADULT PANCREAS; NEUROGENIN 3; TRANSCRIPTION; GENE; LOCI AB The transcription factor Glis-similar 3 (Glis3) has been implicated in the development of neonatal, type 1 and type 2 diabetes. In this study, we examined the spatiotemporal expression of Glis3 protein during embryonic and neonatal pancreas development as well as its function in PP cells. To obtain greater insights into the functions of Glis3 in pancreas development, we examined the spatiotemporal expression of Glis3 protein in a knockin mouse strain expressing a Glis3-EGFP fusion protein. Immunohistochemistry showed that Glis3-EGFP was not detectable during early pancreatic development (E11.5 and E12.5) and at E13.5 and 15.5 was not expressed in Ptf1a(+) cells in the tip domains indicating that Glis3 is not expressed in multipotent pancreatic progenitors. Glis3 was first detectable at E13.5 in the nucleus of bipotent progenitors in the trunk domains, where it co-localized with Sox9, Hnf6, and Pdx1. It remained expressed in preductal and Ngn3(+) endocrine progenitors and at later stages becomes restricted to the nucleus of pancreatic beta and PP cells as well as ductal cells. Glis3-deficiency greatly reduced, whereas exogenous Glis3, induced Ppy expression, as reported for insulin. Collectively, our study demonstrates that Glis3 protein exhibits a temporal and cell type-specific pattern of expression during embryonic and neonatal pancreas development that is consistent with a regulatory role for Glis3 in promoting endocrine progenitor generation, regulating insulin and Ppy expression in beta and PP cells, respectively, and duct morphogenesis. C1 [Kang, Hong Soon; Takeda, Yukimasa; Jeon, Kilsoo; Jetten, Anton M.] NIEHS, Cell Biol Grp, Immun Inflammat & Dis Lab, Div Intramural Res,NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Jetten, AM (reprint author), NIEHS, Cell Biol Grp, Immun Inflammat & Dis Lab, Div Intramural Res,NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM jetten@niehs.nih.gov OI Jetten, Anton/0000-0003-0954-4445 FU National Institute of Environmental Health Sciences, National Institutes of Health [Z01-ES-100485]; Intramural Research Program of the National Institute of Environmental Health Sciences, the National Institutes of Health [Z01-ES-100485] FX Funded by National Institute of Environmental Health Sciences, National Institutes of Health Z01-ES-100485.; This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, the National Institutes of Health [Z01-ES-100485]. The authors thank Laura Miller DeGraff for her excellent assistance with managing the mouse colonies. NR 46 TC 4 Z9 4 U1 1 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 7 PY 2016 VL 11 IS 6 AR e0157138 DI 10.1371/journal.pone.0157138 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO1TC UT WOS:000377561000067 PM 27270601 ER PT J AU Botos, I Majdalani, N Mayclin, SJ McCarthy, JG Lundquist, K Wojtowicz, D Barnard, TJ Gumbart, JC Buchanan, SK AF Botos, Istvan Majdalani, Nadim Mayclin, Stephen J. McCarthy, Jennifer Gehret Lundquist, Karl Wojtowicz, Damian Barnard, Travis J. Gumbart, James C. Buchanan, Susan K. TI Structural and Functional Characterization of the LPS Transporter LptDE from Gram-Negative Pathogens SO STRUCTURE LA English DT Article ID TRANSENVELOPE PROTEIN COMPLEX; OUTER-MEMBRANE BIOGENESIS; ESCHERICHIA-COLI; LIPOPOLYSACCHARIDE TRANSPORT; PSEUDOMONAS-AERUGINOSA; BETA-BARREL; PEPTIDOMIMETIC ANTIBIOTICS; CRYSTAL-STRUCTURE; BAM COMPLEX; EXPORT AB Incorporation of lipopolysaccharide (LPS) into the outer membrane of Gram-negative bacteria is essential for viability, and is accomplished by a two-protein complex called LptDE. We solved crystal structures of the core LptDE complexes from Yersinia pestis, Klebsiella pneumoniae, Pseudomonas aeruginosa, and a full-length structure of the K. pneumoniae LptDE complex. Our structures adopt the same plug and 26-strand beta-barrel architecture found recently for the Shigella flexneri and Salmonella typhimurium LptDE structures, illustrating a conserved fold across the family. A comparison of the only two full-length structures, SfLptDE and our KpLptDE, reveals a 21 degrees rotation of the LptD N-terminal domain that may impart flexibility on the trans-envelope LptCAD scaffold. Utilizingmutagenesis coupled to an in vivo functional assay and molecular dynamics simulations, we demonstrate the critical role of Pro231 and Pro246 in the function of the LptD lateral gate that allows partitioning of LPS into the outer membrane. C1 [Botos, Istvan; Mayclin, Stephen J.; McCarthy, Jennifer Gehret; Barnard, Travis J.; Buchanan, Susan K.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Majdalani, Nadim] NCI, Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. [Lundquist, Karl; Gumbart, James C.] Georgia Inst Technol, Sch Phys, Atlanta, GA 30332 USA. [Wojtowicz, Damian] NIH, Natl Ctr Biotechnol Informat, Bldg 10, Bethesda, MD 20892 USA. RP Buchanan, SK (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM skbuchan@helix.nih.gov FU Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute; National Center for Biotechnology Information; National Science Foundation [MCB-1452464]; NSF [OCI-1053575]; US Department of Energy, Office of Science, Office of Basic Energy Sciences FX This work was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (S.J.M., J.G.M., I.B., T.J.B., and S.K.B.), National Cancer Institute (N.M.), and National Center for Biotechnology Information (D.W.). J.C.G. is supported by a National Science Foundation CAREER award (MCB-1452464). Computational resources were provided through the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by NSF grant number OCI-1053575. We thank the staff at GM/CA and SER-CAT beam lines at the Advanced Photon Source, Argonne National Laboratory, for their assistance during data collection. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences. NR 61 TC 2 Z9 2 U1 8 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD JUN 7 PY 2016 VL 24 IS 6 BP 965 EP 976 DI 10.1016/j.str.2016.03.026 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DO4VE UT WOS:000377782200017 PM 27161977 ER PT J AU Cartagena-Rivera, AX Logue, JS Waterman, CM Chadwick, RS AF Cartagena-Rivera, Alexander X. Logue, Jeremy S. Waterman, Clare M. Chadwick, Richard S. TI Actomyosin Cortical Mechanical Properties in Nonadherent Cells Determined by Atomic Force Microscopy SO BIOPHYSICAL JOURNAL LA English DT Article ID LIVE CELLS; ACTIN NETWORKS; SURFACE; MYOSIN; MORPHOGENESIS; FIBROBLASTS; PRESSURE; TENSION; CORTEX; MODEL AB The organization of filamentous actin and myosin II molecular motor contractility is known to modify the mechanical properties of the cell cortical actomyosin cytoskeleton. Here we describe a novel method, to our knowledge, for using force spectroscopy approach curves with tipless cantilevers to determine the actomyosin cortical tension, elastic modulus, and intracellular pressure of nonadherent cells. We validated the method by measuring the surface tension of water in oil microdrops deposited on a glass surface. We extracted an average tension of T similar to 20.25 nN/mu m, which agrees with macroscopic experimental methods. We then measured cortical mechanical properties in nonadherent human foreskin fibroblasts and THP-1 human monocytes before and after pharmacological perturbations of actomyosin activity. Our results show that myosin II activity and actin polymerization increase cortex tension and intracellular pressure, whereas branched actin networks decreased them. Interestingly, myosin II activity stiffens the cortex and branched actin networks soften it, but actin polymerization has no effect on cortex stiffness. Our method is capable of detecting changes in cell mechanical properties in response to perturbations of the cytoskeleton, allowing characterization with physically relevant parameters. Altogether, this simple method should be of broad application for deciphering the molecular regulation of cell cortical mechanical properties. C1 [Cartagena-Rivera, Alexander X.; Logue, Jeremy S.; Chadwick, Richard S.] Natl Inst Deafness & Other Commun Disorders, Lab Cellular Biol, Sect Auditory Mech, NIH, Bethesda, MD USA. [Logue, Jeremy S.; Waterman, Clare M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Chadwick, RS (reprint author), Natl Inst Deafness & Other Commun Disorders, Lab Cellular Biol, Sect Auditory Mech, NIH, Bethesda, MD USA. EM chadwick@helix.nih.gov FU Intramural Programs of the US National Institute of Deafness and Other Communication Disorders; National Heart, Lung, and Blood Institute FX We are grateful for the support of this work by the Intramural Programs of the US National Institute of Deafness and Other Communication Disorders and National Heart, Lung, and Blood Institute. NR 63 TC 3 Z9 3 U1 5 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD JUN 7 PY 2016 VL 110 IS 11 BP 2528 EP 2539 DI 10.1016/j.bpj.2016.04.034 PG 12 WC Biophysics SC Biophysics GA DN7VO UT WOS:000377288500027 PM 27276270 ER PT J AU Dabin, J Mencarelli, A McMillan, D Romanyukha, A Struelens, L Lee, C AF Dabin, Jeremie Mencarelli, Alessandra McMillan, Dayton Romanyukha, Anna Struelens, Lara Lee, Choonsik TI Validation of calculation algorithms for organ doses in CT by measurements on a 5 year old paediatric phantom SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE CT; organ dose; anthropomorphic phantom; Monte Carlo simulation AB Many organ dose calculation tools for computed tomography (CT) scans rely on the assumptions: (1) organ doses estimated for one CT scanner can be converted into organ doses for another CT scanner using the ratio of the Computed Tomography Dose Index (CTDI) between two CT scanners; and (2) helical scans can be approximated as the summation of axial slices covering the same scan range. The current study aims to validate experimentally these two assumptions. We performed organ dose measurements in a 5 year-old physical anthropomorphic phantom for five different CT scanners from four manufacturers. Absorbed doses to 22 organs were measured using thermoluminescent dosimeters for head-to-torso scans. We then compared the measured organ doses with the values calculated from the National Cancer Institute dosimetry system for CT (NCICT) computer program, developed at the National Cancer Institute. Whereas the measured organ doses showed significant variability (coefficient of variation (CoV) up to 53% at 80 kV) across different scanner models, the CoV of organ doses normalised to CTDIvol substantially decreased (12% CoV on average at 80 kV). For most organs, the difference between measured and simulated organ doses was within +/- 20% except for the bone marrow, breasts and ovaries. The discrepancies were further explained by additional Monte Carlo calculations of organ doses using a voxel phantom developed from CT images of the physical phantom. The results demonstrate that organ doses calculated for one CT scanner can be used to assess organ doses from other CT scanners with 20% uncertainty (k = 1), for the scan settings considered in the study. C1 [Dabin, Jeremie; Mencarelli, Alessandra; Struelens, Lara] Belgian Nucl Res Ctr, Dept Radiat Protect Dosimetry & Calibrat, B-2400 Mol, Belgium. [McMillan, Dayton; Romanyukha, Anna; Lee, Choonsik] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. RP Dabin, J (reprint author), Belgian Nucl Res Ctr, Dept Radiat Protect Dosimetry & Calibrat, B-2400 Mol, Belgium. EM jdabin@sckcen.be FU European Community's Seventh Framework Programme (FP7) [269912] FX These measurements were performed within the framework of the EPI-CT study, supported by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 269912. The authors are thankful to the medical staff for its help during the measurements. NR 16 TC 0 Z9 0 U1 3 U2 6 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUN 7 PY 2016 VL 61 IS 11 BP 4168 EP 4182 DI 10.1088/0031-9155/61/11/4168 PG 15 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA DN9VB UT WOS:000377427700018 PM 27192093 ER PT J AU Reuben, A Tillman, H Fontana, RJ Davern, T McGuire, B Stravitz, RT Durkalski, V Larson, AM Liou, I Fix, O Schilsky, M McCashland, T Hay, JE Murray, N Shaikh, OS Ganger, D Zaman, A Han, SB Chung, RT Smith, A Brown, R Crippin, J Harrison, ME Koch, D Munoz, S Reddy, KR Rossaro, L Satyanarayana, R Hassanein, T Hanje, AJ Olson, J Subramanian, R Karvellas, C Hameed, B Sherker, AH Robuck, P Lee, WM AF Reuben, Adrian Tillman, Holly Fontana, Robert J. Davern, Timothy McGuire, Brendan Stravitz, R. Todd Durkalski, Valerie Larson, Anne M. Liou, Iris Fix, Oren Schilsky, Michael McCashland, Timothy Hay, J. Eileen Murray, Natalie Shaikh, Obaid S. Ganger, Daniel Zaman, Atif Han, Steven B. Chung, Raymond T. Smith, Alastair Brown, Robert Crippin, Jeffrey Harrison, M. Edwyn Koch, David Munoz, Santiago Reddy, K. Rajender Rossaro, Lorenzo Satyanarayana, Raj Hassanein, Tarek Hanje, A. James Olson, Jody Subramanian, Ram Karvellas, Constantine Hameed, Bilal Sherker, Averell H. Robuck, Patricia Lee, William M. TI Outcomes in Adults With Acute Liver Failure Between 1998 and 2013 An Observational Cohort Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID RETROSPECTIVE COHORT; INTENSIVE-CARE; CLINICAL-TRIAL; UNITED-STATES; ENCEPHALOPATHY; COMPLICATIONS; MULTICENTER AB Background: Acute liver failure (ALF) is a rare syndrome of severe, rapid-onset hepatic dysfunction-without prior advanced liver disease-that is associated with high morbidity and mortality. Intensive care and liver transplantation provide support and rescue, respectively. Objective: To determine whether changes in causes, disease severity, treatment, or 21-day outcomes have occurred in recent years among adult patients with ALF referred to U.S. tertiary care centers. Design: Prospective observational cohort study. (ClinicalTrials.gov: NCT00518440) Setting: 31 liver disease and transplant centers in the United States. Patients: Consecutively enrolled patients-without prior advanced liver disease-with ALF (n = 2070). Measurements: Clinical features, treatment, and 21-day outcomes were compared over time annually for trends and were also stratified into two 8-year periods (1998 to 2005 and 2006 to 2013). Results: Overall clinical characteristics, disease severity, and distribution of causes remained similar throughout the study period. The 21-day survival rates increased between the two 8-year periods (overall, 67.1% vs. 75.3%; transplant-free survival [TFS], 45.1% vs. 56.2%; posttransplantation survival, 88.3% vs. 96.3% [P < 0.010 for each]). Reductions in red blood cell infusions (44.3% vs. 27.6%), plasma infusions (65.2% vs. 47.1%), mechanical ventilation (65.7% vs. 56.1%), and vasopressors (34.9% vs. 27.8%) were observed, as well as increased use of N-acetylcysteine (48.9% vs. 69.3% overall; 15.8% vs. 49.4% [P < 0.001] in patients with ALF not due to acetaminophen toxicity). When examined longitudinally, overall survival and TFS increased throughout the 16-year period. Limitations: The duration of enrollment, the number of patients enrolled, and possibly the approaches to care varied among participating sites. The results may not be generalizable beyond such specialized centers. Conclusion: Although characteristics and severity of ALF changed little over 16 years, overall survival and TFS improved significantly. The effects of specific changes in intensive care practice on survival warrant further study. C1 [Lee, William M.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Baylor Univ, Med Ctr, Dallas, TX USA. Med Univ S Carolina, Charleston, SC 29425 USA. Univ Washington, Seattle, WA 98195 USA. Washington Univ, St Louis, MO USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Calif Pacific Med Ctr, San Francisco, CA USA. Univ Nebraska, Omaha, NE 68182 USA. Mt Sinai Med Ctr, New York, NY 10029 USA. Columbia Univ, Med Ctr, New York, NY USA. Mayo Clin, Rochester, MN USA. Univ Pittsburgh, Pittsburgh, PA USA. Northwestern Univ, Chicago, IL 60611 USA. Oregon Hlth & Sci Univ, Portland, OR USA. Univ Calif Los Angeles, Los Angeles, CA USA. Univ Michigan, Ann Arbor, MI 48109 USA. Yale Univ, New Haven, CT USA. Univ Alabama Birmingham, Birmingham, AL USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Duke Univ, Durham, NC USA. Mayo Clin, Scottsdale, AZ USA. Albert Einstein Med Ctr, Philadelphia, PA 19141 USA. Univ Penn, Philadelphia, PA 19104 USA. Virginia Commonwealth Univ, Richmond, VA USA. Univ Calif Davis, Davis, CA 95616 USA. Mayo Clin, Jacksonville, FL 32224 USA. Univ Calif San Diego, San Diego, CA 92103 USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. Emory Univ, Atlanta, GA 30322 USA. Univ Alberta, Edmonton, AB, Canada. NIDDK, Bethesda, MD 20892 USA. RP Lee, WM (reprint author), Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. EM william.lee@utsouthwestern.edu OI Karvellas, Constantine/0000-0002-1555-1089 FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [DK-U-01-58369] FX By the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (DK-U-01-58369). NR 19 TC 6 Z9 6 U1 1 U2 6 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 7 PY 2016 VL 164 IS 11 BP 724 EP + DI 10.7326/M15-2211 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DO1AI UT WOS:000377510100004 PM 27043883 ER PT J AU Ulrich, CM Grady, C AF Ulrich, Connie M. Grady, Christine TI Nurses and Industry: Conflict or Collaboration? SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID EDUCATION C1 [Ulrich, Connie M.] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [Ulrich, Connie M.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Grady, Christine] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Grady, Christine] NIH, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. RP Ulrich, CM (reprint author), Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA.; Ulrich, CM (reprint author), Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. EM culrich@nursing.upenn.edu NR 8 TC 0 Z9 0 U1 2 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 7 PY 2016 VL 164 IS 11 BP 773 EP + DI 10.7326/M16-0707 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DO1AI UT WOS:000377510100010 PM 27042939 ER PT J AU Santhanakrishnan, R Wang, N Larson, MG Magnani, JW McManus, DD Lubitz, SA Ellinor, PT Cheng, S Vasan, RS Lee, DS Wang, TJ Levy, D Benjamin, EJ Ho, JE AF Santhanakrishnan, Rajalakshmi Wang, Na Larson, Martin G. Magnani, Jared W. McManus, David D. Lubitz, Steven A. Ellinor, Patrick T. Cheng, Susan Vasan, Ramachandran S. Lee, Douglas S. Wang, Thomas J. Levy, Daniel Benjamin, Emelia J. Ho, Jennifer E. TI Response to Letter Regarding Article, "Atrial Fibrillation Begets Heart Failure and Vice Versa: Temporal Associations and Differences in Preserved Versus Reduced Ejection Fraction" SO CIRCULATION LA English DT Letter ID COMMUNITY C1 [Santhanakrishnan, Rajalakshmi; Magnani, Jared W.] Boston Univ, Sch Med, Dept Med, Cardiovasc Med Sect, Boston, MA 02118 USA. [Wang, Na] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [McManus, David D.] Univ Massachusetts, Sch Med, Dept Med, Div Cardiol, Boston, MA 02125 USA. [Lubitz, Steven A.; Ellinor, Patrick T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02115 USA. [Cheng, Susan; Levy, Daniel] NHLBI, Framingham, MA USA. [Cheng, Susan; Levy, Daniel] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med & Epidemiol, Boston, MA 02118 USA. [Lee, Douglas S.] Univ Toronto, Inst Clin Evaluat Sci, Toronto, ON M5S 1A1, Canada. [Lee, Douglas S.] Univ Toronto, Toronto Gen Hosp, Toronto, ON M5S 1A1, Canada. [Wang, Thomas J.] Vanderbilt Univ, Dept Med, Div Cardiovasc Med, 221 Kirkland Hall, Nashville, TN 37235 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Ho, Jennifer E.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. RP Santhanakrishnan, R (reprint author), Boston Univ, Sch Med, Dept Med, Cardiovasc Med Sect, Boston, MA 02118 USA. OI Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [K23 HL116780] NR 4 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JUN 7 PY 2016 VL 133 IS 23 BP E692 EP E693 DI 10.1161/CIRCULATIONAHA.116.022835 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DN9ZT UT WOS:000377439900003 PM 27267541 ER PT J AU Katki, HA Kovalchik, SA Berg, CD Cheung, LC Chaturvedi, AK AF Katki, Hormuzd A. Kovalchik, Stephanie A. Berg, Christine D. Cheung, Li C. Chaturvedi, Anil K. TI Development and Validation of Risk Models to Select Ever-Smokers for CT Lung Cancer Screening SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID SERVICES TASK-FORCE; COMPUTED-TOMOGRAPHY; TRIAL; PREDICTION; PROSTATE; GUIDELINES; MANAGEMENT; MORTALITY; BENEFITS; OUTCOMES AB IMPORTANCE The US Preventive Services Task Force (USPSTF) recommends computed tomography (CT) lung cancer screening for ever-smokers aged 55 to 80 years who have smoked at least 30 pack-years with no more than 15 years since quitting. However, selecting ever-smokers for screening using individualized lung cancer risk calculations may be more effective and efficient than current USPSTF recommendations. OBJECTIVE Comparison of modeled outcomes from risk-based CT lung-screening strategies vs USPSTF recommendations. DESIGN, SETTING, AND PARTICIPANTS Empirical risk models for lung cancer incidence and death in the absence of CT screening using data on ever-smokers from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO; 1993-2009) control group. Covariates included age; education; sex; race; smoking intensity, duration, and quit-years; body mass index; family history of lung cancer; and self-reported emphysema. Model validation in the chest radiography groups of the PLCO and the National Lung Screening Trial (NLST; 2002-2009), with additional validation of the death model in the National Health Interview Survey (NHIS; 1997-2001), a representative sample of the United States. Models were applied to US ever-smokers aged 50 to 80 years (NHIS 2010-2012) to estimate outcomes of risk-based selection for CT lung screening, assuming screening for all ever-smokers, yield the percent changes in lung cancer detection and death observed in the NLST. EXPOSURES Annual CT lung screening for 3 years beginning at age 50 years. MAIN OUTCOMES AND MEASURES For model validity: calibration (number of model-predicted cases divided by number of observed cases [estimated/observed]) and discrimination (area under curve [AUC]). For modeled screening outcomes: estimated number of screen-avertable lung cancer deaths and estimated screening effectiveness (number needed to screen [NNS] to prevent 1 lung cancer death). RESULTS Lung cancer incidence and death risk models were well calibrated in PLCO and NLST. The lung cancer death model calibrated and discriminated well for US ever-smokers aged 50 to 80 years (NHIS 1997-2001: estimated/observed = 0.94 [95% CI, 0.84-1.05]; AUC, 0.78 [95% CI, 0.76-0.80]). Under USPSTF recommendations, the models estimated 9.0 million US ever-smokers would qualify for lung cancer screening and 46 488 (95% CI, 43 924-49 053) lung cancer deaths were estimated as screen-avertable over 5 years (estimated NNS, 194 [95% CI, 187-201]). In contrast, risk-based selection screening of the same number of ever-smokers (9.0 million) at highest 5-year lung cancer risk (>= 1.9%) was estimated to avert 20% more deaths (55 717 [95% CI, 53 033-58 400]) and was estimated to reduce the estimated NNS by 17%(NNS, 162 [95% CI, 157-166]). CONCLUSIONS AND RELEVANCE Among a cohort of US ever-smokers aged 50 to 80 years, application of a risk-based model for CT screening for lung cancer compared with a model based on USPSTF recommendations was estimated to be associated with a greater number of lung cancer deaths prevented over 5 years, along with a lower NNS to prevent 1 lung cancer death. C1 [Katki, Hormuzd A.; Berg, Christine D.; Chaturvedi, Anil K.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, 9609 Med Ctr Dr,Room 7E606, Bethesda, MD 20892 USA. [Kovalchik, Stephanie A.] Victoria Univ, Inst Sport Exercise & Act Living, Melbourne, Vic 8001, Australia. [Berg, Christine D.] Johns Hopkins Med, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD USA. [Cheung, Li C.] Informat Management Serv Inc, Calverton, MD USA. RP Katki, HA (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 7E606, Bethesda, MD 20892 USA.; Chaturvedi, AK (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E238, Bethesda, MD 20892 USA. EM katkih@mail.nih.gov; chaturva@mail.nih.gov OI Cheung, Li/0000-0003-1625-4331 FU Intramural Research Program of the US National Institutes of Health (NIH)/National Cancer Institute FX This study was supported by the Intramural Research Program of the US National Institutes of Health (NIH)/National Cancer Institute. NR 40 TC 8 Z9 9 U1 2 U2 5 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 7 PY 2016 VL 315 IS 21 BP 2300 EP 2311 DI 10.1001/jama.2016.6255 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DN6KO UT WOS:000377183100019 PM 27179989 ER PT J AU Gilroy, DW Edin, ML De Maeyer, RPH Bystrom, J Newson, J Lih, FB Stables, M Zeldin, DC Bishop-Bailey, D AF Gilroy, Derek W. Edin, Matthew L. De Maeyer, Roel P. H. Bystrom, Jonas Newson, Justine Lih, Fred B. Stables, Melanie Zeldin, Darryl C. Bishop-Bailey, David TI CYP450-derived oxylipins mediate inflammatory resolution SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE oxylipins; resolution; monocyte; phagocytosis; epoxygenase ID SOLUBLE EPOXIDE HYDROLASE; ISCHEMIA-REPERFUSION INJURY; ARACHIDONIC-ACID; IN-VIVO; EPOXYEICOSATRIENOIC ACIDS; ATHEROSCLEROTIC PLAQUES; ENDOTHELIAL EXPRESSION; VASCULAR INFLAMMATION; BLOOD-PRESSURE; FATTY-ACIDS AB Resolution of inflammation has emerged as an active process in immunobiology, with cells of the mononuclear phagocyte system being critical in mediating efferocytosis and wound debridement and bridging the gap between innate and adaptive immunity. Here we investigated the roles of cytochrome P450 (CYP)-derived epoxy-oxylipins in a well-characterized model of sterile resolving peritonitis in the mouse. Epoxy-oxylipins were produced in a biphasic manner during the peaks of acute (4 h) and resolution phases (24-48 h) of the response. The epoxygenase inhibitor SKF525A (epoxI) given at 24 h selectively inhibited arachidonic acid-and linoleic acid-derived CYP450-epoxy-oxlipins and resulted in a dramatic influx in monocytes. The epoxI-recruited monocytes were strongly GR1(+), Ly6c(hi), CCR2(hi), CCL2(hi), and CX3CR1(lo). In addition, expression of F4/80 and the recruitment of T cells, B cells, and dendritic cells were suppressed. sEH (Ephx2)(-/-) mice, which have elevated epoxy-oxylipins, demonstrated opposing effects to epoxitreated mice: reduced Ly6c(hi) monocytes and elevated F4/80(hi) macrophages and B, T, and dendritic cells. Ly6c(hi) and Ly6c(lo) monocytes, resident macrophages, and recruited dendritic cells all showed a dramatic change in their resolution signature following in vivo epoxI treatment. Markers of macrophage differentiation CD11b, MerTK, and CD103 were reduced, and monocyte-derived macrophages and resident macrophages ex vivo showed greatly impaired phagocytosis of zymosan and efferocytosis of apoptotic thymocytes following epoxI treatment. These findings demonstrate that epoxy-oxylipins have a critical role in monocyte lineage recruitment and activity to promote inflammatory resolution and represent a previously unidentified internal regulatory system governing the establishment of adaptive immunity. C1 [Gilroy, Derek W.; De Maeyer, Roel P. H.; Newson, Justine; Stables, Melanie] UCL, Div Med, Ctr Clin Pharmacol & Therapeut, London WC1E 6JJ, England. [Edin, Matthew L.; Lih, Fred B.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Bystrom, Jonas] Queen Mary Univ London, William Harvey Res Inst, London EC1M 6BQ, England. [Bishop-Bailey, David] Univ London Royal Vet Coll, Comparat Biomed Sci, 32 Belgrave Sq, London NW1 0TU, England. RP Gilroy, DW (reprint author), UCL, Div Med, Ctr Clin Pharmacol & Therapeut, London WC1E 6JJ, England.; Bishop-Bailey, D (reprint author), Univ London Royal Vet Coll, Comparat Biomed Sci, 32 Belgrave Sq, London NW1 0TU, England. EM d.gilroy@ucl.ac.uk; dbishopbailey@rvc.ac.uk FU British Heart Foundation [PG/08/070/25464, PG/11/39/28890]; Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES025034]; Wellcome Trust FX We thank the Mass Spectrometry Core at the NIEHS for their technical assistance and Dr. Mark Paul Clark, Imperial College London, for his help with data analysis. This work was funded by grants from the British Heart Foundation (PG/08/070/25464, PG/11/39/28890) and the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences, Grant Z01 ES025034 (to D.C.Z.). D.W.G. holds a Wellcome Trust Senior Fellowship. NR 59 TC 1 Z9 1 U1 2 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 7 PY 2016 VL 113 IS 23 BP E3240 EP E3249 DI 10.1073/pnas.1521453113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN6BF UT WOS:000377155400010 PM 27226306 ER PT J AU Wang, TY Lee, SY Chen, SL Chang, YH Wang, LJ Chen, PS Chen, SH Chu, CH Huang, SY Tzeng, NS Li, CL Chung, YL Hsieh, TH Lee, IH Chen, KC Yang, YK Hong, JS Lu, RB AF Wang, Tzu-Yun Lee, Sheng-Yu Chen, Shiou-Lan Chang, Yun-Hsuan Wang, Liang-Jen Chen, Po See Chen, Shih-Heng Chu, Chun-Hsien Huang, San-Yuan Tzeng, Nian-Sheng Li, Chia-Ling Chung, Yi-Lun Hsieh, Tsai-Hsin Lee, I. Hui Chen, Kao Chin Yang, Yen Kuang Hong, Jau-Shyong Lu, Ru-Band TI Comparing clinical responses and the biomarkers of BDNF and cytokines between subthreshold bipolar disorder and bipolar II disorder SO SCIENTIFIC REPORTS LA English DT Article ID MAJOR DEPRESSIVE DISORDER; COMORBIDITY SURVEY REPLICATION; INDUCED MICROGLIAL ACTIVATION; NEUROTROPHIC FACTOR; INFLAMMATORY MARKERS; OXIDATIVE STRESS; PRIVATE-PRACTICE; RATING-SCALE; IFN-GAMMA; BRAIN AB Patients with subthreshold hypomania (SBP; subthreshold bipolar disorder) were indistinguishable from those with bipolar disorder (BP)-II on clinical bipolar validators, but their analyses lacked biological and pharmacological treatment data. Because inflammation and neuroprogression underlies BP, we hypothesized that cytokines and brain-derived neurotrophic factor (BDNF) are biomarkers for BP. We enrolled 41 drug-naive patients with SBP and 48 with BP-II undergoing 12 weeks of pharmacological treatment (valproic acid, fluoxetine, risperidone, lorazepam). The Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) were used to evaluate clinical responses at baseline and at weeks 0, 1, 2, 4, 8, and 12. Inflammatory cytokines (tumour necrosis factor [TNF]-alpha, transforming growth factor [TGF]-beta 1, interleukin [IL]-6, IL-8 and IL-1 beta) and BDNF levels were also measured. Mixed models repeated measurement was used to examine the therapeutic effect and changes in BDNF and cytokine levels between the groups. HDRS and YMRS scores significantly (P < 0.001) declined in both groups, the SBP group had significantly lower levels of BDNF (P = 0.005) and TGF-beta 1 (P = 0.02). Patients with SBP and BP-II respond similarly to treatment, but SBP patients may have different neuroinflammation marker expression. C1 [Wang, Tzu-Yun; Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chen, Po See; Li, Chia-Ling; Chung, Yi-Lun; Hsieh, Tsai-Hsin; Lee, I. Hui; Chen, Kao Chin; Yang, Yen Kuang; Lu, Ru-Band] Natl Cheng Kung Univ, Coll Med, Natl Cheng Kung Univ Hosp, Dept Psychiat, Tainan 70101, Taiwan. [Lee, Sheng-Yu] Kaohsiung Vet Gen Hosp, Dept Psychiat, Kaohsiung, Taiwan. [Chen, Shiou-Lan] KMU, Lipid Sci & Aging Res Ctr, Coll Med, Grad Inst Med, Kaohsiung, Taiwan. [Chang, Yun-Hsuan; Lu, Ru-Band] Natl Cheng Kung Univ, Coll Med, Inst Allied Hlth Sci, Tainan 70101, Taiwan. [Chang, Yun-Hsuan] Asia Univ, Dept Psychol, Taichung, Taiwan. [Wang, Liang-Jen] Kaohsiung Chang Gung Mem Hosp, Dept Child & Adolescent Psychiat, Kaohsiung, Taiwan. [Wang, Liang-Jen] Chang Gung Univ, Coll Med, Kaohsiung, Taiwan. [Chen, Po See; Lee, I. Hui; Chen, Kao Chin; Yang, Yen Kuang; Lu, Ru-Band] Natl Cheng Kung Univ, Addict Res Ctr, Tainan 701, Taiwan. [Chen, Shih-Heng; Hong, Jau-Shyong] NIEHS, Neurobiol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Chu, Chun-Hsien] Natl Cheng Kung Univ, Coll Med, Inst Mol Med, Tainan 70101, Taiwan. [Huang, San-Yuan; Tzeng, Nian-Sheng] Triserv Gen Hosp, Natl Def Med Ctr, Dept Psychiat, Taipei, Taiwan. [Tzeng, Nian-Sheng] Natl Def Med Ctr, Student Counseling Ctr, Taipei, Taiwan. [Chung, Yi-Lun] Natl Cheng Kung Univ, Inst Basic Med Sci, Tainan 701, Taiwan. [Yang, Yen Kuang; Lu, Ru-Band] Natl Cheng Kung Univ, Coll Med, Inst Behav Med, Tainan 70101, Taiwan. [Yang, Yen Kuang] Natl Cheng Kung Univ Hosp, Dou Liou Branch, Dept Psychiat, Yunlin, Taiwan. [Lu, Ru-Band] Natl Hlth Res Inst, Ctr Neuropsychiat Res, Miaoli, Taiwan. RP Lu, RB (reprint author), Natl Cheng Kung Univ, Coll Med, Natl Cheng Kung Univ Hosp, Dept Psychiat, Tainan 70101, Taiwan.; Lu, RB (reprint author), Natl Cheng Kung Univ, Coll Med, Inst Allied Hlth Sci, Tainan 70101, Taiwan.; Lu, RB (reprint author), Natl Cheng Kung Univ, Addict Res Ctr, Tainan 701, Taiwan.; Lu, RB (reprint author), Natl Cheng Kung Univ, Coll Med, Inst Behav Med, Tainan 70101, Taiwan.; Lu, RB (reprint author), Natl Hlth Res Inst, Ctr Neuropsychiat Res, Miaoli, Taiwan. EM rblu@mail.ncku.edu.tw FU Taiwan National Science Council [NSC98-2314-B-006-022-MY3, NSC102-2622-B-006-002-CC2, NSC100-2314-B-075B-010-MY3]; Taiwan Department of Health [DOH 95-TD-M-113-055]; Taiwan National Health Research Institute [NHRI-EX-97-9738NI]; National Cheng Kung University Project for Promoting Academic Excellence and Developing World Class Research Centers; National Cheng Kung University Hospital [NCKUH-10505007] FX This work was supported in part by grant NSC98-2314-B-006-022-MY3, NSC102-2622-B-006-002-CC2(to RBL) and grant NSC100-2314-B-075B-010-MY3 (to SYL) from the Taiwan National Science Council, grant DOH 95-TD-M-113-055 (to RBL) from the Taiwan Department of Health, grant NHRI-EX-97-9738NI (to RBL) from the Taiwan National Health Research Institute, the National Cheng Kung University Project for Promoting Academic Excellence and Developing World Class Research Centers, and grant NCKUH-10505007(to TYW) from National Cheng Kung University Hospital. NR 59 TC 1 Z9 1 U1 3 U2 13 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 7 PY 2016 VL 6 AR 27431 DI 10.1038/srep27431 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN6IK UT WOS:000377177200001 PM 27270858 ER PT J AU Spong, CY AF Spong, Catherine Y. TI Understanding Zika virus pathogenesis: an interview with Catherine Spong SO BMC MEDICINE LA English DT Editorial Material DE Zika; Infants; Pregnancy; Neurology; Microcephaly; Miscarriage; Stillbirth; Infectious disease; Cohort; Fetal anomaly AB A recent outbreak of Zika virus has been linked to fetal abnormalities in pregnant women who have been infected. The scientific community is working toward understanding Zika virus pathogenesis to better manage affected women and children. In an interview with Dr. Catherine Spong, we discuss the aims and challenges of a forthcoming longitudinal study of a cohort of pregnant women in areas of current active Zika virus transmission. C1 [Spong, Catherine Y.] NICHHD, Eunice Kennedy Shriver, NIH, Bethesda, MD 20892 USA. RP Spong, CY (reprint author), NICHHD, Eunice Kennedy Shriver, NIH, Bethesda, MD 20892 USA. EM spongc@mail.nih.gov NR 9 TC 0 Z9 0 U1 30 U2 43 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD JUN 6 PY 2016 VL 14 AR 84 DI 10.1186/s12916-016-0628-0 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA DO2DA UT WOS:000377588700001 PM 27268016 ER PT J AU Ohzeki, J Shono, N Otake, K Martins, NMC Kugou, K Kimura, H Nagase, T Larionov, V Earnshaw, WC Masumoto, H AF Ohzeki, Jun-ichirou Shono, Nobuaki Otake, Koichiro Martins, Nuno M. C. Kugou, Kazuto Kimura, Hiroshi Nagase, Takahiro Larionov, Vladimir Earnshaw, William C. Masumoto, Hiroshi TI KAT7/HBO1/MYST2 Regulates CENP-A Chromatin Assembly by Antagonizing Suv39h1-Mediated Centromere Inactivation SO DEVELOPMENTAL CELL LA English DT Article ID HBO1 HISTONE ACETYLASE; FISSION YEAST; ARTIFICIAL CHROMOSOMES; EPIGENETIC REGULATION; ALPHOID DNA; B INTERACTS; HETEROCHROMATIN; KINETOCHORE; NUCLEOSOMES; PROTEINS AB Centromere chromatin containing histone H3 variant CENP-A is required for accurate chromosome segregation as a foundation for kinetochore assembly. Human centromere chromatin assembles on a part of the long a-satellite (alphoid) DNA array, where it is flanked by pericentric heterochromatin. Heterochromatin spreads into adjacent chromatin and represses gene expression, and it can antagonize centromere function or CENP-A assembly. Here, we demonstrate an interaction between CENP-A assembly factor M18BP1 and acetyltransferase KAT7/HBO1/MYST2. Knocking out KAT7 in HeLa cells reduced centromeric CENP-A assembly. Mitotic chromosome misalignment and micronuclei formation increased in the knockout cells and were enhanced when the histone H3-K9 trimethylase Suv39h1 was overproduced. Tethering KAT7 to an ectopic alphoid DNA integration site removed heterochromatic H3K9me3 modification and was sufficient to stimulate new CENP-A or histone H3.3 assembly. Thus, KAT7-containing acetyltransferases associating with the Mis18 complex provides competence for histone turnover/exchange activity on alphoid DNA and prevents Suv39h1-mediated heterochromatin invasion into centromeres. C1 [Ohzeki, Jun-ichirou; Shono, Nobuaki; Otake, Koichiro; Kugou, Kazuto; Masumoto, Hiroshi] Kazusa DNA Res Inst, Dept Frontier Res, Lab Cell Engn, 2-6-7 Kazusa Kamatari, Kisarazu 2920818, Japan. [Martins, Nuno M. C.; Earnshaw, William C.] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3BF, Midlothian, Scotland. [Kimura, Hiroshi] Tokyo Inst Technol, Grad Sch Biosci & Biotechnol, Dept Biol Sci, Yokohama, Kanagawa 2268501, Japan. [Nagase, Takahiro] Kazusa DNA Res Inst, Publ Relat Team, Kisarazu 2920818, Japan. [Larionov, Vladimir] NCI, Genome Struct & Funct Grp, Dev Therapeut Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Masumoto, H (reprint author), Kazusa DNA Res Inst, Dept Frontier Res, Lab Cell Engn, 2-6-7 Kazusa Kamatari, Kisarazu 2920818, Japan. EM masumoto@kazusa.or.jp RI Shono, Nobuaki/C-4130-2017; OI Shono, Nobuaki/0000-0002-9060-1074; Martins, Nuno/0000-0003-3953-9313 FU MEXT KAKENHI grants [23247030, 23114008, 16H04747, 16H01414]; Kazusa DNA Research Institute Foundation; Wellcome Trust [073915]; Japan Society for the Promotion of Science; Ministry of Education, Culture, Sports, Science and Technology of Japan; NIH, National Cancer Institute; Center for Cancer Research FX We would like to thank Hiroko Shinohara, Tomoe Hayashi, and Kazuko Yamada for their technical assistance, Koei Okazaki for discussion, and Naohito Nozaki for producing the antibodies. This work was supported by MEXT KAKENHI grants 23247030, 23114008, 16H04747, and 16H01414, as well as the Kazusa DNA Research Institute Foundation (H.M.). Work in the W.C.E. laboratory is funded by the Wellcome Trust, of which W.C.E. is a Principal Research Fellow (grant no. 073915). Additional experiments were supported by grants-in-aid from the Japan Society for the Promotion of Science and the Ministry of Education, Culture, Sports, Science and Technology of Japan (to H.K.) and the intramural research program of the NIH, National Cancer Institute, and Center for Cancer Research (to V.L.). NR 58 TC 6 Z9 6 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD JUN 6 PY 2016 VL 37 IS 5 BP 413 EP 427 DI 10.1016/j.devcel.2016.05.006 PG 15 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA DN9OC UT WOS:000377408100008 PM 27270040 ER PT J AU Sawyer, LA Dundr, M AF Sawyer, Lain A. Dundr, Miroslav TI Nuclear bodies: Built to boost SO JOURNAL OF CELL BIOLOGY LA English DT Editorial Material ID CAJAL BODIES; ORGANIZATION; PARTICLES; GENOME AB The classic archetypal function of nuclear bodies is to accelerate specific reactions within their crowded space. In this issue, Tatomer et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201504043) provide the first direct evidence that the histone locus body acts to concentrate key factors required for the proper processing of histone pre-mRNAs. C1 [Sawyer, Lain A.; Dundr, Miroslav] Rosalind Franklin Univ Med & Sci, Chicago Med Sch, Dept Cell Biol, N Chicago, IL 60064 USA. [Sawyer, Lain A.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Dundr, M (reprint author), Rosalind Franklin Univ Med & Sci, Chicago Med Sch, Dept Cell Biol, N Chicago, IL 60064 USA. EM mirek.dundr@rosalindfranklin.edu NR 20 TC 1 Z9 1 U1 2 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD JUN 6 PY 2016 VL 213 IS 5 BP 509 EP 511 DI 10.1083/jcb.201605049 PG 3 WC Cell Biology SC Cell Biology GA DO1RA UT WOS:000377555500005 ER PT J AU Timilsina, U Ghimire, D Timalsina, B Nitz, TJ Wild, CT Freed, EO Gaur, R AF Timilsina, Uddhav Ghimire, Dibya Timalsina, Bivek Nitz, Theodore J. Wild, Carl T. Freed, Eric O. Gaur, Ritu TI Identification of potent maturation inhibitors against HIV-1 clade C SO SCIENTIFIC REPORTS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; BETULINIC ACID-DERIVATIVES; GAG SPACER PEPTIDE-1; CA-SP1 CLEAVAGE SITE; BEVIRIMAT; RESISTANCE; POLYMORPHISMS; ENVELOPE; PA-457; STEP AB Antiretroviral therapy has led to a profound improvement in the clinical care of HIV-infected patients. However, drug tolerability and the evolution of drug resistance have limited treatment options for many patients. Maturation inhibitors are a new class of antiretroviral agents for treatment of HIV-1. They act by interfering with the maturation of the virus by blocking the last step in Gag processing: the cleavage of the capsid-spacer peptide 1 (CA-SP1) intermediate to mature CA by the viral protease (PR). The first-in-class maturation inhibitor bevirimat (BVM) failed against a subset of HIV-1 isolates in clinical trials due to polymorphisms present in the CA-SP1 region of the Gag protein. Sequence analysis indicated that these polymorphisms are more common in non-clade B strains of HIV-1 such as HIV-1 clade C. Indeed, BVM was found to be ineffective against HIV-1 clade C molecular clones tested in this study. A number of BVM analogs were synthesized by chemical modifications at the C-28 position to improve its activity. The new BVM analogs displayed potent activity against HIV-1 clade B and C and also reduced infectivity of the virus. This study identifies novel and broadly active BVM analogs that may ultimately demonstrate efficacy in the clinic. C1 [Timilsina, Uddhav; Ghimire, Dibya; Timalsina, Bivek; Gaur, Ritu] South Asian Univ, Fac Life Sci & Biotechnol, New Delhi 110021, India. [Nitz, Theodore J.; Wild, Carl T.] DFH Pharma, Gaithersburg, MD 20886 USA. [Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Dynam & Replicat Program, Ctr Canc Res, Rockville, MD 21702 USA. RP Gaur, R (reprint author), South Asian Univ, Fac Life Sci & Biotechnol, New Delhi 110021, India. EM rgaur@sau.ac.in OI Timalsina, Bivek/0000-0003-0734-0780 FU South Asian University Intramural Research Fund; NIH Intramural to India (I-I) [BT/MB/Indo-US/I-I/02/ 2013] FX This research was supported by South Asian University Intramural Research Fund and the NIH Intramural to India (I-I) [grant BT/MB/Indo-US/I-I/02/ 2013] to Ritu Gaur. The funders had no role in study design, data collection, interpretation and the decision to submit the work for publication. NR 30 TC 2 Z9 2 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 6 PY 2016 VL 6 AR 27403 DI 10.1038/srep27403 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN5TA UT WOS:000377132300001 PM 27264714 ER PT J AU Kellock, J Hopping, G Caughey, B Daggett, V AF Kellock, Jackson Hopping, Gene Caughey, Byron Daggett, Valerie TI Peptides Composed of Alternating L- and D-Amino Acids Inhibit Amyloidogenesis in Three Distinct Amyloid Systems Independent of Sequence SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE beta amyloid; amyloid; toxic oligomer; inhibitor; alpha-sheet ID A-BETA OLIGOMERS; ALZHEIMERS-DISEASE; PRION PROTEIN; CONFORMATIONAL PROPENSITIES; AGGREGATION PATHWAYS; COMMON MECHANISM; SHEET STRUCTURE; ALPHA-SHEET; IN-VITRO; TRANSTHYRETIN AB There is now substantial evidence that soluble oligomers are primary toxic agents in amyloid diseases. The development of an antibody recognizing the toxic soluble oligomeric forms of different and unrelated amyloid species suggests a common conformational intermediate during amyloidogenesis. We previously observed a common occurrence of a novel secondary structure element, which we call alpha-sheet, in molecular dynamics (MD) simulations of various amyloidogenic proteins, and we hypothesized that the toxic conformer is composed of alpha-sheet structure. As such, alpha-sheet may represent a conformational signature of the misfolded intermediates of amyloidogenesis and a potential unique binding target for peptide inhibitors. Recently, we reported the design and characterization of a novel hairpin peptide (alpha 1 or AP90) that adopts stable alpha-sheet structure and inhibits the aggregation of the (beta-Amyloid Peptide A beta 42 and transthyretin. AP90 is a 23-residue hairpin peptide featuring alternating D- and L-amino acids with favorable conformational propensities for alpha-sheet formation, and a designed turn. For this study, we reverse engineered AP90 to identify which of its design features is most responsible for conferring alpha-sheet stability and inhibitory activity. We present experimental characterization (CD and FTIR) of seven peptides designed to accomplish this. In addition, we measured their ability to inhibit aggregation in three unrelated amyloid species: A beta 42, transthyretin, and human islet amylin polypeptide. We found that a hairpin peptide featuring alternating L- and D-amino acids, independent of sequence, is sufficient for conferring alpha-sheet structure and inhibition of aggregation. Additionally, we show a correlation between alpha-sheet structural stability and inhibitory activity. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Kellock, Jackson; Hopping, Gene; Daggett, Valerie] Univ Washington, Dept Bioengn, Seattle, WA 98105 USA. [Caughey, Byron] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Daggett, V (reprint author), Univ Washington, Dept Bioengn, Seattle, WA 98105 USA. EM daggett@uw.edu FU W.H. Coulter Foundation Translational Research Partnership Program; National Science Foundation [CBET-0966977]; National Institute of Health [GM 95808]; Coins for Alzheimer's Research Trust; Intramural Research Program of the NIAID, NIH FX We thank Dr. James Bryers, Dr. David Baker, Dr. Cecilia Giachelli, Dr. Buddy Ratner, and Dr. Pat Stayton for the generous use of equipment. We thank Dr. Tom Schmidlin for his advice on figure design. This study was funded by the W.H. Coulter Foundation Translational Research Partnership Program (to V.D.), grants from the National Science Foundation (CBET-0966977 to V.D.), the National Institute of Health (GM 95808 to V.D.), the Coins for Alzheimer's Research Trust (to V.D.), and the Intramural Research Program of the NIAID, NIH (to B.C.). NR 52 TC 3 Z9 3 U1 11 U2 28 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 5 PY 2016 VL 428 IS 11 BP 2317 EP 2328 DI 10.1016/j.jmb.2016.03.013 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DO4DY UT WOS:000377733200006 PM 27012425 ER PT J AU Botesteanu, DA Lee, JM Levy, D AF Botesteanu, Dana-Adriana Lee, Jung-Min Levy, Doron TI Modeling the Dynamics of High-Grade Serous Ovarian Cancer Progression for Transvaginal Ultrasound-Based Screening and Early Detection SO PLOS ONE LA English DT Article ID BRCA1/2 MUTATION CARRIERS; FALLOPIAN-TUBE; CLINICAL-IMPLICATIONS; FOLLOW-UP; CARCINOMAS; EVOLUTION; SURVIVAL; HISTORY; BREAST; WOMEN AB High-grade serous ovarian cancer (HGSOC) represents the majority of ovarian cancers and accounts for the largest proportion of deaths from the disease. A timely detection of low volume HGSOC should be the goal of any screening studies. However, numerous transvaginal ultrasound (TVU) detection-based population studies aimed at detecting low-volume disease have not yielded reduced mortality rates. A quantitative invalidation of TVU as an effective HGSOC screening strategy is a necessary next step. Herein, we propose a mathematical model for a quantitative explanation on the reported failure of TVU-based screening to improve HGSOC low-volume detectability and overall survival. We develop a novel in silico mathematical assessment of the efficacy of a unimodal TVU monitoring regimen as a strategy aimed at detecting low-volume HGSOC in cancer-positive cases, defined as cases for which the inception of the first malignant cell has already occurred. Our findings show that the median window of opportunity interval length for TVU monitoring and HGSOC detection is approximately 1.76 years. This does not translate into reduced mortality levels or improved detection accuracy in an in silico cohort across multiple TVU monitoring frequencies or detection sensitivities. We demonstrate that even a semiannual, unimodal TVU monitoring protocol is expected to miss detectable HGSOC. Lastly, we find that circa 50% of the simulated HGSOC growth curves never reach the baseline detectability threshold, and that on average, 5-7 infrequent, rate-limiting stochastic changes in the growth parameters are associated with reaching HGSOC detectability and mortality thresholds respectively. Focusing on a malignancy poorly studied in the mathematical oncology community, our model captures the dynamic, temporal evolution of HGSOC progression. Our mathematical model is consistent with recent case reports and prospective TVU screening population studies, and provides support to the empirical recommendation against frequent HGSOC screening. C1 [Botesteanu, Dana-Adriana; Levy, Doron] Univ Maryland, Dept Math, College Pk, MD 20742 USA. [Botesteanu, Dana-Adriana; Levy, Doron] Univ Maryland, Ctr Sci Computat & Math Modeling CSCAMM, College Pk, MD 20742 USA. [Botesteanu, Dana-Adriana; Lee, Jung-Min] NCI, Womens Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Levy, D (reprint author), Univ Maryland, Dept Math, College Pk, MD 20742 USA.; Levy, D (reprint author), Univ Maryland, Ctr Sci Computat & Math Modeling CSCAMM, College Pk, MD 20742 USA. EM dlevy@math.umd.edu FU Intramural Research Program of the National Institutes of Health; Center for Cancer Research, National Cancer Institute as part of a seed grant from the UMD-NCI Partnership for Cancer Technology; John Simon Guggenheim Memorial Foundation FX The work was supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute as part of a seed grant from the UMD-NCI Partnership for Cancer Technology. The work of DL was supported in part by the John Simon Guggenheim Memorial Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 2 Z9 2 U1 1 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 3 PY 2016 VL 11 IS 6 AR e0156661 DI 10.1371/journal.pone.0156661 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN8ZV UT WOS:000377369700096 PM 27257824 ER PT J AU Huang, BN Gomez-Rodriguez, J Preite, S Garrett, LJ Harper, UL Schwartzberg, PL AF Huang, Bonnie Gomez-Rodriguez, Julio Preite, Silvia Garrett, Lisa J. Harper, Ursula L. Schwartzberg, Pamela L. TI CRISPR-Mediated Triple Knockout of SLAMF1, SLAMF5 and SLAMF6 Supports Positive Signaling Roles in NKT Cell Development SO PLOS ONE LA English DT Article ID LINKED LYMPHOPROLIFERATIVE-DISEASE; CONTROLS T-CELL; HUMORAL IMMUNITY; NEGATIVE REGULATION; FAMILY RECEPTORS; GENE-PRODUCT; ADAPTER SAP; B-CELLS; MICE; DIFFERENTIATION AB The SLAM family receptors contribute to diverse aspects of lymphocyte biology and signal via the small adaptor molecule SAP. Mutations affecting SAP lead to X-linked lymphoproliferative syndrome Type 1, a severe immunodysregulation characterized by fulminant mononucleosis, dysgammaglobulinemia, and lymphoproliferation/lymphomas. Patients and mice having mutations affecting SAP also lack germinal centers due to a defect in T:B cell interactions and are devoid of invariant NKT (iNKT) cells. However, which and how SLAM family members contribute to these phenotypes remains uncertain. Three SLAM family members: SLAMF1, SLAMF5 and SLAMF6, are highly expressed on T follicular helper cells and germinal center B cells. SLAMF1 and SLAMF6 are also implicated in iNKT development. Although individual receptor knockout mice have limited iNKT and germinal center phenotypes compared to SAP knockout mice, the generation of multi-receptor knockout mice has been challenging, due to the genomic linkage of the genes encoding SLAM family members. Here, we used Cas9/CRISPR-based mutagenesis to generate mutations simultaneously in Slamf1, Slamf5 and Slamf6. Genetic disruption of all three receptors in triple-knockout mice (TKO) did not grossly affect conventional T or B cell development and led to mild defects in germinal center formation post-immunization. However, the TKO worsened defects in iNKT cells development seen in SLAMF6 single gene-targeted mice, supporting data on positive signaling and potential redundancy between these receptors. C1 [Huang, Bonnie; Gomez-Rodriguez, Julio; Preite, Silvia; Schwartzberg, Pamela L.] NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. [Garrett, Lisa J.] NHGRI, Embryon Stem Cell & Transgen Mouse Core, Bethesda, MD 20892 USA. [Harper, Ursula L.] NHGRI, Genom Core, Bethesda, MD 20892 USA. RP Schwartzberg, PL (reprint author), NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. EM pams@mail.nih.gov FU National Human Genome Research Institute [HG000123, HG200349] FX This work was supported by intramural funding from the National Human Genome Research Institute (HG000123 and HG200349). NR 52 TC 1 Z9 1 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 3 PY 2016 VL 11 IS 6 AR e0156072 DI 10.1371/journal.pone.0156072 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN8ZV UT WOS:000377369700033 PM 27258160 ER PT J AU Deshmukh, L Schwieters, CD Grishaev, A Clore, GM AF Deshmukh, Lalit Schwieters, Charles D. Grishaev, Alexander Clore, G. Marius TI Quantitative Characterization of Configurational Space Sampled by HIV-1 Nucleocapsid Using Solution NMR, X-ray Scattering and Protein Engineering SO CHEMPHYSCHEM LA English DT Article DE HIV-1; nuclear magnetic resonance; nucleocapsid; protein engineering; X-ray scattering ID IMMUNODEFICIENCY-VIRUS TYPE-1; MOLECULAR-STRUCTURE DETERMINATION; LIQUID-CRYSTALLINE PHASE; GAG POLYPROTEIN; STRUCTURAL-CHARACTERIZATION; REVERSE TRANSCRIPTION; XPLOR-NIH; DYNAMICS; RNA; SPECTROSCOPY AB Nucleic-acid-related events in the HIV-1 replication cycle are mediated by nucleocapsid, a small protein comprising two zinc knuckles connected by a short flexible linker and flanked by disordered termini. Combining experimental NMR residual dipolar couplings, solution X-ray scattering and protein engineering with ensemble simulated annealing, we obtain a quantitative description of the configurational space sampled by the two zinc knuckles, the linker and disordered termini in the absence of nucleic acids. We first compute the conformational ensemble (with an optimal size of three members) of an engineered nucleocapsid construct lacking the N- and C-termini that satisfies the experimental restraints, and then validate this ensemble, as well as characterize the disordered termini, using the experimental data from the full-length nucleocapsid construct. The experimental and computational strategy is generally applicable to multidomain proteins. Differential flexibility within the linker results in asymmetric motion of the zinc knuckles which may explain their functionally distinct roles despite high sequence identity. One of the configurations (populated at a level of. 40%) closely resembles that observed in various ligand-bound forms, providing evidence for conformational selection and a mechanistic link between protein dynamics and function. C1 [Deshmukh, Lalit; Clore, G. Marius] NIDDK, Chem Phys Lab, Bldg 2, Bethesda, MD 20892 USA. [Schwieters, Charles D.] Ctr Informat & Technol, Imaging Sci Lab, Bethesda, MD 20892 USA. [Grishaev, Alexander] Univ Maryland, Inst Biosci & Biotechnol Res, Rockville, MD 20850 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, Bldg 2, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov FU DOE [W-31-109-ENG-38, PUP-77]; NIH, NIDDK; CIT; Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH FX We thank Drs. Fang (NCI), Zuo (APS) and Seifert (APS) for assistance with SAXS data collection; Drs. Baber, Cai, Garrett, Ghirlando and Tugarinov for discussions. We acknowledge use of the Advanced Photon Source (DOE contract #W-31-109-ENG-38 and PUP-77 agreement between NCI, NIH and Argonne National Laboratory). This work was supported by the Intramural Program of the NIH, NIDDK (to G.M.C.) and CIT (to C.D.S.), and the Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to G.M.C.). NR 34 TC 1 Z9 1 U1 1 U2 1 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1439-4235 EI 1439-7641 J9 CHEMPHYSCHEM JI ChemPhysChem PD JUN 3 PY 2016 VL 17 IS 11 BP 1548 EP 1552 DI 10.1002/cphc.201600212 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA DT0MM UT WOS:000381177700001 PM 26946052 ER PT J AU Taguchi, Y Allende, ML Mizukami, H Cook, EK Gavrilova, O Tuymetova, G Clarke, BA Chen, WP Olivera, A Proia, RL AF Taguchi, Yoshimitsu Allende, Maria L. Mizukami, Hiroki Cook, Emily K. Gavrilova, Oksana Tuymetova, Galina Clarke, Benjamin A. Chen, Weiping Olivera, Ana Proia, Richard L. TI Sphingosine-1-phosphate Phosphatase 2 Regulates Pancreatic Islet beta-Cell Endoplasmic Reticulum Stress and Proliferation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID UNFOLDED PROTEIN RESPONSE; TYPE-2 DIABETIC-PATIENTS; INSULIN-RESISTANCE; PHOSPHOHYDROLASE; SPHINGOLIPIDS; SPHINGOSINE; MASS; IDENTIFICATION; HOMEOSTASIS; METABOLISM AB Sphingosine-1-phosphate (S1P) is a sphingolipid metabolite that regulates basic cell functions through metabolic and signaling pathways. Intracellular metabolism of S1P is controlled, in part, by two homologous S1P phosphatases (SPPases), 1 and 2, which are encoded by the Sgpp1 and Sgpp2 genes, respectively. SPPase activity is needed for efficient recycling of sphingosine into the sphingolipid synthesis pathway. SPPase 1 is important for skin homeostasis, but little is known about the functional role of SPPase 2. To identify the functions of SPPase 2 in vivo, we studied mice with the Sgpp2 gene deleted. In contrast to Sgpp1(-/)-mice, Sgpp2(-/)-mice had normal skin and were viable into adulthood. Unexpectedly, WT mice expressed Sgpp2 mRNA at high levels in pancreatic islets when compared with other tissues. Sgpp2(-/)-mice had normal pancreatic islet size; however, they exhibited defective adaptive beta-cell proliferation that was demonstrated after treatment with either a high-fat diet or the beta-cell-specific toxin, streptozotocin. Importantly, beta-cells from untreated Sgpp2(-/)-mice showed significantly increased expression of proteins characteristic of the endoplasmic reticulum stress response compared with beta-cells from WT mice, indicating a basal islet defect. Our results show that Sgpp2 deletion causes beta-cell endoplasmic reticulum stress, which is a known cause of beta-cell dysfunction, and reveal a juncture in the sphingolipid recycling pathway that could impact the development of diabetes. C1 [Taguchi, Yoshimitsu; Allende, Maria L.; Cook, Emily K.; Tuymetova, Galina; Clarke, Benjamin A.; Proia, Richard L.] NIDDK, Genet Dev & Dis Branch, Bldg 10,Rm 9D-06,10 Ctr Dr MSC 1821, Bethesda, MD 20892 USA. [Gavrilova, Oksana] NIDDK, Mouse Metab Core Lab, Bethesda, MD 20892 USA. [Chen, Weiping] NIDDK, Genom Core, Bethesda, MD 20892 USA. [Olivera, Ana] NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Mizukami, Hiroki] Hirosaki Univ, Grad Sch Med, Dept Pathol & Mol Med, Hirosaki, Aomori 0368562, Japan. RP Proia, RL (reprint author), NIDDK, Genet Dev & Dis Branch, Bldg 10,Rm 9D-06,10 Ctr Dr MSC 1821, Bethesda, MD 20892 USA. EM proia@nih.gov FU Intramural Research Program of NIDDK, National Institutes of Health; Intramural Research Program of NIAID, National Institutes of Health; Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina [P30 CA138313]; Lipidomics Core in the SC Lipidomics and Pathobiology COBRE [P20 RR017677] FX This research was supported by the Intramural Research Programs of NIDDK and NIAID, National Institutes of Health; the Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina ( Grant P30 CA138313); and the Lipidomics Core in the SC Lipidomics and Pathobiology COBRE ( Grant P20 RR017677). 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 35 TC 1 Z9 1 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 3 PY 2016 VL 291 IS 23 BP 12029 EP 12038 DI 10.1074/jbc.M116.728170 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DO9GJ UT WOS:000378092800007 PM 27059959 ER PT J AU Gottlieb, SL Deal, CD Giersing, B Rees, H Bolan, G Johnston, C Timms, P Gray-Owen, SD Jerse, AE Cameron, CE Moorthy, VS Kiarie, J Broutet, N AF Gottlieb, Sami L. Deal, Carolyn D. Giersing, Birgitte Rees, Helen Bolan, Gail Johnston, Christine Timms, Peter Gray-Owen, Scott D. Jerse, Ann E. Cameron, Caroline E. Moorthy, Vasee S. Kiarie, James Broutet, Nathalie TI The global roadmap for advancing development of vaccines against sexually transmitted infections: Update and next steps SO VACCINE LA English DT Article DE Sexually transmitted infections; Vaccines; STI vaccine development; Roadmap ID HERPES-SIMPLEX-VIRUS; PELVIC-INFLAMMATORY-DISEASE; TREPONEMA-PALLIDUM STRAINS; GENITAL-TRACT INFECTION; NEISSERIA-GONORRHOEAE; CHLAMYDIA-TRACHOMATIS; CHEMICAL MUTAGENESIS; SYSTEMATIC ANALYSIS; COST-EFFECTIVENESS; HIV ACQUISITION AB In 2014, the World Health Organization, the US National Institutes of Health, and global technical partners published a comprehensive roadmap for development of new vaccines against sexually transmitted infections (STIs). Since its publication, progress has been made in several roadmap activities: obtaining better epidemiologic data to establish the public health rationale for STI vaccines, modeling the theoretical impact of future vaccines, advancing basic science research, defining preferred product characteristics for first-generation vaccines, and encouraging investment in STI vaccine development. This article reviews these overarching roadmap activities, provides updates on research and development of individual vaccines against herpes simplex virus, Chlamydia trachomatis, Neisseria gonorrhoeae, and Treponema pallidum, and discusses important next steps to advance the global roadmap for STI vaccine development. (C) 2016 World Health Organization; licensee Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.orgilicensesiby/3.0/). C1 [Gottlieb, Sami L.; Giersing, Birgitte; Moorthy, Vasee S.; Kiarie, James; Broutet, Nathalie] WHO, CH-1211 Geneva 27, Switzerland. [Deal, Carolyn D.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Rees, Helen] Univ Witwatersrand, Wits Reprod Hlth & HIV Inst, Johannesburg, South Africa. [Bolan, Gail] Ctr Dis Control & Prevent, Atlanta, GA USA. [Johnston, Christine] Univ Washington, Seattle, WA 98195 USA. [Timms, Peter] Univ Sunshine Coast, Sunshine Coast, Qld, Australia. [Timms, Peter] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld 4001, Australia. [Gray-Owen, Scott D.] Univ Toronto, Toronto, ON, Canada. [Jerse, Ann E.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Cameron, Caroline E.] Univ Victoria, Victoria, BC, Canada. RP Gottlieb, SL (reprint author), WHO, Dept Reprod Hlth & Res, Ave Appia 20, CH-1211 Geneva 27, Switzerland. EM gottliebs@who.int FU Agenus; Genocea; Vical; Gilead; AiCuris; Sanofi FX Drs. Gottlieb, Deal, Giersing, Rees, Bolan, Timms, Gray-Owen, Jerse, Cameron, Moorthy, Kiarie, and Broutet report no potential conflicts of interest. Dr. Johnston has conducted research at the University of Washington sponsored by the following companies as a principal or co-investigator: Agenus, Genocea, Vical, Gilead, AiCuris, and Sanofi. NR 75 TC 6 Z9 6 U1 6 U2 8 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 3 PY 2016 VL 34 IS 26 SI SI BP 2939 EP 2947 DI 10.1016/j.vaccine.2016.03.111 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DP3AQ UT WOS:000378365200016 PM 27105564 ER PT J AU de Maturana, EL Picornell, A Masson-Lecomte, A Kogevinas, M Marquez, M Carrato, A Tardon, A Lloreta, J Garcia-Closas, M Silverman, D Rothman, N Chanock, S Real, FX Goddard, ME Malats, N AF Lopez de Maturana, E. Picornell, A. Masson-Lecomte, A. Kogevinas, M. Marquez, M. Carrato, A. Tardon, A. Lloreta, J. Garcia-Closas, M. Silverman, D. Rothman, N. Chanock, S. Real, F. X. Goddard, M. E. Malats, N. CA SBC EPICURO Study Investigators TI Prediction of non-muscle invasive bladder cancer outcomes assessed by innovative multimarker prognostic models SO BMC CANCER LA English DT Article DE Multimarker models; Bayesian statistical learning method; Bayesian regression; Bayesian LASSO; AUC-ROC; Determination coefficient; heritability; Bladder cancer outcome; Prognosis; Recurrence; Progression; Genome-wide common SNP; Illumina Infinium HumanHap 1 M array; Predictive ability ID BAYESIAN LASSO; EAU GUIDELINES; DAIRY-CATTLE; RISK; SURVIVAL; PROGRESSION; RECURRENCE; UPDATE AB Background: We adapted Bayesian statistical learning strategies to the prognosis field to investigate if genome-wide common SNP improve the prediction ability of clinico-pathological prognosticators and applied it to non-muscle invasive bladder cancer (NMIBC) patients. Methods: Adapted Bayesian sequential threshold models in combination with LASSO were applied to consider the time-to-event and the censoring nature of data. We studied 822 NMIBC patients followed-up > 10 years. The study outcomes were time-to-first-recurrence and time-to-progression. The predictive ability of the models including up to 171,304 SNP and/or 6 clinico-pathological prognosticators was evaluated using AUC-ROC and determination coefficient. Results: Clinico-pathological prognosticators explained a larger proportion of the time-to-first-recurrence (3.1 %) and time-to-progression (5.4 %) phenotypic variances than SNPs (1 and 0.01 %, respectively). Adding SNPs to the clinico-pathological-parameters model slightly improved the prediction of time-to-first-recurrence (up to 4 %). The prediction of time-to-progression using both clinico-pathological prognosticators and SNP did not improve. Heritability (h(2)) of both outcomes was < 1 % in NMIBC. Conclusions: We adapted a Bayesian statistical learning method to deal with a large number of parameters in prognostic studies. Common SNPs showed a limited role in predicting NMIBC outcomes yielding a very low heritability for both outcomes. We report for the first time a heritability estimate for a disease outcome. Our method can be extended to other disease models. C1 [Lopez de Maturana, E.; Picornell, A.; Masson-Lecomte, A.; Marquez, M.; Malats, N.] Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, C Melchor Fernandez,Almagro 3, Madrid 28029, Spain. [Kogevinas, M.] Ctr Res Environm Epidemiol CREAL, Parc Salut Mar, Barcelona, Spain. [Carrato, A.] Hosp Univ Ramon & Cajal, Serv Oncol, Madrid, Spain. [Carrato, A.] Hosp Univ Elche, Serv Oncol, Elche, Spain. [Tardon, A.] Univ Oviedo, Dept Prevent Med, Oviedo, Spain. [Lloreta, J.] Hosp Mar IMAS, Parc Salut Mar, Barcelona, Spain. [Lloreta, J.] Hosp Mar IMAS, Dept Pathol, Barcelona, Spain. [Garcia-Closas, M.] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Silverman, D.; Rothman, N.; Chanock, S.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Real, F. X.] Spanish Natl Canc Res Ctr CNIO, Epithelial Carcinogenesis Grp, Madrid, Spain. [Real, F. X.] Univ Pompeu Fabra, Dept Ciencies Expt Salut, Barcelona, Spain. [Goddard, M. E.] Univ Melbourne, Dept Environm & Primary Ind, Biosci Res Div, Agribio, Melbourne, Vic, Australia. [Goddard, M. E.] Univ Melbourne, Dept Food & Agr Syst, Melbourne, Vic, Australia. [Tardon, A.] CIBERESP, Madrid, Spain. RP Malats, N (reprint author), Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, C Melchor Fernandez,Almagro 3, Madrid 28029, Spain. EM nmalats@cnio.es RI Kogevinas, Manolis/C-3918-2017; Real, Francisco X/H-5275-2015; OI Real, Francisco X/0000-0001-9501-498X; Malats, Nuria/0000-0003-2538-3784 FU Red Tematica de Investigacion Cooperativa en Cancer [RD12/0036/0050]; Fondo de Investigaciones Sanitarias (FIS); Instituto de Salud Carlos III [PI00-0745, PI05-1436, PI06-1614]; Asociacion Espanola Contra el Cancer (AECC), Spain; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA [NCI NO2-CP-11015]; EU-7FP-HEALTH-TransBioBC [60193]; Sara Borrell fellowship; Instituto de Salud Carlos III, Spain; European Urological Scholarship Program for Research (EUSP Scholarship) [S-01-2013]; [EU-FP7-HEALTH-F2-2008-201663-UROMOL] FX The work was partially supported by Red Tematica de Investigacion Cooperativa en Cancer (#RD12/0036/0050), Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III, (Grant numbers #PI00-0745, #PI05-1436, and #PI06-1614), and Asociacion Espanola Contra el Cancer (AECC), Spain; the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA (Contract NCI NO2-CP-11015); and EU-FP7-HEALTH-F2-2008-201663-UROMOL and EU-7FP-HEALTH-TransBioBC #601933. ELM was funded by a Sara Borrell fellowship, Instituto de Salud Carlos III, Spain; and AML by a fellowship of the European Urological Scholarship Program for Research (EUSP Scholarship S-01-2013). NR 30 TC 0 Z9 0 U1 3 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JUN 3 PY 2016 VL 16 AR 351 DI 10.1186/s12885-016-2361-7 PG 9 WC Oncology SC Oncology GA DN3LY UT WOS:000376964900001 ER PT J AU Robb, ML Eller, LA Kibuuka, H Rono, K Maganga, L Nitayaphan, S Kroon, E Sawe, FK Sinei, S Sriplienchan, S Jagodzinski, LL Malia, J Manak, M de Souza, MS Tovanabutra, S Sanders-Buell, E Rolland, M Dorsey-Spitz, J Eller, MA Milazzo, M Li, Q Lewandowski, A Wu, H Swann, E O'Connell, RJ Peel, S Dawson, P Kim, JH Michael, NL AF Robb, Merlin L. Eller, Leigh A. Kibuuka, Hannah Rono, Kathleen Maganga, Lucas Nitayaphan, Sorachai Kroon, Eugene Sawe, Fred K. Sinei, Samuel Sriplienchan, Somchai Jagodzinski, Linda L. Malia, Jennifer Manak, Mark de Souza, Mark S. Tovanabutra, Sodsai Sanders-Buell, Eric Rolland, Morgane Dorsey-Spitz, Julie Eller, Michael A. Milazzo, Mark Li, Qun Lewandowski, Andrew Wu, Hao Swann, Edith O'Connell, Robert J. Peel, Sheila Dawson, Peter Kim, Jerome H. Michael, Nelson L. CA RV 217 Study Team TI Prospective Study of Acute HIV-1 Infection in Adults in East Africa and Thailand SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID VIRUS TYPE-1 INFECTION; T-CELL-ACTIVATION; VIRAL LOAD; SET-POINT; ANTIRETROVIRAL THERAPY; RNA LEVELS; 1ST YEAR; TRANSMISSION; DYNAMICS; PROGRESSION AB BACKGROUND Acute human immunodeficiency virus type 1 (HIV-1) infection is a major contributor to transmission of HIV-1. An understanding of acute HIV-1 infection may be important in the development of treatment strategies to eradicate HIV-1 or achieve a functional cure. METHODS We performed twice-weekly qualitative plasma HIV-1 RNA nucleic acid testing in 2276 volunteers who were at high risk for HIV-1 infection. For participants in whom acute HIV-1 infection was detected, clinical observations, quantitative measurements of plasma HIV-1 RNA levels (to assess viremia) and HIV antibodies, and results of immuno-phenotyping of lymphocytes were obtained twice weekly. RESULTS Fifty of 112 volunteers with acute HIV-1 infection had two or more blood samples collected before HIV-1 antibodies were detected. The median peak viremia (6.7 log 10 copies per milliliter) occurred 13 days after the first sample showed reactivity on nucleic acid testing. Reactivity on an enzyme immunoassay occurred at a median of 14 days. The nadir of viremia (4.3 log 10 copies per milliliter) occurred at a median of 31 days and was nearly equivalent to the viral-load set point, the steady-state viremia that persists durably after resolution of acute viremia (median plasma HIV-1 RNA level, 4.4 log 10 copies per milliliter). The peak viremia and downslope were correlated with the viralload set point. Clinical manifestations of acute HIV-1 infection were most common just before and at the time of peak viremia. A median of one symptom of acute HIV-1 infection was recorded at a median of two study visits, and a median of one sign of acute HIV-1 infection was recorded at a median of three visits. CONCLUSIONS The viral-load set point occurred at a median of 31 days after the first detection of plasma viremia and correlated with peak viremia. Few symptoms and signs were observed during acute HIV-1 infection, and they were most common before peak viremia. (Funded by the Department of Defense and the National Institute of Allergy and Infectious Diseases.) C1 [Robb, Merlin L.; Eller, Leigh A.; Jagodzinski, Linda L.; Malia, Jennifer; Manak, Mark; Tovanabutra, Sodsai; Sanders-Buell, Eric; Rolland, Morgane; Dorsey-Spitz, Julie; Eller, Michael A.; Milazzo, Mark; Li, Qun; Peel, Sheila; Kim, Jerome H.; Michael, Nelson L.] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD USA. [Robb, Merlin L.; Eller, Leigh A.; Manak, Mark; Tovanabutra, Sodsai; Sanders-Buell, Eric; Rolland, Morgane; Dorsey-Spitz, Julie; Eller, Michael A.; Milazzo, Mark] Henry M Jackson Fdn Adv Mil Med, Rockville, MD USA. [Swann, Edith] NIAID, Div Aids, NIH, Rockville, MD USA. [Lewandowski, Andrew; Wu, Hao; Dawson, Peter] Emmes, Rockville, MD USA. [Kibuuka, Hannah] Makerere Univ, Walter Reed Project, Kampala, Uganda. [Rono, Kathleen; Sawe, Fred K.; Sinei, Samuel] Walter Reed Project, Kericho, Kenya. [Maganga, Lucas] Mbeya Med Res Ctr, Mbeya, Tanzania. [Nitayaphan, Sorachai; Kroon, Eugene; Sriplienchan, Somchai; de Souza, Mark S.; O'Connell, Robert J.] Armed Forces Res Inst Med Sci, Bangkok, Thailand. [Kroon, Eugene; de Souza, Mark S.] SEARCH, Thai Red Cross AIDS Res Ctr, Bangkok, Thailand. [Kim, Jerome H.] Int Vaccine Inst, Seoul, South Korea. RP Robb, ML (reprint author), US Mil HIV Res Program, 6720A Rockledge Dr, Bethesda, MD 20817 USA. EM mrobb@hivresearch.org OI Manak, Mark /0000-0002-9217-9129 FU Department of Defense; National Institute of Allergy and Infectious Diseases FX Funded by the Department of Defense and the National Institute of Allergy and Infectious Diseases. NR 39 TC 12 Z9 12 U1 2 U2 3 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 2 PY 2016 VL 374 IS 22 BP 2120 EP 2130 DI 10.1056/NEJMoa1508952 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EB2RP UT WOS:000387209900005 PM 27192360 ER PT J AU Ocampo, J Chereji, RV Eriksson, PR Clark, DJ AF Ocampo, Josefina Chereji, Razvan V. Eriksson, Peter R. Clark, David J. TI The ISW1 and CHD1 ATP-dependent chromatin remodelers compete to set nucleosome spacing in vivo SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TRANSCRIPTION ELONGATION-FACTORS; SACCHAROMYCES-CEREVISIAE; GENOME-WIDE; LINKER HISTONE; ELECTROSTATIC MECHANISM; CODING REGIONS; YEAST GENOME; GENES; RSC; H1 AB Adenosine triphosphate-dependent chromatin remodeling machines play a central role in gene regulation by manipulating chromatin structure. Most genes have a nucleosome-depleted region at the promoter and an array of regularly spaced nucleosomes phased relative to the transcription start site. In vitro, the three known yeast nucleosome spacing enzymes (CHD1, ISW1 and ISW2) form arrays with different spacing. We used genome-wide nucleosome sequencing to determine whether these enzymes space nucleosomes differently in vivo. We find that CHD1 and ISW1 compete to set the spacing onmost genes, such that CHD1 dominates genes with shorter spacing and ISW1 dominates genes with longer spacing. In contrast, ISW2 plays a minor role, limited to transcriptionally inactive genes. Heavily transcribed genes show weak phasing and extreme spacing, either very short or very long, and are depleted of linker histone (H1). Genes with longer spacing are enriched in H1, which directs chromatin folding. We propose that CHD1 directs short spacing, resulting in eviction of H1 and chromatin unfolding, whereas ISW1 directs longer spacing, allowing H1 to bind and condense the chromatin. Thus, competition between the two remodelers to set the spacing on each gene may result in a highly dynamic chromatin structure. C1 [Ocampo, Josefina; Chereji, Razvan V.; Eriksson, Peter R.; Clark, David J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD 20892 USA. RP Clark, DJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD 20892 USA. EM clarkda@mail.nih.gov OI Chereji, Razvan/0000-0002-0572-6412 FU Intramural Research Program of the NIH (NICHD) FX Intramural Research Program of the NIH (NICHD). Funding for open access charge: Intramural Research Program of the NIH (NICHD). NR 62 TC 7 Z9 7 U1 3 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUN 2 PY 2016 VL 44 IS 10 BP 4625 EP 4635 DI 10.1093/nar/gkw068 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DR2SQ UT WOS:000379754600021 PM 26861626 ER PT J AU Yin, JH Wan, BB Sarkar, J Horvath, K Wu, J Chen, Y Cheng, GJ Wan, K Chin, PJ Lei, M Liu, Y AF Yin, Jinhu Wan, Bingbing Sarkar, Jaya Horvath, Kent Wu, Jian Chen, Yong Cheng, Guangjuan Wan, Ke Chin, Peiju Lei, Ming Liu, Yie TI Dimerization of SLX4 contributes to functioning of the SLX4-nuclease complex SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HOLLIDAY JUNCTION RESOLUTION; DNA-REPAIR; FANCONI-ANEMIA; TELOMERE MAINTENANCE; MAMMALIAN TELOMERES; GENOME MAINTENANCE; ENDONUCLEASES; REPLICATION; NUCLEASES; DOMAIN AB The Fanconi anemia protein SLX4 assembles a genome and telomere maintenance toolkit, consisting of the nucleases SLX1, MUS81 and XPF. Although it is known that SLX4 acts as a scaffold for building this complex, the molecular basis underlying this function of SLX4 remains unclear. Here, we report that functioning of SLX4 is dependent on its dimerization via an oligomerization motif called the BTB domain. We solved the crystal structure of the SLX4(BTB) dimer, identifying key contacts (F681 and F708) that mediate dimerization. Disruption of BTB dimerization abrogates nuclear foci formation and telomeric localization of not only SLX4 but also of its associated nucleases. Furthermore, dimerization-deficient SLX4 mutants cause defective cellular response to DNA interstrand crosslinking agent and telomere maintenance, underscoring the contribution of BTB domain-mediated dimerization of SLX4 in genome and telomere maintenance. C1 [Yin, Jinhu; Sarkar, Jaya; Horvath, Kent; Chin, Peiju; Liu, Yie] NIA, Lab Mol Gerontol, NIH, 251 Bayview Blvd, Baltimore, MD 21044 USA. [Wan, Bingbing; Wu, Jian; Chen, Yong; Lei, Ming] Chinese Acad Sci, Shanghai Inst Biol Sci, State Key Lab Mol Biol, Natl Ctr Prot Sci Shanghai,Inst Biochem & Cell Bi, 333 Haike Rd, Shanghai 200031, Peoples R China. [Wan, Bingbing; Cheng, Guangjuan; Wan, Ke; Lei, Ming] Univ Michigan, Sch Med, Dept Biol Chem, 1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. [Lei, Ming] Chinese Acad Sci, Shanghai Res Ctr, Shanghai 200031, Peoples R China. RP Liu, Y (reprint author), NIA, Lab Mol Gerontol, NIH, 251 Bayview Blvd, Baltimore, MD 21044 USA.; Lei, M (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, State Key Lab Mol Biol, Natl Ctr Prot Sci Shanghai,Inst Biochem & Cell Bi, 333 Haike Rd, Shanghai 200031, Peoples R China.; Lei, M (reprint author), Univ Michigan, Sch Med, Dept Biol Chem, 1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA.; Lei, M (reprint author), Chinese Acad Sci, Shanghai Res Ctr, Shanghai 200031, Peoples R China. EM leim@sibcb.ac.cn; liuyie@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute on Aging; Ministry of Science and Technology of China [2013CB910402]; National Natural Science Foundation of China [31330040]; Strategic Priority Research Program of the Chinese Academy of Sciences [XDB08010201]; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357] FX Intramural Research Program of the National Institutes of Health, National Institute on Aging; Ministry of Science and Technology of China [2013CB910402 to M.L.]; National Natural Science Foundation of China [31330040 to M.L.]; Strategic Priority Research Program of the Chinese Academy of Sciences [XDB08010201 to M.L.]; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]. Funding for open access charge: Intramural Research Program of the National Institutes of Health, National Institute on Aging; Ministry of Science and Technology of China [2013CB910402 to M.L.]; National Natural Science Foundation of China [31330040 to M.L.]; Strategic Priority Research Program of the Chinese Academy of Sciences [XDB08010201 to M.L.]. NR 31 TC 1 Z9 1 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUN 2 PY 2016 VL 44 IS 10 BP 4871 EP 4880 DI 10.1093/nar/gkw354 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DR2SQ UT WOS:000379754600037 PM 27131364 ER PT J AU Wang, R Luo, ZP He, KZ Delaney, MO Chen, D Sheng, J AF Wang, Rui Luo, Zhipu He, Kaizhang Delaney, Michael O. Chen, Doris Sheng, Jia TI Base pairing and structural insights into the 5-formylcytosine in RNA duplex SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MITOCHONDRIAL TRNA(MET); OXIDATIVE DEMETHYLATION; CIRCULAR-DICHROISM; ESCHERICHIA-COLI; NONCODING RNA; DNA; 5-HYDROXYMETHYLCYTOSINE; 5-METHYLCYTOSINE; ANTICODON; SEQUENCE AB 5-Formylcytidine (f(5)C), a previously discovered natural nucleotide in the mitochondrial tRNA of many species including human, has been recently detected as the oxidative product of 5-methylcytidine (m(5)C) through 5-hydroxymethylcytidine (hm(5)C) in total RNA of mammalian cells. The discovery indicated that these cytosine derivatives in RNA might also play important epigenetic roles similar as in DNA, which has been intensively investigated in the past few years. In this paper, we studied the base pairing specificity of f(5)C in different RNA duplex contexts. We found that the 5-formyl group could increase duplex thermal stability and enhance base pairing specificity. We present three high-resolution crystal structures of an octamer RNA duplex [5'-GUA(f(5)C)GUAC-3'](2) that have been solved under three crystallization conditions with different buffers and pH values. Our results showed that the 5-formyl group is located in the same plane as the cytosine base and forms an intra-residue hydrogen bond with the amino group in the N4 position. In addition, this modification increases the base stacking between the f(5)C and the neighboring bases while not causing significant global and local structure perturbations. This work provides insights into the effects of 5-formylcytosine on RNA duplex. C1 [Wang, Rui; Chen, Doris; Sheng, Jia] SUNY Albany, Dept Chem, Albany, NY 12222 USA. [Wang, Rui; Chen, Doris; Sheng, Jia] SUNY Albany, RNA Inst, Albany, NY 12222 USA. [Luo, Zhipu] Argonne Natl Lab, Synchrotron Radiat Res Sect, MCL Natl Canc Inst, Argonne, IL 60439 USA. [He, Kaizhang; Delaney, Michael O.] GE Healthcare, Dharmacon, Lafayette, CO 80026 USA. RP Sheng, J (reprint author), SUNY Albany, Dept Chem, Albany, NY 12222 USA.; Sheng, J (reprint author), SUNY Albany, RNA Inst, Albany, NY 12222 USA. EM jsheng@albany.edu FU University at Albany, State University of New York start-up fund; Simons Foundation Postdoctoral Fellowship [338863]; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX University at Albany, State University of New York start-up fund; Simons Foundation Postdoctoral Fellowship [338863 to R. W.]; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, [W-31-109-Eng-38]. Funding for open access charge: University at Albany, State University of New York start-up fund. NR 61 TC 0 Z9 0 U1 8 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUN 2 PY 2016 VL 44 IS 10 BP 4968 EP 4977 DI 10.1093/nar/gkw235 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DR2SQ UT WOS:000379754600045 PM 27079978 ER PT J AU Goldenberg, RL Thorsten, VR Althabe, F Saleem, S Garces, A Carlo, WA Pasha, O Chomba, E Goudar, S Esamai, F Krebs, NF Derman, RJ Liechty, EA Patel, A Hibberd, PL Buekens, PM Koso-Thomas, M Miodovnik, M Jobe, AH Wallace, DD Belizan, JM McClure, EM AF Goldenberg, Robert L. Thorsten, Vanessa R. Althabe, Fernando Saleem, Sarah Garces, Ana Carlo, Waldemar A. Pasha, Omrana Chomba, Elwyn Goudar, Shivaprasad Esamai, Fabian Krebs, Nancy F. Derman, Richard J. Liechty, Edward A. Patel, Archana Hibberd, Patricia L. Buekens, Pierre M. Koso-Thomas, Marion Miodovnik, Menachem Jobe, Alan H. Wallace, Dennis D. Belizan, Jose M. McClure, Elizabeth M. TI The global network antenatal corticosteroids trial: impact on stillbirth SO REPRODUCTIVE HEALTH LA English DT Article ID MIDDLE-INCOME COUNTRIES; PRETERM BIRTH; NEONATAL DEATH; RISK; MULTICOUNTRY; PREGNANCY; WOMEN AB Background: Antenatal corticosteroids are commonly used to reduce neonatal mortality, but most research to date has been in high-resource settings and few studies have evaluated its impact on stillbirth. In the Antenatal Corticosteroids Trial (ACT), a multi-country trial to assess impact of a multi-faceted intervention including antenatal corticosteroids to reduce neonatal mortality associated with preterm birth, we found an overall increase in 28-day neonatal mortality and stillbirth associated with the intervention. Methods: The ACT was a cluster-randomized trial conducted in 102 clusters across 7 research sites in 6 countries (India [ 2 sites], Pakistan, Zambia, Kenya, Guatemala and Argentina), comparing an intervention to train birth attendants at all levels of the health system to identify women at risk of preterm birth, administer corticosteroids and refer women at risk. Because of inadequate gestational age dating, the <5th percentile birth weight was used as a proxy for preterm birth. A pre-specified secondary outcome of the trial was stillbirth. Results: After adjusting for the pre-trial imbalance in stillbirth rates, the ACT intervention was associated with a non-significant increased risk of stillbirth (aRR 1.08, 95 % CI, 0.99-1.17, p-0.073). Additionally, the stillbirth rate was higher in the term births (1.20 95 % CI 1.06-1.37, 0.004) and among those with signs of maceration (RR 1.18 (1.04-1.35), p = 0.013) in the intervention vs. control clusters. Differences in obstetric care favored the control clusters and maternal infection was likely more common in the intervention clusters. Conclusions: In this pragmatic trial, limited data were available to identify the causes of the increase in stillbirths in the intervention clusters. A higher rate of stillbirth in the intervention clusters prior to the trial, differences in obstetric care and an increase in maternal infection are potential explanations for the observed increase in stillbirths in the intervention clusters during the trial. C1 [Goldenberg, Robert L.; Saleem, Sarah] Columbia Univ, New York, NY USA. [Thorsten, Vanessa R.; Wallace, Dennis D.; McClure, Elizabeth M.] RTI Int, Durham, NC USA. [Althabe, Fernando; Belizan, Jose M.] IECS, Buenos Aires, DF, Argentina. [Saleem, Sarah; Pasha, Omrana] Aga Khan Univ, Karachi, Pakistan. [Carlo, Waldemar A.] Univ Alabama Birmingham, Birmingham, AL USA. [Chomba, Elwyn] Univ Teaching Hosp, Lusaka, Zambia. [Goudar, Shivaprasad] KLE Univ JN Med Coll, Belgaum, India. [Esamai, Fabian] Moi Univ, Eldoret, Kenya. [Krebs, Nancy F.] Univ Colorado, Sch Med, Denver, CO USA. [Derman, Richard J.] Christiana Care, Newark, DE USA. [Liechty, Edward A.] Indiana Univ, Indianapolis, IN 46204 USA. [Patel, Archana] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Hibberd, Patricia L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Buekens, Pierre M.] Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Koso-Thomas, Marion; Miodovnik, Menachem] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Jobe, Alan H.] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Goldenberg, Robert L.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. RP Goldenberg, RL (reprint author), Columbia Univ, New York, NY USA.; Goldenberg, RL (reprint author), Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. EM rlg@columbia.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 HD058322, U01 HD040477, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD058326, U01 HD040636]; Bill and Melinda Gates Foundation FX This trial was funded through grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U01 HD058322, U01 HD040477, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD058326, U01 HD040636). Additional support was also provided by the Bill and Melinda Gates Foundation (FA, KK, JMB) NR 13 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 1742-4755 J9 REPROD HEALTH JI Reprod. Health PD JUN 2 PY 2016 VL 13 AR 68 DI 10.1186/s12978-016-0174-4 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DP6OU UT WOS:000378617300001 PM 27255082 ER PT J AU Knittel, G Liedgens, P Korovkina, D Seeger, JM Al-Baldawi, Y Al-Maarri, M Fritz, C Vlantis, K Bezhanova, S Scheel, AH Wolz, OO Reimann, M Moller, P Lopez, C Schlesner, M Lohneis, P Weber, ANR Trumper, L Staudt, LM Ortmann, M Pasparakis, M Siebert, R Schmitt, CA Klatt, AR Wunderlich, FT Schafer, SC Persigehl, T Montesinos-Rongen, M Odenthal, M Buttner, R Frenzel, LP Kashkar, H Reinhardt, HC AF Knittel, Gero Liedgens, Paul Korovkina, Darya Seeger, Jens M. Al-Baldawi, Yussor Al-Maarri, Mona Fritz, Christian Vlantis, Katerina Bezhanova, Svetlana Scheel, Andreas H. Wolz, Olaf-Oliver Reimann, Maurice Moeller, Peter Lopez, Cristina Schlesner, Matthias Lohneis, Philipp Weber, Alexander N. R. Truemper, Lorenz Staudt, Louis M. Ortmann, Monika Pasparakis, Manolis Siebert, Reiner Schmitt, Clemens A. Klatt, Andreas R. Wunderlich, F. Thomas Schaefer, Stephan C. Persigehl, Thorsten Montesinos-Rongen, Manuel Odenthal, Margarete Buettner, Reinhard Frenzel, Lukas P. Kashkar, Hamid Reinhardt, H. Christian CA German Int Canc Genome Consortium Mol Mech Malignant Lymphoma Sequen TI B-cell-specific conditional expression of Myd88(p.L252P) leads to the development of diffuse large B-cell lymphoma in mice SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; IDENTIFIES RECURRENT MUTATIONS; WALDENSTROM MACROGLOBULINEMIA; SOMATIC MUTATION; GERMINAL CENTER; MYD88 L265P; GENE; DIFFERENTIATION; CLASSIFICATION; ACTIVATION AB The adaptor protein MYD88 is critical for relaying activation of Toll-like receptor signaling to NF-kappa B activation. MYD88 mutations, particularly the p.L265P mutation, have been described in numerous distinct B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL). Twenty-nine percent of activated B-cell-type DLBCL (ABC-DLBCL), which is characterized by constitutive activation of the NF-kappa B pathway, carry the p.L265P mutation. In addition, ABC-DLBCL frequently displays focal copy number gains affecting BCL2. Here, we generated a novel mouse model in which Cre-mediated recombination, specifically in B cells, leads to the conditional expression of Myd88(p.L252P) (the orthologous position of the human MYD88(p.L265P) mutation) from the endogenous locus. These mice develop a lymphoproliferative disease and occasional transformation into clonal lymphomas. The clonal disease displays the morphologic and immunophenotypical characteristics of ABC-DLBCL. Lymphomagenesis can be accelerated by crossing in a further novel allele, which mediates conditional overexpression of BCL2. Cross-validation experiments in human DLBCL samples revealed that both MYD88 and CD79B mutations are substantially enriched in ABC-DLBCL compared with germinal center B-cell DLBCL. Furthermore, analyses of human DLBCL genome sequencing data confirmed that BCL2 amplifications frequently co-occurred with MYD88 mutations, further validating our approach. Finally, in silico experiments revealed that MYD88-mutant ABC-DLBCL cells in particular display an actionable addiction to BCL2. Altogether, we generated a novel autochthonous mouse model of ABC-DLBCL that could be used as a preclinical platform for the development and validation of novel therapeutic approaches for the treatment of ABC-DLBCL. C1 [Knittel, Gero; Liedgens, Paul; Korovkina, Darya; Fritz, Christian; Frenzel, Lukas P.; Reinhardt, H. Christian] Univ Hosp Cologne, Dept Internal Med 1, Weyertal 115B, D-50931 Cologne, Germany. [Knittel, Gero; Liedgens, Paul; Korovkina, Darya; Seeger, Jens M.; Fritz, Christian; Vlantis, Katerina; Pasparakis, Manolis; Frenzel, Lukas P.; Kashkar, Hamid; Reinhardt, H. Christian] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany. [Seeger, Jens M.; Kashkar, Hamid] Univ Hosp Cologne, Fac Med, Inst Microbiol & Hyg, D-50931 Cologne, Germany. [Al-Baldawi, Yussor; Persigehl, Thorsten] Univ Hosp Cologne, Fac Med, Dept Radiol, D-50931 Cologne, Germany. [Al-Maarri, Mona; Wunderlich, F. Thomas] Max Planck Inst Metab Res, Cologne, Germany. [Bezhanova, Svetlana; Scheel, Andreas H.; Ortmann, Monika; Schaefer, Stephan C.; Odenthal, Margarete; Buettner, Reinhard] Univ Hosp Cologne, Inst Pathol, D-50931 Cologne, Germany. [Bezhanova, Svetlana] NN Blokhin Russian Canc Res Ctr, Moscow, Russia. [Wolz, Olaf-Oliver; Weber, Alexander N. R.] Univ Tubingen, Dept Immunol, Interfac Inst Cell Biol, Tubingen, Germany. [Reimann, Maurice; Schmitt, Clemens A.] Charite Univ Med Ctr, Dept Hematol Oncol, Berlin, Germany. [Moeller, Peter] Univ Ulm, Fac Med, Inst Pathol, D-89069 Ulm, Germany. [Lopez, Cristina; Siebert, Reiner] Univ Kiel, Inst Human Genet, Kiel, Germany. [Lopez, Cristina; Siebert, Reiner] Univ Hosp Schleswig Holstein, Kiel, Germany. [Schlesner, Matthias] German Canc Res Ctr, Dept Theoret Bioinformat, Heidelberg, Germany. [Lohneis, Philipp] Charite Univ Med Ctr, Dept Pathol, Berlin, Germany. [Truemper, Lorenz] Univ Gottingen, Dept Hematol & Oncol, Gottingen, Germany. [Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Schmitt, Clemens A.] Helmholtz Assoc, Max Delbruck Ctr Mol Med, Berlin, Germany. [Klatt, Andreas R.] Univ Hosp Cologne, Inst Clin Chem, D-50931 Cologne, Germany. [Montesinos-Rongen, Manuel] Univ Hosp Cologne, Inst Neuropathol, D-50931 Cologne, Germany. [Odenthal, Margarete; Buettner, Reinhard; Frenzel, Lukas P.; Reinhardt, H. Christian] Univ Hosp Cologne, Ctr Integrated Oncol, D-50931 Cologne, Germany. [Buettner, Reinhard; Kashkar, Hamid; Reinhardt, H. Christian] Univ Cologne, Ctr Mol Med, D-50931 Cologne, Germany. RP Reinhardt, HC (reprint author), Univ Hosp Cologne, Dept Internal Med 1, Weyertal 115B, D-50931 Cologne, Germany. EM christian.reinhardt@uk-koeln.de RI Siebert, Reiner/A-8049-2010 FU Volkswagenstiftung (Lichtenberg Program); Deutsche Forschungsgemeinschaft [KFO-286, KA 2853/4-1, SFB-685]; Deutsche Jose Carreras Leukamie Stiftung [R12/26]; Marga und Walter Boll Stiftung [210-05-13]; Helmholtz-Gemeinschaft (Preclinical Comprehensive Cancer Center); Else Kroner-Fresenius Stiftung [EKFS-2014-A06]; Marlene Porsche Foundation for Cancer Prevention; Else-Ubelmesser Stiftung (Juniorprofessoren-Programn); Deutsche Krebshilfe [111724]; German Ministry of Science and Education in the framework of the International CancerGenome Consortium Molecular Mechanisms in Malignant Lymphoma by Sequencing Project [01KU1002A-J] FX This work was supported by the Volkswagenstiftung (Lichtenberg Program [H.C.R.]), the Deutsche Forschungsgemeinschaft (KFO-286 [H.C.R., H.K., F.T.W., and L.P.F.], KA 2853/4-1 [H.K.], and SFB-685 [A.N.R.W., O.-O.W.]), the Deutsche Jose Carreras Leukamie Stiftung (R12/26 [H.C.R. and L.P.F.]), the Marga und Walter Boll Stiftung (210-05-13 [L.P.F.]), the Helmholtz-Gemeinschaft (Preclinical Comprehensive Cancer Center [H.C.R. and C.A.S.]), the Else Kroner-Fresenius Stiftung (EKFS-2014-A06 [H.C.R.]), the Marlene Porsche Foundation for Cancer Prevention (S.B.), the Else-Ubelmesser Stiftung (Juniorprofessoren-Programn [A.N.R.W]), the Deutsche Krebshilfe (111724 [H.C.R.]), and the German Ministry of Science and Education in the framework of the International CancerGenome Consortium Molecular Mechanisms in Malignant Lymphoma by Sequencing Project (01KU1002A-J [C.L., P.M., L.T., and R.S.]). NR 56 TC 6 Z9 6 U1 1 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 2 PY 2016 VL 127 IS 22 BP 2732 EP 2741 DI 10.1182/blood-2015-11684183 PG 10 WC Hematology SC Hematology GA DP2QS UT WOS:000378335400015 PM 27048211 ER PT J AU Green, RC Goddard, KAB Jarvik, GP Amendola, LM Appelbaum, PS Berg, JS Bernhardt, BA Biesecker, LG Biswas, S Blout, CL Bowling, KM Brothers, KB Burke, W Caga-anan, CF Chinnaiyan, AM Chung, WK Clayton, EW Cooper, GM East, K Evans, JP Fullerton, SM Garraway, LA Garrett, JR Gray, SW Henderson, GE Hindorff, LA Holm, IA Lewis, MH Hutter, CM Janne, PA Joffe, S Kaufman, D Knoppers, BM Koenig, BA Krantz, ID Manolio, TA McCullough, L McEwen, J McGuire, A Muzny, D Myers, RM Nickerson, DA Ou, J Parsons, DW Petersen, GM Plon, SE Rehm, HL Roberts, JS Robinson, D Salama, JS Scollon, S Sharp, RR Shirts, B Spinner, NB Tabor, HK Tarczy-Hornoch, P Veenstra, DL Wagle, N Weck, K Wilfond, BS Wilhelmsen, K Wolf, SM Wynn, J Yu, JH AF Green, Robert C. Goddard, Katrina A. B. Jarvik, Gail P. Amendola, Laura M. Appelbaum, Paul S. Berg, Jonathan S. Bernhardt, Barbara A. Biesecker, Leslie G. Biswas, Sawona Blout, Carrie L. Bowling, Kevin M. Brothers, Kyle B. Burke, Wylie Caga-anan, Charlisse F. Chinnaiyan, Arul M. Chung, Wendy K. Clayton, Ellen W. Cooper, Gregory M. East, Kelly Evans, James P. Fullerton, Stephanie M. Garraway, Levi A. Garrett, Jeremy R. Gray, Stacy W. Henderson, Gail E. Hindorff, Lucia A. Holm, Ingrid A. Lewis, Michelle Huckaby Hutter, Carolyn M. Janne, Pasi A. Joffe, Steven Kaufman, David Knoppers, Bartha M. Koenig, Barbara A. Krantz, Ian D. Manolio, Teri A. McCullough, Laurence McEwen, Jean McGuire, Amy Muzny, Donna Myers, Richard M. Nickerson, Deborah A. Ou, Jeffrey Parsons, Donald W. Petersen, Gloria M. Plon, Sharon E. Rehm, Heidi L. Roberts, J. Scott Robinson, Dan Salama, Joseph S. Scollon, Sarah Sharp, Richard R. Shirts, Brian Spinner, Nancy B. Tabor, Holly K. Tarczy-Hornoch, Peter Veenstra, David L. Wagle, Nikhil Weck, Karen Wilfond, Benjamin S. Wilhelmsen, Kirk Wolf, Susan M. Wynn, Julia Yu, Joon-Ho CA CSER Consortium TI Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID OBTAINING INFORMED-CONSENT; GENETIC RESEARCH FINDINGS; ELECTRONIC HEALTH RECORD; INCIDENTAL-FINDINGS; WHOLE-EXOME; MEDSEQ PROJECT; RESEARCH PARTICIPANTS; ACMG RECOMMENDATIONS; BEHAVIORAL ECONOMICS; PERCEIVED UTILITY AB Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstreamcosts of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine. C1 [Green, Robert C.; Blout, Carrie L.] Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Green, Robert C.; Garraway, Levi A.; Rehm, Heidi L.; Wagle, Nikhil] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Green, Robert C.; Gray, Stacy W.; Holm, Ingrid A.; Janne, Pasi A.; Rehm, Heidi L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Green, Robert C.; Rehm, Heidi L.] Partners Personalized Med, Boston, MA 02139 USA. [Goddard, Katrina A. B.] Kaiser Permanente Northwest, Ctr Hlth Res, Portland, OR 97227 USA. [Jarvik, Gail P.; Nickerson, Deborah A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Jarvik, Gail P.; Amendola, Laura M.; Burke, Wylie; Ou, Jeffrey; Salama, Joseph S.; Tarczy-Hornoch, Peter] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Jarvik, Gail P.; Amendola, Laura M.; Burke, Wylie; Ou, Jeffrey; Salama, Joseph S.] Univ Washington, Clin Sequencing Exploratory Res Coordinating Ctr, Seattle, WA 98195 USA. [Appelbaum, Paul S.] Columbia Univ, Med Ctr, Dept Psychiat, New York, NY 10032 USA. [Appelbaum, Paul S.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Berg, Jonathan S.; Evans, James P.; Weck, Karen; Wilhelmsen, Kirk] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Bernhardt, Barbara A.; Biswas, Sawona; Krantz, Ian D.; Spinner, Nancy B.] Univ Penn, Perelman Sch Med, Dept Med, Div Translat Med & Human Genet, Philadelphia, PA 19104 USA. [Biesecker, Leslie G.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. [Biswas, Sawona; Krantz, Ian D.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Bowling, Kevin M.; Cooper, Gregory M.; East, Kelly; Myers, Richard M.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Brothers, Kyle B.] Univ Louisville, Dept Pediat, Louisville, KY 40202 USA. [Burke, Wylie; Fullerton, Stephanie M.] Univ Washington, Dept Med, Dept Bioeth & Humanities, Seattle, WA 98195 USA. [Caga-anan, Charlisse F.] NCI, NIH, Bethesda, MD 20892 USA. [Chinnaiyan, Arul M.; Robinson, Dan] Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA. [Chinnaiyan, Arul M.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Chinnaiyan, Arul M.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Chinnaiyan, Arul M.] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA. [Chinnaiyan, Arul M.] Howard Hughes Med Inst, Ann Arbor, MI 48109 USA. [Chung, Wendy K.; Wynn, Julia] Columbia Univ, Dept Pediat, New York, NY 10029 USA. [Chung, Wendy K.] Columbia Univ, Med Ctr, Dept Med, New York, NY 10032 USA. [Clayton, Ellen W.] Vanderbilt Univ, Ctr Biomed Eth & Soc, Nashville, TN 37203 USA. [Garraway, Levi A.; Wagle, Nikhil] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Garraway, Levi A.; Wagle, Nikhil] Dana Farber Canc Inst, Ctr Canc Precis Med, Boston, MA 02115 USA. [Garraway, Levi A.; Wagle, Nikhil] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Garrett, Jeremy R.] Childrens Mercy Hosp, Childrens Mercy Bioeth Ctr, Kansas City, MO 64108 USA. [Garrett, Jeremy R.] Univ Missouri, Dept Pediat, Kansas City, MO 64110 USA. [Garrett, Jeremy R.] Univ Missouri, Dept Philosophy, Kansas City, MO 64110 USA. [Gray, Stacy W.; Janne, Pasi A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Henderson, Gail E.] Univ N Carolina, Sch Med, Dept Social Med, Chapel Hill, NC 27599 USA. [Hindorff, Lucia A.; Hutter, Carolyn M.; Manolio, Teri A.] NHGRI, Div Genom Med, NIH, Bethesda, MD 20892 USA. [Holm, Ingrid A.] Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA. [Holm, Ingrid A.] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Lewis, Michelle Huckaby] Johns Hopkins, Berman Inst Bioeth, Baltimore, MD 21205 USA. [Joffe, Steven; McGuire, Amy] Univ Penn, Sch Med, Dept Med Eth & Hlth Policy, Philadelphia, PA 19104 USA. [Kaufman, David; McEwen, Jean] NHGRI, Div Genom & Soc, NIH, Bethesda, MD 20892 USA. [Knoppers, Bartha M.] McGill Univ, Dept Human Genet, Fac Med, Ctr Genom & Policy, Montreal, PQ H3A 1B1, Canada. [Koenig, Barbara A.] Univ Calif San Francisco, Inst Hlth & Aging, San Francisco, CA 94118 USA. [McCullough, Laurence; McGuire, Amy] Baylor Coll Med, Ctr Med Eth & Hlth Policy, Houston, TX 77030 USA. [Muzny, Donna] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Parsons, Donald W.; Plon, Sharon E.] Baylor Coll Med, Houston, TX 77030 USA. [Parsons, Donald W.; Plon, Sharon E.] Texas Childrens Canc Ctr, Houston, TX 77030 USA. [Petersen, Gloria M.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Rehm, Heidi L.] Partners HealthCare, Mol Med Lab, Cambridge, MA 02139 USA. [Roberts, J. Scott] Univ Michigan, Sch Publ Hlth, Dept Hlth Behav & Hlth Educ, Ann Arbor, MI 48109 USA. [Scollon, Sarah] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Sharp, Richard R.] Mayo Clin, Coll Med, Biomed Eth Res Program, Rochester, MN 55905 USA. [Shirts, Brian] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Spinner, Nancy B.] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Tabor, Holly K.; Wilfond, Benjamin S.; Yu, Joon-Ho] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Tabor, Holly K.; Wilfond, Benjamin S.] Univ Washington, Seattle Childrens Res Inst, Seattle, WA 98195 USA. [Tarczy-Hornoch, Peter] Univ Washington, Seattle, WA 98105 USA. [Veenstra, David L.] Univ Washington, Dept Pharm, Seattle, WA 98195 USA. [Weck, Karen] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Wolf, Susan M.] Univ Minnesota, Sch Med, Sch Law, Minneapolis, MN 55455 USA. [Wolf, Susan M.] Univ Minnesota, Consortium Law & Values Hlth Environm & Life Sci, Minneapolis, MN 55455 USA. RP Green, RC (reprint author), Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA.; Green, RC (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Green, RC (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA.; Green, RC (reprint author), Partners Personalized Med, Boston, MA 02139 USA. EM rcgreen@genetics.med.harvard.edu OI Tarczy-Hornoch, Peter/0000-0003-1047-179X; Lebo, Matthew/0000-0002-9733-5207; Seifert, Bryce/0000-0001-7970-3611 FU NHGRI; [U01HG0006546]; [U01HG006485]; [U01HG006500]; [U01HG006492]; [UM1HG007301]; [UM1HG007292]; [UM1HG006508]; [U01HG006487]; [U01HG006507]; [U01HG007307]; [U01HG006379]; [U41HG006834]; [U54HG003273]; [R21HG006596]; [P20HG007243]; [P50HG007257]; [R01HG006600]; [R01HG004500]; [R01CA154517]; [R01HG006618]; [R21HG006594]; [R01HG006615]; [R21HG006612]; [5R21HG006613]; [R01HG007063]; [HG008685]; [UL1TR000423]; [UA01AG047109]; [K99HG007076] FX The authors thank Julia Fekecs of the National Human Genome Research Institute (NHGRI) for her technical assistance with Figure 1. The authors would like to thank all of the Clinical Sequencing Exploratory Research (CSER) participants for their involvement in this research. The authors also thank the members of their CSER advisory panel: Katrina Armstrong, MD; Rex L. Chisholm, PhD; Mildred K. Cho, PhD; Chanita H. Halbert, PhD; Elaine Lyon, PhD; Kenneth Offit, MD; Dan Roden, MD; Pamela Sankar, PhD; and Alan Williamson, PhD. The research described in this report was funded by grants U01HG0006546, U01HG006485, U01HG006500, U01HG006492, UM1HG007301, UM1HG007292, UM1HG006508, U01HG006487, U01HG006507, U01HG007307, U01HG006379, U41HG006834, U54HG003273, R21HG006596, P20HG007243, R01HG006600, P50HG007257, R01HG006600, R01HG004500, R01CA154517, R01HG006618, R21HG006594, R01HG006615, R21HG006612, 5R21HG006613, R01HG007063, HG008685, UL1TR000423, UA01AG047109, and K99HG007076. ClinSeq is supported by the NHGRI Intramural Research Program. C.F.C.-A., L.A.H., C.M.H., D.K., T.A.M., and J.M. are members of the NIH CSER staff team, responsible for management of the CSER program. NR 109 TC 12 Z9 12 U1 5 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUN 2 PY 2016 VL 98 IS 6 BP 1051 EP 1066 DI 10.1016/j.ajhg.2016.04.011 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA DN7US UT WOS:000377286000001 PM 27181682 ER PT J AU Amendola, LM Jarvik, GP Leo, MC McLaughlin, HM Akkari, Y Amaral, MD Berg, JS Biswas, S Bowling, KM Conlin, LK Cooper, GM Dorschner, MO Dulik, MC Ghazani, AA Ghosh, R Green, RC Hart, R Horton, C Johnston, JJ Lebo, MS Milosavljevic, A Ou, J Pak, CM Patel, RY Punj, S Richards, CS Salama, J Strande, NT Yang, YP Plon, SE Biesecker, LG Rehm, HL AF Amendola, Laura M. Jarvik, Gail P. Leo, Michael C. McLaughlin, Heather M. Akkari, Yassmine Amaral, Michelle D. Berg, Jonathan S. Biswas, Sawona Bowling, Kevin M. Conlin, Laura K. Cooper, Greg M. Dorschner, Michael O. Dulik, Matthew C. Ghazani, Arezou A. Ghosh, Rajarshi Green, Robert C. Hart, Ragan Horton, Carrie Johnston, Jennifer J. Lebo, Matthew S. Milosavljevic, Aleksandar Ou, Jeffrey Pak, Christine M. Patel, Ronak Y. Punj, Sumit Richards, Carolyn Sue Salama, Joseph Strande, Natasha T. Yang, Yaping Plon, Sharon E. Biesecker, Leslie G. Rehm, Heidi L. TI Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID SPASTIC PARAPLEGIA; GENE; MUTATION; RECOMMENDATIONS; PHENOTYPE; STANDARDS; TESTS; SPG7 AB Evaluating the pathogenicity of a variant is challenging given the plethora of types of genetic evidence that laboratories consider. Deciding how to weigh each type of evidence is difficult, and standards have been needed. In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for the assessment of variants in genes associated with Mendelian diseases. Nine molecular diagnostic laboratories involved in the Clinical Sequencing Exploratory Research (CSER) consortium piloted these guidelines on 99 variants spanning all categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign). Nine variants were distributed to all laboratories, and the remaining 90 were evaluated by three laboratories. The laboratories classified each variant by using both the laboratory's own method and the ACMG-AMP criteria. The agreement between the two methods used within laboratories was high (K-alpha = 0.91) with 79% concordance. However, there was only 34% concordance for either classification system across laboratories. After consensus discussions and detailed review of the ACMG=AMP criteria, concordance increased to 71%. Causes of initial discordance in ACMG-AMP classifications were identified, and recommendations on clarification and increased specification of the ACMG-AMP criteria were made. In summary, although an initial pilot of the ACMG-AMP guidelines did not lead to increased concordance in variant interpretation, comparing variant interpretations to identify differences and having a common framework to facilitate resolution of those differences were beneficial for improving agreement, allowing iterative movement toward increased reporting consistency for variants in genes associated with monogenic disease. C1 [Amendola, Laura M.; Jarvik, Gail P.; Hart, Ragan; Ou, Jeffrey; Salama, Joseph] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Leo, Michael C.] Kaiser Permanente, Ctr Hlth Res, Portland, OR 97227 USA. [McLaughlin, Heather M.; Green, Robert C.; Lebo, Matthew S.; Rehm, Heidi L.] Partners HealthCare Personalized Med, Mol Med Lab, Cambridge, MA 02139 USA. [Akkari, Yassmine; Pak, Christine M.; Punj, Sumit; Richards, Carolyn Sue] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97239 USA. [Amaral, Michelle D.; Bowling, Kevin M.; Cooper, Greg M.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Berg, Jonathan S.; Strande, Natasha T.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Biswas, Sawona; Conlin, Laura K.] Childrens Hosp Philadelphia, Dept Pediat, Div Human Genet, Philadelphia, PA 19104 USA. [Dorschner, Michael O.] Univ Washington, Dept Pathol, Ctr Precis Diagnost, Seattle, WA 98195 USA. [Dulik, Matthew C.] Childrens Hosp Philadelphia, Dept Pathol & LaboratoryMedicine, Philadelphia, PA 19104 USA. [Ghazani, Arezou A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Ghosh, Rajarshi; Milosavljevic, Aleksandar; Patel, Ronak Y.; Yang, Yaping; Plon, Sharon E.] Baylor Coll Med, Houston, TX 77030 USA. [Green, Robert C.; Lebo, Matthew S.; Rehm, Heidi L.] Brigham & Womens Hosp, Cambridge, MA 02115 USA. [Green, Robert C.; Lebo, Matthew S.; Rehm, Heidi L.] Harvard Univ, Sch Med, Cambridge, MA 02115 USA. [Horton, Carrie] Ambry Genet, Clin Diagnost, Aliso Viejo, CA 92656 USA. [Johnston, Jennifer J.; Biesecker, Leslie G.] NHGRI, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Green, Robert C.; Rehm, Heidi L.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. RP Jarvik, GP (reprint author), Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA.; Rehm, HL (reprint author), Partners HealthCare Personalized Med, Mol Med Lab, Cambridge, MA 02139 USA.; Rehm, HL (reprint author), Brigham & Womens Hosp, Cambridge, MA 02115 USA.; Rehm, HL (reprint author), Harvard Univ, Sch Med, Cambridge, MA 02115 USA.; Rehm, HL (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM pair@u.washington.edu; hrehm@partners.org OI Strande, Natasha/0000-0001-5148-9772; Lebo, Matthew/0000-0002-9733-5207 FU National Human Genome Research Institute (NHGRI); National Cancer Institute [UO1HG0006546, U01HG006485, U01HG006500, U01HG006492, UM1HG007301, UM1HG007292, UM1HG006508, U01HG006487, U01HG006507, U01HG007307, U41HG006834]; NIH NHGRI; The National Cancer Institute [R21HG006596, P50HG007257, R01HG006600, R01HG004500, R01CA154517, R01HG006618, R21HG006594-01, R01HG006615-01, R21HG006612, 5R21HG006613-02] FX This work was funded by the National Human Genome Research Institute (NHGRI) and National Cancer Institute (UO1HG0006546, U01HG006485, U01HG006500, U01HG006492, UM1HG007301, UM1HG007292, UM1HG006508, U01HG006487, U01HG006507, U01HG007307, U41HG006834, R21HG006596, R01HG006600, P50HG007257, R01HG006600, R01HG004500, R01CA154517, R01HG006618, R21HG006594-01, R01HG006615-01, R21HG006612, and 5R21HG006613-02) and additional support from the participating laboratories. This research was supported in part by the Intramural Research Program of the NIH NHGRI. We thank the following individuals for contributing to variant assessment at the sites: Hana Zouk, PhD; Steven M. Harrison, PhD; Jillian G. Buchan, PhD; Jessica Booker, PhD; Jim Evans, MD, PhD, Kate Foreman, MS; Gloria Haskell, PhD; Kristy Lee, MS; Julianne O'Daniel, MS; Bradford Powell, MD, PhD; Bryce Seifert, PhD; and Karen Weck, MD. NR 26 TC 26 Z9 26 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUN 2 PY 2016 VL 98 IS 6 BP 1067 EP 1076 DI 10.1016/j.ajhg.2016.03.024 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DN7US UT WOS:000377286000002 PM 27181684 ER PT J AU Sartorius, CA Hanna, CT Gril, B Cruz, H Serkova, NJ Huber, KM Kabos, P Schedin, TB Borges, VF Steeg, PS Cittelly, DM AF Sartorius, C. A. Hanna, C. T. Gril, B. Cruz, H. Serkova, N. J. Huber, K. M. Kabos, P. Schedin, T. B. Borges, V. F. Steeg, P. S. Cittelly, D. M. TI Estrogen promotes the brain metastatic colonization of triple negative breast cancer cells via an astrocyte-mediated paracrine mechanism SO ONCOGENE LA English DT Article ID NERVOUS-SYSTEM METASTASES; RECEPTOR-ALPHA; AROMATASE EXPRESSION; PROGNOSTIC-FACTORS; TUMOR-GROWTH; IN-VITRO; ESTRADIOL; SURVIVAL; S100A4; BETA AB Brain metastases (BM) are a devastating consequence of breast cancer. BM occur more frequently in patients with estrogen receptor-negative (ER-) breast cancer subtypes; HER2 overexpressing (HER2+) tumors and triple-negative (TN) (ER-, progesterone receptor-negative (PR-) and normal HER2) tumors. Young age is an independent risk factor for the development of BM, thus we speculated that higher circulating estrogens in young, pre-menopausal women could exert paracrine effects through the highly estrogen-responsive brain microenvironment. Using a TN experimental metastases model, we demonstrate that ovariectomy decreased the frequency of magnetic resonance imaging-detectable lesions by 56% as compared with estrogen supplementation, and that the combination of ovariectomy and letrozole further reduced the frequency of large lesions to 14.4% of the estrogen control. Human BM expressed 4.2-48.4% ER+ stromal area, particularly ER+ astrocytes. In vitro, E2-treated astrocytes increased proliferation, migration and invasion of 231BR-EGFP cells in an ER-dependent manner. E2 upregulated epidermal growth factor receptor (EGFR) ligands Egf, Ereg and Tgfa mRNA and protein levels in astrocytes, and activated EGFR in brain metastatic cells. Co-culture of 231BR-EGFP cells with E2-treated astrocytes led to the upregulation of the metastatic mediator S100 Calcium-binding protein A4 (S100A4) (1.78-fold, P < 0.05). Exogenous EGF increased S100A4 mRNA levels in 231BR-EGFP cells (1.40 +/- 0.02-fold, P < 0.01 compared with vehicle control) and an EGFR/HER2 inhibitor blocked this effect, suggesting that S100A4 is a downstream effector of EGFR activation. Short hairpin RNA-mediated S100A4 silencing in 231BR-EGFP cells decreased their migration and invasion in response to E2-CM, abolished their increased proliferation in co-cultures with E2-treated astrocytes and decreased brain metastatic colonization. Thus, S100A4 is one effector of the paracrine action of E2 in brain metastatic cells. These studies provide a novel mechanism by which estrogens, acting through ER+ astrocytes in the brain microenvironment, can promote BM of TN breast cancers, and suggests existing endocrine agents may provide some clinical benefit towards reducing and managing BM. C1 [Sartorius, C. A.; Hanna, C. T.; Cruz, H.; Cittelly, D. M.] Univ Colorado Denver, Dept Pathol, Anschutz Med Campus, Aurora, CO 80045 USA. [Gril, B.; Steeg, P. S.] NCI, Womens Malignancies Branch, Bethesda, MD 20892 USA. [Serkova, N. J.; Huber, K. M.] Univ Colorado Denver, Dept Anesthesiol, Anschutz Med, Aurora, CO 80045 USA. [Kabos, P.; Schedin, T. B.; Borges, V. F.] Univ Colorado Denver, Div Med Oncol, Dept Med, Anschutz Med Campus, Aurora, CO 80045 USA. RP Cittelly, DM (reprint author), Univ Colorado Denver, Dept Pathol, Anschutz Med Campus,12801 E 17th Ave MS8104, Aurora, CO 80045 USA. EM Diana.Cittelly@ucdenver.edu FU NCI [P30CA046934, K22CA181250]; CTSA Center grant [UL1TR001082]; DOD BCRP [W81XWH-11-1-0101]; ACS IRG [57-001-53]; NIH [R01 CA140985] FX We thank the University of Colorado Cancer Center Animal Imaging Shared Resources, Tissue Culture Core, Cytometry and Cell Sorting Shared Resource and Functional Genomics Facility supported by NCI P30CA046934 and CTSA UL1TR001082 Center grants. Susan Edgerton provided de-identified tissue. This work was supported by DOD BCRP W81XWH-11-1-0101 (DMC), ACS IRG # 57-001-53 (DMC) and NCI K22CA181250 (DMC). CAS was supported by NIH R01 CA140985. NR 54 TC 3 Z9 3 U1 4 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD JUN 2 PY 2016 VL 35 IS 22 BP 2881 EP 2892 DI 10.1038/onc.2015.353 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DO0MT UT WOS:000377473700008 PM 26411365 ER PT J AU Tweedie, D Fukui, K Li, YZ Yu, QS Barak, S Tamargo, IA Rubovitch, V Holloway, HW Lehrmann, E Wood, WH Zhang, YQ Becker, KG Perez, E Van Praag, H Luo, Y Hoffer, BJ Becker, RE Pick, CG Greig, NH AF Tweedie, David Fukui, Koji Li, Yazhou Yu, Qian-sheng Barak, Shani Tamargo, Ian A. Rubovitch, Vardit Holloway, Harold W. Lehrmann, Elin Wood, William H., III Zhang, Yongqing Becker, Kevin G. Perez, Evelyn Van Praag, Henriette Luo, Yu Hoffer, Barry J. Becker, Robert E. Pick, Chaim G. Greig, Nigel H. TI Cognitive Impairments Induced by Concussive Mild Traumatic Brain Injury in Mouse Are Ameliorated by Treatment with Phenserine via Multiple Non-Cholinergic and Cholinergic Mechanisms SO PLOS ONE LA English DT Article ID OBJECT RECOGNITION MEMORY; FLUID-PERCUSSION INJURY; CORTICAL IMPACT INJURY; ALZHEIMERS-DISEASE; HEAD-INJURY; OXIDATIVE STRESS; CHOLINESTERASE-INHIBITORS; ACETYLCHOLINESTERASE INHIBITION; PARKINSON DISEASE; RECEPTOR-BINDING AB Traumatic brain injury (TBI), often caused by a concussive impact to the head, affects an estimated 1.7 million Americans annually. With no approved drugs, its pharmacological treatment represents a significant and currently unmet medical need. In our prior development of the anti-cholinesterase compound phenserine for the treatment of neurodegenerative disorders, we recognized that it also possesses non-cholinergic actions with clinical potential. Here, we demonstrate neuroprotective actions of phenserine in neuronal cultures challenged with oxidative stress and glutamate excitotoxicity, two insults of relevance to TBI. These actions translated into amelioration of spatial and visual memory impairments in a mouse model of closed head mild TBI (mTBI) two days following cessation of clinically translatable dosing with phenserine (2.5 and 5.0 mg/kg BID x 5 days initiated post mTBI) in the absence of anti-cholinesterase activity. mTBI elevated levels of thiobarbituric acid reactive substances (TBARS), a marker of oxidative stress. Phenserine counteracted this by augmenting homeostatic mechanisms to mitigate oxidative stress, including superoxide dismutase [SOD] 1 and 2, and glutathione peroxidase [GPx], the activity and protein levels of which were measured by specific assays. Microarray analysis of hippocampal gene expression established that large numbers of genes were exclusively regulated by each individual treatment with a substantial number of them co-regulated between groups. Molecular pathways associated with lipid peroxidation were found to be regulated by mTBI, and treatment of mTBI animals with phenserine effectively reversed injury-induced regulations in the 'Blalock Alzheimer's Disease Up' pathway. Together these data suggest that multiple phenserine-associated actions underpin this compound's ability to ameliorate cognitive deficits caused by mTBI, and support the further evaluation of the compound as a therapeutic for TBI. C1 [Tweedie, David; Fukui, Koji; Li, Yazhou; Yu, Qian-sheng; Tamargo, Ian A.; Holloway, Harold W.; Becker, Robert E.; Greig, Nigel H.] NIA, Translat Gerontol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Fukui, Koji] Shibaura Inst Technol, Div Biosci & Engn, Saitama 3378570, Japan. [Barak, Shani; Rubovitch, Vardit; Pick, Chaim G.] Tel Aviv Univ, Sackler Sch Med, Dept Anat & Anthropol, IL-69978 Tel Aviv, Israel. [Lehrmann, Elin; Wood, William H., III; Zhang, Yongqing; Becker, Kevin G.] NIA, Lab Genet & Genom, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Perez, Evelyn] NIA, Lab Behav Neurosci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Van Praag, Henriette] NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Luo, Yu; Hoffer, Barry J.] Case Western Reserve Univ, Sch Med, Dept Neurosurg, Cleveland, OH USA. [Becker, Robert E.] 7123 Pinebrook Rd, Park City, UT 84098 USA. [Pick, Chaim G.] Tel Aviv Univ, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel. RP Greig, NH (reprint author), NIA, Translat Gerontol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM greign@mail.nih.gov RI van Praag, Henriette/F-3939-2015 OI van Praag, Henriette/0000-0002-5727-434X FU Intramural Research Program of the National Institute on Aging, National Institutes of Health; Ari and Regine Aprijaskis Fund, at Tel-Aviv University; Israel Science Foundation [108/09] FX This research was supported in part by (i) the Intramural Research Program of the National Institute on Aging, National Institutes of Health, (ii) the Ari and Regine Aprijaskis Fund, at Tel-Aviv University, and (iii) a grant from the Israel Science Foundation, grant number 108/09. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; This research was supported in part by (i) the Intramural Research Program of the National Institute on Aging, National Institutes of Health, (ii) the Ari and Regine Aprijaskis Fund, at Tel-Aviv University, and (iii) a grant from the Israel Science Foundation, grant number 108/09. NR 127 TC 0 Z9 0 U1 3 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 2 PY 2016 VL 11 IS 6 AR e0156493 DI 10.1371/journal.pone.0156493 PG 26 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN6XB UT WOS:000377218700033 PM 27254111 ER PT J AU Sutherland, MT Riedel, MC Flannery, JS Yanes, JA Fox, PT Stein, EA Laird, AR AF Sutherland, Matthew T. Riedel, Michael C. Flannery, Jessica S. Yanes, Julio A. Fox, Peter T. Stein, Elliot A. Laird, Angela R. TI Chronic cigarette smoking is linked with structural alterations in brain regions showing acute nicotinic drug-induced functional modulations SO BEHAVIORAL AND BRAIN FUNCTIONS LA English DT Article DE Cigarettes; Nicotine; Addiction; Gray matter; Morphometry; Insula; Mediodorsal thalamus; Ventromedial prefrontal cortex; Cerebellum ID GRAY-MATTER VOLUME; INTRINSIC CONNECTIVITY NETWORKS; VOXEL-BASED MORPHOMETRY; YOUNG-ADULT SMOKERS; NEUROIMAGING DATA; DECISION-MAKING; METAANALYTIC CONNECTIVITY; ACETYLCHOLINE-RECEPTORS; COGNITIVE-PROCESSES; CORTICAL THICKNESS AB Background: Whereas acute nicotine administration alters brain function which may, in turn, contribute to enhanced attention and performance, chronic cigarette smoking is linked with regional brain atrophy and poorer cognition. However, results from structural magnetic resonance imaging (MRI) studies comparing smokers versus nonsmokers have been inconsistent and measures of gray matter possess limited ability to inform functional relations or behavioral implications. The purpose of this study was to address these interpretational challenges through metaanalytic techniques in the service of clarifying the impact of chronic smoking on gray matter integrity and more fully contextualizing such structural alterations. Methods: We first conducted a coordinate-based meta-analysis of structural MRI studies to identify consistent structural alterations associated with chronic smoking. Subsequently, we conducted two additional meta-analytic assessments to enhance insight into potential functional and behavioral relations. Specifically, we performed a multimodal meta-analytic assessment to test the structural-functional hypothesis that smoking-related structural alterations overlapped those same regions showing acute nicotinic drug-induced functional modulations. Finally, we employed database driven tools to identify pairs of structurally impacted regions that were also functionally related via meta-analytic connectivity modeling, and then delineated behavioral phenomena associated with such functional interactions via behavioral decoding. Results: Across studies, smoking was associated with convergent structural decreases in the left insula, right cerebellum, parahippocampus, multiple prefrontal cortex (PFC) regions, and the thalamus. Indicating a structural-functional relation, we observed that smoking-related gray matter decreases overlapped with the acute functional effects of nicotinic agonist administration in the left insula, ventromedial PFC, and mediodorsal thalamus. Suggesting structural-behavioral implications, we observed that the left insula's task-based, functional interactions with multiple other structurally impacted regions were linked with pain perception, the right cerebellum's interactions with other regions were associated with overt body movements, interactions between the parahippocampus and thalamus were linked with memory processes, and interactions between medial PFC regions were associated with face processing. Conclusions: Collectively, these findings emphasize brain regions (e.g., ventromedial PFC, insula, thalamus) critically linked with cigarette smoking, suggest neuroimaging paradigms warranting additional consideration among smokers (e.g., pain processing), and highlight regions in need of further elucidation in addiction (e.g., cerebellum). C1 [Sutherland, Matthew T.; Riedel, Michael C.; Flannery, Jessica S.] Florida Int Univ, Dept Psychol, AHC 4,RM 312,11200 SW 8th St, Miami, FL 33199 USA. [Riedel, Michael C.; Laird, Angela R.] Florida Int Univ, Dept Phys, Miami, FL 33199 USA. [Yanes, Julio A.] Auburn Univ, Dept Psychol, Auburn, AL 36849 USA. [Fox, Peter T.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Fox, Peter T.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Fox, Peter T.] Univ Hong Kong, State Key Lab Brain & Cognit Sci, Hong Kong, Hong Kong, Peoples R China. [Stein, Elliot A.] NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH DHHS, Baltimore, MD USA. RP Sutherland, MT (reprint author), Florida Int Univ, Dept Psychol, AHC 4,RM 312,11200 SW 8th St, Miami, FL 33199 USA. EM masuther@fiu.edu OI Sutherland, Matthew/0000-0002-6091-4037 FU National Institute on Drug Abuse of the NIH [K01-DA037819]; National Institute of Mental Health of the NIH [R01-MH074457, R56-MH097870]; Intramural Research Program of the National Institute on Drug Abuse FX This work was supported by the National Institute on Drug Abuse (K01-DA037819, MTS) and the National Institute of Mental Health (R01-MH074457 and R56-MH097870, ARL and PTF) of the NIH. EAS is supported by the Intramural Research Program of the National Institute on Drug Abuse. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 112 TC 1 Z9 1 U1 3 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-9081 J9 BEHAV BRAIN FUNCT JI Behav. Brain Funct. PD JUN 2 PY 2016 VL 12 AR 16 DI 10.1186/s12993-016-0100-5 PG 15 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DN4TV UT WOS:000377061000001 PM 27251183 ER PT J AU Kubben, N Zhang, WQ Wang, LX Voss, TC Yang, JP Qu, J Liu, GH Misteli, T AF Kubben, Nard Zhang, Weiqi Wang, Lixia Voss, Ty C. Yang, Jiping Qu, Jing Liu, Guang-Hui Misteli, Tom TI Repression of the Antioxidant NRF2 Pathway in Premature Aging SO CELL LA English DT Article ID GILFORD-PROGERIA-SYNDROME; MESENCHYMAL STEM-CELLS; DNA-DAMAGE RESPONSES; OXIDATIVE STRESS; INFLAMMATORY RESPONSE; DEFECTIVE MATURATION; TRANSCRIPTION FACTOR; ROS GENERATION; LAMIN; ACTIVATION AB Hutchinson-Gilford progeria syndrome (HGPS) is a rare, invariably fatal premature aging disorder. The disease is caused by constitutive production of progerin, a mutant form of the nuclear architectural protein lamin A, leading, through unknown mechanisms, to diverse morphological, epigenetic, and genomic damage and to mesenchymal stem cell (MSC) attrition in vivo. Using a high-throughput siRNA screen, we identify the NRF2 antioxidant pathway as a driver mechanism in HGPS. Progerin sequesters NRF2 and thereby causes its subnuclear mislocalization, resulting in impaired NRF2 transcriptional activity and consequently increased chronic oxidative stress. Suppressed NRF2 activity or increased oxidative stress is sufficient to recapitulate HGPS aging defects, whereas reactivation of NRF2 activity in HGPS patient cells reverses progerin-associated nuclear aging defects and restores in vivo viability of MSCs in an animal model. These findings identify repression of the NRF2-mediated antioxidative response as a key contributor to the premature aging phenotype. C1 [Kubben, Nard; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. [Zhang, Weiqi; Wang, Lixia; Yang, Jiping; Liu, Guang-Hui] Chinese Acad Sci, Inst Biophys, CAS Ctr Excellence Biomacromol, Natl Lab Biomacromol, Beijing 100101, Peoples R China. [Zhang, Weiqi; Liu, Guang-Hui] Foshan Univ, FSU CAS Innovat Inst, Foshan 528000, Guangdong, Peoples R China. [Wang, Lixia; Qu, Jing] Chinese Acad Sci, Inst Zool, State Key Lab Stem Cell & Reprod Biol, Beijing 100101, Peoples R China. [Voss, Ty C.] NCI, High Throughput Imaging Facil, NIH, Bethesda, MD 20892 USA. [Liu, Guang-Hui] Beijing Inst Brain Disorders, Beijing 100069, Peoples R China. [Wang, Lixia; Yang, Jiping; Qu, Jing; Liu, Guang-Hui] Univ Chinese Acad Sci, Beijing 100049, Peoples R China. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA.; Liu, GH (reprint author), Chinese Acad Sci, Inst Biophys, CAS Ctr Excellence Biomacromol, Natl Lab Biomacromol, Beijing 100101, Peoples R China.; Liu, GH (reprint author), Foshan Univ, FSU CAS Innovat Inst, Foshan 528000, Guangdong, Peoples R China.; Liu, GH (reprint author), Beijing Inst Brain Disorders, Beijing 100069, Peoples R China.; Liu, GH (reprint author), Univ Chinese Acad Sci, Beijing 100049, Peoples R China. EM ghliu@ibp.ac.cn; mistelit@mail.nih.gov FU National Basic Research Program of China (973 Program) [2015CB964800, 2014CB910503]; Strategic Priority Research Program of the Chinese Academy of Sciences [XDA01020312]; National High Technology Research and Development Program of China [2015AA020307]; National Natural Science Foundation of China [81330008, 31222039, 31201111, 81371342, 81300261, 81300677, 81271266, 81471414, 81422017, 81401159]; Program of Beijing Municipal Science and Technology Commission [Z151100003915072]; Beijing Natural Science Foundation [7141005, 5142016]; Key Research Program of the Chinese Academy of Sciences [KJZDEW-TZ-L05]; Thousand Young Talents program of China; Intramural Research Program of the NIH/NCI/CCR; Progeria Research Foundation grant FX We thank the T.M. lab members, P. Scaffidi, Y. Xiong, and J.C. Izpisua Belmonte for sharing feedback, data, and reagents. The G.-H.L. and J.Q. labs were supported by the National Basic Research Program of China (973 Program, 2015CB964800 and 2014CB910503), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA01020312), the National High Technology Research and Development Program of China (2015AA020307), the National Natural Science Foundation of China (81330008, 31222039, 31201111, 81371342, 81300261, 81300677, 81271266, 81471414, 81422017, and 81401159), the Program of Beijing Municipal Science and Technology Commission (Z151100003915072), the Beijing Natural Science Foundation (7141005 and 5142016), the Key Research Program of the Chinese Academy of Sciences (KJZDEW-TZ-L05), and the Thousand Young Talents program of China. The T.M. lab was supported by the Intramural Research Program of the NIH/NCI/CCR and a Progeria Research Foundation grant. NR 62 TC 4 Z9 4 U1 28 U2 46 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 2 PY 2016 VL 165 IS 6 BP 1361 EP 1374 DI 10.1016/j.cell.2016.05.017 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DN4NV UT WOS:000377045400011 PM 27259148 ER PT J AU Lu, FL Liu, YT Inoue, A Suzuki, T Zhao, KJ Zhang, Y AF Lu, Falong Liu, Yuting Inoue, Azusa Suzuki, Tsukasa Zhao, Keji Zhang, Yi TI Establishing Chromatin Regulatory Landscape during Mouse Preimplantation Development SO CELL LA English DT Article ID MASTER TRANSCRIPTION FACTORS; TO-ZYGOTIC TRANSITION; GENE-EXPRESSION; HYPERSENSITIVE SITES; DNA LANDSCAPES; CELL FATE; GENOME; ACCESSIBILITY; EMBRYO; DYNAMICS AB How the chromatin regulatory landscape in the inner cell mass cells is established from differentially packaged sperm and egg genomes during preimplantation development is unknown. Here, we develop a low-input DNase I sequencing (liDNase-seq) method that allows us to generate maps of DNase I-hypersensitive site (DHS) of mouse preimplantation embryos from 1-cell to morula stage. The DHS landscape is progressively established with a drastic increase at the 8-cell stage. Paternal chromatin accessibility is quickly reprogrammed after fertilization to the level similar to maternal chromatin, while imprinted genes exhibit allelic accessibility bias. We demonstrate that transcription factor Nfya contributes to zygotic genome activation and DHS formation at the 2-cell stage and that Oct4 contributes to the DHSs gained at the 8-cell stage. Our study reveals the dynamic chromatin regulatory landscape during early development and identifies key transcription factors important for DHS establishment in mammalian embryos. C1 [Lu, Falong; Liu, Yuting; Inoue, Azusa; Suzuki, Tsukasa; Zhang, Yi] Boston Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. [Lu, Falong; Liu, Yuting; Inoue, Azusa; Suzuki, Tsukasa; Zhang, Yi] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Lu, Falong; Liu, Yuting; Inoue, Azusa; Suzuki, Tsukasa; Zhang, Yi] Boston Childrens Hosp, Div Hematol Oncol, Dept Pediat, Boston, MA 02115 USA. [Zhang, Yi] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Zhang, Yi] Harvard Stem Cell Inst, WAB 149G,200 Longwood Ave, Boston, MA 02115 USA. [Zhao, Keji] NHLBI, Syst Biol Ctr, Div Intramural Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Zhang, Y (reprint author), Boston Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA.; Zhang, Y (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.; Zhang, Y (reprint author), Boston Childrens Hosp, Div Hematol Oncol, Dept Pediat, Boston, MA 02115 USA.; Zhang, Y (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.; Zhang, Y (reprint author), Harvard Stem Cell Inst, WAB 149G,200 Longwood Ave, Boston, MA 02115 USA. EM yzhang@genetics.med.harvard.edu RI Lu, Falong/Q-3013-2016 FU HHMI; Charles A. King Trust FX We thank Dr. Shinpei Yamaguchi for helpful discussion and Dr. Luis Tuesta for critical reading of the manuscript. This project is supported by HHMI. F.L. is supported by a Charles A. King Trust Postdoctoral Research Fellowship. Y.Z. is an investigator of the Howard Hughes Medical Institute. NR 41 TC 9 Z9 9 U1 14 U2 25 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 2 PY 2016 VL 165 IS 6 BP 1375 EP 1388 DI 10.1016/j.cell.2016.05.050 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DN4NV UT WOS:000377045400012 PM 27259149 ER PT J AU Haque, N Hogg, JR AF Haque, Nazmul Hogg, J. Robert TI Easier, Better, Faster, Stronger: Improved Methods for RNA-Protein Interaction Studies SO MOLECULAR CELL LA English DT Editorial Material ID GENERATION; CLIP AB The RNA field has been revolutionized by methods that allow genome-scale identification of RNA-protein interaction sites. Two reports now introduce more efficient approaches, opening the technology to wider adoption (Van Nostrand et al., 2016; Zarnegar et al., 2016). C1 [Haque, Nazmul; Hogg, J. Robert] NHLBI, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Hogg, JR (reprint author), NHLBI, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM j.hogg@nih.gov OI Hogg, J. Robert/0000-0001-5729-5135 NR 8 TC 0 Z9 0 U1 2 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD JUN 2 PY 2016 VL 62 IS 5 BP 650 EP 651 DI 10.1016/j.molcel.2016.05.019 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DN4PK UT WOS:000377049500002 PM 27259196 ER PT J AU Thompson, PJ Macfarlan, TS Lorincz, MC AF Thompson, Peter J. Macfarlan, Todd S. Lorincz, Matthew C. TI Long Terminal Repeats: From Parasitic Elements to Building Blocks of the Transcriptional Regulatory Repertoire SO MOLECULAR CELL LA English DT Review ID EMBRYONIC STEM-CELLS; HUMAN ENDOGENOUS RETROVIRUSES; DNA METHYLATION LANDSCAPE; MOUSE ES CELLS; TRANSPOSABLE ELEMENTS; NONCODING RNA; HUMAN GENOME; GENE-EXPRESSION; PREIMPLANTATION EMBRYOS; CHIMERIC TRANSCRIPTS AB The life cycle of endogenous retroviruses (ERVs), also called long terminal repeat (LTR) retrotransposons, begins with transcription by RNA polymerase II followed by reverse transcription and re-integration into the host genome. While most ERVs are relics of ancient integration events, "young'' proviruses competent for retro-transposition-found in many mammals, but not humans-represent an ongoing threat to host fitness. As a consequence, several restriction pathways have evolved to suppress their activity at both transcriptional and post-transcriptional stages of the viral life cycle. Nevertheless, accumulating evidence has revealed that LTR sequences derived from distantly related ERVs have been exapted as regulatory sequences for many host genes in a wide range of cell types throughout mammalian evolution. Here, we focus on emerging themes from recent studies cataloging the diversity of ERV LTRs acting as important transcriptional regulatory elements in mammals and explore the molecular features that likely account for LTR exaptation in developmental and tissue-specific gene regulation. C1 [Thompson, Peter J.; Lorincz, Matthew C.] Univ British Columbia, Inst Life Sci, Dept Med Genet, Vancouver, BC V6T 1Z3, Canada. [Macfarlan, Todd S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Thompson, Peter J.] Univ Calif San Francisco, Dept Med, Ctr Diabet, San Francisco, CA 94143 USA. RP Lorincz, MC (reprint author), Univ British Columbia, Inst Life Sci, Dept Med Genet, Vancouver, BC V6T 1Z3, Canada.; Macfarlan, TS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM todd.macfarlan@nih.gov; mlorincz@mail.ubc.ca FU Canadian Institutes of Health Research [MOP-133417]; NIH [1ZIAHD008933] FX We wish to thank Dixie Mager and Cedric Feschotte for critical reading of the manuscript. This work was supported by Canadian Institutes of Health Research Grant MOP-133417 (M.C.L.) and NIH grant 1ZIAHD008933 (T.S.M.). NR 112 TC 6 Z9 6 U1 3 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD JUN 2 PY 2016 VL 62 IS 5 BP 766 EP 776 DI 10.1016/j.molcel.2016.03.029 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DN4PK UT WOS:000377049500013 PM 27259207 ER PT J AU Mertins, P Mani, DR Ruggles, KV Gillette, MA Clauser, KR Wang, P Wang, XL Qiao, JW Cao, S Petralia, F Kawaler, E Mundt, F Krug, K Tu, ZD Lei, JT Gatza, ML Wilkerson, M Perou, CM Yellapantula, V Huang, KL Lin, CW McLellan, MD Yan, P Davies, SR Townsend, RR Skates, SJ Wang, J Zhang, B Kinsinger, CR Mesri, M Rodriguez, H Ding, L Paulovich, AG Fenyo, D Ellis, MJ Carr, SA AF Mertins, Philipp Mani, D. R. Ruggles, Kelly V. Gillette, Michael A. Clauser, Karl R. Wang, Pei Wang, Xianlong Qiao, Jana W. Cao, Song Petralia, Francesca Kawaler, Emily Mundt, Filip Krug, Karsten Tu, Zhidong Lei, Jonathan T. Gatza, Michael L. Wilkerson, Matthew Perou, Charles M. Yellapantula, Venkata Huang, Kuan-lin Lin, Chenwei McLellan, Michael D. Yan, Ping Davies, Sherri R. Townsend, R. Reid Skates, Steven J. Wang, Jing Zhang, Bing Kinsinger, Christopher R. Mesri, Mehdi Rodriguez, Henry Ding, Li Paulovich, Amanda G. Fenyo, David Ellis, Matthew J. Carr, Steven A. CA NCI CPTAC TI Proteogenomics connects somatic mutations to signalling in breast cancer SO NATURE LA English DT Article ID ONCOGENIC PIK3CA MUTATIONS; GENE-EXPRESSION SIGNATURES; MOLECULAR PORTRAITS; TUMORS; RECEPTOR; PATHWAYS; PHOSPHORYLATION; HETEROGENEITY; SUBTYPES; REVEALS AB Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. Here we describe quantitative mass-spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers, of which 77 provided high-quality data. Integrated analyses provided insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. Interrogation of the 5q trans-effects against the Library of Integrated Network-based Cellular Signatures, connected loss of CETN3 and SKP1 to elevated expression of epidermal growth factor receptor (EGFR), and SKP1 loss also to increased SRC tyrosine kinase. Global proteomic data confirmed a stromal-enriched group of proteins in addition to basal and luminal clusters, and pathway analysis of the phosphoproteome identified a G-protein-coupled receptor cluster that was not readily identified at the mRNA level. In addition to ERBB2, other amplicon-associated highly phosphorylated kinases were identified, including CDK12, PAK1, PTK2, RIPK2 and TLK2. We demonstrate that proteogenomic analysis of breast cancer elucidates the functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets. C1 [Mertins, Philipp; Mani, D. R.; Gillette, Michael A.; Clauser, Karl R.; Qiao, Jana W.; Mundt, Filip; Krug, Karsten; Carr, Steven A.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Ruggles, Kelly V.; Kawaler, Emily; Fenyo, David] NYU, Langone Med Ctr, Dept Biochem & Mol Pharmacol, New York, NY 10016 USA. [Gillette, Michael A.] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Wang, Pei; Petralia, Francesca; Tu, Zhidong] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA. [Wang, Xianlong; Lin, Chenwei; Yan, Ping; Paulovich, Amanda G.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Cao, Song; Yellapantula, Venkata; Huang, Kuan-lin; McLellan, Michael D.; Ding, Li] Washington Univ, Sch Med, Siteman Canc Ctr, Dept Med,McDonnell Genome Inst, St Louis, MO 63108 USA. [Mundt, Filip] Karolinska Inst, Dept Oncol Pathol, S-17176 Stockholm, Sweden. [Lei, Jonathan T.; Ellis, Matthew J.] Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA. [Lei, Jonathan T.; Ellis, Matthew J.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Lei, Jonathan T.; Ellis, Matthew J.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Gatza, Michael L.; Wilkerson, Matthew; Perou, Charles M.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Genet, Chapel Hill, NC 27599 USA. [Davies, Sherri R.; Townsend, R. Reid] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Skates, Steven J.] Massachusetts Gen Hosp, Ctr Canc, Biostat Ctr, Boston, MA 02114 USA. [Wang, Jing; Zhang, Bing] Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37232 USA. [Wang, Jing; Zhang, Bing] Vanderbilt Univ, Sch Med, Dept Canc Biol, Nashville, TN 37232 USA. [Kinsinger, Christopher R.; Mesri, Mehdi; Rodriguez, Henry] NCI, NIH, Bethesda, MD 20892 USA. RP Mertins, P; Carr, SA (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Ellis, MJ (reprint author), Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA.; Ellis, MJ (reprint author), Baylor Coll Med, Dept Med, Houston, TX 77030 USA.; Ellis, MJ (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. EM pmertins@broadinstitute.org; Matthew.Ellis@bcm.edu; scarr@broad.mit.edu OI Lei, Jonathan/0000-0002-0209-8051; Yellapantula, Venkata/0000-0001-9848-3263; Fenyo, David/0000-0001-5049-3825; Ruggles, Kelly/0000-0002-0152-0863 FU National Cancer Institute (NCI) [U24CA160034, U24CA160036, U24CA160019, U24CA159988, U24CA160035]; CPRIT grant [RR140033]; Leidos contract [13XS068]; National Cancer Institute (NCI) CPTAC award [U24CA160035]; NCI Cancer Center Support Grant [P30 CA91842]; NIH/NCRR Washington University-ICTS [UL1 RR024992]; Susan G. Komen for the Cure [KG 090422]; Swedish Research Council [Dnr 2014-323]; [SUB-R01GM108711] FX This work was supported by National Cancer Institute (NCI) CPTAC awards U24CA160034 (Broad Institute; Fred Hutchinson Cancer Research Center), U24CA160036 (Johns Hopkins University), U24CA160019 (Pacific Northwest National Laboratory), U24CA159988 (Vanderbilt University), U24CA160035 (Washington University, St. Louis; University of North Carolina, Chapel Hill). P.W. and F.P. were also supported by SUB-R01GM108711 and MJE by CPRIT grant RR140033. M.J.E. is also a McNair Foundation Scholar. D.F. was supported by Leidos contract 13XS068. Primary genomics data for this study were generated by The Cancer Genome Atlas pilot project established by the NCI and the National Human Genome Research Institute. Resequencing of select samples conducted in this study was supported by National Cancer Institute (NCI) CPTAC award U24CA160035. Information about TCGA and the investigators and institutions that constitute the TCGA research network can be found at http://cancergenome.nih.gov/. We also acknowledge the expert assistance of J. Snider, P. Erdmann-Gilmore and R. Connors for the preparation of the tumour tissues for solubilization. We thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, for the use of the Tissue Procurement Core, which provided accessioning, histologic processing and review for the TCGA samples included in this study. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant #P30 CA91842 (see more at http://www.siteman.wustl.edu/ContentPage.aspx?id=243#sthash.mEU0QuXx.dpu f). We also thank the HAMLET Core at The Washington University in St. Louis for providing breast cancer xenograft tumors. The HAMLET Core was supported in part by grants from NIH/NCRR Washington University-ICTS (UL1 RR024992) and Susan G. Komen for the Cure (KG 090422). F.M. was also supported by The Swedish Research Council (Dnr 2014-323). We also thank A. Subramanian, C. Flynn and J. Asiedu at the Broad Institute for their guidance and assistance in accessing LINCS to run a large number of enrichment queries. NR 41 TC 45 Z9 46 U1 24 U2 46 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 2 PY 2016 VL 534 IS 7605 BP 55 EP + DI 10.1038/nature18003 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN3LB UT WOS:000376962300032 PM 27251275 ER PT J AU Chen, II Caprioli, A Ohnuki, H Kwak, H Porcher, C Tosato, G AF Chen, Inn-Inn Caprioli, Arianna Ohnuki, Hidetaka Kwak, Hyeongil Porcher, Catherine Tosato, Giovanna TI EphrinB2 regulates the emergence of a hemogenic endothelium from the aorta SO SCIENTIFIC REPORTS LA English DT Article ID HEMATOPOIETIC STEM-CELLS; HAEMOGENIC ENDOTHELIUM; MOUSE EMBRYO; VASCULAR DEVELOPMENT; YOLK-SAC; DORSAL AORTA; CARDIOVASCULAR DEVELOPMENT; DEFINITIVE HEMATOPOIESIS; FATE ACQUISITION; MAMMALIAN EMBRYO AB Adult-type intraembryonic hematopoiesis arises from specialized endothelial cells of the dorsal aorta (DA). Despite the critical importance of this specialized endothelium for establishment of hematopoietic stem cells and adult hematopoietic lineages, the mechanisms regulating its emergence are incompletely understood. We show that EphrinB2, a principal regulator of endothelial cell function, controls the development of endothelium producing adult-type hematopoiesis. The absence of EphrinB2 impairs DA-derived hematopoiesis. Transmembrane EphrinB2 and its EphB4 receptor interact in the emerging DA, which transiently harbors EphrinB2(+) and EphB4(+) endothelial cells, thereby providing an opportunity for bi-directional cell-to-cell signaling to control the emergence of the hemogenic endothelium. Embryonic Stem (ES) cell-derived EphrinB2(+) cells are enriched with hemogenic endothelial precursors. EphrinB2 silencing impairs ES generation of hematopoietic cells but not generation of endothelial cells. The identification of EphrinB2 as an essential regulator of adult hematopoiesis provides important insight in the regulation of early hematopoietic commitment. C1 [Chen, Inn-Inn; Caprioli, Arianna; Ohnuki, Hidetaka; Kwak, Hyeongil; Tosato, Giovanna] NCI, Lab Cellular Oncol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chen, Inn-Inn; Porcher, Catherine] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, MRC Mol Haematol Unit, Oxford OX3 9DS, England. [Caprioli, Arianna] Marymount Univ, 2807 N Glebe Rd, Arlington, VA 22207 USA. RP Tosato, G (reprint author), NCI, Lab Cellular Oncol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM tosatog@mail.nih.gov FU NCI, CCR FX We thank Drs. S. Raft, Y. Mukouyama, S.E. Jacobsen, D. Sanchez-Martin, O. Salvucci and Dr. D. Lowy for mice, cells and other help. The Intramural Research Program at NCI, CCR funded this work. NR 72 TC 1 Z9 1 U1 1 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 2 PY 2016 VL 6 AR 27195 DI 10.1038/srep27195 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN2BI UT WOS:000376868700001 PM 27250641 ER PT J AU Innis, R AF Innis, R. TI POSITRON EMISSION TOMOGRAPHY OF HUMAN BRAIN CAN MONITOR NEUROINFLAMMATION AND CAMP SIGNALING: APPLICATIONS TO ALZHEIMER'S DISEASE AND DEPRESSION SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract C1 [Innis, R.] NIMH, Mol Imaging Branch, NIH, Bathesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUN PY 2016 VL 36 SU 1 MA 36 BP 8 EP 9 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA EL9QY UT WOS:000394956300015 ER PT J AU Santisakultarm, T Kersbergen, C Bandy, D Ide, D Choi, S Silva, A AF Santisakultarm, T. Kersbergen, C. Bandy, D. Ide, D. Choi, S. Silva, A. TI LONGITUDINAL TWO-PHOTON IMAGING OF CORTICAL MICROVESSELS AND NEURAL ACTIVATION IN AWAKE MARMOSET MONKEYS SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract C1 [Santisakultarm, T.; Kersbergen, C.; Choi, S.; Silva, A.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Bandy, D.; Ide, D.] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUN PY 2016 VL 36 SU 1 MA 72 BP 25 EP 26 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA EL9QY UT WOS:000394956300032 ER PT J AU Kobayashi, M Jenko, KJ Zoghbi, SS Morse, C Rallis-Frutos, D Page, E Lohith, TG Ikawa, M Jiang, T Hong, J Pike, VW Innis, RB Fujita, M AF Kobayashi, M. Jenko, K. J. Zoghbi, S. S. Morse, C. Rallis-Frutos, D. Page, E. Lohith, T. G. Ikawa, M. Jiang, T. Hong, J. Pike, V. W. Innis, R. B. Fujita, M. TI BLOCKADE OF TRANSLOCATOR PROTEIN (TSPO) BY XBD173 TO MEASURE SPECIFIC BINDING OF 11C-(R)-PK 11195 IN HUMAN BRAIN: AN ONGOING STUDY SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract C1 [Kobayashi, M.; Jenko, K. J.; Zoghbi, S. S.; Morse, C.; Rallis-Frutos, D.; Page, E.; Lohith, T. G.; Ikawa, M.; Jiang, T.; Hong, J.; Pike, V. W.; Innis, R. B.; Fujita, M.] NIMH, NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUN PY 2016 VL 36 SU 1 MA 174 BP 91 EP 92 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA EL9QY UT WOS:000394956300104 ER PT J AU Yen, C Papoti, D Silva, A AF Yen, C. Papoti, D. Silva, A. TI Investigating the Spatiotemporal Characteristics of the BOLD and the Non-BOLD Response Across Cortical Layers in Awake Marmosets SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract C1 [Yen, C.; Papoti, D.; Silva, A.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUN PY 2016 VL 36 SU 1 MA 214 BP 121 EP 122 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA EL9QY UT WOS:000394956300134 ER PT J AU Sarles, C Aizenstein, H O'Hare, C Rosso, A Launer, L Kritchevsky, S Yaffe, K Newman, A Rosano, C AF Sarles, C. Aizenstein, H. O'Hare, C. Rosso, A. Launer, L. Kritchevsky, S. Yaffe, K. Newman, A. Rosano, C. TI LONG-TERM RELATIONSHIP OF SERUM BRAIN-DERIVED NEUROTROPHIC FACTOR WITH CEREBRAL BLOOD FLOW AND COGNITION IN COGNITIVELY NORMAL ELDERS SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract C1 [Sarles, C.; Rosso, A.; Newman, A.; Rosano, C.] Univ Pittsburgh, Grad Sch Publ Hlth, Epidemiol, Pittsburgh, PA USA. [Aizenstein, H.] Univ Pittsburgh, Psychiat, Pittsburgh, PA USA. [O'Hare, C.] Trinity Coll Dublin, Med Gerontol, Dublin, Ireland. [Launer, L.] NIA, Neuroepidemiol Sect, Bethesda, MD 20892 USA. [Kritchevsky, S.] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Yaffe, K.] Univ Calif San Francisco, Psychiat, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUN PY 2016 VL 36 SU 1 MA 311 BP 180 EP 181 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA EL9QY UT WOS:000394956300198 ER PT J AU Morton, PD Korotcova, L Lewis, B Kim, D Kumar, V Shaikh, F Short, E Frank, JA Gallo, V Jonas, RA Ishibashi, N AF Morton, P. D. Korotcova, L. Lewis, B. Kim, D. Kumar, V. Shaikh, F. Short, E. Frank, J. A. Gallo, V. Jonas, R. A. Ishibashi, N. TI PROLONGED HYPOXIA DEPLETES SVZ NEURAL STEM/PROGENITOR CELL POOLS CRITICAL FOR CORTICAL DEVELOPMENT IN PIGLETS SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract C1 [Morton, P. D.; Korotcova, L.; Kim, D.; Kumar, V.; Shaikh, F.; Short, E.; Gallo, V.; Jonas, R. A.; Ishibashi, N.] Childrens Natl Med Ctr, Ctr Res Neurosci, Washington, DC 20010 USA. [Lewis, B.; Frank, J. A.] NIH, Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUN PY 2016 VL 36 SU 1 MA 356 BP 222 EP 223 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA EL9QY UT WOS:000394956300243 ER PT J AU Ikawa, M Lohith, TG Jenko, KJ Shrestha, SS Telu, S Zoghbi, SS Fujita, M Pike, VW Innis, RB AF Ikawa, M. Lohith, T. G. Jenko, K. J. Shrestha, S. S. Telu, S. Zoghbi, S. S. Fujita, M. Pike, V. W. Innis, R. B. TI DIFFERENTIAL IN VITRO AND IN VIVO SENSITIVITY OF [C-11]ER176 TO A SINGLE NUCLEOTIDE POLYMORPHISM IN THE GENE FOR TRANSLOCATOR PROTEIN SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract C1 [Ikawa, M.; Lohith, T. G.; Jenko, K. J.; Shrestha, S. S.; Telu, S.; Zoghbi, S. S.; Fujita, M.; Pike, V. W.; Innis, R. B.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUN PY 2016 VL 36 SU 1 MA 413 BP 277 EP 278 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA EL9QY UT WOS:000394956300300 ER PT J AU Lyoo, CH Ikawa, M Liow, JS Zoghbi, SS Morse, C Pike, VW Fujita, M Innis, RB Kreisl, WC AF Lyoo, C. H. Ikawa, M. Liow, J. S. Zoghbi, S. S. Morse, C. Pike, V. W. Fujita, M. Innis, R. B. Kreisl, W. C. TI RATIO METHOD FOR 11C-PBR28 IS MORE SENSITIVE FOR DETECTING THE REGIONS WITH INCREASED TRANSLOCATOR PROTEIN BINDING IN ALZHEIMER'S DISEASE SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract C1 [Lyoo, C. H.] Yonsei Univ, Gangnam Severance Hosp, Coll Med, Neurol, Seoul, South Korea. [Ikawa, M.; Liow, J. S.; Zoghbi, S. S.; Morse, C.; Pike, V. W.; Fujita, M.; Innis, R. B.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Kreisl, W. C.] Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUN PY 2016 VL 36 SU 1 MA 416 BP 280 EP 281 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA EL9QY UT WOS:000394956300303 ER PT J AU Fujita, M Turtzo, C Shenouda, C Fennell, E Rallis-Frutos, D Zoghbi, S Telu, S Hong, J Dsurney, J Pike, V Innis, R Diaz-Arrastia, R Latour, L AF Fujita, M. Turtzo, C. Shenouda, C. Fennell, E. Rallis-Frutos, D. Zoghbi, S. Telu, S. Hong, J. Dsurney, J. Pike, V. Innis, R. Diaz-Arrastia, R. Latour, L. TI CHRONIC INFLAMMATION IN BRAIN PARENCHYMA DETECTED BY PET IMAGING OF TRANSLOCATOR PROTEIN FOLLOWING A SUBDURAL HEMATOMA, ABSENT OF MRI FINDINGS OF BRAIN INJURY SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract C1 [Fujita, M.; Fennell, E.; Rallis-Frutos, D.; Zoghbi, S.; Telu, S.; Hong, J.; Pike, V.; Innis, R.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Turtzo, C.] NIH, Diagnost Radiol, Bldg 10, Bethesda, MD 20892 USA. [Shenouda, C.; Dsurney, J.] NIH, Rehabil Med, Bldg 10, Bethesda, MD 20892 USA. [Diaz-Arrastia, R.] NIMH, Ctr Neurosci & Regenerat Med, Rockville, MD 20857 USA. [Latour, L.] NINDS, Acute Stroke Res Sect, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUN PY 2016 VL 36 SU 1 MA 541 BP 397 EP 398 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA EL9QY UT WOS:000394956300428 ER PT J AU Choi, SH Arai, A Silva, AC AF Choi, S. H. Arai, A. Silva, A. C. TI MONOACYLGLYCEROL LIPASE INHIBITORS REDUCE INFARCT VOLUME AND IMPROVE FUNCTIONAL OUTCOME IN A RAT MODEL OF FOCAL CEREBRAL ISCHEMIA SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract C1 [Choi, S. H.; Silva, A. C.] NINDS, Lab Funct & Mol Imaging, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Arai, A.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUN PY 2016 VL 36 SU 1 MA 766 BP 598 EP 598 PG 1 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA EL9QY UT WOS:000394956301140 ER PT J AU Shrestha, S Jenko, KJ Liow, JS Ikawa, M Zoghbi, SS Innis, RB AF Shrestha, S. Jenko, K. J. Liow, J. S. Ikawa, M. Zoghbi, S. S. Innis, R. B. TI CUMI-101 BINDS TO A1 ADRENOCEPTORS IN HUMAN CEREBELLUM AND IS NOT A SUITABLE REFERENCE REGION. SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract C1 [Shrestha, S.; Jenko, K. J.; Liow, J. S.; Ikawa, M.; Zoghbi, S. S.; Innis, R. B.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUN PY 2016 VL 36 SU 1 MA 819 BP 653 EP 653 PG 1 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA EL9QY UT WOS:000394956301193 ER PT J AU Liow, JS Hu, S Hall, MD Hines, CS Zoghbi, SS Shetty, HU Pike, VW Kreisl, WC Herscovitch, P Gottesman, MM Theodore, WH Innis, RB AF Liow, J. S. Hu, S. Hall, M. D. Hines, C. S. Zoghbi, S. S. Shetty, H. U. Pike, V. W. Kreisl, W. C. Herscovitch, P. Gottesman, M. M. Theodore, W. H. Innis, R. B. TI [18F]FCWAY, A SEROTONIN 1A RECEPTOR RADIOLIGAND, IS A WEAK SUBSTRATE FOR EFFLUX TRANSPORTERS AT THE HUMAN BLOOD-BRAIN BARRIER SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract C1 [Liow, J. S.; Zoghbi, S. S.; Shetty, H. U.; Pike, V. W.; Innis, R. B.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Hu, S.] Cent S Univ, Nucl Med, XiangYa Hosp, Changsha, Hunan, Peoples R China. [Hall, M. D.; Gottesman, M. M.] NCI, Cell Biol Lab, Bldg 37, Bethesda, MD 20892 USA. [Hines, C. S.] Univ Texas Hlth Sci Ctr San Antonio, Psychiat, San Antonio, TX 78229 USA. [Kreisl, W. C.] Columbia Univ, Neurol, New York, NY USA. [Herscovitch, P.] NIH, Clin Ctr PET, Bldg 10, Bethesda, MD 20892 USA. [Theodore, W. H.] NINDS, Clin Epilepsy Sect, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUN PY 2016 VL 36 SU 1 MA 864 BP 692 EP 693 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA EL9QY UT WOS:000394956301238 ER PT J AU Wang, J Wang, J Yang, L Greig, N AF Wang, J. Wang, J. Yang, L. Greig, N. TI NEUROPROTECTIVE EFFECTS AND MECHANISM OF POMALIDOMIDE AGAINST TRAUMATIC BRAIN INJURY SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract C1 [Wang, J.; Wang, J.; Yang, L.] Taipei Med Univ, Grad Inst Med Sci, Taipei, Taiwan. [Greig, N.] NIA, Drug Design & Dev Sect, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUN PY 2016 VL 36 SU 1 MA 1018 BP 813 EP 813 PG 1 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA EL9QY UT WOS:000394956301392 ER PT J AU Yoshida, S Martines, J Lawn, JE Wall, S Souza, JP Rudan, I Cousens, S Aaby, P Adam, I Adhikari, RK Ambalavanan, N El Arifeen, S Aryal, DR Asiruddin, SK Baqui, A Barros, AJD Benn, CS Bhandari, V Bhatnagar, S Bhattacharya, S Bhutta, ZA Black, RE Blencowe, H Bose, C Brown, J Buhrer, C Carlo, W Cecatti, JG Cheung, PY Clark, R Colbourn, T Conde-Agudelo, A Corbett, E Czeizel, AE Das, A Day, LT Deal, C Deorari, A Dilmen, U English, M Engmann, C Esamai, F Fall, C Ferriero, DM Gisore, P Hazir, T Higgins, RD Homer, CSE Hoque, DE Irgens, L Islam, MT de Graft-Johnson, J Joshua, MA Keenan, W Khatoon, S Kieler, H Kramer, MS Lackritz, EM Lavender, T Lawintono, L Luhanga, R Marsh, D McMillan, D McNamara, PJ Mol, BJ Molyneux, E Mukasa, GK Mutabazi, M Nacul, LC Nakakeeto, M Narayanan, I Olusanya, B Osrin, D Paul, V Poets, C Reddy, UM Santosham, M Sayed, R Schlabritz-Loutsevitch, NE Singhal, N Smith, MA Smith, PG Soofi, S Spong, CY Sultana, S Tshefu, A van Bel, F Gray, LV Waiswa, P Wang, W Williams, SLA Wright, L Zaidi, A Zhang, YF Zhong, N Zuniga, I Bahl, R AF Yoshida, Sachiyo Martines, Jose Lawn, Joy E. Wall, Stephen Souza, Joao Paulo Rudan, Igor Cousens, Simon Aaby, Peter Adam, Ishag Adhikari, Ramesh Kant Ambalavanan, Namasivayam El Arifeen, Shams Aryal, Dhana Raj Asiruddin, Sk Baqui, Abdullah Barros, Aluisio J. D. Benn, Christine S. Bhandari, Vineet Bhatnagar, Shinjini Bhattacharya, Sohinee Bhutta, Zulfiqar A. Black, Robert E. Blencowe, Hannah Bose, Carl Brown, Justin Buehrer, Christoph Carlo, Wally Cecatti, Jose Guilherme Cheung, Po-Yin Clark, Robert Colbourn, Tim Conde-Agudelo, Agustin Corbett, Erica Czeizel, Andrew E. Das, Abhik Day, Louise Tina Deal, Carolyn Deorari, Ashok Dilmen, Ugur English, Mike Engmann, Cyril Esamai, Fabian Fall, Caroline Ferriero, Donna M. Gisore, Peter Hazir, Tabish Higgins, Rosemary D. Homer, Caroline S. E. Hoque, D. E. Irgens, Lorentz Islam, M. T. de Graft-Johnson, Joseph Joshua, Martias Alice Keenan, William Khatoon, Soofia Kieler, Helle Kramer, Michael S. Lackritz, Eve M. Lavender, Tina Lawintono, Laurensia Luhanga, Richard Marsh, David McMillan, Douglas McNamara, Patrick J. Mol, Ben Willem J. Molyneux, Elizabeth Mukasa, G. K. Mutabazi, Miriam Nacul, Luis Carlos Nakakeeto, Margaret Narayanan, Indira Olusanya, Bolajoko Osrin, David Paul, Vinod Poets, Christian Reddy, Uma M. Santosham, Mathuram Sayed, Rubayet Schlabritz-Loutsevitch, Natalia E. Singhal, Nalini Smith, Mary Alice Smith, Peter G. Soofi, Sajid Spong, Catherine Y. Sultana, Shahin Tshefu, Antoinette van Bel, Frank Gray, Lauren Vestewig Waiswa, Peter Wang, Wei Williams, Sarah L. A. Wright, Linda Zaidi, Anita Zhang, Yanfeng Zhong, Nanbert Zuniga, Isabel Bahl, Rajiv CA Neonatal Hlth Res Priority Setting TI Setting research priorities to improve global newborn health and prevent stillbirths by 2025 SO JOURNAL OF GLOBAL HEALTH LA English DT Article ID SYSTEMATIC ANALYSIS; CHILD HEALTH; RESEARCH INVESTMENTS; PRETERM BIRTH; TIME TRENDS; ACTION PLAN; DIARRHEA; BURDEN; PNEUMONIA; MORTALITY AB Background In 2013, an estimated 2.8 million newborns died and 2.7 million were stillborn. A much greater number suffer from long term impairment associated with preterm birth, intrauterine growth restriction, congenital anomalies, and perinatal or infectious causes. With the approaching deadline for the achievement of the Millennium Development Goals (MDGs) in 2015, there was a need to set the new research priorities on newborns and stillbirth with a focus not only on survival but also on health, growth and development. We therefore carried out a systematic exercise to set newborn health research priorities for 2013-2025. Methods We used adapted Child Health and Nutrition Research Initiative (CHNRI) methods for this prioritization exercise. We identified and approached the 200 most productive researchers and 400 program experts, and 132 of them submitted research questions online. These were collated into a set of 205 research questions, sent for scoring to the 600 identified experts, and were assessed and scored by 91 experts. Results Nine out of top ten identified priorities were in the domain of research on improving delivery of known interventions, with simplified neonatal resuscitation program and clinical algorithms and improved skills of community health workers leading the list. The top 10 priorities in the domain of development were led by ideas on improved Kangaroo Mother Care at community level, how to improve the accuracy of diagnosis by community health workers, and perinatal audits. The 10 leading priorities for discovery research focused on stable surfactant with novel modes of administration for preterm babies, ability to diagnose fetal distress and novel tocolytic agents to delay or stop preterm labour. Conclusion These findings will assist both donors and researchers in supporting and conducting research to close the knowledge gaps for reducing neonatal mortality, morbidity and long term impairment. WHO, SNL and other partners will work to generate interest among key national stakeholders, governments, NGOs, and research institutes in these priorities, while encouraging research funders to support them. We will track research funding, relevant requests for proposals and trial registers to monitor if the priorities identified by this exercise are being addressed C1 [Yoshida, Sachiyo; Bahl, Rajiv] World Hlth Org, Newborn Child & Adolescent Hlth, Dept Maternal, 20 Ave Appia, CH-1211 Geneva 27, Switzerland. [Martines, Jose] Univ Bergen, Ctr Int Hlth, Ctr Intervent Sci Maternal & Child Hlth, N-5020 Bergen, Norway. [Lawn, Joy E.; Cousens, Simon] London Sch Hyg & Trop Med, London, England. [Lawn, Joy E.; Wall, Stephen] Save Children, Saving Newborn Lives, Washington, DC USA. [Souza, Joao Paulo] Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Social Med, Sao Paulo, Brazil. [Rudan, Igor] Univ Edinburgh, Sch Med, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Rudan, Igor] Univ Edinburgh, Sch Med, Global Hlth Acad, Edinburgh, Midlothian, Scotland. [Aaby, Peter] Bandim Hlth Project Indepth Network, Bissau, Guinea Bissau. [Adam, Ishag] Univ Khartoum, Fac Med, Khartoum, Sudan. [Adhikari, Ramesh Kant] Kathmandu Med Coll, Kathmandu, Nepal. [Ambalavanan, Namasivayam] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [El Arifeen, Shams] Int Ctr Diar rhoeal Dis Res, Ctr Child & Adolescent Hlth, Dhaka, Bangladesh. [Aryal, Dhana Raj] Paropakar Matern & womens Hosp, Dept Neonatol, Kathmandu, Nepal. [Asiruddin, Sk] Univ Res Co LLC, TRAct Bangladesh Project, Chevy Chase, MD USA. [Baqui, Abdullah] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Barros, Aluisio J. D.] Univ Fed Pelotas, Ctr Pesquisas Epidemiol, Pelotas, Brazil. [Benn, Christine S.] Univ Southern Denmark, Odense Univ Hosp, Res Ctr Vitamins, Odense, Denmark. [Benn, Christine S.] Univ Southern Denmark, Odense Univ Hosp, Statens Serum Inst, Odense, Denmark. [Bhandari, Vineet] Yale Univ, Sch Med, Program Perinatal Res, New Haven, CT 06520 USA. [Bhatnagar, Shinjini] Translat Hlth Sci & Technol Inst, Pediat Biol Ctr, Pali, India. [Bhattacharya, Sohinee] Univ Aberdeen, Aberdeen, Scotland. [Bhutta, Zulfiqar A.] Aga Khan Univ, Ctr Excellence Women & Child Hlth, Karachi, Pakistan. [Black, Robert E.] Johns Hopkins Bloomberg Sch Publ Hlth, Inst Int Programs, Baltimore, MD USA. [Blencowe, Hannah] London Sch Hyg & Trop Med, London, England. [Bose, Carl] Univ N Carolina, Chapel Hill Sch Med, Chapel Hill, NC USA. [Brown, Justin] Thrasher Res Fund, Salt Lake City, UT USA. [Buehrer, Christoph] Charles Univ Prague, Med Ctr, Dept Neonatol, Berlin, Germany. [Carlo, Wally] Univ Alabama Birmingham, Birmingham, AL USA. [Cecatti, Jose Guilherme] Univ Estadual Campinas, Sch Med Sci, Dept Obstet & Gynaecol, Campinas, SP, Brazil. [Cheung, Po-Yin] Univ Alberta, Dept Pediat, Pharmacol & Surg, Edmonton, AB, Canada. [Clark, Robert] Charities, New Orleans, LA USA. [Colbourn, Tim] Univ Coll London Inst Global Hlth, London, England. [Conde-Agudelo, Agustin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Natl Inst Hlth, Dept Hlth & Human Serv, Bethesda, MD USA. [Corbett, Erica] Independent consultant maternal Hlth Res, Kigali, Rwanda. [Czeizel, Andrew E.] Fdn Commun Control Hereditary Dis, Budapest, Hungary. [Das, Abhik] RTI Int, Biostatist & Epidemiol, Res Triangle Pk, NC USA. [Day, Louise Tina] LAMB Integrated Rural Hlth & Dev, Dinajpur, Bangladesh. [Deal, Carolyn] Natl Inst Allergy & Infect Dis Natl Inst Hlth, Div Microbiol & Infect Dis, Salt Lake City, UT USA. [Deorari, Ashok] All India Inst Med Sci, New Delhi, India. [Dilmen, Ugur] Yildirim Beyazit Univ, Fac Med, Pediat & Neonatol, Ankara, Turkey. [English, Mike] Univ Oxford, Nuffield Dept Med, Oxford, England. [English, Mike] Univ Oxford, Dept Paediat, Oxford, England. [English, Mike] KEMRi Wellcome Trust Res Programme, Nairobi, Kenya. [Engmann, Cyril] Bill Melinda Gates Fdn, Newborn Hlth Family Hlth Div, Seattle, WA USA. [Engmann, Cyril] Univ N Carolina, Sch Med & Publ Hlth, Chapel Hill, NC 27515 USA. [Esamai, Fabian] Moi Univ, Sch Med, Eldoret, Kenya. [Fall, Caroline] Univ Southampton, Med Res Council, Lifecourse Epidemiol Unit, Int Paediat Epidemiol, Southampton, Hants, England. [Ferriero, Donna M.] UCSF Benioff Childrens Hosp, Dept Pediat, San Francisco, CA USA. [Gisore, Peter] Moi Univ, Sch Med Child Hlth & Pediat, Eldoret, Kenya. [Hazir, Tabish] Childrens Hosp, Pakistan Inst Med Sci, Lahore, Pakistan. [Higgins, Rosemary D.] Eunice Kennedy Shriver NICHD Neonatal Res Network, Pregnancy & Perinatol Branch, Natl Inst Hlth, Bethesda, MD USA. [Homer, Caroline S. E.] Univ Technol, Ctr Midwifery Child & Family Hlth, Sydney, NSW, Australia. [Hoque, D. E.] Int Ctr Diarrhoeal Dis Res, Ctr Child & Adolescent Hlth, Dhaka, Bangladesh. [Irgens, Lorentz] Univ Bergen, Bergen, Norway. [Irgens, Lorentz] Norwegian Inst Publ Hlth, Bergen, Norway. [Islam, M. T.] Japan Int Cooperat Agcy JICA, Dhaka, Bangladesh. [de Graft-Johnson, Joseph] Save Children, Fairfield, CT USA. [Joshua, Martias Alice] Zomba Cent Hosp, Minist Hlth, Zomba, Malawi. [Keenan, William] St Louis Univ, St Louis, MO USA. [Khatoon, Soofia] Shaheed Suhrawardy Med Coll, Paediat & Head Dept, Dhaka, Bangladesh. [Kieler, Helle] Karolinska Inst, Ctr Pharmacoepidemiol, Solna, Sweden. [Kramer, Michael S.] McGill Univ, Fac Med, Biostat & Occupat Hlth, Dept Pediat & Epidemiol, Montreal, PQ, Canada. [Lackritz, Eve M.] Global Alliance Prevent Prematur & Stillbirth GAP, Seattle, WA USA. [Lavender, Tina] Univ Manchester, Sch Nursing Midwifery & Social Work, Manchester, Lancs, England. [Lawintono, Laurensia] Indonesian Midw Assoc, Jakarta, Indonesia. [Luhanga, Richard] Save Children, Lilongwe, Malawi. [Marsh, David] Save Children, Fairfield, CT USA. [McMillan, Douglas] Dalhousie Univ, Dept Paediat, Halifax, NS, Canada. [McNamara, Patrick J.] Univ Toronto, Dept Paediat & Physiol, Toronto, ON, Canada. [McNamara, Patrick J.] Hosp Sick Children, Physiol & Expt Med program, Toronto, ON, Canada. [Mol, Ben Willem J.] Acad Med Ctr, Dept Obstet & Gynaecol, Amsterdam, Netherlands. [Molyneux, Elizabeth] Coll Med, Paediat & Child Hlth, Lilongwe, Malawi. [Mukasa, G. K.] Int Baby Food Act Network, Kampala, Uganda. [Mutabazi, Miriam] STRIDES Family Hlth, Management Sci Hlth, Kampala, Uganda. [Nacul, Luis Carlos] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London, England. [Nakakeeto, Margaret] Kampala Childrens Hosp Ltd & Childhealth Advocacy, Kampala, Uganda. [Narayanan, Indira] United States Agcy Int Dev, Maternal & Child Hlth Integrated Program, Washington, DC USA. [Olusanya, Bolajoko] Ctr Healthy Start Initiat, Lagos, Nigeria. [Osrin, David] UCL, Inst Global Hlth, Wellcome Trust Senior Res Fellow Clin Sci, London, England. [Paul, Vinod] All India Inst Med Sci, Patna, Bihar, India. [Poets, Christian] Univ Tubingen, Tubingen, Germany. [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dev Natl Inst Hlth, Cambridge, MD USA. [Santosham, Mathuram] Johns Hopkins Bloomberg, Sch Publ Hlth, Ctr Amer Indian Hlth, Baltimore, MD USA. [Sayed, Rubayet] Save Children, Dhaka, Bangladesh. [Schlabritz-Loutsevitch, Natalia E.] Univ Tennessee, Hlth Sci Ctr, Dept Obstet & Gynecol, Knoxville, TN 37996 USA. [Singhal, Nalini] Univ Calgary, Calgary, AB, Canada. [Smith, Mary Alice] Univ Georgia, Dept Environm Hlth Sci, Athens, GA 30602 USA. [Smith, Peter G.] London Sch Hyg & Trop Med, Trop Epidemiol Grp, London, England. [Soofi, Sajid] Aga Khan Univ, Women & Child Hlth Div, Dept Pediat & Child Hlth, Karachi, Pakistan. [Spong, Catherine Y.; Zaidi, Anita] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Sultana, Shahin] Minist Hlth & Family Welf, Natl Inst Populat Res & Training NIPORT, Dhaka, Bangladesh. [Tshefu, Antoinette] Univ Kinshasa, Sch Med, Kinshasa Sch Publ Hlth, Kinshasa, DEM REP CONGO. [van Bel, Frank] Univ Utrecht, Dept Neonatol, Utrecht, Netherlands. [Gray, Lauren Vestewig] Rice Univ, Inst Global Hlth Technol, Houston, TX 77251 USA. [Waiswa, Peter] Karolinska Inst, Div Global Hlth, Stockholm, Sweden. [Williams, Sarah L. A.] Edith Cowan Univ, Sch Med Sci, Churchlands, WA 6018, Australia. [Wright, Linda] Capital Med Univ, Sch Publ Hlth, Beijing, Peoples R China. [Wright, Linda] Save Children UK, London, England. [Zaidi, Anita] Aga Khan Univ, Karachi, Pakistan. [Zhang, Yanfeng] Capital Inst Paediat, Dept Integrated Early Childhood Dev, Beijing, Peoples R China. [Zhong, Nanbert] New York State Inst Basic Res Dev Disabil, Lab Dev Genet, New York, NY USA. [Zuniga, Isabel] Medecins Sans Frontieres, Brussels, Belgium. RP Bahl, R (reprint author), World Hlth Org, Newborn Child & Adolescent Hlth, Dept Maternal, 20 Ave Appia, CH-1211 Geneva 27, Switzerland. EM bahlr@who.int RI Souza, Joao Paulo/G-1982-2010; OI Souza, Joao Paulo/0000-0002-2288-4244; Homer, Caroline/0000-0002-7454-3011 FU Save the Children FX This work was supported by Save the Children. NR 35 TC 0 Z9 0 U1 1 U2 98 PU UNIV EDINBURGH, GLOBAL HEALTH SOC PI EDINBURGH PA CENTRE POPULATION HEALTH SCIENCES, TEVIOT PL, EDINBURGH, EH8 9AG, ENGLAND SN 2047-2978 EI 2047-2986 J9 J GLOB HEALTH JI J. Glob. Health PD JUN PY 2016 VL 6 IS 1 AR 010508 DI 10.7189/jogh.06.010508 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EO8YM UT WOS:000396976400026 PM 26401272 ER PT J AU Pholphirul, P Teimtad, S AF Pholphirul, Piriya Teimtad, Siwat TI Economics of Pre-Primary Education in Thailand SO APPLIED ECONOMICS JOURNAL LA English DT Article DE Pre-Primary Education; Long-Term Impacts; Education Performance; Thailand ID PRIMARY-SCHOOL; OUTCOMES; LONG AB Several research papers have assessed the long-term benefits of pre-primary education in terms of academic performance and labor market outcomes. This study analyzes data obtained from the Program for International Student Assessment (PISA) to estimate the effects of preschool enrollment of Thai students on producing long-term benefits in their academic performance. Results show that a mother's educational attainment has a significant impact on the decision to enroll her child in preschool. Regarding the long-term benefits, our findings show that pre-primary education bears a significant and positive association with cognitive skills in all three areas of literacy tested under PISA, namely, reading, mathematics, and the sciences. Regarding the economic status of students' families, results indicate that the benefits of pre-primary education in cognitive skill improvement tend to be greatest in the case of students from low-to middle-income families. Evidence supports the promotion of long-term benefits of pre-primary education and, thus, the universal early childhood education policy. In particular, support should be given to childhood education programs that specifically target children from disadvantaged groups and low-income households. C1 [Pholphirul, Piriya; Teimtad, Siwat] NIDA, Grad Sch Dev Econ, Bangkok 10240, Thailand. [Pholphirul, Piriya] Int Coll Natl Inst Dev Adm ICO NIDA, Bangkok 10240, Thailand. RP Pholphirul, P (reprint author), NIDA, Grad Sch Dev Econ, Bangkok 10240, Thailand.; Pholphirul, P (reprint author), Int Coll Natl Inst Dev Adm ICO NIDA, Bangkok 10240, Thailand. EM pholphir@hotmail.com; tae.siwat@gmail.com FU Wisdom Society for Public Opinion Research of Thailand FX This paper is financially support by The Wisdom Society for Public Opinion Research of Thailand under the management of the CP All, Public, Company. NR 31 TC 0 Z9 0 U1 2 U2 2 PU KASERSART UNIV, FAC ECONOMICS PI BANGKOK PA CENTER APPLIED ECONOMICS RESEARCH, 50 PHAHON YOTHIN RD, JATUJAK, BANGKOK, 10900, THAILAND SN 0858-9291 J9 APPL ECON J JI Appl. Econ. J. PD JUN PY 2016 VL 23 IS 1 BP 1 EP 34 PG 34 WC Economics SC Business & Economics GA EJ7PI UT WOS:000393414200002 ER PT J AU Patmasiriwat, D Hengpatana, S AF Patmasiriwat, Direk Hengpatana, Suwimon TI Income, Saving, and Wealth of Thai Rural Households: A Case Study of Saving Adequacies SO APPLIED ECONOMICS JOURNAL LA English DT Article DE Income; saving; wealth; saving inadequacy; socio-economic factors; rural household; Thailand AB This paper investigates the savings and wealth of Thai rural households with an emphasis on the issue of saving inadequacies. We use the household survey conducted by the National Statistical Office in 2009 as a database. First, we hypothesize an interrelationship between household income, saving, and assets. Further, we estimate the scope of the relationship using an econometric technique and examine savings predicted over the household's lifecycle. Our findings indicate that: (i) approximately 29% of Thai rural households overspent their income; indeed, this group failed to save and incurred negative savings, (ii) 47% of Thai rural households inadequately saved due to a "weak definition" which signifies the amount saved is inadequate or too little to cope with future risks and uncertainties. Calculations related to the probabilities of saving inadequacies compared age-cohorts, occupations, and levels of education. The last section discusses long-term implications of saving inadequacies, and limitations of the model for improving saving practices within Thai rural households. C1 [Patmasiriwat, Direk] NIDA, Sch Dev Econ, Seri Thai Rd, Bangkok 10240, Thailand. [Hengpatana, Suwimon] Srinakharinwirot Univ, Sch Econ & Publ Policy, Bangkok 10110, Thailand. RP Patmasiriwat, D (reprint author), NIDA, Sch Dev Econ, Seri Thai Rd, Bangkok 10240, Thailand. EM direk.p@nida.ac.th; suwimonh@g.swu.ac.th NR 6 TC 0 Z9 0 U1 0 U2 0 PU KASERSART UNIV, FAC ECONOMICS PI BANGKOK PA CENTER APPLIED ECONOMICS RESEARCH, 50 PHAHON YOTHIN RD, JATUJAK, BANGKOK, 10900, THAILAND SN 0858-9291 J9 APPL ECON J JI Appl. Econ. J. PD JUN PY 2016 VL 23 IS 1 BP 75 EP 91 PG 17 WC Economics SC Business & Economics GA EJ7PI UT WOS:000393414200005 ER PT J AU Muthigi, A George, AK Brancato, SJ Agarwal, PK AF Muthigi, Akhil George, Arvin K. Brancato, Sam J. Agarwal, Piyush K. TI Novel immunotherapeutic approaches to the treatment of urothelial carcinoma SO THERAPEUTIC ADVANCES IN UROLOGY LA English DT Review DE immunotherapy; NMIBC; urothelial carcinoma ID BACILLUS-CALMETTE-GUERIN; SUPERFICIAL BLADDER-CANCER; TRANSITIONAL-CELL-CARCINOMA; CHIMERIC ANTIGEN RECEPTOR; MODIFIED T-CELLS; MYCOBACTERIUM-BOVIS; IFN-GAMMA; INTRAVESICAL TREATMENT; ONCOLYTIC ADENOVIRUS; BCG IMMUNOTHERAPY AB Immunotherapy has long played a role in urothelial cancers with the use of bacille Calmette Guerin (BCG) being a mainstay in the treatment of nonmuscle invasive bladder cancer. Novel therapeutic approaches have not significantly impacted mortality in this population and so a renaissance in immunotherapy has resulted. This includes recombinant BCG, oncolytic viruses, monoclonal antibodies, vaccines, and adoptive T-cell therapy. Herein, we provide a review of the current state of the art and future therapies regarding immunotherapeutic strategies for urothelial carcinoma. C1 [Muthigi, Akhil; George, Arvin K.; Brancato, Sam J.; Agarwal, Piyush K.] NCI, Urol Oncol Branch, NIH, Bldg 10 Hatfield CRC,Room 2-5952, Bethesda, MD 20892 USA. RP Agarwal, PK (reprint author), NCI, Urol Oncol Branch, NIH, Bldg 10 Hatfield CRC,Room 2-5952, Bethesda, MD 20892 USA. EM piyush.agarwal@nih.gov RI Brancato, Sam/K-3266-2014 OI Brancato, Sam/0000-0002-3760-5818 FU National Institutes of Health (NIH), National Cancer Institute; NIH FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute.; This research was made possible through the National Institutes of Health (NIH) Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, American Association for Dental Research, Howard Hughes Medical Institute, and the Colgate-Palmolive Company, as well as alumni of student research programs and other individual supporters. NR 73 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1756-2872 EI 1756-2880 J9 THER ADV UROL JI Ther. Adv. Urol. PD JUN PY 2016 VL 8 IS 3 BP 203 EP 214 DI 10.1177/1756287216628784 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA EK2EX UT WOS:000393741700005 PM 27247630 ER PT J AU Feng, S Bucuvalas, J Demetris, A Spain, K Kanaparthi, S Magee, J Mazariegos, G AF Feng, S. Bucuvalas, J. Demetris, A. Spain, K. Kanaparthi, S. Magee, J. Mazariegos, G. CA iWITH Investigators TI Primary Outcome of iWITH: A Multi-Center Clinical Trial of Complete Immunosuppression Withdrawal (ISW) in Stable Pediatric Liver Transplant (LT) Recipients SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY JUN 11-15, 2016 CL Boston, MA C1 [Feng, S.] UCSF, San Francisco, CA USA. [Bucuvalas, J.] CCHMC, Cincinnati, OH USA. [Demetris, A.; Mazariegos, G.] Univ Pitt, Pittsburgh, PA USA. [Spain, K.] Rho, Chapel Hill, NC USA. [Kanaparthi, S.] ITN, Bethesda, MD USA. [Magee, J.] Univ Mich, Ann Arbor, MI USA. [iWITH Investigators] NIDDK, NIAID, ITN, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUN PY 2016 VL 16 SU 3 SI SI MA 185.1 BP 269 EP 269 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA DW1AB UT WOS:000383373902186 ER PT J AU Zuckerman, W Feingold, B Zeevi, A Bentlejewski, C Addonizio, L Blume, E Canter, C Dipchand, A Hsu, D Shaddy, R Mahle, W Much, K Armstrong, B Ikle, D Diop, H Odim, J Webber, S AF Zuckerman, W. Feingold, B. Zeevi, A. Bentlejewski, C. Addonizio, L. Blume, E. Canter, C. Dipchand, A. Hsu, D. Shaddy, R. Mahle, W. Much, K. Armstrong, B. Ikle, D. Diop, H. Odim, J. Webber, S. TI Solid Phase Assay Demonstrates High Rates of Allosensitization in Pediatric Heart Recipients. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY JUN 11-15, 2016 CL Boston, MA C1 [Zuckerman, W.; Addonizio, L.] Columbia Univ, Nyc, NY USA. [Feingold, B.; Zeevi, A.; Bentlejewski, C.] Univ Pittsburgh, Pittsburgh, PA USA. [Blume, E.] Boston Childrens Hosp, Boston, MA USA. [Canter, C.] Washington Univ, St Louis, MO USA. [Dipchand, A.] Sick Kids, Toronto, ON, Canada. [Hsu, D.] Montefiore, Childrens Hosp, Nyc, NY USA. [Shaddy, R.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Mahle, W.] CHOA, Atlanta, GA USA. [Much, K.; Armstrong, B.; Ikle, D.] Rho, Chapel Hill, NC USA. [Diop, H.; Odim, J.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Webber, S.] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUN PY 2016 VL 16 SU 3 SI SI MA 15 BP 210 EP 210 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA DW1AB UT WOS:000383373902015 ER PT J AU Shaked, A Feng, S Punch, J Reyes, J Levitsky, J Klintmalm, G Kopetskie, H DesMarais, M Priore, A Bridges, N Sayre, P AF Shaked, A. Feng, S. Punch, J. Reyes, J. Levitsky, J. Klintmalm, G. Kopetskie, H. DesMarais, M. Priore, A. Bridges, N. Sayre, P. TI Early Post-Transplant Immunosuppression (IS) Withdrawal - Final Outcomes of the ITN030ST AWISH Study SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY JUN 11-15, 2016 CL Boston, MA C1 [Shaked, A.] UPenn, Philadelphia, PA USA. [Feng, S.; DesMarais, M.; Sayre, P.] UCSF, San Francisco, CA USA. [Punch, J.] Univ Michigan, Ann Arbor, MI 48109 USA. [Reyes, J.] Univ Washington, Seattle, WA 98195 USA. [Levitsky, J.] Northwestern, Chicago, IL USA. [Klintmalm, G.] Baylor, Dallas, TX USA. [Kopetskie, H.] RhoFed, Chapel Hill, NC USA. [Priore, A.; Bridges, N.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUN PY 2016 VL 16 SU 3 SI SI MA 185 BP 269 EP 269 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA DW1AB UT WOS:000383373902185 ER PT J AU Suarez-Fuentes, C Broin, O Bao, Y Akalin, E AF Suarez-Fuentes, C. Broin, O. Bao, Y. Akalin, E. TI Effect of Angiotensin Converting Enzyme Inhibitor (ACEI) or Angiotensin Receptor Blockade (ARB) Exposure on Intragraft Gene Expression of Kidney Transplant Patients SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY JUN 11-15, 2016 CL Boston, MA C1 [Suarez-Fuentes, C.; Bao, Y.; Akalin, E.] Montefiore Med Ctr, Kidney Transplant, 111 E 210th St, Bronx, NY 10467 USA. [Suarez-Fuentes, C.; Akalin, E.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Broin, O.] Natl Univ Ireland Galway Univ, Galway, Ireland. [Suarez-Fuentes, C.] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUN PY 2016 VL 16 SU 3 SI SI MA 341 BP 323 EP 324 PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA DW1AB UT WOS:000383373902342 ER PT J AU Chan, J Singh, A Corcoran, P Thomas, M Lewis, B Ayares, D Horvath, K Mohiuddin, M AF Chan, J. Singh, A. Corcoran, P. Thomas, M., III Lewis, B. Ayares, D. Horvath, K. Mohiuddin, M. TI Inclusion of Human Tissue Factor Pathway Inhibitor or Thrombomodulin Transgenes Attenuates Critical Consumptive Thrombocytopenia in Cardiac Xenotransplantation. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY JUN 11-15, 2016 CL Boston, MA C1 [Chan, J.; Singh, A.; Corcoran, P.; Horvath, K.; Mohiuddin, M.] NHLBI, Cardiothorac Surg Res Program, NIH, Bldg 10, Bethesda, MD 20892 USA. [Thomas, M., III; Lewis, B.] NIH, Div Vet Resources, Bldg 10, Bethesda, MD 20892 USA. [Ayares, D.] Revivicor Inc, Blacksburg, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUN PY 2016 VL 16 SU 3 SI SI MA 361 BP 329 EP 329 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA DW1AB UT WOS:000383373902361 ER PT J AU Horvath, K Singh, A Chan, J Thomas, M Lewis, B Ayares, D Corcoran, P Mohiuddin, M AF Horvath, K. Singh, A. Chan, J. Thomas, M. Lewis, B. Ayares, D. Corcoran, P. Mohiuddin, M. TI The Impact of Sequential Gene Modifications on Cardiac Xenograft Survival SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY JUN 11-15, 2016 CL Boston, MA C1 [Horvath, K.; Singh, A.; Chan, J.; Corcoran, P.; Mohiuddin, M.] NHLBI, CSRP, NIH, Bldg 10, Bethesda, MD 20892 USA. [Thomas, M.; Lewis, B.] NIH, DVR, ORS, Bldg 10, Bethesda, MD 20892 USA. [Lewis, B.; Ayares, D.] Revivicor Inc, Blacksburg, VA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUN PY 2016 VL 16 SU 3 SI SI MA 360 BP 329 EP 329 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA DW1AB UT WOS:000383373902360 ER PT J AU Singh, A Chan, J Corcoran, P Lewis, B Thomas, M Ayares, D Horvath, K Mohiuddin, M AF Singh, A. Chan, J. Corcoran, P. Lewis, B. Thomas, M. Ayares, D. Horvath, K. Mohiuddin, M. TI Costimulation Blockade by Anti CD40 Antibody Prevents Humoral and Cellular Rejection of Heterotopic Pig Cardiac Xenograft. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY JUN 11-15, 2016 CL Boston, MA C1 [Singh, A.; Chan, J.; Corcoran, P.; Horvath, K.; Mohiuddin, M.] CSRP NHLBI, NIH, Bethesda, MD USA. [Lewis, B.; Thomas, M.] NIH, DVR ORS, Bldg 10, Bethesda, MD 20892 USA. [Ayares, D.] Revivicor Inc, Blacksburg, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUN PY 2016 VL 16 SU 3 SI SI MA 362 BP 329 EP 330 PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA DW1AB UT WOS:000383373902362 ER PT J AU Webber, S Addonizio, L Blume, E Dipchand, A Shaddy, R Feingold, B Canter, C Hsu, D Mahle, W Zeevi, A Much, K Ikle, D Diop, H Odim, J AF Webber, S. Addonizio, L. Blume, E. Dipchand, A. Shaddy, R. Feingold, B. Canter, C. Hsu, D. Mahle, W. Zeevi, A. Much, K. Ikle, D. Diop, H. Odim, J. CA CTOTC-04 Investigators TI Pediatric Heart Transplantation Across a Positive Cross-Match Is Associated with High Rates of AMR but No Difference in Short Term Graft Loss, Dysfunction and Death (CTOTC-04 study). SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY JUN 11-15, 2016 CL Boston, MA C1 [Webber, S.] Vanderbilt, Nashville, TN USA. [Addonizio, L.] Columbia Univ, Nyc, NY USA. [Blume, E.] Boston Childrens, Boston, MA USA. [Dipchand, A.] Sick Kids, Toronto, ON, Canada. [Shaddy, R.] CHOP, Philadelphia, PA USA. [Feingold, B.; Zeevi, A.] CHP UPMC, Pittsburgh, PA USA. [Canter, C.] Washington Univ, St Louis, MO USA. [Hsu, D.] Montefiore, Childrens Hosp, Nyc, NY USA. [Mahle, W.] CHOA, Atlanta, GA USA. [Much, K.; Ikle, D.] Rho, Chapel Hill, NC USA. [Diop, H.; CTOTC-04 Investigators] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUN PY 2016 VL 16 SU 3 SI SI MA 572 BP 331 EP 331 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA DW1AB UT WOS:000383373902367 ER PT J AU Mannon, R Stock, P Mehta, A Ikle, D Watson, N Bridges, N Robien, M Newell, K AF Mannon, R. Stock, P. Mehta, A. Ikle, D. Watson, N. Bridges, N. Robien, M. Newell, K. TI Avoidance of CNI and Steroids Using Belatacept - A Preliminary Report of CTOT-16. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY JUN 11-15, 2016 CL Boston, MA C1 [Mannon, R.] UAB, Birmingham, AL USA. [Stock, P.] UCSF, San Francisco, CA USA. [Mehta, A.; Newell, K.] Emory, Atlanta, GA USA. [Ikle, D.] Rho, Chapel Hill, NC USA. [Watson, N.; Bridges, N.; Robien, M.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUN PY 2016 VL 16 SU 3 SI SI MA 566 BP 401 EP 402 PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA DW1AB UT WOS:000383373902571 ER PT J AU Mohiuddin, M Singh, A Chan, J Corcoran, P Thomas, M Lewis, B Ayares, D Horvath, K AF Mohiuddin, M. Singh, A. Chan, J. Corcoran, P. Thomas, M., III Lewis, B. Ayares, D. Horvath, K. TI Long Term Heterotopic Cardiac Xenograft Survival from Donor Pigs with Six Gene Modifications SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY JUN 11-15, 2016 CL Boston, MA C1 [Mohiuddin, M.; Singh, A.; Chan, J.; Corcoran, P.; Horvath, K.] NHLBI, CSRP, NIH, Bldg 10, Bethesda, MD 20892 USA. [Thomas, M., III; Lewis, B.] NIH, DVR, RS, Bldg 10, Bethesda, MD 20892 USA. [Ayares, D.] Revivicor Inc, Blacksburgh, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUN PY 2016 VL 16 SU 3 SI SI MA B37 BP 512 EP 512 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA DW1AB UT WOS:000383373903339 ER PT J AU Feng, XS Juan, AH Wang, HA Ko, KD Zare, H Sartorelli, V AF Feng, Xuesong Juan, Aster H. Wang, Hongjun A. Ko, Kyung Dae Zare, Hossein Sartorelli, Vittorio TI Polycomb Ezh2 controls the fate of GABAergic neurons in the embryonic cerebellum SO DEVELOPMENT LA English DT Article DE Polycomb; Ezh2; PRC2; Cerebellum; Neurogenesis; Purkinje cells ID RECEPTOR ROR ALPHA; LARGE GENE LISTS; STEM-CELLS; SONIC HEDGEHOG; RHOMBIC-LIP; HISTONE METHYLTRANSFERASE; ISTHMIC ORGANIZER; MOUSE DEVELOPMENT; NERVOUS-SYSTEM; PURKINJE-CELLS AB Although the genetic interactions between signaling pathways and transcription factors have been largely decoded, much remains to be learned about the epigenetic regulation of cerebellar development. Here, we report that cerebellar deletion of Ezh2, the methyltransferase subunit of the PRC2 complex, results in reduced H3K27me3 and profound transcriptional dysregulation, including that of a set of transcription factors directly involved in cerebellar neuronal cell-type specification and differentiation. Such transcriptional changes lead to increased GABAergic interneurons and decreased Purkinje cells. Transcriptional changes also inhibit the proliferation of granule precursor cells derived from the rhombic lip. The loss of both cell types ultimately results in cerebellar hypoplasia. These findings indicate Ezh2/PRC2 plays crucial roles in regulating neurogenesis from both cerebellar germinal zones. C1 [Feng, Xuesong; Juan, Aster H.; Wang, Hongjun A.; Ko, Kyung Dae; Zare, Hossein; Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, 50 South Dr, Bethesda, MD 20892 USA. RP Sartorelli, V (reprint author), NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM sartorev@mail.nih.gov FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at the National Institutes of Health. Deposited in PMC for release after 12 months. NR 78 TC 0 Z9 0 U1 2 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD JUN 1 PY 2016 VL 143 IS 11 BP 1971 EP 1980 DI 10.1242/dev.132902 PG 10 WC Developmental Biology SC Developmental Biology GA EE4QG UT WOS:000389588800014 PM 27068104 ER PT J AU Hudak, ML Park, CH Annett, RD Hale, DE McGovern, PM McLaughlin, TJ Dole, N Kaar, JL Balsam, MJ AF Hudak, Mark L. Park, Christina H. Annett, Robert D. Hale, Daniel E. McGovern, Patricia M. McLaughlin, Thomas J. Dole, Nancy Kaar, Jill L. Balsam, Marion J. TI The National Children's Study: An Introduction and Historical Overview SO PEDIATRICS LA English DT Article ID RECRUITMENT AB The National Children's Study (NCS) was an ambitious attempt to map children's health and development in a large representative group of children in the United States. In this introduction, we briefly review the background of the NCS and the history of the multiple strategies that were tested to recruit women and children. Subsequent articles then detail the protocols and outcomes of 4 of the recruitment strategies. It is hoped that lessons learned from these attempts to define a study protocol that could achieve the initial aims of the NCS will inform future efforts to conceptualize and execute strategies to provide generalizable insights on the longitudinal health of our nation's children. C1 [Hudak, Mark L.] Univ Florida, Coll Med Jacksonville, Dept Pediat, 653-1 W 8th St, Jacksonville, FL 32209 USA. [Park, Christina H.; Balsam, Marion J.] NICHHD, Bethesda, MD 20892 USA. [Annett, Robert D.] Univ Mississippi, Med Ctr, Div Child Dev, Jackson, MS 39216 USA. [Hale, Daniel E.] Univ Texas Hlth Sci Ctr San Antonio, Div Endocrinol & Diabet, San Antonio, TX 78229 USA. [McGovern, Patricia M.] Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Serv, Minneapolis, MN USA. [McLaughlin, Thomas J.] Univ Massachusetts, Dept Pediat, Worcester, MA 01605 USA. [Dole, Nancy] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. [Kaar, Jill L.] Univ Colorado, Sch Med, Dept Pediat, Denver, CO USA. RP Hudak, ML (reprint author), Univ Florida, Coll Med Jacksonville, Dept Pediat, 653-1 W 8th St, Jacksonville, FL 32209 USA. EM mark.hudak@jax.ufl.edu FU NICHD; National Institutes of Health (NIH) FX Supported in part by NICHD contracts. Funded by the National Institutes of Health (NIH). NR 7 TC 0 Z9 0 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD JUN PY 2016 VL 137 SU 4 AR e20154410B DI 10.1542/peds.2015-4410B PG 6 WC Pediatrics SC Pediatrics GA EE2KQ UT WOS:000389413300002 PM 27251867 ER PT J AU McLaughlin, TJ Aupont, O Kozinetz, CA Hubble, D Moore-Simas, TA Davis, D Park, C Brenner, R Sepavich, D Felice, M Caviness, C Downs, T Selwyn, BJ Forman, MR AF McLaughlin, Thomas J. Aupont, Onesky Kozinetz, Claudia A. Hubble, David Moore-Simas, Tiffany A. Davis, Deborah Park, Christina Brenner, Ruth Sepavich, Deidre Felice, Marianne Caviness, Chantal Downs, Tim Selwyn, Beatrice J. Forman, Michele R. TI Multilevel Provider-Based Sampling for Recruitment of Pregnant Women and Mother-Newborn Dyads SO PEDIATRICS LA English DT Article ID NATIONAL PROBABILITY SAMPLES; LOW-PREVALENCE DISEASES; SERVICES UTILIZATION; HIV COST; CHILDRENS AB OBJECTIVE: In 2010, the National Children's Study launched 3 alternative recruitment methods to test possible improvements in efficiency compared with traditional household-based recruitment and participant enrollment. In 2012, a fourth method, provider-based sampling (PBS), tested a probability-based sampling of prenatal provider locations supplemented by a second cohort of neonates born at a convenience sample of maternity hospitals. METHODS: From a sampling frame of 472 prenatal care provider locations and 59 maternity hospitals, 49 provider and 7 hospital locations within or just outside 3 counties participated in study recruitment. During first prenatal care visits or immediately postdelivery at these locations, face-to-face contact was used to screen and recruit eligible women. RESULTS: Of 1450 screened women, 1270 were eligible. Consent rates at prenatal provider locations (62%-74% by county) were similar to those at birth locations (64%-77% by county). During 6 field months, 3 study centers enrolled a total prenatal cohort of 530 women (the majority in the first trimester) and during 2 months enrolled a birth cohort of an additional 320 mother-newborn dyads. As personnel became experienced in the field, the time required to enroll a woman in the prenatal cohort declined from up to 200 hours to 50 to 100 hours per woman recruited. CONCLUSIONS: We demonstrated that PBS was feasible and operationally efficient in recruiting a representative cohort of newborns from 3 diverse US counties. Our findings suggest that PBS is a practical approach to recruit large pregnancy and birth cohorts across the United States. C1 [McLaughlin, Thomas J.; Aupont, Onesky; Moore-Simas, Tiffany A.; Sepavich, Deidre; Felice, Marianne] Univ Massachusetts, Worcester, MA 01605 USA. [Kozinetz, Claudia A.] East Tennessee State Univ, Johnson City, TN USA. [Hubble, David] Westat Corp, Rockville, MD USA. [Davis, Deborah] Univ Louisville, Louisville, KY 40292 USA. [Park, Christina; Brenner, Ruth] NICHHD, Rockville, MD USA. [Caviness, Chantal] Baylor Coll Med, Houston, TX 77030 USA. [Downs, Tim] Clark Univ, Worcester, MA 01610 USA. [Selwyn, Beatrice J.] Univ Texas Sch Publ Hlth, Houston, TX USA. [Forman, Michele R.] Univ Texas Austin, Austin, TX 78712 USA. RP McLaughlin, TJ (reprint author), Univ Massachusetts, Dept Pediat, Sch Med, 222 Maple Ave, Shrewsbury, MA 01545 USA. EM thomas.mclaughlin@umassmed.edu FU National Institute for Child Health and Human Development [HHSN275200800020C, HHSC275200800006C, HHSN267200700024C]; National Institutes of Health (NIH) FX Supported in part by National Institute for Child Health and Human Development Contracts HHSN275200800020C, HHSC275200800006C, and HHSN267200700024C. Funded by the National Institutes of Health (NIH). NR 9 TC 0 Z9 0 U1 1 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD JUN PY 2016 VL 137 SU 4 AR e20154410F DI 10.1542/peds.2015-4410F PG 10 WC Pediatrics SC Pediatrics GA EE2KQ UT WOS:000389413300006 PM 27251871 ER PT J AU Kamp, WM Wang, PY Hwang, PM AF Kamp, William M. Wang, Ping-yuan Hwang, Paul M. TI TP53 mutation, mitochondria and cancer SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Article ID LI-FRAUMENI-SYNDROME; TUMOR-SUPPRESSOR P53; MUTANT P53; BREAST-CANCER; METABOLIC-REGULATION; GLUCOSE-METABOLISM; RECEPTOR PROMOTER; PANCREATIC-CANCER; FAMILIAL SYNDROME; OXIDATIVE STRESS AB Under normal conditions, basal levels of wild-type p53 promote mitochondrial function through multiple mechanisms. Remarkably, some missense mutations of p53, in contrast to the null state, can result in the retention of its metabolic activities. These effects are particularly prominent in the mitochondria and demonstrate a functional role for mutant p53 in cancer metabolism. This review summarizes accumulating data on the mechanisms by which p53 missense mutations can regulate mitochondrial metabolism and promote the viability and survival of both normal and cancer cells, thus acting as a double edged sword for the host. Greater understanding of these mechanisms may provide insights for developing new treatment or preventive strategies against cancer. C1 [Kamp, William M.; Wang, Ping-yuan; Hwang, Paul M.] NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Hwang, PM (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. EM hwangp@mail.nih.gov FU intramural program of National Heart, Lung and Blood Institute (NHLBI), NIH FX We wish to thank Jie (Jerry) Li for assistance with the artwork and other members of our laboratory Ju-Gyeong Kang, Ji-Hoon Park, and Jie Zhuang for helpful discussions and critical review of the manuscript. This work was supported by the intramural program of National Heart, Lung and Blood Institute (NHLBI), NIH. NR 85 TC 6 Z9 6 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X EI 1879-0380 J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD JUN PY 2016 VL 38 BP 16 EP 22 DI 10.1016/j.gde.2016.02.007 PG 7 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA EA6LH UT WOS:000386740200004 PM 27003724 ER PT J AU Rouault, TA AF Rouault, Tracey A. TI Mitochondrial iron overload: causes and consequences SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Article ID SIDEROBLASTIC ANEMIA-MLASA; SULFUR CLUSTER BIOGENESIS; RESPIRATORY COMPLEX I; FE-S CLUSTERS; LACTIC-ACIDOSIS; FRIEDREICHS-ATAXIA; CAUSES MYOPATHY; INTERACTING PROTEIN; RING SIDEROBLASTS; ASSEMBLY COMPLEX AB Pathological overload of iron in the mitochondrial matrix has been observed in numerous diseases, including sideroblastic anemias, which have many causes, and in genetic diseases that affect iron-sulfur cluster biogenesis, heme synthesis, and mitochondrial protein translation and its products. Although high expression of the mitochondrial iron importer, mitoferrin, appears to be an underlying common feature, it is unclear what drives high mitoferrin expression and what other proteins are involved in trapping excess toxic iron in the mitochondrial matrix. Numerous examples of human diseases and model systems suggest that mitochondrial iron homeostasis is coordinated through transcriptional remodeling. A cytosolic/nuclear molecule may affect a transcriptional factor to coordinate the events that lead to iron accumulation, but no candidates for this role have yet been identified. C1 [Rouault, Tracey A.] NICHHD, Eunice Kennedy Shriver, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), NICHHD, Eunice Kennedy Shriver, Bethesda, MD 20892 USA. EM Rouault@mail.nih.gov FU intramural program of NICHD FX The author thanks the intramural program of NICHD for support, and members of the Rouault lab for their help with this mini-review. NR 73 TC 2 Z9 3 U1 3 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X EI 1879-0380 J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD JUN PY 2016 VL 38 BP 31 EP 37 DI 10.1016/j.gde.2016.02.004 PG 7 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA EA6LH UT WOS:000386740200006 PM 27026139 ER PT J AU Young, MJ Copeland, WC AF Young, Matthew J. Copeland, William C. TI Human mitochondrial DNA replication machinery and disease SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Article ID PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; STRUCTURE-FUNCTION DEFECTS; RECESSIVE TWINKLE MUTATIONS; POLYMERASE GAMMA-SUBUNITS; IMPAIR MTDNA REPLICATION; MULTIPLE DELETIONS; ACCESSORY SUBUNIT; HELICASE TWINKLE; MAMMALIAN EMBRYOGENESIS; RNA-POLYMERASE AB The human mitochondrial genome is replicated by DNA polymerase gamma in concert with key components of the mitochondrial DNA (mtDNA) replication machinery. Defects in mtDNA replication or nucleotide metabolism cause deletions, point mutations, or depletion of mtDNA. The resulting loss of cellular respiration ultimately induces mitochondrial genetic diseases, including mtDNA depletion syndromes (MDS) such as Alpers or early infantile hepatocerebral syndromes, and mtDNA deletion disorders such as progressive external ophthalmoplegia, ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy. Here we review the current literature regarding human mtDNA replication and heritable disorders caused by genetic changes of the POLG, POLG2, Twinkle, RNASEH1, DNA2, and MGME1 genes. C1 [Young, Matthew J.; Copeland, William C.] NIEHS, Genome Integr & Struct Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. [Young, Matthew J.] Southern Illinois Univ, Dept Biochem & Mol Biol, Sch Med, Carbondale, IL 62901 USA. RP Copeland, WC (reprint author), NIEHS, Genome Integr & Struct Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [ES 065078, ES 065080]; NIH Pathway to Independence Award [1K99ES022638-01] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ES 065078 and ES 065080 to WCC) and by a NIH Pathway to Independence Award to MJY (1K99ES022638-01). NR 88 TC 4 Z9 4 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X EI 1879-0380 J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD JUN PY 2016 VL 38 BP 52 EP 62 DI 10.1016/j.gde.2016.03.005 PG 11 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA EA6LH UT WOS:000386740200009 PM 27065468 ER PT J AU Simonsick, EM Glynn, NW Jerome, GJ Shardell, M Schrack, JA Ferrucci, L AF Simonsick, Eleanor M. Glynn, Nancy W. Jerome, Gerald J. Shardell, Michelle Schrack, Jennifer A. Ferrucci, Luigi TI Fatigued, but Not Frail: Perceived Fatigability as a Marker of Impending Decline in Mobility-Intact Older Adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE fatigability; mobility decline; aging ID PHYSICAL PERFORMANCE-MEASURES; GAIT SPEED; VITAL EXHAUSTION; HEALTH ABC; DISABILITY; IMPAIRMENT; LIMITATION; INDICATOR; WALKING; RISK AB OBJECTIVES: To evaluate perceived fatigability as a predictor of meaningful functional decline in non-mobilitylimited older adults. DESIGN: Longitudinal analysis of data from the Baltimore Longitudinal Study of Aging (BLSA). SETTING: National Institute on Aging, Clinical Research Unit, Baltimore, Maryland. PARTICIPANTS: Men and women aged 60 to 89 participating in the BLSA with concurrent perceived fatigability and functional assessments and follow-up functional assessment within 1 to 3 years (N = 540). MEASUREMENTS: Perceived fatigability was ascertained using the Borg rating of perceived exertion (RPE) after 5 minutes of treadmill walking at 1.5 miles per hour. Functional assessments included usual and fast gait speed, the Health, Aging and Body Composition physical performance battery (HABC PPB) and reported walking ability. Reported tiredness and energy level were examined as complementary predictors. Covariates included age, age squared, race, follow- up time, and baseline function. Meaningful decline was defined as 0.05 m/s per year for usual gait speed, 0.07 m/s per year for fast gait speed, 0.12 points/year for HABC PPB, and 1 point for walking ability index. RESULTS: Over a mean 2.1 years, 20-31% of participants declined across functional assessments. Fatigability was associated with a 13-19% greater likelihood of meaningful decline in all measures (P =.002-.02) per 1-unit RPE increase. After considering tiredness and energy level separately, findings were essentially unchanged, and neither was associated with gait speed or physical performance decline. In contrast, each separately predicted decline in reported walking ability independent of fatigability (P=.03 and P<.001, respectively). CONCLUSION: Routine assessment of fatigability may help identify older persons vulnerable to greater-than-expected functional decline. C1 [Simonsick, Eleanor M.; Shardell, Michelle; Ferrucci, Luigi] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Glynn, Nancy W.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Jerome, Gerald J.] Towson Univ, Coll Hlth Profess, Dept Kinesiol, Towson, MD USA. [Schrack, Jennifer A.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Simonsick, EM (reprint author), 3001 S Hanover St,5th Floor, Baltimore, MD 21225 USA. EM simonsickel@mail.nih.gov OI Glynn, Nancy/0000-0003-2265-0162 FU Intramural Research Program, National Institute on Aging, National Institutes of Health; Intramural Research Program of the National Institute on Aging FX Funded by the Intramural Research Program, National Institute on Aging, National Institutes of Health. The BLSA is supported by the Intramural Research Program of the National Institute on Aging. NR 31 TC 2 Z9 2 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUN PY 2016 VL 64 IS 6 BP 1287 EP 1292 DI 10.1111/jgs.14138 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DW3MY UT WOS:000383546900017 PM 27253228 ER PT J AU Pitzer, VE Aguas, R Riley, S Loeffen, WLA Wood, JLN Grenfell, BT AF Pitzer, Virginia E. Aguas, Ricardo Riley, Steven Loeffen, Willie L. A. Wood, James L. N. Grenfell, Bryan T. TI High turnover drives prolonged persistence of influenza in managed pig herds SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE influenza; swine; surveillance; mathematical modelling; transmission dynamics ID RESPIRATORY SYNDROME VIRUS; H1N1 2009 VIRUS; A VIRUS; UNITED-STATES; TRANSMISSION DYNAMICS; POPULATION-DYNAMICS; GLOBAL CIRCULATION; MEASLES EPIDEMICS; COMMUNITY SIZE; FADE-OUT AB Pigs have long been hypothesized to play a central role in the emergence of novel human influenza A virus (IAV) strains, by serving as mixing vessels for mammalian and avian variants. However, the key issue of viral persistence in swine populations at different scales is ill understood. We address this gap using epidemiological models calibrated against seroprevalence data from Dutch finishing pigs to estimate the 'critical herd size' (CHS) for IAV persistence. We then examine the viral phylogenetic evidence for persistence by comparing human and swine IAV. Models suggest a CHS of approximately 3000 pigs above which influenza was likely to persist, i.e. orders of magnitude lower than persistence thresholds for IAV and other acute viruses in humans. At national and regional scales, we found much stronger empirical signatures of prolonged persistence of IAV in swine compared with human populations. These striking levels of persistence in small populations are driven by the high recruitment rate of susceptible piglets, and have significant implications for management of swine and for overall patterns of genetic diversity of IAV. C1 [Pitzer, Virginia E.] Yale Univ, Yale Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT 06520 USA. [Pitzer, Virginia E.; Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Rockville, MD 20850 USA. [Aguas, Ricardo; Riley, Steven] Imperial Coll, Sch Publ Hlth, Dept Infect Dis Epidemiol, MRC Ctr Outbreak Anal & Modelling, London SW7 2AZ, England. [Loeffen, Willie L. A.] Cent Vet Inst, Dept Virol, NL-8200 AB Lelystad, Netherlands. [Wood, James L. N.] Univ Cambridge, Dept Vet Med, Dis Dynam Unit, Cambridge CB3 0ES, England. [Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. RP Pitzer, VE (reprint author), Yale Univ, Yale Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT 06520 USA.; Pitzer, VE (reprint author), NIH, Fogarty Int Ctr, Rockville, MD 20850 USA. EM virginia.pitzer@yale.edu FU RAPIDD program of the Science and Technology Directorate; Department of Homeland Security; Fogarty International Center, National Institutes of Health; Bill & Melinda Gates Foundation; Alborada Trust; European Union FP7 project ANTIGONE [278976]; BBSRC sLOLA [BB/L001330/1] FX This work was supported by the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health (V.E.P., S.R., J.L.N.W. and B.T.G.) and the Bill & Melinda Gates Foundation (V.E.P. and B.T.G.). J.L.N.W. is also supported by the Alborada Trust, the European Union FP7 project ANTIGONE (contract no. 278976) and by BBSRC sLOLA BB/L001330/1. NR 51 TC 1 Z9 1 U1 0 U2 0 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 EI 1742-5662 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD JUN 1 PY 2016 VL 13 IS 119 AR 20160138 DI 10.1098/rsif.2016.0138 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA6FP UT WOS:000386722200006 ER PT J AU Journy, N Morton, LM Kleinerman, RA Bekelman, JE de Gonzalez, AB AF Journy, N. Morton, L. -M. Kleinerman, R. -A. Bekelman, J. -E. de Gonzalez, A. Berrington TI Intensity-modulated radiation therapy in the treatment of localized prostate cancers and risk of second cancers SO BULLETIN DU CANCER LA French DT Meeting Abstract C1 [Journy, N.; Morton, L. -M.; Kleinerman, R. -A.; de Gonzalez, A. Berrington] NCI, Rockville, MD USA. [Bekelman, J. -E.] Univ Penn, Dept Radiat Oncol, Perelman Sch Med,Leonard Davis Inst Hlth Econ,Abr, Ctr Clin Epidemiol & Biostat,Dept Biostat & Epide, Philadelphia, PA 19104 USA. EM njourny@netcourrier.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN LIBBEY EUROTEXT LTD PI MONTROUGE PA 127 AVE DE LA REPUBLIQUE, 92120 MONTROUGE, FRANCE SN 0007-4551 EI 1769-6917 J9 B CANCER JI Bull. Cancer PD JUN PY 2016 VL 103 IS 6 SU 1 MA PC- 03 BP S114 EP S114 PG 1 WC Oncology SC Oncology GA ED3DK UT WOS:000388729300026 ER PT J AU de la Hoya, M Soukarieh, O Lopez-Perolio, I Vega, A Walker, LC van Ierland, Y Baralle, D Santamarina, M Lattimore, V Wijnen, J Whiley, P Blanco, A Raponi, M Hauke, J Wappenschmidt, B Becker, A Hansen, TVO Behar, R Niederacher, D Arnold, N Dworniczak, B Steinemann, D Faust, U Rubinstein, W Hulick, PJ Houdayer, C Caputo, SM Castera, L Pesaran, T Chao, E Brewer, C Southey, MC van Asperen, CJ Singer, CF Sullivan, J Poplawski, N Mai, P Peto, J Johnson, N Burwinkel, B Surowy, H Bojesen, SE Flyger, H Lindblom, A Margolin, S Chang-Claude, J Rudolph, A Radice, P Galastri, L Olson, JE Hallberg, E Giles, G Milne, RL Andrulis, IL Glendon, G Hall, P Czene, K Blows, F Shah, M Wang, Q Dennis, J Michailidou, K McGuffog, L Bolla, MK Antoniou, AC Easton, DF Couch, FJ Tavtigian, S Vreeswijk, MP Parsons, M Meeks, HD Martins, A Goldgar, DE Spurdle, AB AF de la Hoya, Miguel Soukarieh, Omar Lopez-Perolio, Irene Vega, Ana Walker, Logan C. van Ierland, Yvette Baralle, Diana Santamarina, Marta Lattimore, Vanessa Wijnen, Juul Whiley, Philip Blanco, Ana Raponi, Michela Hauke, Jan Wappenschmidt, Barbara Becker, Alexandra Hansen, Thomas V. O. Behar, Raquel Niederacher, Diether Arnold, Norbert Dworniczak, Bernd Steinemann, Doris Faust, Ulrike Rubinstein, Wendy Hulick, Peter J. Houdayer, Claude Caputo, Sandrine M. Castera, Laurent Pesaran, Tina Chao, Elizabeth Brewer, Carole Southey, Melissa C. van Asperen, Christi J. Singer, Christian F. Sullivan, Jan Poplawski, Nicola Phuong Mai Peto, Julian Johnson, Nichola Burwinkel, Barbara Surowy, Harald Bojesen, Stig E. Flyger, Henrik Lindblom, Annika Margolin, Sara Chang-Claude, Jenny Rudolph, Anja Radice, Paolo Galastri, Laura Olson, Janet E. Hallberg, Emily Giles, GrahamG. Milne, Roger L. Andrulis, Irene L. Glendon, Gord Hall, Per Czene, Kamila Blows, Fiona Shah, Mitul Wang, Qin Dennis, Joe Michailidou, Kyriaki McGuffog, Lesley Bolla, Manjeet K. Antoniou, Antonis C. Easton, Douglas F. Couch, Fergus J. Tavtigian, Sean Vreeswijk, Maaike P. Parsons, Michael Meeks, Huong D. Martins, Alexandra Goldgar, David E. Spurdle, Amanda B. CA KConFaB Investigators TI Combined genetic and splicing analysis of BRCA1 c.[594-2A > C; 641A > G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms SO HUMAN MOLECULAR GENETICS LA English DT Article ID SEQUENCE VARIANTS; CLINICAL-SIGNIFICANCE; ASSAY; GUIDELINES; PROTEIN; BREAST; SITE AB We confirm that BRCA1c.[594-2A > C;641A > G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes. C1 [de la Hoya, Miguel; Lopez-Perolio, Irene; Behar, Raquel] Hosp Clin San Carlos, IdISSC, Mol Oncol Lab, C Martin Lagos S-N, Madrid 28040, Spain. [Soukarieh, Omar; Martins, Alexandra] Univ Rouen, Normandy Ctr Genom & Personalized Med, INSERM, U1079,IRIB, Rouen, France. [Vega, Ana; Blanco, Ana] USC, Fdn Publ Galega Med Xenom SERGAS, Grp Med Xenom, IDIS,CIBERER, Santiago De Compostela 15706, Spain. [Walker, Logan C.; Lattimore, Vanessa] Univ Otago, Dept Pathol, Christchurch 8140, New Zealand. [van Ierland, Yvette; Wijnen, Juul; van Asperen, Christi J.; Vreeswijk, Maaike P.] Leiden Univ, Dept Clin Genet, Med Ctr, NL-2300 Leiden, Netherlands. [Baralle, Diana; Raponi, Michela] Univ Southampton, Human Dev & Hlth, Fac Med, Southampton SO16 5YA, Hants, England. [Santamarina, Marta] Univ Santiago de Compostela, CIBERER, Grp Med Xenom, Fdn Galega Med Xenom SERGAS, Santiago De Compostela 15706, Spain. [Wijnen, Juul] Leiden Univ, Dept Clin Genet, Med Ctr, NL-2300 Leiden, Netherlands. [Whiley, Philip; Parsons, Michael; Spurdle, Amanda B.] QIMR Berghofer Med Res Inst, Dept Genet & Computat Biol, Brisbane, Qld 4006, Australia. [Hauke, Jan; Wappenschmidt, Barbara; Becker, Alexandra] Univ Hosptial Cologne, Fac Med, Ctr Integrated Oncol CIO, Ctr Hereditary Breast & Ovarian Canc, D-50931 Cologne, Germany. [Hansen, Thomas V. O.] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, DK-2100 Copenhagen, Denmark. [KConFaB Investigators] Univ Melbourne, Peter MacCallum Canc Ctr, Melbourne, Vic 3002, Australia. [Niederacher, Diether] Univ Dusseldorf, Univ Hosp Dusseldorf, Dept Gynaecol & Obstet, D-40225 Dusseldorf, Germany. [Arnold, Norbert] Univ Kiel, Dept Gynaecol & Obstet, Univ Hosp Schleswig Holstein, Campus Kiel, D-24105 Kiel, Germany. [Dworniczak, Bernd] Univ Munster, Inst Human Genet, D-48149 Munster, Germany. [Steinemann, Doris] Hannover Med Sch, Inst Human Genet, D-30625 Hannover, Germany. [Faust, Ulrike] Univ Tubingen Hosp, Inst Med Genet & Appl Genom, D-72076 Tubingen, Germany. [Rubinstein, Wendy] NIH, Bldg 10, Bethesda, MD 20892 USA. [Hulick, Peter J.] Univ Chicago, NorthShore Univ Hlth Syst, Pritzker Sch Med, Ctr Med Genet, Evanston, IL 60201 USA. [Houdayer, Claude] Inst Curie, Dept Biol Tumeurs, Serv Genet, Paris, France. [Houdayer, Claude] Inst Curie, Ctr Rech, INSERM, U830, Paris, France. [Houdayer, Claude] Univ Paris 05, Sorbonne Paris Cite, F-75248 Paris, France. [Caputo, Sandrine M.] Inst Curie, Dept Biol Tumeurs, Serv Genet, F-75248 Paris, France. [Castera, Laurent] Ctr Francois Baclesse, Lab Biol & Genet Canc, F-14076 Caen, France. [Pesaran, Tina; Chao, Elizabeth] Ambry Genet, Aliso Viejo, CA 92656 USA. [Brewer, Carole] Royal Devon & Exeter Hosp, Dept Clin Genet, Exeter, Devon, England. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic 3010, Australia. [Singer, Christian F.] Med Univ Vienna, Dept Obstet & Gynaecol, Waehringer Guertel 18-20, A-1090 Vienna, Austria. [Sullivan, Jan] Christchurch Hosp, Genet Hlth Serv NZ, South Isl Hub, Christchurch 8140, New Zealand. [Poplawski, Nicola] Womens & Childrens Hosp, SA Pathol, South Australian Clin Genet Serv, Adult Genet Unit, Adelaide, SA 5067, Australia. [Poplawski, Nicola] Univ Adelaide, Univ Dept Paediat, North Terrace, Adelaide, SA 5000, Australia. [Phuong Mai] NCI, Clin Genet Branch, DCEG, NIH, Bethesda, MD 20892 USA. [Peto, Julian] London Sch Hyg & Trop Med, London WC1E 7HT, England. [Johnson, Nichola] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Johnson, Nichola] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England. [Burwinkel, Barbara; Surowy, Harald] Heidelberg Univ, Dept Gynecol & Obstet, Mol Biol Breast Canc, D-69120 Heidelberg, Germany. [Burwinkel, Barbara; Surowy, Harald] DKFZ, Mol Epidemiol Grp, German Canc Res Ctr, D-69120 Heidelberg, Germany. [Bojesen, Stig E.] Herlev & Gentofte Hosp, Copenhagen Gen Populat Study, DK-2730 Copenhagen, Denmark. [Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, DK-2730 Herlev, Denmark. [Bojesen, Stig E.] Univ Copenhagen, Fac Hlth & Med Sci, DK-1165 Copenhagen, Denmark. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Breast Surg, DK-2730 Herlev, Denmark. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, SE-17177 Stockholm, Sweden. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, SE-17177 Stockholm, Sweden. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. [Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, UCCH, D-20246 Hamburg, Germany. [Radice, Paolo] Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, I-20139 Milan, Italy. [Galastri, Laura] Assoc Volontari Italiani Sangue AVIS Comunale Mil, I-20139 Milan, Italy. [Olson, Janet E.; Hallberg, Emily; Couch, Fergus J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Giles, GrahamG.; Milne, Roger L.] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic 3010, Australia. [Giles, GrahamG.; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3004, Australia. [Andrulis, Irene L.; Glendon, Gord] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON M5B 1W8, Canada. [Hall, Per; Czene, Kamila] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Blows, Fiona; Shah, Mitul] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Wang, Qin; Dennis, Joe; Michailidou, Kyriaki; McGuffog, Lesley; Bolla, Manjeet K.; Antoniou, Antonis C.; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Michailidou, Kyriaki] Cyprus Inst Neurol & Genet, Dept Electron Microscopy Mol Pathol, CY-1683 Nicosia, Cyprus. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Tavtigian, Sean; Meeks, Huong D.] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Oncol Sci, Salt Lake City, UT 84132 USA. [Goldgar, David E.] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Dermatol, Salt Lake City, UT 84132 USA. RP de la Hoya, M (reprint author), Hosp Clin San Carlos, IdISSC, Mol Oncol Lab, C Martin Lagos S-N, Madrid 28040, Spain.; Spurdle, AB (reprint author), QIMR Berghofer Med Res Inst, 300 Herston Rd, Brisbane, Qld 4006, Australia. EM mhoya@hotmail.com; amanda.spurdle@qimr.edu.au RI Arnold, Norbert/E-3012-2010 OI Arnold, Norbert/0000-0003-4523-8808 FU Spanish Instituto de Salud Carlos III - European Regional Development FEDER Funds [PI12/00539, PI15/00059, PI13/02030]; French Ministry of Higher Education and Research; University of Otago; Mackenzie Charitable Foundation; Health Research Council of New Zealand; UK Higher Education Funding Council; University of Southampton; Cancer research UK; FamilienHede Nielsen Foundation; Cancer Research-UK; National Institute of Health [CA128978, CA11616]; NIH [CA128978, P50 CA116201]; US Breast Cancer Research Foundation; French National Cancer Institute; Direction Generale de l'Offre des Soins (INCa-DGOS AAP/CFB/CI); French North-West Canceropole (CNO); Cancer Council Queensland [APP1086286]; NHMRC [1061779, 1010719]; National Breast Cancer Foundation; National Health and Medical Research Council; Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Tasmania; Cancer Council of South Australia; Cancer Foundation of Western Australia; German Cancer Aid [109076]; Center for Molecular Medicine Cologne (CMMC); Cancer Research UK [C1287/A10118, C1287/A11990, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C1287/A12014]; National Cancer Institute [UM1 CA164920]; Breast Cancer Campaign forming Breast Cancer Now; NHS; Dietmar-Hopp Foundation; Helmholtz Society; German Cancer Research Center (DKFZ); Chief Physician Johan Boserup and LiseBoserup Fund; Danish Medical Research Council; Herlev Hospital; Stockholm City Council; KarolinskaInstitutet; Stockholm Cancer Foundation; Swedish Cancer Society; Deutsche Krebshilfee.V. [70-2892-BR I]; Hamburg Cancer Society; German Cancer Research Center; Federal Ministry of Education and Research (BMBF) Germany [01KH0402]; Italian Association for Cancer Research (AIRC); Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; Breast Cancer Research Foundation; VicHealth; Cancer Council Victoria; Australian NHMRC [209057, 251553, 504711]; Marit and Hans Rausings Initiative Against Breast Cancer; Swedish Medical Research Counsel; CRUK [A490/A11021, C490/A16561]; European Community [223175 (HEALTH-F2-2009-223175), 223175, HEALTH-F2-2009-223175]; National Institutes of Health [CA128978]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer; Komen Foundation for the Cure; Ovarian Cancer Research Fund; Cancer Research-UK [C1287/A10118, C12292/A11174] FX The research described was supported by Spanish Instituto de Salud Carlos III funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds [PI12/00539 and PI15/00059 to M.d.H., PI13/02030 to A.V.]; the French Ministry of Higher Education and Research [to O.S.]; the University of Otago, Mackenzie Charitable Foundation, Maria Lupton, and .Health Research Council of New Zealand [to L.W.]; UK Higher Education Funding Council Senior Fellowship Scheme, the University of Southampton [to D.B.]; Cancer research UK [to D.B., M.R.]; FamilienHede Nielsen Foundation fund [to T.V.O.H.]; Cancer Research-UK Senior Cancer Research Fellowship [to A.C.A.]; National Institute of Health [CA128978 and CA11616 to F.J.C.]; an NIH specialized program of research excellence in breast cancer to the Mayo Clinic [P50 CA116201 to F.J.C.]; and the US Breast Cancer Research Foundation [to F.J.C.]; translational grant from the French National Cancer Institute and Direction Generale de l'Offre des Soins (INCa-DGOS AAP/CFB/CI) and a grant from the French North-West Canceropole (CNO) [to A.M.]; The Cancer Council Queensland [APP1086286 to A.B.S.]; the NHMRC Senior Research Fellowship Scheme [ID 1061779 to A.B.S.]; NHMRC Project grant scheme [ID 1010719 to A.B.S.].; Additional infrastructure support to consortium members is as follows: kConFab infrastructure has been supported by funding from the National Breast Cancer Foundation, National Health and Medical Research Council, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia [to kConFab, and the kConFab Clinical Follow-up study].; 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 French consortium is supported by the French National Cancer Institute.; EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990.; 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, commercial products, or organizations imply endorsement by the US Government or the BCFR.; The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer (recently merged with Breast Cancer Campaign forming Breast Cancer Now) and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN).; The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ).; The CGPS was supported by the Chief Physician Johan Boserup and LiseBoserup Fund, the Danish Medical Research Council and Herlev Hospital; KARBAC was supported financially through the regional agreement on medical training and clinical research (ALF) between Stockholm City Council and KarolinskaInstitutet, and from the Stockholm Cancer Foundation and the Swedish Cancer Society.; The MARIE study was supported by the Deutsche Krebshilfee.V. [70-2892-BR I], the Hamburg Cancer Society, the German Cancer Research Center 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 according to Italian laws in support of the Fondazione IRCCS IstitutoNazionaleTumori.; The MCBCS was supported by the NIH grant CA128978 and a Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], 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.; OFBCR 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, commercial products, or organizations imply endorsement by the US Government or the BCFR.; The pKARMA study was supported by Marit and Hans Rausings Initiative Against Breast Cancer, and the Swedish Medical Research Counsel.; SEARCH was supported by grants CRUK A490/A11021, C490/A16561.; Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund.; CIMBA data management was supported by Cancer Research-UK grant C12292/A11174 and C1287/A10118.; BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Communitys Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). NR 25 TC 0 Z9 0 U1 6 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUN 1 PY 2016 VL 25 IS 11 BP 2256 EP 2268 DI 10.1093/hmg/ddw094 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA ED0TK UT WOS:000388554700011 PM 27008870 ER PT J AU Hansen, MEB Hunt, SC Stone, RC Horvath, K Herbig, U Ranciaro, A Hirbo, J Beggs, W Reiner, AP Wilson, JG Kimura, M De Vivo, I Chen, MM Kark, JD Levy, D Nyambo, T Tishkoff, SA Aviv, A AF Hansen, Matthew E. B. Hunt, Steven C. Stone, Rivka C. Horvath, Kent Herbig, Utz Ranciaro, Alessia Hirbo, Jibril Beggs, William Reiner, Alexander P. Wilson, James G. Kimura, Masayuki De Vivo, Immaculata Chen, Maxine M. Kark, Jeremy D. Levy, Daniel Nyambo, Thomas Tishkoff, Sarah A. Aviv, Abraham TI Shorter telomere length in Europeans than in Africans due to polygenetic adaptation SO HUMAN MOLECULAR GENETICS LA English DT Article ID PANCREATIC-CANCER; PRECURSOR LESIONS; PROSTATE-CANCER; BREAST-CANCER; LUNG-CANCER; MELANOMA; RISK; ASSOCIATION; METAANALYSIS; BIOLOGY AB Leukocyte telomere length (LTL), which reflects telomere length in other somatic tissues, is a complex genetic trait. Eleven SNPs have been shown in genome-wide association studies to be associated with LTL at a genome-wide level of significance within cohorts of European ancestry. It has been observed that LTL is longer in African Americans than in Europeans. The underlying reason for this difference is unknown. Here we show that LTL is significantly longer in sub-Saharan Africans than in both Europeans and African Americans. Based on the 11 LTL-associated alleles and genetic data in phase 3 of the 1000 Genomes Project, we show that the shifts in allele frequency within Europe and between Europe and Africa do not fit the pattern expected by neutral genetic drift. Our findings suggest that differences in LTL within Europeans and between Europeans and Africans is influenced by polygenic adaptation and that differences in LTL between Europeans and Africans might explain, in part, ethnic differences in risks for human diseases that have been linked to LTL. C1 [Hansen, Matthew E. B.; Ranciaro, Alessia; Hirbo, Jibril; Beggs, William; Tishkoff, Sarah A.] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Hansen, Matthew E. B.] Univ Penn, Sch Med, Ctr Excellence Environm Toxicol, Philadelphia, PA 19104 USA. [Tishkoff, Sarah A.] Univ Penn, Dept Biol, Sch Arts & Sci, Philadelphia, PA 19104 USA. [Hunt, Steven C.] Weill Cornell Med Coll, Dept Med Genet, Doha, Qatar. [Hunt, Steven C.] Univ Utah, Sch Med, Cardiovasc Genet Div, Salt Lake City, UT 84108 USA. [Stone, Rivka C.; Horvath, Kent; Herbig, Utz; Kimura, Masayuki; Aviv, Abraham] Rutgers, New Jersey Med Sch, Ctr Human Dev & Aging, Newark, NJ 07103 USA. [Reiner, Alexander P.] Univ Washington, Dept Epidemiol, Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Wilson, James G.] Univ Mississippi, Dept Physiol & Biophys, Jackson, MS 38677 USA. [De Vivo, Immaculata; Chen, Maxine M.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. [Kark, Jeremy D.] Hebrew Univ Jerusalem, Epidemiol Unit, Hadassah Sch Publ Hlth & Community Med, IL-9112001 Jerusalem, Israel. [Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Nyambo, Thomas] Muhimbili Univ Hlth & Allied Sci, Dept Biochem, Dar Es Salaam 35091, Tanzania. RP Aviv, A (reprint author), Univ Med & Dent New Jersey, Ctr Human Dev & Aging, 185 South Orange Ave, Newark, NJ 07103 USA. EM avivab@njms.rutgers.edu FU National Institutes of Health [T32ES019851, 5DP1ES022577, 1R01DK104339, 1R01GM113657, R01GM113657, 8DP1ES022577, R01-AG020132, R01-HL116446, R01CA136533, R01CA184572, R01AG18734]; Center of Excellence for Environmental Toxicology (CEET) at the University of Pennsylvania; National Heart Lung Blood Institute [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; National Institute on Minority Health and Health Disparities FX M.E.B.H. is supported by National Institutes of Health training grant T32ES019851 and the Center of Excellence for Environmental Toxicology (CEET) at the University of Pennsylvania. This research is supported by National Institutes of Health grants 5DP1ES022577, 1R01DK104339, and 1R01GM113657 to S.A.T., and National Institutes of Health grants R01GM113657, 8DP1ES022577, R01-AG020132, R01-HL116446, R01CA136533, R01CA184572, R01AG18734. The Jackson Heart Study is supported by contracts (HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C) from the National Heart Lung Blood Institute and the National Institute on Minority Health and Health Disparities. NR 49 TC 3 Z9 3 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUN 1 PY 2016 VL 25 IS 11 BP 2324 EP 2330 DI 10.1093/hmg/ddw070 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA ED0TK UT WOS:000388554700016 PM 26936823 ER PT J AU Serrano, KJ Yu, M Coa, KI Collins, LM Atienza, AA AF Serrano, Katrina J. Yu, Mandi Coa, Kisha I. Collins, Linda M. Atienza, Audie A. TI Mining Health App Data to Find More and Less Successful Weight Loss Subgroups SO JOURNAL OF MEDICAL INTERNET RESEARCH LA English DT Article DE weight loss; mobile health; mobile app; data mining; classification ID PHYSICAL-ACTIVITY; ECONOMIC BURDEN; LOSS TRIAL; OBESITY; CLASSIFICATION; PROGRAM; INTERVENTIONS; MAINTENANCE; OVERWEIGHT; REGRESSION AB Background: More than half of all smartphone app downloads involve weight, diet, and exercise. If successful, these lifestyle apps may have far-reaching effects for disease prevention and health cost-savings, but few researchers have analyzed data from these apps. Objective: The purposes of this study were to analyze data from a commercial health app (Lose It!) in order to identify successful weight loss subgroups via exploratory analyses and to verify the stability of the results. Methods: Cross-sectional, de-identified data from Lose It! were analyzed. This dataset (n=12,427,196) was randomly split into 24 subsamples, and this study used 3 subsamples (combined n=972,687). Classification and regression tree methods were used to explore groupings of weight loss with one subsample, with descriptive analyses to examine other group characteristics. Data mining validation methods were conducted with 2 additional subsamples. Results: In subsample 1, 14.96% of users lost 5% or more of their starting body weight. Classification and regression tree analysis identified 3 distinct subgroups: "the occasional users" had the lowest proportion (4.87%) of individuals who successfully lost weight; "the basic users" had 37.61% weight loss success; and "the power users" achieved the highest percentage of weight loss success at 72.70%. Behavioral factors delineated the subgroups, though app-related behavioral characteristics further distinguished them. Results were replicated in further analyses with separate subsamples. Conclusions: This study demonstrates that distinct subgroups can be identified in "messy" commercial app data and the identified subgroups can be replicated in independent samples. Behavioral factors and use of custom app features characterized the subgroups. Targeting and tailoring information to particular subgroups could enhance weight loss success. Future studies should replicate data mining analyses to increase methodology rigor. C1 [Serrano, Katrina J.; Yu, Mandi] NCI, 9609 Med Ctr Dr, Bethesda, MD 20814 USA. [Coa, Kisha I.; Atienza, Audie A.] ICF Int, Rockville, MD USA. [Collins, Linda M.] Penn State Univ, State Coll, PA USA. RP Serrano, KJ (reprint author), NCI, 9609 Med Ctr Dr, Bethesda, MD 20814 USA. EM katrina.serrano@nih.gov RI Emchi, Karma/Q-1952-2016; OI Serrano, Katrina/0000-0003-4431-3589; Coa, Kisha/0000-0001-5637-259X; Atienza, Audie/0000-0001-8745-0167 NR 40 TC 0 Z9 0 U1 5 U2 5 PU JMIR PUBLICATIONS, INC PI TORONTO PA 59 WINNERS CIRCLE, TORONTO, ON M4L 3Y7, CANADA SN 1438-8871 J9 J MED INTERNET RES JI J. Med. Internet Res. PD JUN PY 2016 VL 18 IS 6 AR e154 DI 10.2196/jmir.5473 PG 11 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA EC9WO UT WOS:000388495200014 PM 27301853 ER PT J AU Flegel, WA AF Flegel, Willy Albert TI Red cell alloimmunisation: incidence and prevention SO LANCET HAEMATOLOGY LA English DT Editorial Material C1 [Flegel, Willy Albert] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Flegel, WA (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM waf@nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2352-3026 J9 LANCET HAEMATOL JI Lancet Haematol. PD JUN PY 2016 VL 3 IS 6 BP E260 EP E261 DI 10.1016/S2352-3026(16)30043-6 PG 2 WC Hematology SC Hematology GA ED7SB UT WOS:000389069100004 PM 27264033 ER PT J AU Bok, K Prevots, DR Binder, AM Parra, GI Strollo, S Fahle, GA Behrle-Yardley, A Johnson, JA Levenson, EA Sosnovtsev, SV Holland, SM Palmore, TN Green, KY AF Bok, Karin Prevots, D. Rebecca Binder, Alison M. Parra, Gabriel I. Strollo, Sara Fahle, Gary A. Behrle-Yardley, Allison Johnson, Jordan A. Levenson, Eric A. Sosnovtsev, Stanislav V. Holland, Steven M. Palmore, Tara N. Green, Kim Y. TI Epidemiology of Norovirus Infection Among Immunocompromised Patients at a Tertiary Care Research Hospital, 2010-2013 SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE epidemiology; immunocompromised; norovirus ID NORWALK-LIKE VIRUSES; ORGAN TRANSPLANT RECIPIENTS; HEMATOPOIETIC STEM-CELL; MONOCLONAL-ANTIBODIES; UNITED-STATES; IN-VIVO; GASTROENTERITIS; EVOLUTION; TRANSMISSION; POPULATIONS AB Background. Noroviruses are a major cause of infectious gastroenteritis worldwide, and viruses can establish persistent infection in immunocompromised individuals. Risk factors and transmission in this population are not fully understood. Methods. From 2010 through 2013, we conducted a retrospective review among immunocompromised patients (n = 268) enrolled in research studies at the National Institutes of Health Clinical Center and identified a subset of norovirus-positive patients (n = 18) who provided stool specimens for norovirus genotyping analysis. Results. Norovirus genome was identified by reverse-transcription quantitative polymerase chain reaction in stools of 35 (13%) of the 268 immunocompromised patients tested, and infection prevalence was 21% (11 of 53) in persons with primary immune deficiencies and 12% (20 of 166) among persons with solid tumors or hematologic malignancies. Among 18 patients with norovirus genotyping information, norovirus GII. 4 was the most prevalent genotype (14 of 18, 78%). Persistent norovirus infection (>= 6 months) was documented in 8 of 18 (44%) individuals. Phylogenetic analysis of the GII. 4 capsid protein sequences identified at least 5 now-displaced GII. 4 variant lineages, with no evidence of their nosocomial transmission in the Clinical Center. Conclusions. Norovirus was a leading enteric pathogen identified in this immunocompromised population. Both acute and chronic norovirus infections were observed, and these were likely community-acquired. Continued investigation will further define the role of noroviruses in these patients and inform efforts toward prevention and treatment. C1 [Bok, Karin; Parra, Gabriel I.; Behrle-Yardley, Allison; Johnson, Jordan A.; Levenson, Eric A.; Sosnovtsev, Stanislav V.; Green, Kim Y.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. [Prevots, D. Rebecca; Binder, Alison M.; Strollo, Sara; Holland, Steven M.; Palmore, Tara N.] NIAID, Lab Clin Infect Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Palmore, Tara N.] NIH, Hosp Epidemiol Serv, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Fahle, Gary A.] NIH, Microbiol Serv, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Bok, Karin] US Dept HHS, Natl Vaccine Program Off, Off Assistant Secretary Hlth, Washington, DC USA. RP Green, KY (reprint author), NIAID, Caliciviruses Sect, Infect Dis Lab, NIH, 50 South Dr,Bldg 50,Room 6318, Bethesda, MD 20892 USA. EM kgreen@niaid.nih.gov OI Parra, Gabriel/0000-0002-1102-4740 NR 47 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD SUM PY 2016 VL 3 IS 3 DI 10.1093/ofid/ofw169 PG 8 WC Infectious Diseases SC Infectious Diseases GA ED0YZ UT WOS:000388571700011 ER PT J AU Clancy, CJ Meslin, C Badrane, H Cheng, SJ Losada, LC Nierman, WC Vergidis, P Clark, NL Nguyen, MH AF Clancy, Cornelius J. Meslin, Camille Badrane, Hassan Cheng, Shaoji Losada, Liliana C. Nierman, William C. Vergidis, Pascalis Clark, Nathan L. Nguyen, M. Hong TI Candida albicans Transcriptional Profiling Within Biliary Fluid From a Patient With Cholangitis, Before and After Antifungal Treatment and Surgical Drainage SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE Candida albicans; cholangitis; fluconazole; RNA-Seq; transcriptional profiling ID DIFFERENTIAL EXPRESSION ANALYSIS; GENE-EXPRESSION; RNA-SEQ; HOST; INFECTION AB We used ribonucleic acid sequencing to profile Candida albicans transcription within biliary fluid from a patient with cholangitis; samples were collected before and after treatment with fluconazole and drainage. Candida albicans transcriptomes at the infection site distinguished treated from untreated cholangitis. After treatment, 1131 C. albicans genes were differentially expressed in biliary fluid. Up-regulated genes were enriched in hyphal growth, cell wall organization, adhesion, oxidation reduction, biofilm, and fatty acid and ergosterol biosynthesis. This is the first study to define Candida global gene expression during deep-seated human infection. Successful treatment of cholangitis induced C. albicans genes involved in fluconazole responses and pathogenesis. C1 [Clancy, Cornelius J.; Badrane, Hassan; Cheng, Shaoji; Vergidis, Pascalis; Nguyen, M. Hong] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. [Clancy, Cornelius J.] Univ Pittsburgh, Sch Med, Div Infect Dis, VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15260 USA. [Meslin, Camille; Clark, Nathan L.] Univ Pittsburgh, Sch Med, Dept Computat & Syst Biol, Pittsburgh, PA 15260 USA. [Losada, Liliana C.; Nierman, William C.] J Craig Venter Inst, Rockville, MD USA. [Losada, Liliana C.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Nguyen, MH (reprint author), Univ Pittsburgh, Scaife Hall,Suite 871,3550 Terrace St, Pittsburgh, PA 15261 USA. EM mhn5@pitt.edu NR 15 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD SUM PY 2016 VL 3 IS 3 DI 10.1093/ofid/ofw120 PG 5 WC Infectious Diseases SC Infectious Diseases GA ED0YZ UT WOS:000388571700016 ER PT J AU Cha, SA Yun, JS Lim, TS Hwang, S Yim, EJ Song, KH Yoo, KD Park, YM Ahn, YB Ko, SH AF Cha, Seon-Ah Yun, Jae-Seung Lim, Tae-Seok Hwang, Seawon Yim, Eun-Jung Song, Ki-Ho Yoo, Ki-Dong Park, Yong-Moon Ahn, Yu-Bae Ko, Seung-Hyun TI Severe Hypoglycemia and Cardiovascular or All-Cause Mortality in Patients with Type 2 Diabetes SO DIABETES & METABOLISM JOURNAL LA English DT Article DE Cardiovascular diseases; Diabetes mellitus; type 2; Mortality; Severe hypoglycemia ID ASSOCIATION; EVENTS; RISK; DEATH; COMPLICATIONS; MANAGEMENT; INCREASE; DISEASE AB Background: We investigated the association between severe hypoglycemia (SH) and the risk of cardiovascular (CV) or all-cause mortality in patients with type 2 diabetes. Methods: The study included 1,260 patients aged 25 to 75 years with type 2 diabetes from the Vincent Type 2 Diabetes Resgistry (VDR), who consecutively enrolled (n= 1,260) from January 2000 to December 2010 and were followed up until May 2015 with a median follow-up time of 10.4 years. Primary outcomes were death from any cause or CV death. We investigated the association between the CV or all-cause mortality and various covariates using Cox proportional hazards regression analysis. Results: Among the 906 participants (71.9%) who completed follow-up, 85 patients (9.4%) had at least one episode of SH, and 86 patients (9.5%) died (9.1 per 1,000 patient-years). Patients who had died were older, had a longer duration of diabetes and hypertension, received more insulin, and had more diabetic microvascular complications at baseline, as compared with surviving patients. The experience of SH was significantly associated with an increased risk of all-cause mortality (hazard ratio [HR], 2.64; 95% confidence interval [CI], 1.39 to 5.02; P= 0.003) and CV mortality (HR, 6.34; 95% CI, 2.02 to 19.87; P= 0.002) after adjusting for sex, age, diabetic duration, hypertension, mean glycosylated hemoglobin levels, diabetic nephropathy, lipid profiles, and insulin use. Conclusion: We found a strong association between SH and increased risk of all-cause and CV mortality in patients with type 2 diabetes. C1 [Cha, Seon-Ah; Yun, Jae-Seung; Lim, Tae-Seok; Hwang, Seawon; Yim, Eun-Jung; Song, Ki-Ho; Ahn, Yu-Bae; Ko, Seung-Hyun] Catholic Univ Korea, Coll Med, Dept Internal Med, Div Endocrinol & Metab, Seoul, South Korea. [Yoo, Ki-Dong] Catholic Univ Korea, Coll Med, Dept Internal Med, Div Cardiol, Seoul, South Korea. [Park, Yong-Moon] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Ko, SH (reprint author), Catholic Univ Korea, St Vincents Hosp, Div Endocrinol & Metab, Dept Internal Med,Coll Med, 93 Jungbu Daero, Suwon 16247, South Korea. EM kosh@catholic.ac.kr OI Ko, Seung-Hyun/0000-0003-3703-1479 NR 30 TC 3 Z9 3 U1 1 U2 1 PU KOREAN DIABETES ASSOC PI SEOUL PA 1010 RENAISSANCE TOWER BLDG, 14 MANRIJAE-RO, MAPO-GUO, SEOUL, 121-706, SOUTH KOREA SN 2233-6079 EI 2233-6087 J9 DIABETES METAB J JI Diabetes Metab. J. PD JUN PY 2016 VL 40 IS 3 BP 202 EP 210 DI 10.4093/dmj.2016.40.3.202 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EC4DZ UT WOS:000388077700005 ER PT J AU Mensah, GA AF Mensah, George A. TI From Framingham and Bethesda to North Karelia and Back Turning Prevention and Population Science Discoveries into Heart Health SO GLOBAL HEART LA English DT Editorial Material ID CARDIOVASCULAR-DISEASE PREVENTION; COMMUNITY INTERVENTION TRIALS; STANFORD 5-CITY PROJECT; FOLLOW-UP EXPERIENCE; RISK-FACTORS; PROGRAM; IMPLEMENTATION; FRAMEWORK C1 [Mensah, George A.] NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Mensah, George A.] NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Mensah, GA (reprint author), NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA.; Mensah, GA (reprint author), NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. EM George.Mensah@nih.gov NR 22 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 2211-8160 EI 2211-8179 J9 GLOB HEART JI Glob. Heart PD JUN PY 2016 VL 11 IS 2 BP 247 EP 249 DI 10.1016/j.gheart.2016.05.002 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DW3OF UT WOS:000383550200014 PM 27242095 ER PT J AU Thein, MS Thein, SL AF Thein, Mya S. Thein, Swee L. TI World Sickle Cell Day 2016: A time for appraisal SO INDIAN JOURNAL OF MEDICAL RESEARCH LA English DT Editorial Material ID RISK-FACTORS; BABY HUG; DISEASE; CHILDREN; ANEMIA; HYDROXYUREA; HEMOGLOBIN; MANAGEMENT; MORTALITY; SURVIVAL C1 [Thein, Mya S.; Thein, Swee L.] NHLBI, Sickle Cell Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Thein, SL (reprint author), NHLBI, Sickle Cell Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM sl.thein@nih.gov NR 25 TC 0 Z9 0 U1 0 U2 0 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 0971-5916 J9 INDIAN J MED RES JI Indian J. Med. Res. PD JUN PY 2016 VL 143 BP 678 EP 681 DI 10.4103/0971-5916.191917 PG 4 WC Immunology; Medicine, General & Internal; Medicine, Research & Experimental SC Immunology; General & Internal Medicine; Research & Experimental Medicine GA EA4VC UT WOS:000386612600002 PM 27748290 ER PT J AU Zhang, L Moss, J AF Zhang, Li Moss, Joel TI Genetic studies yield clues to the pathogenesis of Langerhans cell histiocytosis SO EUROPEAN RESPIRATORY JOURNAL LA English DT Editorial Material ID ERDHEIM-CHESTER DISEASE; NRAS MUTATIONS; HIGH PREVALENCE; LYMPHANGIOLEIOMYOMATOSIS; SIROLIMUS; MAP2K1; CANCER; TSC2; RARE; LCH C1 [Zhang, Li; Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Room 6D05,Bldg 10, Bethesda, MD 20892 USA. RP Moss, J (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Room 6D05,Bldg 10, Bethesda, MD 20892 USA. EM mossj@nhlbi.nih.gov NR 34 TC 0 Z9 0 U1 0 U2 0 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD JUN PY 2016 VL 47 IS 6 BP 1629 EP 1631 DI 10.1183/13993003.00568-2016 PG 3 WC Respiratory System SC Respiratory System GA DZ6FE UT WOS:000385956200009 PM 27246079 ER PT J AU Llanos, OL Galiatsatos, P Guzman-Velez, E Patil, SP Smith, PL Magnuson, T Schweitzer, M Steele, K Polotsky, VY Schwartz, AR AF Llanos, Oscar L. Galiatsatos, Panagis Guzman-Velez, Edmarie Patil, Susheel P. Smith, Philip L. Magnuson, Thomas Schweitzer, Michael Steele, Kimberley Polotsky, Vsevolod Y. Schwartz, Alan R. TI Pharyngeal collapsibility during sleep is elevated in insulin-resistant females with morbid obesity SO EUROPEAN RESPIRATORY JOURNAL LA English DT Article ID UPPER AIRWAY COLLAPSIBILITY; HOMEOSTASIS MODEL ASSESSMENT; EXPIRATORY LUNG-VOLUME; FAT DISTRIBUTION; VENTILATORY CONTROL; GLUCOSE-METABOLISM; WEIGHT-LOSS; DIABETES-MELLITUS; APNEA SEVERITY; WOMEN AB Insulin resistance is associated with sleep apnoea, leading us to hypothesise that it is also associated with elevations in pharyngeal collapsibility, even in the absence of sleep apnoea. 90 bariatric patients were characterised for sleep apnoea, pharyngeal collapsibility and insulin resistance. Patients with a respiratory disturbance index (RDI) > 10 events.h(-1), diabetes mellitus, tonsillar hypertrophy and pulmonary disease were excluded. The remaining 14 females underwent collapsibility measurements (passive critical pressure, Pcritp) during non-rapid eye movement sleep. The homeostasis model assessment (HOMA) index, a measure of insulin resistance, was derived from measurements of fasting glucose and insulin levels, and compared to Pcritp. Groups with high Pcritp compared to low Pcritp did not differ in age, body mass index or RDI. HOMA and insulin were elevated in the high Pcritp group compared to the low Pcritp group (p<0.02). Pcritp correlated with HOMA (Spearman's rho=0.565, 95% CI 0.104-0.862; p=0.035) and insulin (Spearman's rho=0.609 95% CI 0.196-0.835; p=0.021). Obese insulin-resistant subjects without frank diabetes or sleep apnoea demonstrate preclinical elevations in pharyngeal collapsibility, which may increase their susceptibility to sleep apnoea. Our findings suggest that insulin resistance could play a significant role in sleep apnoea pathogenesis by generating requisite elevations in pharyngeal collapsibility. C1 [Llanos, Oscar L.] Univ Arkansas, Dept Med, Little Rock, AR 72204 USA. [Galiatsatos, Panagis] NIH, Crit Care Med, Bldg 10, Bethesda, MD 20892 USA. [Guzman-Velez, Edmarie] Univ Iowa, Dept Psychol & Brain Sci, Iowa City, IA USA. [Patil, Susheel P.; Smith, Philip L.; Polotsky, Vsevolod Y.; Schwartz, Alan R.] Johns Hopkins Univ, Div Pulm & Crit Care Med, Dept Med, Baltimore, MD USA. [Magnuson, Thomas; Schweitzer, Michael; Steele, Kimberley] Johns Hopkins Univ, Dept Surg, Baltimore, MD USA. RP Schwartz, AR (reprint author), Johns Hopkins Sleep Disorders Ctr, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA. EM aschwar2@jhmi.edu FU National Institutes of Health [R01 HL50381, HL128970, HL080105] FX National Institutes of Health: R01 HL50381, HL128970 and HL080105. Funding information for this article has been deposited with FundRef. NR 46 TC 1 Z9 1 U1 0 U2 0 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD JUN PY 2016 VL 47 IS 6 BP 1718 EP 1726 DI 10.1183/13993003.00918-2015 PG 9 WC Respiratory System SC Respiratory System GA DZ6FE UT WOS:000385956200019 PM 27103392 ER PT J AU Eder, AF Ryu, JH Moss, J AF Eder, Anne F. Ryu, Jay H. Moss, Joel TI Should lymphangioleiomyomatosis patients be permitted to donate blood? SO EUROPEAN RESPIRATORY JOURNAL LA English DT Letter ID CELLS C1 [Eder, Anne F.] NIH, Ctr Clin, Dept Transfus Med, Blood Serv Sect, Bldg 10, Bethesda, MD 20892 USA. [Ryu, Jay H.] Mayo Clin, Coll Med, Div Pulm & Crit Care Med, Rochester, MN USA. [Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Moss, J (reprint author), NIH, Bldg 10,Room 6D05,MSC 1590, Bethesda, MD 20892 USA. EM mossj@nhlbi.nih.gov NR 9 TC 0 Z9 0 U1 2 U2 2 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD JUN PY 2016 VL 47 IS 6 BP 1883 EP 1884 DI 10.1183/13993003.00410-2016 PG 2 WC Respiratory System SC Respiratory System GA DZ6FE UT WOS:000385956200041 PM 27103385 ER PT J AU Larson, KB Cressey, TR Yogev, R Wiznia, A Hazra, R Jean-Philippe, P Graham, B Gonzalez, A Britto, P Carey, VJ Acosta, EP AF Larson, Kajal B. Cressey, Tim R. Yogev, Ram Wiznia, Andrew Hazra, Rohan Jean-Philippe, Patrick Graham, Bobbie Gonzalez, Amy Britto, Paula Carey, Vincent J. Acosta, Edward P. CA Int Maternal Pediat Adolescent AIDS Clin Trial Protoco TI Pharmacokinetics of Once-Daily Darunavir/Ritonavir With and Without Etravirine in Human Immunodeficiency Virus-Infected Children, Adolescents, and Young Adults SO JOURNAL OF THE PEDIATRIC INFECTIOUS DISEASES SOCIETY LA English DT Article DE antiretrovirals; darunavir; etravirine; pediatrics; pharmacokinetics; ritonavir ID PLASMA; HIV; PHARMACOLOGY; RALTEGRAVIR; MG AB Background. Limited data are available for once-daily (QD) darunavir (DRV)/ritonavir (r) in the pediatric population. Coadministration of etravirine (ETR) may alter the pharmacokinetics (PK) of DRV. We evaluated the PK interactions between DRV/r (QD) and ETR QD or twice-daily (BID) in children, adolescents, and young adults. Methods. Human immunodeficiency virus-infected subjects 9 to <24 years old on optimized background therapy including DRV/r 800/100 mg QD alone or combined with ETR 200 mg BID or ETR 400 mg QD were enrolled. Protocol-defined target drug exposure ranges based on adult data were used to assess the adequacy of each regimen. Intensive 24-hour blood sampling was performed, and PK parameters were determined using noncompartmental analysis. Results. Thirty-one subjects (14 males) completed the study; 16 received DRV/r QD alone (group 1), 6 received DRV/r plus ETR BID (group 2A), and 9 received DRV/r plus ETR QD (group 2B). The geometric mean (90% confidence interval [CI] geometric mean) for DRV area under the curve at 24 hours (AUC(24)) was 57.9 (49.6-67.6), 74.9 (44.4-126.5), and 66.4 (50.8-86.9) mg x h/L for patients in groups 1, 2A, and 2B, respectively. The increased DRV exposure when coadministered with ETR was not statistically significant. The geometric mean (90% CI geometric mean) of ETR AUC(24) was 8.6 (4.4-16.8) and 11.9 (7.5-18.9) mg x h/L for groups 2A and 2B, respectively, with comparable C-24. Conclusions. The results suggest that DRV/r QD with ETR 400 mg QD or 200 mg BID is appropriate and support further evaluation of the safety and efficacy of the once-daily regimen in older children, adolescents, and young adults. C1 [Larson, Kajal B.; Acosta, Edward P.] Univ Alabama, Birmingham B15 2TT, W Midlands, England. [Cressey, Tim R.] Chiang Mai Univ, Fac Associated Med Sci, Program HIV Prevent & Treatment, Dept Med Technol, Chiang Mai, Thailand. [Yogev, Ram] Northwestern Univ, Feinberg Sch Med, Childrens Mem Hosp, Chicago, IL 60611 USA. [Wiznia, Andrew] Jacobi Med Ctr, Bronx, NY USA. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Maternal & Pediat Infect Dis Branch, Bethesda, MD USA. [Jean-Philippe, Patrick] Div Henry M Jackson Fdn Adv Mil Med Inc, HJF DAIDS, Bethesda, MD USA. [Graham, Bobbie; Gonzalez, Amy] Frontier Sci & Technol, Amherst, NY USA. [Britto, Paula] Harvard Sch Publ Hlth, Boston, MA USA. RP Acosta, EP (reprint author), Univ Alabama Birmingham, Div Clin Pharmacol, Sch Med, 1670 Univ Blvd,Volker Hall,Room 258, Birmingham, AL 35294 USA. EM eacosta@uab.edu FU NIAID NIH HHS [UM1 AI068616] NR 20 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2048-7193 EI 2048-7207 J9 J PEDIATR INFECT DIS JI J. Pediatr. Infect. Dis. Soc. PD JUN PY 2016 VL 5 IS 2 BP 131 EP 137 DI 10.1093/jpids/piu142 PG 7 WC Infectious Diseases SC Infectious Diseases GA DZ8QB UT WOS:000386134800008 PM 27199469 ER PT J AU Musci, RJ Hart, SR Ballard, ED Newcomer, A Van Eck, K Ialongo, N Wilcox, H AF Musci, Rashelle J. Hart, Shelley R. Ballard, Elizabeth D. Newcomer, Alison Van Eck, Kathryn Ialongo, Nicholas Wilcox, Holly TI Trajectories of Suicidal Ideation from Sixth through Tenth Grades in Predicting Suicide Attempts in Young Adulthood in an Urban African American Cohort SO SUICIDE AND LIFE-THREATENING BEHAVIOR LA English DT Article ID DIAGNOSTIC INTERVIEW SCHEDULE; RISK-FACTORS; PREVENTION PROGRAM; ADOLESCENT SUICIDE; OUTCOME EVALUATION; BLACK-ADOLESCENTS; BEHAVIOR; INTERVENTIONS; CHILDREN; LIFE AB The trajectory of suicidal ideation across early adolescence may inform the timing of suicide prevention program implementation. This study aimed to identify developmental trajectories of suicidal ideation among an urban cohort of community-residing African Americans (AA) longitudinally followed from middle school through early adulthood (ages 11-19 years). Subtypes based on the developmental course of suicidal ideation from late childhood through midadolescence were identified using longitudinal latent class analysis (LLCA) with 581 AA adolescents (52.7% male; 71.1% free or reduced school meals). The developmental trajectories of suicidal ideation were then used to predict suicide attempts in young adulthood. Our LLCA indicated two subtypes (i.e., ideators and nonideators), with 8% of the sample in the ideator class. This trajectory class shows a peak of suicidal ideation in seventh grade and a steady decline in ideation in subsequent grades. Additionally, suicidal ideation trajectories significantly predicted suicide attempt. Results of these analyses suggest the need for suicide prevention approaches prior to high school for AA youth. C1 [Musci, Rashelle J.] Johns Hopkins Bloomberg Sch Publ Hlth, 624 N Broadway,Rm 841, Baltimore, MD 21205 USA. [Hart, Shelley R.] Calif State Univ Chico, Dept Child Dev, Chico, CA 95929 USA. [Ballard, Elizabeth D.] NIMH, Baltimore, MD USA. [Newcomer, Alison] Catholic Univ Amer, Dept Psychol, Washington, DC 20064 USA. [Van Eck, Kathryn] Johns Hopkins Sch Med, Dept Pediat, Baltimore, MD USA. [Ialongo, Nicholas] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Wilcox, Holly] Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. RP Musci, RJ (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, 624 N Broadway,Rm 841, Baltimore, MD 21205 USA. EM rmusci1@jhu.edu NR 53 TC 2 Z9 2 U1 10 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0363-0234 EI 1943-278X J9 SUICIDE LIFE-THREAT JI Suicide Life-Threat. Behav. PD JUN PY 2016 VL 46 IS 3 BP 255 EP 265 DI 10.1111/sltb.12191 PG 11 WC Psychiatry; Psychology, Multidisciplinary SC Psychiatry; Psychology GA DZ2XK UT WOS:000385705800001 PM 26395337 ER PT J AU Krist, AH Glasgow, RE Heurtin-Roberts, S Sabo, RT Roby, DH Gorin, SNS Balasubramanian, BA Estabrooks, PA Ory, MG Glenn, BA Phillips, SM Kessler, R Johnson, SB Rohweder, CL Fernandez, ME AF Krist, Alex H. Glasgow, Russell E. Heurtin-Roberts, Suzanne Sabo, Roy T. Roby, Dylan H. Gorin, Sherri N. Sheinfeld Balasubramanian, Bijal A. Estabrooks, Paul A. Ory, Marcia G. Glenn, Beth A. Phillips, Siobhan M. Kessler, Rodger Johnson, Sallie Beth Rohweder, Catherine L. Fernandez, Maria E. CA Mohr Study Grp TI The impact of behavioral and mental health risk assessments on goal setting in primary care SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Article DE Health risk assessment; Primary care; Patient reported measures; Health behaviors; Mental health; Pragmatic trial ID STRATEGY; IMPLEMENTATION; INTERVENTIONS; PHYSICIANS; DELIVERY; OUTCOMES; PROJECT; DIETARY; SYSTEMS; DEATH AB Patient-centered health risk assessments (HRAs) that screen for unhealthy behaviors, prioritize concerns, and provide feedback may improve counseling, goal setting, and health. To evaluate the effectiveness of routinely administering a patient-centered HRA, My Own Health Report, for diet, exercise, smoking, alcohol, drug use, stress, depression, anxiety, and sleep, 18 primary care practices were randomized to ask patients to complete My Own Health Report (MOHR) before an office visit (intervention) or continue usual care (control). Intervention practice patients were more likely than control practice patients to be asked about each of eight risks (range of differences 5.3-15.8 %, p < 0.001), set goals for six risks (range of differences 3.8-16.6 %, p < 0.01), and improve five risks (range of differences 5.4-13.6 %, p < 0.01). Compared to controls, intervention patients felt clinicians cared more for them and showed more interest in their concerns. Patient-centered health risk assessments improve screening and goal setting. C1 [Krist, Alex H.; Sabo, Roy T.] Virginia Commonwealth Univ, Dept Family Med & Populat Hlth, POB 980101, Richmond, VA 23298 USA. [Glasgow, Russell E.] Univ Colorado, Sch Med, Dept Family Med, Denver, CO USA. [Heurtin-Roberts, Suzanne] NCI, Implementat Sci Team, Div Canc Control & Populat Sci, Rockville, MD USA. [Sabo, Roy T.] Virginia Commonwealth Univ, Dept Biostat, Richmond, VA USA. [Gorin, Sherri N. Sheinfeld] NCI, Div Canc Control & Populat Sci, Leidos Biomed Res Inc, Rockville, MD USA. [Balasubramanian, Bijal A.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Dallas, TX USA. [Estabrooks, Paul A.; Johnson, Sallie Beth] Carilion Clin, Dept Family & Community Med, Roanoke, VA USA. [Estabrooks, Paul A.; Johnson, Sallie Beth] Virginia Tech, Human Nutr Foods & Exercise, Blacksburg, VA USA. [Ory, Marcia G.] Texas A&M Hlth Sci Ctr, Sch Publ Hlth, Dept Hlth Promot & Community Hlth Sci, College Stn, TX USA. [Glenn, Beth A.] Univ Calif Los Angeles, Dept Hlth Policy & Management, Fielding Sch Publ Hlth, Los Angeles, CA USA. [Phillips, Siobhan M.] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Kessler, Rodger] Univ Vermont, Dept Family Med, Burlington, VT USA. [Rohweder, Catherine L.] Univ N Carolina, Gillings Sch Global Publ Hlth, Consortium Implementat Sci, Chapel Hill, NC USA. [Fernandez, Maria E.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Houston, TX 77030 USA. [Roby, Dylan H.] Univ Maryland, Sch Publ Hlth, College Pk, MD 20742 USA. RP Krist, AH (reprint author), Virginia Commonwealth Univ, Dept Family Med & Populat Hlth, POB 980101, Richmond, VA 23298 USA. EM ahkrist@vcu.edu FU National Cancer Institute; Agency for Healthcare Research and Quality; Office of Behavioral and Social Sciences Research; National Center for Advancing Translational Sciences (CTSA) [ULTR00058] FX Funding for the MOHR project was provided by the National Cancer Institute, Agency for Healthcare Research and Quality, Office of Behavioral and Social Sciences Research, and National Center for Advancing Translational Sciences (CTSA Grant Number ULTR00058). The opinions expressed in this manuscript are those of the authors and do not necessarily reflect those of the funders. NR 37 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1869-6716 EI 1613-9860 J9 TRANSL BEHAV MED JI Transl. Behav. Med. PD JUN PY 2016 VL 6 IS 2 BP 212 EP 219 DI 10.1007/s13142-015-0384-2 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DY6TL UT WOS:000385261100007 PM 27356991 ER PT J AU Bangdiwala, SI Bhargava, A O'Connor, DP Robinson, TN Michie, S Murray, DM Stevens, J Belle, SH Templin, TN Pratt, CA AF Bangdiwala, Shrikant I. Bhargava, Alok O'Connor, Daniel P. Robinson, Thomas N. Michie, Susan Murray, David M. Stevens, June Belle, Steven H. Templin, Thomas N. Pratt, Charlotte A. TI Statistical methodologies to pool across multiple intervention studies SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Article DE Statistical pooling of studies; Random-effects metaanalysis; Study-level meta-regression; Multilevel meta-regression; Multilevel structural models ID WOMENS HEALTH TRIAL; MINORITY POPULATIONS; CHILDHOOD OBESITY; FEASIBILITY; PREDICTORS; TAXONOMY; EQUATION; TESTS AB Combining and analyzing data from heterogeneous randomized controlled trials of complex multiple-component intervention studies, or discussing them in a systematic review, is not straightforward. The present article describes certain issues to be considered when combining data across studies, based on discussions in an NIH-sponsored workshop on pooling issues across studies in consortia (see Belle et al. in Psychol Aging, 18(3): 396-405, 2003). Several statistical methodologies are described and their advantages and limitations are explored. Whether weighting the different studies data differently, or via employing random effects, one must recognize that different pooling methodologies may yield different results. Pooling can be used for comprehensive exploratory analyses of data from RCTs and should not be viewed as replacing the standard analysis plan for each study. Pooling may help to identify intervention components that may be more effective especially for subsets of participants with certain behavioral characteristics. Pooling, when supported by statistical tests, can allow exploratory investigation of potential hypotheses and for the design of future interventions. C1 [Bangdiwala, Shrikant I.] Univ North Carolina Chapel Hill, Dept Biostat, Chapel Hill, NC 27599 USA. [Bangdiwala, Shrikant I.] Univ South Africa, Inst Social & Hlth Sci, Johannesburg, South Africa. [Bhargava, Alok] Univ Maryland, Sch Publ Policy, College Pk, MD 20742 USA. [O'Connor, Daniel P.] Univ Houston, Texas Obes Res Ctr, Dept Hlth & Human Performance, Houston, TX USA. [Robinson, Thomas N.] Stanford Univ, Ctr Hlth Weight, Stanford, CA 94305 USA. [Michie, Susan] UCL, Ctr Behav Change, London, England. [Michie, Susan] UCL, Dept Clin Educ & Hlth Psychol, London, England. [Murray, David M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, NIH, Rockville, MD USA. [Stevens, June] Univ North Carolina Chapel Hill, Dept Nutr, Chapel Hill, NC USA. [Belle, Steven H.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Templin, Thomas N.] Wayne State Univ, Coll Nursing, Off Hlth Res, Detroit, MI 48202 USA. [Pratt, Charlotte A.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. RP Bangdiwala, SI (reprint author), Univ North Carolina Chapel Hill, Dept Biostat, Chapel Hill, NC 27599 USA.; Bangdiwala, SI (reprint author), Univ South Africa, Inst Social & Hlth Sci, Johannesburg, South Africa. EM kant@unc.edu FU NIH National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Development; NIH Office of Behavioral and Social Sciences Research; NIH Office of Disease Prevention; Centers for Disease Control and Prevention FX This manuscript is one of three presented in this journal and was supported the NIH National Heart, Lung, and Blood Institute, the Eunice Kennedy Shriver National Institute of Child Health and Development, the NIH Office of Behavioral and Social Sciences Research, the NIH Office of Disease Prevention, and the Centers for Disease Control and Prevention. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 26 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1869-6716 EI 1613-9860 J9 TRANSL BEHAV MED JI Transl. Behav. Med. PD JUN PY 2016 VL 6 IS 2 BP 228 EP 235 DI 10.1007/s13142-016-0386-8 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DY6TL UT WOS:000385261100009 PM 27356993 ER PT J AU Tate, DF Lytle, LA Sherwood, NE Haire-Joshu, D Matheson, D Moore, SM Loria, CM Pratt, C Ward, DS Belle, SH Michie, S AF Tate, Deborah F. Lytle, Leslie A. Sherwood, Nancy E. Haire-Joshu, Debra Matheson, Donna Moore, Shirley M. Loria, Catherine M. Pratt, Charlotte Ward, Dianne S. Belle, Steven H. Michie, Susan TI Deconstructing interventions: approaches to studying behavior change techniques across obesity interventions SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Article DE Intervention science; Taxonomy; Pooled analysis ID EVALUATING COMPLEX INTERVENTIONS; WEIGHT-LOSS INTERVENTIONS; PHYSICAL-ACTIVITY; IMPROVE HEALTH; TAXONOMY; FIDELITY; TRIALS; ADULTS; LIFE; IMPLEMENTATION AB Deconstructing interventions into the specific techniques that are used to change behavior represents a new frontier in behavioral intervention research. This paper considers opportunities and challenges in employing the Behavior Change Techniques Taxonomy (BCTTv1) developed by Michie and colleagues, to code the behavior change techniques (BCTs) across multiple interventions addressing obesity and capture dose received at the technique level. Numerous advantages were recognized for using a shared framework for intervention description. Coding interventions at levels of the social ecological framework beyond the individual level, separate coding for behavior change initiation vs. maintenance, fidelity of BCT delivery, accounting for BCTs mode of delivery, and tailoring BCTs, present both challenges and opportunities. Deconstructing interventions and identifying the dose required to positively impact health-related outcomes could enable important gains in intervention science. C1 [Tate, Deborah F.; Lytle, Leslie A.] Univ North Carolina Chapel Hill, Gillings Sch Global Publ Hlth, Dept Hlth Behav, Chapel Hill, NC 27599 USA. [Tate, Deborah F.; Ward, Dianne S.] Univ North Carolina Chapel Hill, Gillings Sch Global Publ Hlth, Dept Nutr, Chapel Hill, NC 27599 USA. [Sherwood, Nancy E.] HealthPartners Inst Educ & Res, Bloomington, MN USA. [Haire-Joshu, Debra] Washington Univ, Brown Sch, St Louis, MO USA. [Matheson, Donna] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA. [Matheson, Donna] Stanford Univ, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. [Moore, Shirley M.] Case Western Reserve Univ, Frances Payne Bolton Sch Nursing, Cleveland, OH 44106 USA. [Loria, Catherine M.; Pratt, Charlotte] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Belle, Steven H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Michie, Susan] UCL, Dept Clin Educ & Hlth Psychol, Ctr Behav Change, London, England. RP Tate, DF (reprint author), Univ North Carolina Chapel Hill, Gillings Sch Global Publ Hlth, Dept Hlth Behav, Chapel Hill, NC 27599 USA.; Tate, DF (reprint author), Univ North Carolina Chapel Hill, Gillings Sch Global Publ Hlth, Dept Nutr, Chapel Hill, NC 27599 USA. EM dtate@unc.edu FU National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health (NIH) Office of Behavioral and Social Science Research; NIH Office of Disease Prevention, National Institute of Digestive, Diabetes, and Kidney Diseases, National Center for Complementary and Integrative Health, National Cancer Institute, Office of Research on Women's Health; Centers for Disease Control and Prevention (CDC) FX Funding for this work comes from the National Heart, Lung, and Blood Institute, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health (NIH) Office of Behavioral and Social Science Research, the NIH Office of Disease Prevention, National Institute of Digestive, Diabetes, and Kidney Diseases, National Center for Complementary and Integrative Health, National Cancer Institute, Office of Research on Women's Health, and the Centers for Disease Control and Prevention (CDC). NR 53 TC 3 Z9 3 U1 4 U2 4 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1869-6716 EI 1613-9860 J9 TRANSL BEHAV MED JI Transl. Behav. Med. PD JUN PY 2016 VL 6 IS 2 BP 236 EP 243 DI 10.1007/s13142-015-0369-1 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DY6TL UT WOS:000385261100010 PM 27356994 ER PT J AU Belle, SH Stevens, J Cella, D Foltz, JL Loria, CM Murray, DM Czajkowski, SM Arteaga, SS Thom, E Pratt, CA AF Belle, Steven H. Stevens, June Cella, David Foltz, Jennifer L. Loria, Catherine M. Murray, David M. Czajkowski, Susan M. Arteaga, S. Sonia Thom, Elizabeth Pratt, Charlotte A. TI Overview of the obesity intervention taxonomy and pooled analysis working group SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Review DE Intervention science; Taxonomy; Pooled analysis ID RESEARCH DEMONSTRATION PROJECT; HEALTH BEHAVIOR-CHANGE; CHILDHOOD OBESITY; CORD; CONSORTIUM; OPPORTUNITIES; PREVENTION; DESIGN; TRIALS AB The National Heart, Lung, and Blood Institute and the National Institutes of Health Office of Disease Prevention convened a meeting on August 29-30,2013 entitled "Obesity Intervention Taxonomy and Pooled Analysis." The overarching goals of the meeting were to understand how to decompose interventions targeting behavior change, and in particular, those that focus on obesity and to combine data from groups of related intervention studies to supplement what can be learned from the individual studies. This paper summarizes the workshop recommendations and provides an overview of the two other papers that originated from the workshop and that address decomposition of behavioral change interventions and pooling of data across diverse studies within a consortium. C1 [Belle, Steven H.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15260 USA. [Stevens, June] Univ N Carolina, Chapel Hill, NC USA. [Cella, David] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Foltz, Jennifer L.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Foltz, Jennifer L.] US PHS, Washington, DC USA. [Loria, Catherine M.; Czajkowski, Susan M.; Arteaga, S. Sonia; Pratt, Charlotte A.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Murray, David M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Rockville, MD USA. [Thom, Elizabeth] George Washington Univ, Washington, DC USA. RP Belle, SH (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15260 USA. EM belle@edc.pitt.edu FU National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH Office of Behavioral and Social Science Research; NIH Office of Disease Prevention; Centers for Disease Control and Prevention (CDC); National Institute of Digestive, Diabetes, and Kidney Diseases; National Center for Complementary and Integrative Health; National Cancer Institute; Office of Research on Women's Health FX The three manuscripts described in this journal were supported by the National Heart, Lung, and Blood Institute, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the NIH Office of Behavioral and Social Science Research, the NIH Office of Disease Prevention, National Institute of Digestive, Diabetes, and Kidney Diseases, National Center for Complementary and Integrative Health, National Cancer Institute, Office of Research on Women's Health, and the Centers for Disease Control and Prevention (CDC). The findings and conclusions are those of the authors and do not necessarily represent the official position of the National Institutes of Health or the Centers for Disease Control and Prevention. NR 19 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1869-6716 EI 1613-9860 J9 TRANSL BEHAV MED JI Transl. Behav. Med. PD JUN PY 2016 VL 6 IS 2 BP 244 EP 259 DI 10.1007/s13142-015-0365-5 PG 16 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DY6TL UT WOS:000385261100011 PM 27356995 ER PT J AU Hekler, EB Klasnja, P Riley, WT Buman, MP Huberty, J Rivera, DE Martin, CA AF Hekler, Eric B. Klasnja, Predrag Riley, William T. Buman, Matthew P. Huberty, Jennifer Rivera, Daniel E. Martin, Cesar A. TI Agile science: creating useful products for behavior change in the real world SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Article DE Behavior change; Implementation science; Research methods ID INTERVENTIONS; HEALTH; FEASIBILITY; GUIDANCE; SYSTEMS; DESIGN; PILOT AB Evidence-based practice is important for behavioral interventions but there is debate on how best to support real-world behavior change. The purpose of this paper is to define products and a preliminary process for efficiently and adaptively creating and curating a knowledge base for behavior change for real-world implementation. We look to evidence-based practice suggestions and draw parallels to software development. We argue to target three products: (1) the smallest, meaningful, self-contained, and repurposable behavior change modules of an intervention; (2) "computational models" that define the interaction between modules, individuals, and context; and (3) "personalization" algorithms, which are decision rules for intervention adaptation. The "agile science" process includes a generation phase whereby contender operational definitions and constructs of the three products are created and assessed for feasibility and an evaluation phase, whereby effect size estimates/casual inferences are created. The process emphasizes early-and-often sharing. If correct, agile science could enable a more robust knowledge base for behavior change. C1 [Hekler, Eric B.; Buman, Matthew P.; Huberty, Jennifer; Rivera, Daniel E.; Martin, Cesar A.] Arizona State Univ, Sch Nutr & Hlth Promot, 500 N 3rd St, Phoenix, AZ 85003 USA. [Klasnja, Predrag] Univ Michigan, Ann Arbor, MI 48109 USA. [Riley, William T.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Hekler, EB (reprint author), Arizona State Univ, Sch Nutr & Hlth Promot, 500 N 3rd St, Phoenix, AZ 85003 USA. EM ehekler@asu.edu OI Rivera, Daniel/0000-0002-3141-0577 FU Robert Wood Johnson Foundation [71995]; National Science Foundation [IIS-1449751]; National Heart Lung and Blood Institute [R01HL125440] FX This work was funded primarily by a grant from the Robert Wood Johnson Foundation (PI: Hekler, 71995). The example work described was funded by the National Science Foundation ( PI: Hekler, IIS-1449751) and the National Heart Lung and Blood Institute (PI: Klasnja, R01HL125440). NR 61 TC 3 Z9 3 U1 2 U2 2 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1869-6716 EI 1613-9860 J9 TRANSL BEHAV MED JI Transl. Behav. Med. PD JUN PY 2016 VL 6 IS 2 BP 317 EP 328 DI 10.1007/s13142-016-0395-7 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DY6TL UT WOS:000385261100020 PM 27357001 ER PT J AU Campbell-Washburn, AE Xue, H Lederman, RJ Faranesh, AZ Hansen, MS AF Campbell-Washburn, Adrienne E. Xue, Hui Lederman, Robert J. Faranesh, Anthony Z. Hansen, Michael S. TI Real-Time Distortion Correction of Spiral and Echo Planar Images Using the Gradient System Impulse Response Function SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE interventional; spiral; EPI; gradient impulse response; gradient calibration; off-resonance correction ID OFF-RESONANCE CORRECTION; MAGNETIC-RESONANCE; FIELD MAP; MRI AB Purpose: MRI-guided interventions demand high frame rate imaging, making fast imaging techniques such as spiral imaging and echo planar imaging (EPI) appealing. In this study, we implemented a real-time distortion correction framework to enable the use of these fast acquisitions for interventional MRI. Methods: Distortions caused by gradient waveform inaccuracies were corrected using the gradient impulse response function (GIRF), which was measured by standard equipment and saved as a calibration file on the host computer. This file was used at runtime to calculate the predicted k-space trajectories for image reconstruction. Additionally, the off-resonance reconstruction frequency was modified in real time to interactively deblur spiral images. Results: Real-time distortion correction for arbitrary image orientations was achieved in phantoms and healthy human volunteers. The GIRF-predicted k-space trajectories matched measured k-space trajectories closely for spiral imaging. Spiral and EPI image distortion was visibly improved using the GIRF-predicted trajectories. The GIRF calibration file showed no systematic drift in 4 months and was demonstrated to correct distortions after 30 min of continuous scanning despite gradient heating. Interactive off-resonance reconstruction was used to sharpen anatomical boundaries during continuous imaging. Conclusions: This real-time distortion correction framework will enable the use of these high frame rate imaging methods for MRI-guided interventions. (C) 2015 Wiley Periodicals, Inc. C1 [Campbell-Washburn, Adrienne E.; Xue, Hui; Lederman, Robert J.; Faranesh, Anthony Z.; Hansen, Michael S.] NHLBI, Pulm & Cardiovasc Branch, Div Intramural Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Campbell-Washburn, AE (reprint author), NIH, 9000 Rockville Pike,Bldg 10,Room B1D416, Bethesda, MD 20892 USA. EM adrienne.campbell@nih.gov OI lederman, robert/0000-0003-1202-6673 FU National Heart, Lung, and Blood Institute, Division of Intramural Research [Z01-HL006039, Z01-HL005062] FX Grant sponsor: National Heart, Lung, and Blood Institute, Division of Intramural Research; Grant numbers: Z01-HL006039, Z01-HL005062. NR 21 TC 1 Z9 1 U1 4 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUN PY 2016 VL 75 IS 6 BP 2278 EP 2285 DI 10.1002/mrm.25788 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DY3LS UT WOS:000384994700006 PM 26114951 ER PT J AU Talagala, SL Sarlls, JE Liu, SY Inati, SJ AF Talagala, S. Lalith Sarlls, Joelle E. Liu, Siyuan Inati, Souheil J. TI Improvement of Temporal Signal-to-Noise Ratio of GRAPPA Accelerated Echo Planar Imaging Using a FLASH Based Calibration Scan SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE GRAPPA; temporal SNR; EPI; FLASH; calibration scan ID RECONSTRUCTIONS; ACQUISITION; ARRAYS; MRI AB Purpose: To demonstrate that the temporal signal-to-noise ratio (SNR) of generalized autocalibrating partially parallel acquisitions (GRAPPA) accelerated echo planar imaging (EPI) can be enhanced and made more spatially uniform by using a fast low angle shot (FLASH) based calibration scan. Methods: EPI of a phantom and human brains were acquired at 3 Tesla without and with GRAPPA acceleration factor of 2. The GRAPPA accelerated data were reconstructed using calibration scans acquired with EPI and FLASH acquisition schemes. The increase in temporal signal fluctuation due to GRAPPA reconstruction was quantified and compared. Simulated g-factor maps were also created for different calibration scans. Results: GRAPPA accelerated phantom data exhibited areas with high g values when using the EPI based calibration for reconstruction. The g-factor maps were uniform when using the FLASH calibration scan. g was greater than 1.1 in 74% of pixels in 64 x 64 data reconstructed with the EPI calibration compared with only 15% when using the FLASH calibration scan. Human data also showed abnormally high g regions when using the EPI calibration but not when using the FLASH calibration scan. Use of the FLASH calibration scan increased the whole brain temporal SNR by similar to 12% without affecting the image quality. Experimental observations were confirmed by simulations. Conclusion: A calibration scan based on a FLASH acquisition scheme can be used to improve the temporal SNR of GRAPPA accelerated EPI time series. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Talagala, S. Lalith; Sarlls, Joelle E.] NINDS, NIH MRI Res Facil, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Liu, Siyuan] Natl Inst Deafness & Other Commun Disorders, Language Sect, Voice Speech & Language Branch, NIH, Bethesda, MD USA. [Inati, Souheil J.] NIMH, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. RP Talagala, SL (reprint author), NIH, NIH MRI Res Facil, Bldg 10 Room B1D69,10 Ctr Dr, Bethesda, MD 20892 USA. EM talagala@nih.gov FU National Institute of Neurological Disorders and Stroke, National Institute of Mental Health; National Institute on Deafness and Other Communication Disorders at NIH FX This research was supported by the intramural research programs of the National Institute of Neurological Disorders and Stroke, National Institute of Mental Health and National Institute on Deafness and Other Communication Disorders at NIH. NR 17 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUN PY 2016 VL 75 IS 6 BP 2362 EP 2371 DI 10.1002/mrm.25846 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DY3LS UT WOS:000384994700015 PM 26192822 ER PT J AU Bouhrara, M Reiter, DA Celik, H Fishbein, KW Kijowski, R Spencer, RG AF Bouhrara, Mustapha Reiter, David A. Celik, Hasan Fishbein, Kenneth W. Kijowski, Richard Spencer, Richard G. TI Analysis of mcDESPOT- and CPMG-Derived Parameter Estimates for Two-Component Nonexchanging Systems SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE mcDESPOT; CPMG; sloppiness; energy surface, accuracy; precision; quantitative MRI ID STATE FREE PRECESSION; STOCHASTIC REGION CONTRACTION; MULTICOMPONENT T2 ANALYSIS; WHITE-MATTER DEVELOPMENT; MULTIPLE-SPIN SYSTEMS; MYELIN WATER FRACTION; ECHO NMR EXPERIMENTS; MAGNETIZATION-TRANSFER; GRADIENT-ECHO; OFF-RESONANCE AB Purpose: To compare the reliability and stability of the multicomponent-driven equilibrium single pulse observation of T-1 and T-2 (mcDESPOT) and Carl-Purcell-Meiboom-Gill (CPMG) approaches to parameter estimation. Methods: The stability and reliability of mcDESPOT and CPMG-derived parameter estimates were compared through examination of energy surfaces, evaluation of model sloppiness, and Monte Carlo simulations. Comparisons were performed on an equal time basis and assuming a two-component system. Parameter estimation bias, reflecting accuracy, and dispersion, reflecting precision, were derived for a range of signal-to-noise ratios (SNRs) and relaxation parameters. Results: The energy surfaces for parameters incorporated into the mcDESPOT signal model exhibit flatness, a complex structure of local minima, and instability to noise to a much greater extent than the corresponding surfaces for CPMG. Although both mcDESPOT and CPMG performed well at high SNR, the CPMG approach yielded parameter estimates of considerably greater accuracy and precision at lower SNR. Conclusion: mcDESPOT and CPMG both permit high-quality parameter estimates under SNR that are clinically achievable under many circumstances, depending upon available hardware and resolution and acquisition time constraints. At moderate to high SNR, the mcDESPOT approach incorporating two-step phase increments can yield accurate parameter estimates while providing values for longitudinal relaxation times that are not available through CPMG. However, at low SNR, the CPMG approach is more stable and provides superior parameter estimates. (C) 2015 Wiley Periodicals, Inc. C1 [Bouhrara, Mustapha; Reiter, David A.; Celik, Hasan; Fishbein, Kenneth W.; Spencer, Richard G.] NIA, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. [Kijowski, Richard] Univ Wisconsin, Dept Radiol, Madison, WI 53706 USA. RP Spencer, RG (reprint author), NIA, Intramural Res Program, BRC 04B-116,251 Bayview Blvd, Baltimore, MD 21224 USA. EM spencer@helix.nih.gov OI Fishbein, Kenneth/0000-0002-6353-4603 FU National Institute on Aging, National Institutes of Health Intramural Research Program FX Grant sponsor: National Institute on Aging, National Institutes of Health Intramural Research Program. NR 89 TC 2 Z9 2 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUN PY 2016 VL 75 IS 6 BP 2406 EP 2420 DI 10.1002/mrm.25801 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DY3LS UT WOS:000384994700020 PM 26140371 ER PT J AU Campbell-Washburn, AE Atkinson, D Nagy, Z Chan, RW Josephs, O Lythgoe, MF Ordidge, RJ Thomas, DL AF Campbell-Washburn, Adrienne E. Atkinson, David Nagy, Zoltan Chan, Rachel W. Josephs, Oliver Lythgoe, Mark F. Ordidge, Roger J. Thomas, David L. TI Using the Robust Principal Component Analysis Algorithm to Remove RF Spike Artifacts from MR Images SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE spike noise; robust principal component analysis; stripe artifact ID MATRIX DECOMPOSITION; DYNAMIC MRI; NOISE; REGISTRATION AB Purpose: Brief bursts of RF noise during MR data acquisition ("k-space spikes") cause disruptive image artifacts, manifesting as stripes overlaid on the image. RF noise is often related to hardware problems, including vibrations during gradient-heavy sequences, such as diffusion-weighted imaging. In this study, we present an application of the Robust Principal Component Analysis (RPCA) algorithm to remove spike noise from k-space. Methods: Corrupted k-space matrices were decomposed into their low-rank and sparse components using the RPCA algorithm, such that spikes were contained within the sparse component and artifact-free k-space data remained in the low-rank component. Automated center refilling was applied to keep the peaked central cluster of k-space from misclassification in the sparse component. Results: This algorithm was demonstrated to effectively remove k-space spikes from four data types under conditions generating spikes: (i) mouse heart T-1 mapping, (ii) mouse heart cine imaging, (iii) human kidney diffusion tensor imaging (DTI) data, and (iv) human brain DTI data. Myocardial T-1 values changed by 86.1 +/- 171 ms following despiking, and fractional anisotropy values were recovered following despiking of DTI data. Conclusion: The RPCA despiking algorithm will be a valuable postprocessing method for retrospectively removing stripe artifacts without affecting the underlying signal of interest. (C) 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. C1 [Campbell-Washburn, Adrienne E.; Lythgoe, Mark F.] UCL, Ctr Adv Biomed Imaging, London, England. [Campbell-Washburn, Adrienne E.] NHLBI, Div Intramural Res, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Atkinson, David; Chan, Rachel W.] UCL, Ctr Med Imaging, London, England. [Nagy, Zoltan; Josephs, Oliver] UCL, UCL Inst Neurol, Wellcome Trust Ctr Neuroimaging, London, England. [Nagy, Zoltan] Univ Zurich, Dept Econ, Lab Social & Neural Syst Res SNS Lab, Zurich, Switzerland. [Josephs, Oliver] Birkbeck Coll, Birkbeck UCL Ctr Neuroimaging, London, England. [Ordidge, Roger J.] Univ Melbourne, Dept Anat & Neurosci, Melbourne, Vic, Australia. [Thomas, David L.] UCL, UCL Inst Neurol, Dept Brain Repair & Rehabil, London, England. RP Campbell-Washburn, AE (reprint author), NIH, 9000 Rockville Pike,Bldg 10,Room B1D416, Bethesda, MD 20892 USA. EM adrienne.campbell@nih.gov RI Atkinson, David/C-2270-2008; OI Atkinson, David/0000-0003-1124-6666; Thomas, David/0000-0003-1491-1641; Ordidge, Roger/0000-0002-1005-3654; Nagy, Zoltan/0000-0001-6611-6362 FU Wellcome Trust [091593/Z/10/Z]; British Heart Foundation; Engineering and Physical Sciences Research Council [EP/I018700/1]; National Institute for Health Research University College London Hospitals Biomedical Research Centre FX Grant sponsor: the Wellcome Trust; Grant number: 091593/Z/10/Z; Grant sponsor: British Heart Foundation; Grant sponsor: Engineering and Physical Sciences Research Council; Grant number: EP/I018700/1; and support from the National Institute for Health Research University College London Hospitals Biomedical Research Centre. NR 18 TC 2 Z9 2 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUN PY 2016 VL 75 IS 6 BP 2517 EP 2525 DI 10.1002/mrm.25851 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DY3LS UT WOS:000384994700031 PM 26193125 ER PT J AU Qian, CQ Duan, Q Dodd, S Koretsky, A Murphy-Boesch, J AF Qian, Chunqi Duan, Qi Dodd, Steve Koretsky, Alan Murphy-Boesch, Joe TI Sensitivity Enhancement of an Inductively Coupled Local Detector Using a HEMT-Based Current Amplifier SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE HEMT; negative resistance; current amplifier; MRI; inductive coupling ID PHASED-ARRAY; FIELD; NMR; MRI; DYNAMICS; FEEDBACK AB Purpose: To improve the signal transmission efficiency and sensitivity of a local detection coil that is weakly inductively coupled to a larger receive coil. Methods: The resonant detection coil is connected in parallel with the gate of a high electron mobility transistor (HEMT) transistor without impedance matching. When the drain of the transistor is capacitively shunted to ground, current amplification occurs in the resonator by feedback that transforms a capacitive impedance on the transistor's source to a negative resistance on its gate. Results: High resolution images were obtained from a mouse brain using a small, 11 mm diameter surface coil that was inductively coupled to a commercial, phased array chest coil. Although the power consumption of the amplifier was only 88 mW, 14 dB gain was obtained with excellent noise performance. Conclusion: An integrated current amplifier based on a HEMT can enhance the sensitivity of inductively coupled local detectors when weakly coupled. This amplifier enables efficient signal transmission between customized user coils and commercial clinical coils, without the need for a specialized signal interface. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Qian, Chunqi; Duan, Qi; Dodd, Steve; Koretsky, Alan; Murphy-Boesch, Joe] NINDS, Lab Funct & Mol Imaging, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Qian, Chunqi] Michigan State Univ, Dept Radiol, E Lansing, MI 48824 USA. RP Qian, CQ (reprint author), NIH, 10 Ctr Dr Room 1D48, Bethesda, MD 20892 USA. EM qianc2@ninds.nih.gov RI Duan, Qi/J-7916-2016 OI Duan, Qi/0000-0002-2407-6611 FU Intramural Research Program of the NINDS at NIH [R00EB016753] FX Grant sponsor: Intramural Research Program of the NINDS at NIH; Grant number: R00EB016753. NR 22 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUN PY 2016 VL 75 IS 6 BP 2573 EP 2578 DI 10.1002/mrm.25850 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DY3LS UT WOS:000384994700037 PM 26192998 ER PT J AU Dogan, BA Berker, D Arduc, A Tuna, MM Nasiroglu, NI Karakilic, E Basaran, MN Isik, S Tutuncu, Y Unal, M Guler, S AF Dogan, Bercem A. Berker, Dilek Arduc, Ayse Tuna, Mazhar M. Nasiroglu, Narin I. Karakilic, Ersen Basaran, Mehtap N. Isik, Serhat Tutuncu, Yasemin Unal, Mustafa Guler, Serdar TI Insulin resistance and androgen levels in eugonadic and hypogonadic women with prolactinoma SO MINERVA ENDOCRINOLOGICA LA English DT Article DE Prolactinoma; Androgens; Insulin Resistance ID HYPERPROLACTINEMIC WOMEN; CHORIONIC-GONADOTROPIN; HORMONE; STEROIDOGENESIS; RECEPTOR; BINDING AB BACKGROUND: Hyperprolactinemia is the most common endocrinologic disorder in causing menstrual irregularities. Although the correlation between hyperprolactinemia and menstrual dysfunction is widely known, the etiology of menstrual cycle disorders is not profoundly understood in patients with prolactinoma. We aimed to investigate the correlation between prolactin levels and insulin resistance and hyperandrogenism in patients with prolactinoma. METHODS: Sixty-four patients with microprolactinoma and 33 healthy women were enrolled. Thirty-six of these patients with prolactinoma (group 1) had an estradiol (E2) level under 30 pg/mL, and 28 (group 2) had an E2 level greater than 30 pg/mL. Blood samples were drawn to measure the levels of the following hormones: Follicle stimulating hormone (FSH), luteinizing hormone (LH), E2, prolactin (PRL), total testosterone (TT), androstenedione (AS) and dehydroepiandrostenedione sulphate (DHEAS). Body Mass Index (BMI of >= 30 kg/m(2)) was excluded from the study. Insulin resistance (IR) was calculated by the HOMA-IR. RESULTS: BMI was higher in patients with prolactinoma than the control group (P=0.02, P=0.025, respectively). IR and glucose intolerance existence were higher in patients with prolactinoma (P=0.007, P=0.097, respectively) than the healthy women, but these differences did not exist between eugonadic and hypogonadic women with prolactinoma (P=0.020, P=0.032, respectively, Bonferroni correction). TT and AS were higher in eugonadic women with prolactinoma than the control group (P=0.004, P=0.003, Bonferroni correction, respectively). CONCLUSIONS: Our study revealed that the relationship between hyperprolactinemia and IR/glucose intolerance is irrespective of gonadal status in women with prolactinoma. Also, the study concluded that hyperandrogenism may be a cause of menstrual dysfunction in eugonadic women with prolactinoma. C1 [Dogan, Bercem A.; Berker, Dilek; Arduc, Ayse; Nasiroglu, Narin I.; Karakilic, Ersen; Basaran, Mehtap N.; Isik, Serhat; Tutuncu, Yasemin; Unal, Mustafa; Guler, Serdar] Ankara Numune Training & Res Hosp, Endocrinol & Metab Dis, Ankara, Turkey. [Arduc, Ayse] NIDDK, Diabet Endocrine & Obes Branch, NIH, Bethesda, MD 20892 USA. [Tuna, Mazhar M.] Dicle Univ, Endocrinol & Metab Dis Dept, Diyarbakir, Turkey. [Guler, Serdar] Hitit Univ, Endocrinol & Metab Dis Dept, Corum, Turkey. RP Dogan, BA (reprint author), Ankara Numune Training & Res Hosp, Dept Endocrinol & Metab, Ankara, Turkey. EM bercemay@gmail.com NR 22 TC 0 Z9 0 U1 0 U2 0 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 0391-1977 EI 1827-1634 J9 MINERVA ENDOCRINOL JI Minerva Endocrinol. PD JUN PY 2016 VL 41 IS 2 BP 175 EP 182 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DY2TM UT WOS:000384945000004 PM 25288097 ER PT J AU Deshpande, N Simonsick, E Metter, EJ Ko, S Ferrucci, L Studenski, S AF Deshpande, Nandini Simonsick, Eleanor Metter, E. Jeffrey Ko, Seunguk Ferrucci, Luigi Studenski, Stephanie TI Ankle proprioceptive acuity is associated with objective as well as self-report measures of balance, mobility, and physical function SO AGE LA English DT Article DE Ankle proprioception; Threshold for perception of passive movement; Balance; Gait speed; Mobility; Aging ID OLDER-ADULTS; PERFORMANCE; POPULATION; MUSCLE; YOUNG; SWAY; AGE AB Ankle proprioceptive information is integrated by the central nervous system to generate and modulate muscle contractions for maintaining standing balance. This study evaluated the association of ankle joint proprioception with objective and self-report measures of balance, mobility, and physical function across the adult life span. Seven hundred and ninety participants (age range 24-97 years, 362 women) who completed ankle proprioception assessment between 2010 and 2014 were included in the present study from the population-based cohort of the Baltimore Longitudinal Study of Aging (BLSA), USA. Outcome measures included ankle joint proprioception measured as threshold for perception of passive movement (TPPM); single leg stance time; perceived difficulty for standing balance; usual, fastest, and narrow-path gait speed; walking index; short physical performance battery score; and self-reported activity restriction due to fear of falling. Descriptive variables included age, sex, body mass index, education, strength, and cognition. Analyses of covariance (ANCOVA) in general linear model (GLM) or multinomial logistic regression analyses were performed, as appropriate, to test the hypothesis that balance, mobility, and physical function were significantly different according to TPPM quintiles even after adjusting for relevant covariates. Those with TPPM >2.2 degrees consistently demonstrated poor balance, mobility, and physical function. However, with increase in challenge (single leg stance, fastest walking speed, and SPPB), TPPM >1.4 degrees was associated with significantly worse performance. In conclusion, ankle proprioceptive acuity has an overall graded relationship with objective and self-report measures of balance, mobility, and physical function. However, the cutoff proprioceptive acuity associated with substantial decline or inability to perform could depend on the challenge induced. C1 [Deshpande, Nandini] Queens Univ, Fac Hlth Sci, Louise D Acton Bldg,31 George St, Kingston, ON K7L 3N6, Canada. [Simonsick, Eleanor; Ferrucci, Luigi; Studenski, Stephanie] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Metter, E. Jeffrey] Univ Tennessee, Med Ctr, Dept Neurol, Memphis, TN USA. [Ko, Seunguk] Chonnam Natl Univ, Dept Mech Engn, Gwangju, Jeonnam, South Korea. RP Deshpande, N (reprint author), Queens Univ, Fac Hlth Sci, Louise D Acton Bldg,31 George St, Kingston, ON K7L 3N6, Canada. EM nandinijd@yahoo.com FU National Institute on Aging's Intramural Research Funds FX The Baltimore Longitudinal Study of Aging was conducted as a component of the Intramural Research Program of the National Institute on Aging. This study was funded by National Institute on Aging's Intramural Research Funds. NR 29 TC 1 Z9 1 U1 1 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0161-9152 EI 1574-4647 J9 AGE JI Age PD JUN PY 2016 VL 38 IS 3 AR 53 DI 10.1007/s11357-016-9918-x PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA DX9RZ UT WOS:000384734100006 PM 27146830 ER PT J AU Sterling, NW Lichtenstein, M Lee, EY Lewis, MM Evans, A Eslinger, PJ Du, GW Gao, X Chen, HL Kong, L Huang, XM AF Sterling, Nicholas W. Lichtenstein, Maya Lee, Eun-Young Lewis, Mechelle M. Evans, Alicia Eslinger, Paul J. Du, Guangwei Gao, Xiang Chen, Honglei Kong, Lan Huang, Xuemei TI Higher Plasma LDL-Cholesterol is Associated with Preserved Executive and Fine Motor Functions in Parkinson's Disease SO AGING AND DISEASE LA English DT Article DE Parkinson's disease; cholesterol; low density lipoprotein cholesterol (LDL-cholesterol); cognition; neuroprotection; executive function ID MILD COGNITIVE IMPAIRMENT; GLIA-DERIVED CHOLESTEROL; SERUM-CHOLESTEROL; RISK-FACTORS; REDUCED RISK; DEMENTIA; SYNAPTOGENESIS; MULTICENTER; DENERVATION; ASSESSMENTS AB Plasma low density lipoprotein (LDL) cholesterol has been associated both with risk of Parkinson's disease (PD) and with age-related changes in cognitive function. This prospective study examined the relationship between baseline plasma LDL-cholesterol and cognitive changes in PD and matched Controls. Fasting plasma LDL-cholesterol levels were obtained at baseline from 64 non-demented PD subjects (62.7 +/- 7.9 y) and 64 Controls (61.3 +/- 6.8 y). Subjects underwent comprehensive neuropsychological testing at baseline, 18-, and 36-months. Linear mixed-effects modeling was used to assess the relationships between baseline LDL-cholesterol levels and longitudinal cognitive changes. At baseline, PD patients had lower scores of fine motor (p< 0.0001), executive set shifting (p= 0.018), and mental processing speed (p= 0.049) compared to Controls. Longitudinally, Controls demonstrated improved fine motor and memory test scores (p= 0.044, and p= 0.003), whereas PD patients demonstrated significantly accelerated loss in fine motor skill (p= 0.002) compared to Controls. Within the PD group, however, higher LDL-cholesterol levels were associated with improved executive set shifting (beta= 0.003, p< 0.001) and fine motor scores (beta= 0.002, p= 0.030) over time. These associations were absent in Controls (p> 0.7). The cholesterol - executive set shifting association differed significantly between PDs and Controls (interaction p= 0.005), whereas the cholesterol fine motor association difference did not reach significance (interaction, p= 0.104). In summary, higher plasma LDL-cholesterol levels were associated with better executive function and fine motor performance over time in PD, both of which may reflect an effect on nigrostriatal mediation. Confirmation of these results and elucidation of involved mechanisms are warranted, and might lead to feasible therapeutic strategies. C1 [Sterling, Nicholas W.; Lichtenstein, Maya; Lee, Eun-Young; Lewis, Mechelle M.; Evans, Alicia; Eslinger, Paul J.; Du, Guangwei; Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA. [Eslinger, Paul J.; Kong, Lan] Penn State Univ, Milton S Hershey Med Ctr, Dept Pharmacol, Hershey, PA 17033 USA. [Lewis, Mechelle M.; Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Publ Hlth Sci, Hershey, PA 17033 USA. [Eslinger, Paul J.; Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Radiol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurosurg, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Kinesiol, Hershey, PA 17033 USA. [Gao, Xiang] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. [Chen, Honglei] NIEHS, Epidemiol Branch, Aging & Neuroepidemiol Grp, Res Triangle Pk, NC 27709 USA. RP Huang, XM (reprint author), Penn State Univ, Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA.; Huang, XM (reprint author), Penn State Univ, Milton S Hershey Med Ctr, Dept Pharmacol, Hershey, PA 17033 USA.; Huang, XM (reprint author), Penn State Univ, Milton S Hershey Med Ctr, Dept Kinesiol, Hershey, PA 17033 USA. EM xuemei@psu.edu OI Chen, Honglei/0000-0003-3446-7779 FU National Institute Neurological Disorders and Stroke [NS060722, NS082151]; Hershey Medical Center GCRC (National Institute of Health) [M01RR10732]; GCRC Construction Grant [C06RR016499]; Pennsylvania Department of Health Tobacco CURE Funds; intramural research program of the National Institute of Environmental Health Sciences [Z01-ES-101986] FX This work was supported by the National Institute Neurological Disorders and Stroke (NS060722 and NS082151 to XH), the Hershey Medical Center GCRC (National Institute of Health M01RR10732), the GCRC Construction Grant (C06RR016499), the Pennsylvania Department of Health Tobacco CURE Funds, and the intramural research program of the National Institute of Environmental Health Sciences (Z01-ES-101986). All analyses, interpretations, and conclusions are those of the authors and not the research sponsors. NR 50 TC 0 Z9 0 U1 2 U2 3 PU INT SOC AGING & DISEASE PI FORT WORTH PA EDITORIAL OFF, 3400 CAMP BOWIE BLVD, FORT WORTH, TX 76106 USA SN 2152-5250 J9 AGING DIS JI Aging Dis. PD JUN PY 2016 VL 7 IS 3 BP 237 EP 245 DI 10.14336/AD.2015.1030 PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA DY1FJ UT WOS:000384840000005 PM 27330838 ER PT J AU Freedman, DM Wu, JC Chen, HL Engels, EA Enewold, LR Freedman, ND Goedert, JJ Kuncl, RW Gail, MH Pfeiffer, RM AF Freedman, D. Michal Wu, Jincao Chen, Honglei Engels, Eric A. Enewold, Lindsey R. Freedman, Neal D. Goedert, James J. Kuncl, Ralph W. Gail, Mitchell H. Pfeiffer, Ruth M. TI Associations between cancer and Parkinson's disease in US elderly adults SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Cancer; Parkinson's disease; Medicare; SEER Program ID REPRODUCTIVE FACTORS; PROSPECTIVE COHORT; MALIGNANT-MELANOMA; MEDICARE DATA; EPIDEMIOLOGY; RISK; DIAGNOSIS; SMOKING; AGE; SURVEILLANCE AB Background: Several studies suggest that cancer is reduced before and after a Parkinson's disease (PD) diagnosis. However, determining relationships among diseases of ageing is challenging due to possible biases in ascertaining disease. This study evaluates the PD and cancer relationship, addressing potential biases. Methods: Using Surveillance, Epidemiology, and End Results-Medicare linked data (1992-2005) of adults >= 65 years, we assessed PD risk after cancer comparing PD in 743 779 cancer patients with PD in a non-cancer group (n = 419 432) in prospective cohort analyses. We also conducted a case-control study of 836 947 cancer cases and 142 869 controls to assess cancer following PD. We applied Cox proportional hazards models to estimate hazards ratios (HRs) for PD after cancer and unconditional logistic regression to estimate odds ratios (ORs) for PD preceding cancer, controlling for physician visits and other factors. To explore biases in ascertaining cancer, we examined relationships between cancer and automobile accident injuries, which we expected to be null. Results: No association was observed between cancer and subsequent PD [ HR = 0.97; 95% confidence interval (CI) = 0.92-1.01] nor between cancer and subsequent automobile injuries (HR = 1.03; 95% CI = 0.98-1.07). One site, lung cancer, was associated with subsequent reduced PD, which may reflect confounding by smoking. In the case-control analysis, PD was associated with reduced subsequent cancer, overall (OR = 0.77; 95% CI = 0.71-0.82) and for several cancer sites. However, the automobile injury/subsequent cancer association was similar (OR = 0.83; 95% CI = 0.78-0.88), suggesting a cancer detection bias after serious health outcomes. Conclusions: In totality, our data do not support a biological relationship between PD and cancer. C1 [Freedman, D. Michal; Wu, Jincao; Engels, Eric A.; Freedman, Neal D.; Goedert, James J.; Gail, Mitchell H.; Pfeiffer, Ruth M.] NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,7E538, Rockville, MD 20850 USA. [Wu, Jincao] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Chen, Honglei] NIEHS, Aging & Neuroepidemiol Grp, POB 12233, Res Triangle Pk, NC 27709 USA. [Enewold, Lindsey R.] NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,7E538, Rockville, MD 20850 USA. [Kuncl, Ralph W.] Univ Redlands, Dept Biol, Redlands, CA 92373 USA. RP Freedman, DM (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,7E538, Rockville, MD 20850 USA. EM freedmam@mail.nih.gov OI Chen, Honglei/0000-0003-3446-7779 FU Intramural Research Program of the National Cancer Institute; National Institute of Environmental Health Sciences, National Institutes of Health; US Public Health Service FX This work was supported by the Intramural Research Program of the National Cancer Institute and the National Institute of Environmental Health Sciences, National Institutes of Health and the US Public Health Service. NR 37 TC 2 Z9 2 U1 4 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2016 VL 45 IS 3 BP 741 EP 751 DI 10.1093/ije/dyw016 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DX8QG UT WOS:000384653200028 PM 26989123 ER PT J AU Anantharaman, D Muller, DC Lagiou, P Ahrens, W Holcatova, I Merletti, F Kjaerheim, K Polesel, J Simonato, L Canova, C Castellsague, X Macfarlane, TV Znaor, A Thomson, P Robinson, M Conway, DI Healy, CM Tjonneland, A Westin, U Ekstrom, J Chang-Claude, J Kaaks, R Overvad, K Drogan, D Hallmans, G Laurell, G Bueno-de-Mesquita, HB Peeters, PH Agudo, A Larranaga, N Travis, RC Palli, D Barricarte, A Trichopoulou, A George, S Trichopoulos, D Quiros, JR Grioni, S Sacerdote, C Navarro, C Sanchez, MJ Tumino, R Severi, G Boutron-Ruault, MC Clavel-Chapelon, F Panico, S Weiderpass, E Lund, E Gram, IT Riboli, E Pawlita, M Waterboer, T Kreimer, AR Johansson, M Brennan, P AF Anantharaman, Devasena Muller, David C. Lagiou, Pagona Ahrens, Wolfgang Holcatova, Ivana Merletti, Franco Kjaerheim, Kristina Polesel, Jerry Simonato, Lorenzo Canova, Cristina Castellsague, Xavier Macfarlane, Tatiana V. Znaor, Ariana Thomson, Peter Robinson, Max Conway, David I. Healy, Claire M. Tjonneland, Anne Westin, Ulla Ekstrom, Johanna Chang-Claude, Jenny Kaaks, Rudolf Overvad, Kim Drogan, Dagmar Hallmans, Goran Laurell, Goran Bueno-de-Mesquita, H. B. Peeters, Petra H. Agudo, Antonio Larranaga, Nerea Travis, Ruth C. Palli, Domenico Barricarte, Aurelio Trichopoulou, Antonia George, Saitakis Trichopoulos, Dimitrios Ramon Quiros, J. Grioni, Sara Sacerdote, Carlotta Navarro, Carmen Sanchez, Maria-Jose Tumino, Rosario Severi, Gianluca Boutron-Ruault, Marie-Christine Clavel-Chapelon, Francoise Panico, Salvatore Weiderpass, Elisabete Lund, Eiliv Gram, Inger T. Riboli, Elio Pawlita, Michael Waterboer, Tim Kreimer, Aimee R. Johansson, Mattias Brennan, Paul TI Combined effects of smoking and HPV16 in oropharyngeal cancer SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Human papillomavirus; tobacco smoking; interaction; head and neck cancer risk; oropharynx cancer ID HUMAN-PAPILLOMAVIRUS SEROLOGY; NECK-CANCER; INTERNATIONAL AGENCY; DATA-COLLECTION; POOLED ANALYSIS; HEAD; ALCOHOL; TOBACCO; RISK; ASSOCIATION AB Background: Although smoking and HPV infection are recognized as important risk factors for oropharyngeal cancer, how their joint exposure impacts on oropharyngeal cancer risk is unclear. Specifically, whether smoking confers any additional risk to HPV-positive oropharyngeal cancer is not understood. Methods: Using HPV serology as a marker of HPV-related cancer, we examined the interaction between smoking and HPV16 in 459 oropharyngeal (and 1445 oral cavity and laryngeal) cancer patients and 3024 control participants from two large European multicentre studies. Odds ratios and credible intervals [CrI], adjusted for potential confounders, were estimated using Bayesian logistic regression. Results: Both smoking [odds ratio (OR [CrI]: 6.82 [4.52, 10.29]) and HPV seropositivity (OR [CrI]: 235.69 [99.95, 555.74]) were independently associated with oropharyngeal cancer. The joint association of smoking and HPV seropositivity was consistent with that expected on the additive scale (synergy index [CrI]: 1.32 [0.51, 3.45]), suggesting they act as independent risk factors for oropharyngeal cancer. Conclusions: Smoking was consistently associated with increase in oropharyngeal cancer risk in models stratified by HPV16 seropositivity. In addition, we report that the prevalence of oropharyngeal cancer increases with smoking for both HPV16-positive and HPV16-negative persons. The impact of smoking on HPV16-positive oropharyngeal cancer highlights the continued need for smoking cessation programmes for primary prevention of head and neck cancer. C1 [Anantharaman, Devasena; Muller, David C.; Johansson, Mattias; Brennan, Paul] Int Agcy Res Canc, Genet Epidemiol Grp, Lyon, France. [Lagiou, Pagona; George, Saitakis] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, Athens, Greece. [Ahrens, Wolfgang] BIPS, Leibniz Inst Prevent Res & Epidemiol, Bremen, Germany. [Ahrens, Wolfgang] Univ Bremen, Fac Math & Comp Sci, Bremen, Germany. [Holcatova, Ivana] Charles Univ Prague, Fac Med 1, Inst Hyg & Epidemiol, Prague, Czech Republic. [Merletti, Franco] Univ Turin, Dept Med Sci, Canc Epidemiol Unit, Turin, Italy. [Kjaerheim, Kristina] Canc Registry Norway, Oslo, Norway. [Polesel, Jerry] CRO Aviano Natl Canc Inst, Unit Epidemiol & Biostat, Aviano, Italy. [Simonato, Lorenzo; Canova, Cristina] Univ Padua, Dept Mol Med, Lab Publ Hlth & Populat Studies, Padua, Italy. [Castellsague, Xavier] CIBERESP, IDIBELL, ICO, Unit Infect & Canc, Barcelona, Spain. [Macfarlane, Tatiana V.] Univ Aberdeen, Sch Med & Dent, Aberdeen, Scotland. [Znaor, Ariana] Croatian Natl Inst Publ Hlth, Croatian Natl Canc Registry, Zagreb, Croatia. [Znaor, Ariana] Int Agcy Res Canc, Sect Canc Surveillance, Lyon, France. [Thomson, Peter; Robinson, Max] Newcastle Univ, Ctr Oral Hlth Res, Newcastle Upon Tyne, Tyne & Wear, England. [Conway, David I.] Univ Glasgow, Sch Dent, Coll Med Vet & Life Sci, Glasgow, Lanark, Scotland. [Healy, Claire M.] Trinity Coll Dublin, Sch Dent Sci, Dublin, Ireland. [Tjonneland, Anne] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Westin, Ulla] Lund Univ, Dept Otorhinolaryngol Malmo & Lund, Lund, Sweden. [Ekstrom, Johanna] Lund Univ, Dept Clin Sci, Lund, Sweden. [Chang-Claude, Jenny; Kaaks, Rudolf] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Overvad, Kim] Inst Publ Hlth, Aarhus, Denmark. [Drogan, Dagmar] German Inst Human Nutr Potsdam Rehbruecke DIfE, Nuthetal, Germany. [Hallmans, Goran] Umea Univ, Dept Biobank Res, Umea, Sweden. [Laurell, Goran] Uppsala Univ, Dept Surg Sci, Uppsala, Sweden. [Bueno-de-Mesquita, H. B.] Natl Inst Publ Hlth & Environm RIVM, Dept Determinants Chron Dis DCD, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. B.] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Bueno-de-Mesquita, H. B.] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Bueno-de-Mesquita, H. B.] Univ Malaya, Fac Med, Dept Social & Prevent Med, Kuala Lumpur, Malaysia. [Peeters, Petra H.] Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, Utrecht, Netherlands. [Peeters, Petra H.] Imperial Coll London, Sch Publ Hlth, MRC PHE, London, England. [Agudo, Antonio] ICO, Unit Nutr & Canc, Barcelona, Spain. [Larranaga, Nerea] BIODonostia Res Inst, Basque Hlth Dept, Publ Hlth Div Gipuzkoa, San Sebastian, Spain. [Larranaga, Nerea; Barricarte, Aurelio; Navarro, Carmen; Sanchez, Maria-Jose] CIBER Epidemiol & Publ Hlth CIBERESP, Madrid, Spain. [Travis, Ruth C.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England. [Palli, Domenico] Canc Res & Prevent Inst ISPO, Mol & Nutr Epidemiol Unit, Florence, Italy. [Barricarte, Aurelio] Navarre Publ Hlth Inst, Pamplona, Spain. [Trichopoulou, Antonia; George, Saitakis; Trichopoulos, Dimitrios] Hellen Hlth Fdn, Athens, Greece. [Trichopoulou, Antonia; Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Trichopoulos, Dimitrios] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Ramon Quiros, J.] Publ Hlth Directorate Asturias, Oviedo, Spain. [Grioni, Sara] Fdn IRCCS, Ist Nazl Tumori, Epidemiol & Prevent Unit, Milan, Italy. [Sacerdote, Carlotta] Univ Turin, Citta Salute & Sci Hosp, Canc Epidemiol Unit, Turin, Italy. [Sacerdote, Carlotta] Ctr Canc Prevent CPO, Turin, Italy. [Navarro, Carmen] IMIB Arrixaca, Murcia Reg Hlth Council, Dept Epidemiol, Murcia, Spain. [Navarro, Carmen] Univ Murcia, Dept Hlth & Social Sci, Murcia, Spain. [Sanchez, Maria-Jose] Univ Granada, Inst Invest Biosanitaria, Granada, Spain. [Tumino, Rosario] Civ MP Arezzo Hosp, Canc Registry, Asp Ragusa, Ragusa, Italy. [Tumino, Rosario] Civ MP Arezzo Hosp, Histopathol Unit, Asp Ragusa, Ragusa, Italy. [Severi, Gianluca] Human Genet Fdn HuGeF, Turin, Italy. [Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Severi, Gianluca] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia. [Boutron-Ruault, Marie-Christine; Clavel-Chapelon, Francoise] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, Villejuif, France. [Boutron-Ruault, Marie-Christine; Clavel-Chapelon, Francoise] Univ Paris 11, Villejuif, France. [Boutron-Ruault, Marie-Christine; Clavel-Chapelon, Francoise] Inst Gustave Roussy, Villejuif, France. [Panico, Salvatore] Univ Naples Federico II, Dipartimento Med Clin & Chirurgia, Naples, Italy. [Weiderpass, Elisabete; Lund, Eiliv; Gram, Inger T.] Arctic Univ Norway, Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Canc Registry Norway, Oslo, Norway. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Weiderpass, Elisabete] Folkhalsan Res Ctr, Dept Genet Epidemiol, Helsinki, Finland. [Riboli, Elio] Imperial Coll London, Sch Publ Hlth, London, England. [Pawlita, Michael; Waterboer, Tim] German Canc Res Ctr, Heidelberg, Germany. [Kreimer, Aimee R.] NCI, NIH, Bethesda, MD 20892 USA. RP Brennan, P (reprint author), Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon 08, France. EM gep@iarc.fr RI Waterboer, Tim/G-1252-2010; Grioni, Sara/K-5320-2016; Weiderpass, Elisabete/M-4029-2016; Castellsague Pique, Xavier/N-5795-2014 OI Grioni, Sara/0000-0002-5891-8426; Weiderpass, Elisabete/0000-0003-2237-0128; Sacerdote, Carlotta/0000-0002-8008-5096; Healy, Claire M/0000-0001-7940-4611; Pawlita, Michael/0000-0002-4720-8306; Ahrens, Wolfgang/0000-0003-3777-570X; Castellsague Pique, Xavier/0000-0002-0802-3595 FU European Commission's 5th Framework Program [QLK1-2001-00182]; Europe Against Cancer Program of the European Commission (SANCO); Deutsche Krebshilfe; Deutsches Krebsforschungszentrum; German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund (FIS) of the Spanish Ministry of Health; Spanish Regional Government of Andalucia; Spanish Regional Government of Asturias; Spanish Regional Government of Basque Country; Spanish Regional Government of Murcia; Spanish Regional Government of Navarra; Catalan Institute of Oncology, Spain; ISCIII of the Spanish Ministry of Health [RETICC DR06/0020]; Cancer Research UK; Medical Research Council, UK; Greek Ministry of Health; Stavros Niarchos Foundation; Hellenic Health Foundation; Italian Association for Research on Cancer (AIRC); Italian National Research Council; Fondazione-IstitutoBanco Napoli, Italy; Associazione Italiana per la Ricerca sul Cancro-AIRC Milan; Compagnia di San Paolo; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Swedish Cancer Society; Swedish Scientific Council; Regional Government of Vasterbotten, Sweden; NordForsk (Centre of excellence programme HELGA), Norway; French League against Cancer (LNCC), France; National Institute for Health and Medical Research (INSERM), France; Mutuelle Generale de l'Education Nationale (MGEN), France; 3M Co, France; Gustave Roussy Institute (IGR), France; General Councils of France; National Cancer Institute Intramural Research Program; European Commission [FP7-HEALTH-2011-282562]; Health General Directorate of the French Social Affairs and Health Ministry FX The ARCAGE study was supported by a grant from the European Commission's 5th Framework Program (contract QLK1-2001-00182). The EPIC study has been supported by the Europe Against Cancer Program of the European Commission (SANCO); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund (FIS) of the Spanish Ministry of Health, Spanish Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra; Catalan Institute of Oncology, Spain; the ISCIII of the Spanish Ministry of Health (RETICC DR06/0020); Cancer Research UK; Medical Research Council, UK; Greek Ministry of Health; Stavros Niarchos Foundation; Hellenic Health Foundation; Italian Association for Research on Cancer (AIRC); Italian National Research Council, Fondazione-IstitutoBanco Napoli, Italy; Associazione Italiana per la Ricerca sul Cancro-AIRC Milan; Compagnia di San Paolo; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Swedish Cancer Society; Swedish Scientific Council; Regional Government of Vasterbotten, Sweden; NordForsk (Centre of excellence programme HELGA), Norway; French League against Cancer (LNCC), France; National Institute for Health and Medical Research (INSERM), France; Mutuelle Generale de l'Education Nationale (MGEN), France; 3M Co, France; Gustave Roussy Institute (IGR), France; and General Councils of France. The serology testing of EPIC prospective study was supported by the National Cancer Institute Intramural Research Program. The work done in this study was supported in part by a grant from the European Commission's 7th Framework Program (contract FP7-HEALTH-2011-282562) and partly by the Health General Directorate of the French Social Affairs and Health Ministry. NR 30 TC 1 Z9 1 U1 4 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2016 VL 45 IS 3 BP 752 EP 761 DI 10.1093/ije/dyw069 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DX8QG UT WOS:000384653200029 PM 27197530 ER PT J AU Cai, H Ye, F Michel, A Murphy, G Sasazuki, S Taylor, PR Qiao, YL Park, SK Yoo, KY Jee, SH Cho, ER Kim, J Chen, SC Abnet, CC Tsugane, S Cai, QY Shu, XO Zheng, W Pawlita, M Epplein, M AF Cai, Hui Ye, Fei Michel, Angelika Murphy, Gwen Sasazuki, Shizuka Taylor, Philip R. Qiao, You-Lin Park, Sue K. Yoo, Keun-Young Jee, Sun Ha Cho, Eo Rin Kim, Jeongseon Chen, Sheau-Chiann Abnet, Christian C. Tsugane, Shoichiro Cai, Qiuyin Shu, Xiao-Ou Zheng, Wei Pawlita, Michael Epplein, Meira TI Helicobacter pylori blood biomarker for gastric cancer risk in East Asia SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Helicobacter pylori; stomach neoplasms; gastric cancer; biomarkers; East Asia ID PACIFIC CONSENSUS GUIDELINES; MULTIPLEX SEROLOGY; PREVENTION; ANTIBODIES; INFECTION; ANTIGENS; PROTEINS; COHORT; HEALTH AB Background: Incidence and mortality rates for gastric cancer, the fifth most commonly diagnosed and third most deadly cancer worldwide, are highest in East Asia. We sought to identify gastric cancer risk biomarkers among eight prospective studies from China, Japan and Korea. Methods: This pooled nested case-control study included 1608 incident non-cardia gastric cancer cases and 1958 matched controls. Pre-diagnostic antibody levels to 15 Helicobacter pylori proteins were assessed using multiplex serology. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results: Sero-positivity to 10 H. pylori antigens (Omp, CagA, VacA, HcpC, HP 0305, GroEL, NapA, HyuA, Cad, HpaA) was associated with a 1.29- to 3.26-fold increase in odds of gastric cancer. Omp and HP 0305 consistently remained associated with gastric cancer risk after mutually adjusting for all other markers. Sero-positivity to both Omp and HP 0305 was associated with an over 4-fold increase in gastric cancer incidence (OR, 4.09; 95% CI 3.26-5.13). When limited to only those who are CagA + H. pylori+, Omp/HP 0305 sero-positivity remained strongly associated with an over 3-fold increase in the odds of gastric cancer (OR, 3.34; 95% CI 2.27-4.91). The results were highly consistent among the cohorts. Conclusions: We have confirmed new H. pylori biomarkers that are strongly associated with gastric cancer risk, even among those infected with the known H. pylori virulence factor CagA. These results may help to design cost-efficient prevention strategies to reduce gastric cancer incidence in East Asia. C1 [Cai, Hui; Cai, Qiuyin; Shu, Xiao-Ou; Zheng, Wei; Epplein, Meira] Vanderbilt Univ, Med Ctr, Vanderbilt Epidemiol Ctr, 2525 West End Ave,6th Floor, Nashville, TN 37203 USA. [Cai, Hui; Cai, Qiuyin; Shu, Xiao-Ou; Zheng, Wei; Epplein, Meira] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, 2525 West End Ave,6th Floor, Nashville, TN 37203 USA. [Ye, Fei; Chen, Sheau-Chiann] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Quantitat Sci, 2525 West End Ave,6th Floor, Nashville, TN 37203 USA. [Michel, Angelika; Pawlita, Michael] German Canc Res Ctr DFKZ, Div Mol Diagnost Oncogen Infect, Heidelberg, Germany. [Murphy, Gwen; Taylor, Philip R.; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Sasazuki, Shizuka; Tsugane, Shoichiro] Natl Canc Ctr, Epidemiol & Prevent Grp, Tokyo, Japan. [Qiao, You-Lin] Chinese Acad Med Sci, Dept Canc Epidemiol, Beijing, Peoples R China. [Qiao, You-Lin] Peking Union Med Coll, Beijing, Peoples R China. [Park, Sue K.] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Canc Res Inst, Seoul, South Korea. [Park, Sue K.; Yoo, Keun-Young] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Jee, Sun Ha; Cho, Eo Rin] Yonsei Univ, Inst Hlth Promot, Dept Epidemiol & Hlth Promot, Seoul, South Korea. [Kim, Jeongseon] Natl Canc Ctr, Res Inst, Div Canc Epidemiol & Prevent, Goyang, South Korea. RP Epplein, M (reprint author), Vanderbilt Univ, Med Ctr, Div Epidemiol, 2525 West End Ave,6th Floor, Nashville, TN 37203 USA. EM meira.epplein@vanderbilt.edu RI Zheng, Wei/O-3351-2013; Waterboer, Tim/G-1252-2010; Abnet, Christian/C-4111-2015 OI Zheng, Wei/0000-0003-1226-070X; Abnet, Christian/0000-0002-3008-7843 FU National Cancer Institute at the National Institutes of Health [R01 CA174853, K07 CA151782] FX This work was supported by the National Cancer Institute at the National Institutes of Health (R01 CA174853 and K07 CA151782 to M.E.). The funders of the study had no role in study design; in the collection, analysis or interpretation of the data; or in writing the report. M.E. had full access to all study data and had final responsibility for the decision to submit for publication. NR 23 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2016 VL 45 IS 3 BP 774 EP 781 DI 10.1093/ije/dyw078 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DX8QG UT WOS:000384653200031 PM 27170766 ER PT J AU Koutros, S Silverman, DT Alavanja, MCR Andreotti, G Lerro, CC Heltshe, S Lynch, CF Sandler, DP Blair, A Freeman, LEB AF Koutros, Stella Silverman, Debra T. Alavanja, Michael C. R. Andreotti, Gabriella Lerro, Catherine C. Heltshe, Sonya Lynch, Charles F. Sandler, Dale P. Blair, Aaron Freeman, Laura E. Beane TI Occupational exposure to pesticides and bladder cancer risk SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Pesticides; bladder cancer; epidemiology ID AGRICULTURAL HEALTH; URINARY-BLADDER; PHENOXY HERBICIDES; DIESEL EXHAUST; FARMERS; WORKERS; MEN; METAANALYSIS; MORTALITY; ETIOLOGY AB Background: In the developed world, occupational exposures are a leading cause of bladder cancer. A few studies have suggested a link between pesticide exposures among agricultural populations and bladder cancer. Methods: We used data from the Agricultural Health Study, a prospective cohort study which includes 57 310 pesticide applicators with detailed information on pesticide use, to evaluate the association between pesticides and bladder cancer. We used Poisson regression to calculate rate ratios (RRs) and 95% confidence intervals (CIs) to estimate the association between each of 65 pesticides and 321 incident bladder cancer cases which accrued over the course of follow-up (1993-2011), adjusting for lifestyle and demographic and nonpesticide farm-related exposures, including those previously linked to bladder cancer. We conducted additional analyses stratified by smoking status (never, former, current). Results: We observed associations with bladder cancer risk for two imidazolinone herbicides, imazethapyr and imazaquin, which are aromatic amines. Ever use of imazaquin (RR = 1.54, 95% CI: 1.05, 2.26) was associated with increased risk whereas the excess risk among users of imazethapyr was evident among never smokers (RR in highest quartile vs non-exposed = 3.03, 95% CI: 1.46, 6.29, P-interaction = 0.005). We also observed increased risks overall and among never smokers for use of several chlorinated pesticides including chlorophenoxy herbicides and organochlorine insecticides. Conclusions: Several associations between specific pesticides and bladder cancer risk were observed, many of which were stronger among never smokers, suggesting that possible risk factors for bladder cancer may be more readily detectable in those unexposed to potent risk factors like tobacco smoke. C1 [Koutros, Stella; Silverman, Debra T.; Alavanja, Michael C. R.; Andreotti, Gabriella; Lerro, Catherine C.; Blair, Aaron; Freeman, Laura E. Beane] NCI, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Heltshe, Sonya] Univ Washington, Sch Med, Dept Pediat, Seattle Childrens Hosp,Res Inst, Seattle, WA 98195 USA. [Lynch, Charles F.] Univ Iowa, Coll Publ Hlth, Iowa City, IA USA. [Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Koutros, S (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM KoutrosS@mail.nih.gov RI Beane Freeman, Laura/C-4468-2015; OI Beane Freeman, Laura/0000-0003-1294-4124; Sandler, Dale/0000-0002-6776-0018 FU Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics [Z01CP010119]; NIEHS [Z01ES0490300]; Iowa Cancer Registry [HHSN261201300020I]; Iowa's Holden Comprehensive Cancer Center [P30CA086862]; NIEHS-funded Environmental Health Sciences Research Center at the University of Iowa [P30ES005605] FX This work was supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics (Z01CP010119), NIEHS (Z01ES0490300), the Iowa Cancer Registry (HHSN261201300020I) and Iowa's Holden Comprehensive Cancer Center (P30CA086862) as well as the NIEHS-funded Environmental Health Sciences Research Center at the University of Iowa (P30ES005605). NR 49 TC 3 Z9 3 U1 7 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2016 VL 45 IS 3 BP 792 EP 805 DI 10.1093/ije/dyv195 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DX8QG UT WOS:000384653200033 PM 26411407 ER PT J AU Berthiller, J Straif, K Agudo, A Ahrens, W dos Santos, AB Boccia, S Cadoni, G Canova, C Castellsague, X Chen, C Conway, D Curado, MP Dal Maso, L Daudt, AW Fabianova, E Fernandez, L Franceschi, S Fukuyama, EE Hayes, RB Healy, C Herrero, R Holcatova, I Kelsey, K Kjaerheim, K Koifman, S Lagiou, P La Vecchia, C Lazarus, P Levi, F Lissowska, J Macfarlane, T Mates, D McClean, M Menezes, A Merletti, F Morgenstern, H Muscat, J Olshan, AF Purdue, M Ramroth, H Rudnai, P Schwartz, SM Serraino, D Shangina, O Smith, E Sturgis, EM Szeszenia-Dabrowska, N Thomson, P Vaughan, TL Vilensky, M Wei, QY Winn, DM Wunsch-Filho, V Zhang, ZF Znaor, A Ferro, G Brennan, P Boffetta, P Hashibe, M Lee, YCA AF Berthiller, Julien Straif, Kurt Agudo, Antonio Ahrens, Wolfgang dos Santos, Alexandre Bezerra Boccia, Stefania Cadoni, Gabriella Canova, Cristina Castellsague, Xavier Chen, Chu Conway, David Curado, Maria Paula Dal Maso, Luigino Daudt, Alexander W. Fabianova, Eleonora Fernandez, Leticia Franceschi, Silvia Fukuyama, Erica E. Hayes, Richard B. Healy, Claire Herrero, Rolando Holcatova, Ivana Kelsey, Karl Kjaerheim, Kristina Koifman, Sergio Lagiou, Pagona La Vecchia, Carlo Lazarus, Philip Levi, Fabio Lissowska, Jolanta Macfarlane, Tatiana Mates, Dana McClean, Michael Menezes, Ana Merletti, Franco Morgenstern, Hal Muscat, Joshua Olshan, Andrew F. Purdue, Mark Ramroth, Heribert Rudnai, Peter Schwartz, Stephen M. Serraino, Diego Shangina, Oxana Smith, Elaine Sturgis, Erich M. Szeszenia-Dabrowska, Neonila Thomson, Peter Vaughan, Thomas L. Vilensky, Marta Wei, Qingyi Winn, Deborah M. Wunsch-Filho, Victor Zhang, Zuo-Feng Znaor, Ariana Ferro, Gilles Brennan, Paul Boffetta, Paolo Hashibe, Mia Lee, Yuan-Chin Amy TI Low frequency of cigarette smoking and the risk of head and neck cancer in the INHANCE consortium pooled analysis SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Head and neck cancer; low frequency cigarette smoking; risk factors; pooled analysis ID EPIDEMIOLOGY CONSORTIUM; INTERNATIONAL HEAD; TOBACCO; ALCOHOL; TRACT AB Background: Cigarette smoking is a major risk factor for head and neck cancer (HNC). To our knowledge, low cigarette smoking (<10 cigarettes per day) has not been extensively investigated in fine categories or among never alcohol drinkers. Methods: We conducted a pooled analysis of individual participant data from 23 independent case-control studies including 19 660 HNC cases and 25 566 controls. After exclusion of subjects using other tobacco products including cigars, pipes, snuffed or chewed tobacco and straw cigarettes (tobacco product used in Brazil), as well as subjects smoking more than 10 cigarettes per day, 4093 HNC cases and 13 416 controls were included in the analysis. The lifetime average frequency of cigarette consumption was categorized as follows: never cigarette users, >0-3, >3-5, >5-10 cigarettes per day. Results: Smoking >0-3 cigarettes per day was associated with a 50% increased risk of HNC in the study population [ odds ratio (OR) = 1.52, 95% confidence interval (CI): (1.21, 1.90). Smoking >3-5 cigarettes per day was associated in each subgroup from OR = 2.01 (95% CI: 1.22, 3.31) among never alcohol drinkers to OR = 2.74 (95% CI: 2.01, 3.74) among women and in each cancer site, particularly laryngeal cancer (OR = 3.48, 95% CI: 2.40, 5.05). However, the observed increased risk of HNC for low smoking frequency was not found among smokers with smoking duration shorter than 20 years. Conclusion: Our results suggest a public health message that low frequency of cigarette consumption contributes to the development of HNC. However, smoking duration seems to play at least an equal or a stronger role in the development of HNC. C1 [Berthiller, Julien; Straif, Kurt; Franceschi, Silvia; Herrero, Rolando; Ferro, Gilles; Brennan, Paul] Int Agcy Res Canc, Lyon, France. [Berthiller, Julien] Hosp Civils Lyon, Pole Informat Med Evaluat Rech, Lyon, France. [Agudo, Antonio; Castellsague, Xavier] Catalan Inst Oncol ICO IDIBELL, Barcelona, Spain. [Ahrens, Wolfgang] Bremen Inst Prevent Res & Social Med BIPS, Bremen, Germany. [dos Santos, Alexandre Bezerra; Fukuyama, Erica E.] Inst Canc Estado Sao Paulo ICESP, Sao Paulo, Brazil. [Boccia, Stefania] Univ Cattolica Sacro Cuore, Sect Hyg, Inst Publ Hlth, Rome, Italy. [Boccia, Stefania] Ist Ricovero & Cura Carattere Sci IRCCS, Rome, Italy. [Cadoni, Gabriella] Univ Cattolica Sacro Cuore, Inst Otorhinolaryngol, Head & Neck Surg Dept, Rome, Italy. [Canova, Cristina] Univ Padua, Padua, Italy. [Castellsague, Xavier] CIBER Epidemiol & Salud Publ CIBERESP, Barcelona, Spain. [Chen, Chu; Schwartz, Stephen M.; Vaughan, Thomas L.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Conway, David] Univ Glasgow, Coll Med Vet & Life Sci, Sch Dent, Glasgow, Lanark, Scotland. [Curado, Maria Paula] Int Prevent Res Inst, Lyon, France. [Dal Maso, Luigino] Aviano Canc Ctr, Aviano, Italy. [Daudt, Alexander W.] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Fabianova, Eleonora] Reg Author Publ Hlth, Banska Bystrica, Slovakia. [Fernandez, Leticia] Inst Oncol & Radiobiol, Havana, Cuba. [Hayes, Richard B.] NYU, Sch Med, Div Epidemiol, New York, NY USA. [Healy, Claire] Trinity Coll Dublin, Sch Dent Sci, Dublin, Ireland. [Holcatova, Ivana] Inst Hyg & Epidemiol, Prague, Czech Republic. [Kelsey, Karl] Brown Univ, Providence, RI 02912 USA. [Kjaerheim, Kristina] Canc Registry Norway, Oslo, Norway. [Koifman, Sergio] Fundacao Oswaldo Cruz, Escola Nacl Saude Publ, Rio De Janeiro, Brazil. [Lagiou, Pagona] Univ Athens, Sch Med, Athens, Greece. [La Vecchia, Carlo] Ist Ricovero & Cura Carattere Sci IRCCS, Milan, Italy. [Lazarus, Philip] Washington State Univ, Coll Pharm, Spokane, WA USA. [Levi, Fabio] Lausanne Univ Hosp CHUV, Inst Social & Prevent Med IUMSP, Lausanne, Switzerland. [Lissowska, Jolanta] M Skasodowska Curie Mem Canc Ctr, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Macfarlane, Tatiana] Univ Aberdeen, Sch Dent, Aberdeen, Scotland. [Mates, Dana] Natl Inst Publ Hlth, Bucharest, Romania. [McClean, Michael] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Menezes, Ana] Univ Fed Pelotas, Pelotas, Brazil. [Merletti, Franco] Univ Turin, Turin, Italy. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Urol, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Morgenstern, Hal] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Muscat, Joshua] Penn State Coll Med, Hershey, PA USA. [Olshan, Andrew F.] UNC Sch Publ Hlth, Chapel Hill, NC USA. [Purdue, Mark; Winn, Deborah M.] NICHHD, NIH, Bethesda, MD 20892 USA. [Ramroth, Heribert] Heidelberg Univ, Heidelberg, Germany. [Rudnai, Peter] Natl Inst Environm Hlth, Budapest, Hungary. [Shangina, Oxana] Canc Res Ctr, Moscow, Russia. [Smith, Elaine] Univ Iowa, Coll Publ Hlth, Iowa City, IA USA. [Sturgis, Erich M.; Wei, Qingyi] UT MD Anderson Canc Ctr, Houston, TX USA. [Szeszenia-Dabrowska, Neonila] Inst Occupat Med, Lodz, Poland. [Thomson, Peter] Newcastle Univ, Newcastle Upon Tyne, Tyne & Wear, England. [Vilensky, Marta] Univ Buenos Aires, Inst Oncol Angel H Roffo, Buenos Aires, DF, Argentina. [Wunsch-Filho, Victor] Univ Sao Paulo, Sao Paulo, Brazil. [Zhang, Zuo-Feng] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Znaor, Ariana] Croatian Natl Canc Registry, Zagreb, Croatia. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA. [Hashibe, Mia] Univ Utah, Sch Med, Huntsman Canc Inst, 375 Chipeta Way, Salt Lake City, UT 84108 USA. [Hashibe, Mia; Lee, Yuan-Chin Amy] Univ Utah, Sch Med, 375 Chipeta Way, Salt Lake City, UT 84108 USA. RP Lee, YCA (reprint author), Univ Utah, Sch Med, Div Publ Hlth, Dept Family & Prevent Med, 375 Chipeta Way, Salt Lake City, UT 84108 USA. EM amy.lee@utah.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; Healy, Claire M/0000-0001-7940-4611; Ahrens, Wolfgang/0000-0003-3777-570X; Curado, Maria Paula/0000-0001-8172-2483; dal maso, luigino/0000-0001-6163-200X; Macfarlane, Tatiana/0000-0002-9392-0812; Serraino, Diego/0000-0003-0565-8920; La Vecchia, Carlo/0000-0003-1441-897X; Hayes, Richard/0000-0002-0918-661X FU National Cancer Institute [R03CA113157]; National Institute of Dental and Craniofacial Research [R03DE016611]; Italian Association for Research on Cancer [10068]; Italian Association for Research on Cancer (AIRC); Italian League Against Cancer; Italian Ministry of Research; Swiss League against Cancer; Swiss Research against Cancer/Oncosuisse [KFS-700, OCS-1633]; World Cancer Research Fund; European Commission INCO-COPERNICUS Program [IC15-CT98-0332]; National Institute of Health [P01CA068384 K07CA104231, R01CA048996, R01DE012609, NIDCR R01DE011979, NIDCR R01DE013110, FIRCA TW001500, R01CA061188, P01CA068384, K07CA104231, R01DE013158, P50CA090388, R01DA011386, R03CA077954]; Veterans Affairs Merit Review Funds; 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 intramural programs; 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; AIRC (Italian Agency for Research on Cancer); Intramural Program of the National Cancer Institute, National Institute of Health, United States; Fundacao de Ampara a Pesquisa no Estado de Sao Paulo (FAPESP) [10/51168-0]; European Community (5th Frame work Programme) [QLK1-CT-2001-00182]; German Ministry of Education and Research [01GB9702/3]; NIH [T32CA009142, U01CA096134, R21ES011667, R01ES011740, R01CA100264, R01CA078609, R01CA100679, R01CA051845, R01CA030022] FX The pooled data coordination team (PBoffetta, MH, Y-CAL) were supported by National Cancer Institute grant R03CA113157 and by National Institute of Dental and Craniofacial Research grant R03DE016611r The Milan study (CLV) was supported by the Italian Association for Research on Cancer (Grant no. 10068).r The Aviano study (LDM) was supported by a grant from the Italian Association for Research on Cancer (AIRC), Italian League Against Cancer and Italian Ministry of Researchr The Italy Multicenter study (DS) was supported by the Italian Association for Research on Cancer (AIRC), Italian League Against Cancer and Italian Ministry of Research.r The Study from Switzerland (FL) was supported by the Swiss League against Cancer and the Swiss Research against Cancer/Oncosuisse [KFS-700, OCS-1633].r The central Europe study (PBoffetta, PBrenan, EF, JL, DM, PR, OS, NS-D) was supported by the World Cancer Research Fund and the European Commission INCO-COPERNICUS Program [Contract No. IC15-CT98-0332]r The New York multicentre study (JM) was supported by a grant from National Institute of Health [P01CA068384 K07CA104231].r The study from the Fred Hutchison Cancer Research Center from Seattle (CC, SMS) was supported by a National Institute of Health grant [R01CA048996, R01DE012609].r The Iowa study (ES) was supported by National Institute of Health [NIDCR R01DE011979, NIDCR R01DE013110, FIRCA TW001500] and Veterans Affairs Merit Review Funds.r The North Carolina studies (AFO) were supported by National Institute of Health [R01CA061188], and in part by a grant from the National Institute of Environmental Health Sciences [P30ES010126].r The Tampa study (PLazarus, JM) was supported by National Institute of Health grants [P01CA068384, K07CA104231, R01DE013158]r The Los Angeles study (Z-F Z, HM) was supported by grants from National Institute of Health [P50CA090388, R01DA011386, R03CA077954, T32CA009142, U01CA096134, R21ES011667] and the Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center.r The Houston study (EMS, GL) was supported by a grant from National Institute of Health [R01ES011740, R01CA100264].r The Puerto Rico study (RBH, MPP) was supported by a grant from National Institutes of Health (NCI) US and NIDCR intramural programs.r The Latin America study (PBoffetta, PBrenan, MV, LF, MPC, AM, AWD, SK, VW-F) was supported by 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]r The IARC multicentre study (SF, RH, XC) was supported by 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.r The Boston study (KKelsey, MMcC) was supported by a grant from National Institute of Health [R01CA078609, R01CA100679].r The Rome study (SB, GC) was supported by AIRC (Italian Agency for Research on Cancer).r The US multicentre study (BW) was supported by The Intramural Program of the National Cancer Institute, National Institute of Health, United States.r The Sao Paolo study (V W-F) was supported by Fundacao de Ampara a Pesquisa no Estado de Sao Paulo (FAPESP No 10/51168-0)r The MSKCC study (SS, G-P Y) was supported by a grant from National Institute of Health [R01CA051845].; r The Seattle-Leo stud (FV) was supported by a grant from National Institute of Health [R01CA030022]r The western Europe Study (PBoffetta, IH, WA, PLagiou, DS, LS, FM, CH, KKjaerheim, DC, TMc, PT, AA, AZ) was supported by European Community (5th Frame work Programme) grant no QLK1-CT-2001-00182.r The Germany Heidelberg study (HR) was supported by the grant No. 01GB9702/3 from the German Ministry of Education and Research. NR 14 TC 3 Z9 3 U1 5 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2016 VL 45 IS 3 BP 835 EP 845 DI 10.1093/ije/dyv146 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DX8QG UT WOS:000384653200037 PM 26228584 ER PT J AU Freedman, ND Abnet, CC Caporaso, NE Fraumeni, JF Murphy, G Hartge, P Hollenbeck, AR Park, Y Shiels, MS Silverman, DT AF Freedman, Neal D. Abnet, Christian C. Caporaso, Neil E. Fraumeni, Joseph F., Jr. Murphy, Gwen Hartge, Patricia Hollenbeck, Albert R. Park, Yikyung Shiels, Meredith S. Silverman, Debra T. TI Impact of changing US cigarette smoking patterns on incident cancer: risks of 20 smoking-related cancers among the women and men of the NIH-AARP cohort SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Cigarette smoking; cohort; cancer; men and women ID UNITED-STATES; LUNG-CANCER; BLADDER-CANCER; MORTALITY; ASSOCIATION; ALCOHOL; TOBACCO; SMOKERS; DESIGN; ADULTS AB Background: Historically, US women started smoking at a later age than men and had lower relative risks for smoking-related cancers. However, more recent birth cohorts of women and men have similar smoking histories and have now reached the high-risk age for cancer. The impact of these changes on cancer incidence has not been systematically examined. Methods: Relative risks (RR), 95% confidence intervals (CI) and attributable fractions were calculated for cigarette smoking and incidence of 20 smoking-related cancers in 186 057 women and 266 074 men of the National Institutes of Health-AARP cohort, aged 50 to 71 years in 1995 and followed for 11 years. Results: In the cohort, which included participants born between 1924 and 1945, most women and men started smoking as teenagers. RRs for current vs never smoking were similar in women and men for the following cancers: lung squamous-cell (RR women: 121.4, 95% CI: 57.3-257.4; RR men: 114.6, 95% CI: 61.2-214.4), lung adenocarcinoma (RR women: 11.7, 95% CI: 9.8-14.0; RR men: 15.6, 95% CI: 12.5-19.6), laryngeal (RR women: 37.0, 95% CI: 14.9-92.3; RR men: 13.8, 95% CI: 9.3-20.2), oral cavity-pharyngeal (RR women: 4.4, 95% CI: 3.3-6.0; RR men: 3.8, 95% CI: 3.0-4.7), oesophageal squamous cell (RR women: 7.3, 95% CI: 3.5-15.5; RR men: 6.2, 95% CI: 2.8-13.7), bladder (RR women: 4.7, 95% CI: 3.7-5.8; RR men: 4.0, 95% CI: 3.5-4.5), colon (RR women: 1.3, 95% CI: 1.2-1.5; RR men: 1.3, 95% CI: 1.1-1.4), and at other sites, with similar attributable fractions. Conclusions: RRs for current smoking and incidence of many smoking-related cancers are now similar in US women and men, likely reflecting converging smoking patterns. C1 [Freedman, Neal D.; Abnet, Christian C.; Caporaso, Neil E.; Fraumeni, Joseph F., Jr.; Murphy, Gwen; Hartge, Patricia; Shiels, Meredith S.; Silverman, Debra T.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. [Park, Yikyung] Washington Univ, Sch Med St Louis, Div Publ Hlth Sci, St Louis, MO USA. RP Freedman, ND (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,MSC9768, Bethesda, MD 20892 USA. EM freedmanne@mail.nih.gov RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 31 TC 2 Z9 2 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2016 VL 45 IS 3 BP 846 EP 856 DI 10.1093/ije/dyv175 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DX8QG UT WOS:000384653200038 PM 26411408 ER PT J AU Dixon, SC Nagle, CM Thrift, AP Pharoah, PDP Pearce, CL Zheng, W Painter, JN Chenevix-Trench, G Fasching, PA Beckmann, MW Lambrechts, D Vergote, I Lambrechts, S Van Nieuwenhuysen, E Rossing, MA Doherty, JA Wicklund, KG Chang-Claude, J Rudolph, A Moysich, KB Odunsi, K Goodman, MT Wilkens, LR Thompson, PJ Shvetsov, YB Dork, T Park-Simon, TW Hillemanns, P Bogdanova, N Butzow, R Nevanlinna, H Pelttari, LM Leminen, A Modugno, F Ness, RB Edwards, RP Kelley, JL Heitz, F Karlan, BY Kjaer, SK Hogdall, E Jensen, A Goode, EL Fridley, BL Cunningham, JM Winham, SJ Giles, GG Bruinsma, F Milne, RL Southey, MC Hildebrandt, MAT Wu, XF Lu, KH Liang, D Levine, DA Bisogna, M Schildkraut, JM Berchuck, A Cramer, DW Terry, KL Bandera, EV Olson, SH Salvesen, HB Thomsen, LC Kopperud, RK Bjorge, L Kiemeney, LA Massuger, LFAG Pejovic, T Cook, LS Le, ND Swenerton, KD Brooks-Wilson, A Kelemen, LE Lubinski, J Huzarski, T Gronwald, J Menkiszak, J Wentzensen, N Brinton, L Yang, H Lissowska, J Hogdall, CK Lundvall, L Song, HL Tyrer, JP Campbell, I Eccles, D Paul, J Glasspool, R Siddiqui, N Whittemore, AS Sieh, W McGuire, V Rothstein, JH Narod, SA Phelan, C Risch, HA McLaughlin, JR Anton-Culver, H Ziogas, A Menon, U Gayther, SA Ramus, SJ Gentry-Maharaj, A Wu, AH Pike, MC Tseng, CC Kupryjanczyk, J Dansonka-Mieszkowska, A Budzilowska, A Spiewankiewicz, B Webb, PM AF Dixon, Suzanne C. Nagle, Christina M. Thrift, Aaron P. Pharoah, Paul D. P. Pearce, Celeste Leigh Zheng, Wei Painter, Jodie N. Chenevix-Trench, Georgia Fasching, Peter A. Beckmann, Matthias W. Lambrechts, Diether Vergote, Ignace Lambrechts, Sandrina Van Nieuwenhuysen, Els Rossing, Mary Anne Doherty, Jennifer A. Wicklund, Kristine G. Chang-Claude, Jenny Rudolph, Anja Moysich, Kirsten B. Odunsi, Kunle Goodman, Marc T. Wilkens, Lynne R. Thompson, Pamela J. Shvetsov, Yurii B. Doerk, Thilo Park-Simon, Tjoung-Won Hillemanns, Peter Bogdanova, Natalia Butzow, Ralf Nevanlinna, Heli Pelttari, Liisa M. Leminen, Arto Modugno, Francesmary Ness, Roberta B. Edwards, Robert P. Kelley, Joseph L. Heitz, Florian Karlan, Beth Y. Kjaer, Susanne K. Hogdall, Estrid Jensen, Allan Goode, Ellen L. Fridley, Brooke L. Cunningham, Julie M. Winham, Stacey J. Giles, Graham G. Bruinsma, Fiona Milne, Roger L. Southey, Melissa C. Hildebrandt, Michelle A. T. Wu, Xifeng Lu, Karen H. Liang, Dong Levine, Douglas A. Bisogna, Maria Schildkraut, Joellen M. Berchuck, Andrew Cramer, Daniel W. Terry, Kathryn L. Bandera, Elisa V. Olson, Sara H. Salvesen, Helga B. Thomsen, Liv Cecilie Kopperud, Reidun K. Bjorge, Line Kiemeney, Lambertus A. Massuger, Leon F. A. G. Pejovic, Tanja Cook, Linda S. Le, Nhu D. Swenerton, Kenneth D. Brooks-Wilson, Angela Kelemen, Linda E. Lubinski, Jan Huzarski, Tomasz Gronwald, Jacek Menkiszak, Janusz Wentzensen, Nicolas Brinton, Louise Yang, Hannah Lissowska, Jolanta Hogdall, Claus K. Lundvall, Lene Song, Honglin Tyrer, Jonathan P. Campbell, Ian Eccles, Diana Paul, James Glasspool, Rosalind Siddiqui, Nadeem Whittemore, Alice S. Sieh, Weiva McGuire, Valerie Rothstein, Joseph H. Narod, Steven A. Phelan, Catherine Risch, Harvey A. McLaughlin, John R. Anton-Culver, Hoda Ziogas, Argyrios Menon, Usha Gayther, Simon A. Ramus, Susan J. Gentry-Maharaj, Aleksandra Wu, Anna H. Pike, Malcolm C. Tseng, Chiu-Chen Kupryjanczyk, Jolanta Dansonka-Mieszkowska, Agnieszka Budzilowska, Agnieszka Spiewankiewicz, Beata Webb, Penelope M. CA AOCS Grp Australian Canc Study Ovarian Canc Ovarian Canc Assoc Consortium TI Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Body mass index; obesity; ovarian neoplasms; Mendelian randomization analysis ID METAANALYSIS; REGRESSION; OBESITY; SUSCEPTIBILITY; INSTRUMENTS AB Background: Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC. Methods: We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects metaanalysis. Results: Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95% CI 1.33-2.81). Conclusions: Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence. C1 [Dixon, Suzanne C.; Nagle, Christina M.; Webb, Penelope M.] QIMR Berghofer Med Res Inst, Gynaecol Canc Grp, Brisbane, Qld, Australia. [Dixon, Suzanne C.; Nagle, Christina M.; Webb, Penelope M.] Univ Queensland, Sch Publ Hlth, Brisbane, Qld, Australia. [Thrift, Aaron P.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Thrift, Aaron P.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Pharoah, Paul D. P.] Univ Cambridge, Ctr Canc Genet Epidemiol, Cambridge, England. [Pearce, Celeste Leigh] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Pearce, Celeste Leigh; Gayther, Simon A.; Ramus, Susan J.; Wu, Anna H.; Tseng, Chiu-Chen] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Painter, Jodie N.] QIMR Berghofer Med Res Inst, Mol Canc Epidemiol Grp, Brisbane, Qld, Australia. [Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Canc Genet Grp, Brisbane, Qld, Australia. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Fasching, Peter A.; Beckmann, Matthias W.] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen Nuremberg, Dept Gynecol & Obstet, Univ Hosp Erlangen, Erlangen, Germany. [Lambrechts, Diether] VIB, Vesalius Res Ctr, Leuven, Belgium. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Vergote, Ignace; Lambrechts, Sandrina; Van Nieuwenhuysen, Els] Univ Hosp Leuven, Dept Obstet & Gynaecol, Div Gynecol Oncol, Leuven, Belgium. [Vergote, Ignace; Lambrechts, Sandrina; Van Nieuwenhuysen, Els] Univ Hosp Leuven, Leuven Canc Inst, Leuven, Belgium. [Rossing, Mary Anne; Wicklund, Kristine G.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, 1124 Columbia St, Seattle, WA 98104 USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Doherty, Jennifer A.] Geisel Sch Med Dartmouth, Dept Epidemiol, Hanover, NH USA. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Odunsi, Kunle] Roswell Pk Canc Inst, Dept Gynecol Oncol, Buffalo, NY 14263 USA. [Goodman, Marc T.; Thompson, Pamela J.] Cedars Sinai Med Ctr, Canc Prevent & Control, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Goodman, Marc T.] Cedars Sinai Med Ctr, Dept Biomed Sci, Community & Populat Hlth Res Inst, Los Angeles, CA 90048 USA. [Wilkens, Lynne R.; Shvetsov, Yurii B.] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA. [Doerk, Thilo; Park-Simon, Tjoung-Won; Hillemanns, Peter] Hannover Med Sch, Clin Obstet, Hannover, Germany. [Doerk, Thilo; Park-Simon, Tjoung-Won; Hillemanns, Peter] Hannover Med Sch, Clin Gynaecol, Hannover, Germany. [Bogdanova, Natalia] Hannover Med Sch, Radiat Oncol Res Unit, Hannover, Germany. [Butzow, Ralf] Univ Helsinki, Dept Pathol, Helsinki, Finland. [Butzow, Ralf; Nevanlinna, Heli; Pelttari, Liisa M.; Leminen, Arto] Helsinki Univ Hosp, Helsinki, Finland. [Nevanlinna, Heli; Pelttari, Liisa M.; Leminen, Arto] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Modugno, Francesmary; Edwards, Robert P.; Kelley, Joseph L.] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Div Gynecol Oncol, Pittsburgh, PA USA. [Modugno, Francesmary; Edwards, Robert P.] Magee Womens Res Inst, Womens Canc Res Program, Ovarian Canc Ctr Excellence, Pittsburgh, PA USA. [Modugno, Francesmary; Edwards, Robert P.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Ness, Roberta B.] Univ Texas Sch Publ Hlth, Houston, TX USA. [Heitz, Florian] Knappschaft GmbH, Evang Huyssens Stiftung, Kliniken Essen Mitte, Dept Gynecol & Gynecol Oncol, Essen, Germany. [Heitz, Florian] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany. [Karlan, Beth Y.] Cedars Sinai Med Ctr, Womens Canc Program, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Kjaer, Susanne K.; Hogdall, Estrid; Jensen, Allan] Danish Canc Soc Res Ctr, Dept Virus Lifestyle & Genes, Copenhagen, Denmark. [Kjaer, Susanne K.; Hogdall, Claus K.; Lundvall, Lene] Univ Copenhagen, Rigshosp, Dept Gynaecol, Copenhagen, Denmark. [Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark. [Goode, Ellen L.] Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN USA. [Fridley, Brooke L.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Winham, Stacey J.] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN USA. [Giles, Graham G.; Bruinsma, Fiona; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.; Milne, Roger L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. [Giles, Graham G.] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia. [Hildebrandt, Michelle A. T.; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Lu, Karen H.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Liang, Dong] Texas Southern Univ, Coll Pharm & Hlth Sci, Houston, TX USA. [Levine, Douglas A.; Bisogna, Maria] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10021 USA. [Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Schildkraut, Joellen M.] Duke Canc Inst, Canc Control & Populat Sci, Durham, NC USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Cramer, Daniel W.; Terry, Kathryn L.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA. [Bandera, Elisa V.] Rutgers Canc Inst New Jersey, Canc Prevent & Control Program, New Brunswick, NJ USA. [Olson, Sara H.; Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Salvesen, Helga B.; Thomsen, Liv Cecilie; Kopperud, Reidun K.; Bjorge, Line] Haukeland Hosp, Dept Gynecol & Obstet, Bergen, Norway. [Salvesen, Helga B.; Thomsen, Liv Cecilie; Kopperud, Reidun K.; Bjorge, Line] Univ Bergen, Dept Clin Sci, Ctr Canc Biomarkers, Bergen, Norway. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands. [Massuger, Leon F. A. G.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Dept Gynaecol, Nijmegen, Netherlands. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Cook, Linda S.] Univ New Mexico, Div Epidemiol & Biostat, Dept Internal Med, Albuquerque, NM 87131 USA. [Le, Nhu D.] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada. [Swenerton, Kenneth D.] Univ British Columbia, Dept Med, Vancouver, BC, Canada. [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, Canada. [Kelemen, Linda E.] Med Univ South Carolina, Dept Publ Hlth Sci, Charleston, SC USA. [Lubinski, Jan; Huzarski, Tomasz; Gronwald, Jacek] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Menkiszak, Janusz] Pomeranian Med Univ, Dept Gynecol Surg & Gynecol Oncol Adults & Adoles, Szczecin, Poland. [Wentzensen, Nicolas; Brinton, Louise; Yang, Hannah] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lissowska, Jolanta] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Song, Honglin; Tyrer, Jonathan P.] Univ Cambridge, Dept Oncol, Strangeways Res Lab, Cambridge, England. [Campbell, Ian] Peter MacCallum Canc Ctr, Div Res, Canc Genet Lab, Melbourne, Vic, Australia. [Campbell, Ian] Univ Melbourne, Dept Pathol, Parkville, Vic, Australia. [Eccles, Diana] Univ Southampton, Fac Med, Southampton, Hants, England. [Paul, James; Glasspool, Rosalind] Beatson West Scotland Canc Ctr, Glasgow, Lanark, Scotland. [Siddiqui, Nadeem] Glasgow Royal Infirm, Dept Gynaecol Oncol, Glasgow, Lanark, Scotland. [Whittemore, Alice S.; Sieh, Weiva; McGuire, Valerie; Rothstein, Joseph H.] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA. [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. [Risch, Harvey A.] Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [McLaughlin, John R.] Publ Hlth Ontario, Toronto, ON, Canada. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Anton-Culver, Hoda] Univ Calif Irvine, Sch Med, UCI Ctr Canc Genet Res & Prevent, Genet Epidemiol Res Inst, Irvine, CA 92717 USA. [Menon, Usha; Gentry-Maharaj, Aleksandra] UCL, Inst Womens Hlth, Womens Canc, London, England. [Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Budzilowska, Agnieszka] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Pathol & Lab Diagnost, Warsaw, Poland. [Spiewankiewicz, Beata] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Gynecol Oncol, Warsaw, Poland. RP Dixon, SC (reprint author), Royal Brisbane Hosp, QIMR Berghofer Med Res Inst, Gynaecol Canc Grp, Locked Bag 2000, Herston, Qld 4029, Australia. EM Suzanne.Dixon@qimrberghofer.edu.au RI Menkiszak, Janusz/I-4036-2014; Zheng, Wei/O-3351-2013; Gronwald, Jacek/A-4576-2017; Dork, Thilo/J-8620-2012; Bjorge, Line/C-1307-2017; salvesen, Helga/C-1187-2017; Brooks-Wilson, Angela/E-9399-2012; OI Zheng, Wei/0000-0003-1226-070X; Gronwald, Jacek/0000-0002-3643-2871; Bjorge, Line/0000-0002-0240-2770; salvesen, Helga/0000-0002-4438-8831; Brooks-Wilson, Angela/0000-0003-1009-6408; Winham, Stacey/0000-0002-8492-9102 FU National Cancer Institute at the U.S. National Institutes of Health [K07-CA095666, K07-CA80668, K07-CA143047, K22-CA138563, N01-CN025403, N01-CN55424, N01-PC67001, N01-PC67010, P01-CA17054, P30-CA072720, P30-CA008748, P30-CA14089, P30-CA15083, P50-CA105009, P50-CA136393, P50-CA159981, R01-CA058860, R01 CA063678, R01 CA063682, R01-CA092044, R01-CA095023, R01-CA16056, R01-CA54419, R01-CA58598, R01-CA61107, R01-CA61132, R01-CA76016, R01-CA83918, R01-CA87538, R01-CA112523, R01-CA122443, R03-CA113148, R03-CA115195, U01-CA69417, U01-CA71966]; European Commission [223175 HEALTH F2 2009-223175]; Cancer Research UK [C490/A16561, C536/A13086, C536/A6689, C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565]; National Institutes of Health [CA128978]; Cancer Post-GWAS Initiative [1U19-CA148537, 1U19-CA148065, 1U19-CA148112]; U.S. Department of Defense [DAMD17-02-1-0669, W81XWH-07-0449, DAMD17-02-1-0666, W81XWH-10-1-0280, W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR) [MOP-86727, MSH-87734]; CIHR Team in Familial Risks of Breast Cancer; Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; U.S. Army Medical Research and Materiel Command [DAMD17-02-1-0669, DAMD17-01-1-0729]; National Health and Medical Research Council of Australia [199600, 400281, 209057, 251533, 396414, 504715, 1073898]; Cancer Australia [191, 211, 182]; Cancer Council Queensland; Cancer Council Victoria; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; ELAN Program of the University of Erlangen-Nuremberg; Nationaal Kankerplan of Belgium; German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research [01GB 9401]; German Cancer Research Center; Roswell Park Cancer Institute Alliance Foundation [P30 CA016056]; Rudolf-Bartling Foundation; Helsinki University Central Hospital Research Fund; National Institutes of Health/National Center for Research Resources/General Clinical Research Center [M01-RR000056]; American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; National Center for Advancing Translational Sciences (NCATS) [UL1TR000124]; Danish Cancer Society [94-222-52]; Mermaid I project; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; Cancer Institute of New Jersey; Helse Vest; Norwegian Cancer Society; Research Council of Norway; Radboud University Medical Centre; Oregon Health and Science University (OHSU) Foundation; Pomeranian Medical University; UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University College London Hospital; Royal Marsden Hospital; Imperial Experimental Cancer Research Centre [C1312/A15589]; U.S. Public Health Service [PSA-042205]; Lon V. Smith Foundation [LVS-39420]; Eve Appeal; Oak Foundation; California Cancer Research Program [00-01389V-20170, 2II0200]; Polish Ministry of Science and Higher Education [4 PO5C 028 14, 2 PO5A 068 27]; Maria Sklodowska-Curie Memorial Cancer Center; Institute of Oncology, Warsaw FX This work was supported by: the National Cancer Institute at the U.S. National Institutes of Health [K07-CA095666, K07-CA80668, K07-CA143047, K22-CA138563, N01-CN025403, N01-CN55424, N01-PC67001, N01-PC67010, P01-CA17054, P30-CA072720, P30-CA008748, P30-CA14089, P30-CA15083, P50-CA105009, P50-CA136393, P50-CA159981, R01-CA058860, R01 CA063678, R01 CA063682, R01-CA092044, R01-CA095023, R01-CA16056, R01-CA54419, R01-CA58598, R01-CA61107, R01-CA61132, R01-CA76016, R01-CA83918, R01-CA87538, R01-CA112523, R01-CA122443, R03-CA113148, R03-CA115195, U01-CA69417, U01-CA71966 and Intramural Research funds]; the European Commission's Seventh Framework Programme [agreement number 223175 HEALTH F2 2009-223175]; Cancer Research UK [C490/A16561, C536/A13086, C536/A6689, C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, and C8197/A16565]; a National Institutes of Health (CA128978), Cancer Post-GWAS Initiative [1U19-CA148537, 1U19-CA148065 and 1U19-CA148112 - the Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative]; the U.S. Department of Defense [DAMD17-02-1-0669, W81XWH-07-0449, DAMD17-02-1-0666, W81XWH-10-1-0280 and W81XWH-10-1-0341]; the Canadian Institutes of Health Research (CIHR) [MOP-86727 and MSH-87734 to L.E.K.] and the CIHR Team in Familial Risks of Breast Cancer; the Komen Foundation for the Cure; the Breast Cancer Research Foundation; the Ovarian Cancer Research Fund (thanks to donations by the family and friends of Kathryn Sladek Smith); the U.S. Army Medical Research and Materiel Command [DAMD17-01-1-0729 and DAMD17-02-1-0669]; the National Health and Medical Research Council of Australia [199600, 400281, 209057, 251533, 396414, 504715, 1073898 and fellowships to G.C-T. and P.M.W.]; Cancer Australia [Multi-State Grant Application Numbers 191, 211 and 182]; Cancer Council Queensland; Cancer Council Victoria; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the ELAN Program of the University of Erlangen-Nuremberg; the Nationaal Kankerplan of Belgium; the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research [01GB 9401]; the German Cancer Research Center; the Roswell Park Cancer Institute Alliance Foundation [P30 CA016056]; the Rudolf-Bartling Foundation; the Helsinki University Central Hospital Research Fund; the National Institutes of Health/National Center for Research Resources/General Clinical Research Center [M01-RR000056]; an American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN to B.Y.K.]; the National Center for Advancing Translational Sciences (NCATS) [UL1TR000124 to B.Y.K.]; the Danish Cancer Society [94-222-52]; the Mermaid I project; the Mayo Foundation; the Minnesota Ovarian Cancer Alliance; the Fred C. and Katherine B. Andersen Foundation; the Cancer Institute of New Jersey; Helse Vest; the Norwegian Cancer Society; the Research Council of Norway; Radboud University Medical Centre; the Oregon Health and Science University (OHSU) Foundation; Pomeranian Medical University; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, University College London Hospital and the Royal Marsden Hospital; the Imperial Experimental Cancer Research Centre [C1312/A15589]; the U.S. Public Health Service [PSA-042205]; the Lon V.; Smith Foundation [LVS-39420]; the Eve Appeal; the Oak Foundation; the California Cancer Research Program [00-01389V-20170 and 2II0200]; the Polish Ministry of Science and Higher Education [4 PO5C 028 14 and 2 PO5A 068 27]; and the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 29 TC 3 Z9 3 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2016 VL 45 IS 3 BP 884 EP 895 DI 10.1093/ije/dyw158 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DX8QG UT WOS:000384653200041 PM 27401727 ER PT J AU Jung, SY Wang, M Anderson, K Baglietto, L Bergkvist, L Bernstein, L van den Brandt, PA Brinton, L Buring, JE Eliassen, AH Falk, R Gapstur, SM Giles, GG Goodman, G Hoffman-Bolton, J Horn-Ross, PL Inoue, M Kolonel, LN Krogh, V Lof, M Maas, P Miller, AB Neuhouser, ML Park, Y Robien, K Rohan, TE Scarmo, S Schouten, LJ Sieri, S Stevens, VL Tsugane, S Visvanathan, K Wilkens, LR Wolk, A Weiderpass, E Willett, WC Zeleniuch-Jacquotte, A Zhang, SM Zhang, XH Ziegler, RG Smith-Warner, SA AF Jung, Seungyoun Wang, Molin Anderson, Kristin Baglietto, Laura Bergkvist, Leif Bernstein, Leslie van den Brandt, Piet A. Brinton, Louise Buring, Julie E. Eliassen, A. Heather Falk, Roni Gapstur, Susan M. Giles, Graham G. Goodman, Gary Hoffman-Bolton, Judith Horn-Ross, Pamela L. Inoue, Manami Kolonel, Laurence N. Krogh, Vittorio Lof, Marie Maas, Paige Miller, Anthony B. Neuhouser, Marian L. Park, Yikyung Robien, Kim Rohan, Thomas E. Scarmo, Stephanie Schouten, Leo J. Sieri, Sabina Stevens, Victoria L. Tsugane, Schoichiro Visvanathan, Kala Wilkens, Lynne R. Wolk, Alicja Weiderpass, Elisabete Willett, Walter C. Zeleniuch-Jacquotte, Anne Zhang, Shumin M. Zhang, Xuehong Ziegler, Regina G. Smith-Warner, Stephanie A. TI Alcohol consumption and breast cancer risk by estrogen receptor status: in a pooled analysis of 20 studies SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Alcohol; folate; breast cancer; estrogen receptor; progesterone receptor; pooled analyses; epidemiology; cohort study ID DIETARY-FOLATE INTAKE; BASE-LINE CHARACTERISTICS; ONE-CARBON METABOLISM; II NUTRITION COHORT; POSTMENOPAUSAL WOMEN; VITAMIN-C; PROPENSITY SCORE; PLASMA FOLATE; HEALTH; METAANALYSIS AB Background: Breast cancer aetiology may differ by estrogen receptor (ER) status. Associations of alcohol and folate intakes with risk of breast cancer defined by ER status were examined in pooled analyses of the primary data from 20 cohorts. Methods: During a maximum of 6-18 years of follow-up of 1 089 273 women, 21 624 ER+ and 5113 ER- breast cancers were identified. Study-specific multivariable relative risks (RRs) were calculated using Cox proportional hazards regression models and then combined using a random-effects model. Results: Alcohol consumption was positively associated with risk of ER+ and ER- breast cancer. The pooled multivariable RRs (95% confidence intervals) comparing >= 30 g/d with 0 g/day of alcohol consumption were 1.35 (1.23-1.48) for ER+ and 1.28 (1.10-1.49) for ER+ breast cancer (P-trend <= 0.001; Pcommon-effects by ER status: 0.57). Associations were similar for alcohol intake from beer, wine and liquor. The associations with alcohol intake did not vary significantly by total (from foods and supplements) folate intake (P-interaction >= 0.26). Dietary (from foods only) and total folate intakes were not associated with risk of overall, ER+ and ER- breast cancer; pooled multivariable RRs ranged from 0.98 to 1.02 comparing extreme quintiles. Following-up US studies through only the period before mandatory folic acid fortification did not change the results. The alcohol and folate associations did not vary by tumour subtypes defined by progesterone receptor status. Conclusions: Alcohol consumption was positively associated with risk of both ER+ and ER- breast cancer, even among women with high folate intake. Folate intake was not associated with breast cancer risk. C1 [Jung, Seungyoun; Willett, Walter C.; Smith-Warner, Stephanie A.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Jung, Seungyoun; Wang, Molin; Buring, Julie E.; Eliassen, A. Heather; Willett, Walter C.; Smith-Warner, Stephanie A.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Jung, Seungyoun] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, 660 Redwood St,Howard Hall 100A, Baltimore, MD 21201 USA. [Wang, Molin] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Anderson, Kristin] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Anderson, Kristin] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA. [Baglietto, Laura; Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic, Australia. [Baglietto, Laura; Giles, Graham G.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Bergkvist, Leif] Cent Hosp Vasteras, Dept Surg, Vasteras, Sweden. [Bergkvist, Leif] Cent Hosp Vasteras, Clin Res Ctr, Vasteras, Sweden. [Bernstein, Leslie] Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, Duarte, CA USA. [Bernstein, Leslie] City Hope Natl Med Ctr, 1500 E Duarte Rd, Duarte, CA 91010 USA. [van den Brandt, Piet A.; Schouten, Leo J.] Maastricht Univ, GROW Sch Oncol & Dev Biol, Dept Epidemiol, Maastricht, Netherlands. [Brinton, Louise; Falk, Roni; Maas, Paige; Ziegler, Regina G.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Buring, Julie E.; Zhang, Shumin M.] Harvard Med Sch, Brigham & Womens Hosp, Div Prevent Med, Dept Med, Boston, MA USA. [Eliassen, A. Heather; Willett, Walter C.; Zhang, Xuehong] Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA USA. [Eliassen, A. Heather; Willett, Walter C.; Zhang, Xuehong] Harvard Med Sch, Boston, MA USA. [Gapstur, Susan M.; Stevens, Victoria L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Goodman, Gary; Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Hoffman-Bolton, Judith; Visvanathan, Kala] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Horn-Ross, Pamela L.] Canc Prevent Inst Calif, Fremont, CA USA. [Inoue, Manami; Tsugane, Schoichiro] Natl Canc Ctr, Epidemiol & Prevent Grp, Res Ctr Canc Prevent & Screening, Tokyo, Japan. [Inoue, Manami] Univ Tokyo, Grad Sch Med, AXA Dept Hlth & Human Secur, Tokyo, Japan. [Kolonel, Laurence N.; Wilkens, Lynne R.] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Krogh, Vittorio; Sieri, Sabina] Fdn IRCCS Ist Nazl Tumori, Epidemiol & Prevent Unit, Milan, Italy. [Lof, Marie] Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden. [Miller, Anthony B.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Park, Yikyung] Washington Univ, Sch Med, Dept Surg, Div Publ Hlth Sci, St Louis, MO 63110 USA. [Robien, Kim] George Washington Univ, Milken Inst, Sch Publ Hlth, Dept Epidemiol & Biostat, Washington, DC USA. [Rohan, Thomas E.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Scarmo, Stephanie; Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Dept Environm Med, Div Epidemiol, New York, NY USA. [Wolk, Alicja] Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, Stockholm, Sweden. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Weiderpass, Elisabete] Univ Tromso, Dept Community Med, Fac Hlth Sci, Tromso, Norway. [Weiderpass, Elisabete] Canc Registry Norway, Dept Res, Oslo, Norway. [Weiderpass, Elisabete] Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki, Finland. RP Jung, SY (reprint author), Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, 660 Redwood St,Howard Hall 100A, Baltimore, MD 21201 USA. EM sjung@epi.umaryland.edu RI Weiderpass, Elisabete/M-4029-2016; OI Weiderpass, Elisabete/0000-0003-2237-0128; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU National Institute of Health [CA55075]; Breast Cancer Research Foundation FX This work was supported by a National Institute of Health grant CA55075 and a Breast Cancer Research Foundation grant. NR 74 TC 2 Z9 2 U1 6 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2016 VL 45 IS 3 BP 916 EP 928 DI 10.1093/ije/dyv156 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DX8QG UT WOS:000384653200044 PM 26320033 ER PT J AU Guertin, KA Freedman, ND Loftfield, E Graubard, BI Caporaso, NE Sinha, R AF Guertin, Kristin A. Freedman, Neal D. Loftfield, Erikka Graubard, Barry I. Caporaso, Neil E. Sinha, Rashmi TI Coffee consumption and incidence of lung cancer in the NIH-AARP Diet and Health Study SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Coffee; caffeine; lung cancer; smoking; tobacco ID HISTOLOGICAL TYPES; PROSPECTIVE COHORT; CIGARETTE-SMOKING; NEVER-SMOKERS; RISK-FACTORS; MORTALITY; TEA; DRINKING; METAANALYSIS; ASSOCIATION AB Background: Coffee drinkers had a higher risk of lung cancer in some previous studies, but as heavy coffee drinkers tend to also be cigarette smokers, such findings could be confounded. Therefore, we examined this association in the nearly half a million participants of the US NIH-AARP Diet and Health Study. Methods: Typical coffee intake and smoking history were queried at baseline. During 4 155 256 person-years of follow-up, more than 9000 incident lung cancer cases occurred. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals for coffee intake and subsequent incidence of lung cancer. We also comprehensively adjusted for tobacco smoking and examined associations by detailed strata of tobacco use. Results: Coffee drinkers were far more likely to smoke than non-drinkers. Although coffee drinking was associated with lung cancer in age-and sex-adjusted models (HR for >= 6 cups/day compared with none: 4.56, 4.08-5.10), this association was substantially attenuated after adjusting for smoking (HR: 1.27, 1.14-1.42). Similar findings were observed for each different histological type of lung cancer, and for participants drinking predominantly caffeinated or decaffeinated coffee. Little evidence for an association was observed in our stratified analyses, either within never smokers or in most categories of tobacco use. Conclusions: Coffee drinking was positively associated with lung cancer in our study, although the association was substantially attenuated after adjustment for tobacco smoking. As our adjustment for lifetime tobacco use was imperfect, it is likely that the remaining association is due to residual confounding by smoking, although other explanations are possible. C1 [Guertin, Kristin A.; Freedman, Neal D.; Loftfield, Erikka; Sinha, Rashmi] NCI, Nutr Epidemiol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Graubard, Barry I.] NCI, Biostat Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Caporaso, Neil E.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Guertin, KA (reprint author), NCI, NIH, 9609 Med Ctr Dr RM 6E326,MSC 9760, Bethesda, MD 20892 USA. EM kristin.guertin@nih.gov FU Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX This work was supported by the Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 50 TC 5 Z9 5 U1 3 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2016 VL 45 IS 3 BP 929 EP 939 DI 10.1093/ije/dyv104 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DX8QG UT WOS:000384653200045 PM 26082405 ER PT J AU Major, EO Nath, A AF Major, Eugene O. Nath, Avindra TI A link between long-term natalizumab dosing in MS and PML Putting the puzzle together SO NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION LA English DT Editorial Material ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; JC VIRUS C1 [Major, Eugene O.; Nath, Avindra] NINDS, Div Neuroimmunol & Neurovirol, Intramural Res Program, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Major, EO (reprint author), NINDS, Div Neuroimmunol & Neurovirol, Intramural Res Program, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM majorg@ninds.nih.gov NR 10 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 2332-7812 J9 NEUROL-NEUROIMMUNOL JI Neurol.-Neuroimmunol. Neuroinflammation PD JUN PY 2016 VL 3 IS 3 AR e235 DI 10.1212/NXI.0000000000000235 PG 3 WC Neurosciences SC Neurosciences & Neurology GA DX7OO UT WOS:000384577900017 PM 27213175 ER PT J AU Sylvetsky, AC Blau, JE Rother, KI AF Sylvetsky, Allison C. Blau, Jenny E. Rother, Kristina I. TI Understanding the metabolic and health effects of low-calorie sweeteners: methodological considerations and implications for future research SO REVIEWS IN ENDOCRINE & METABOLIC DISORDERS LA English DT Article DE Diet soda; Artificial sweeteners; Low-calorie sweeteners; Obesity; Weight; Beverages; Metabolism; Study design ID RANDOMIZED CLINICAL-TRIAL; DIET SODA INTAKE; FOOD-INTAKE; ARTIFICIAL SWEETENERS; BODY-WEIGHT; GLUCOSE-HOMEOSTASIS; NONNUTRITIVE SWEETENERS; OVERWEIGHT SUBJECTS; DIABETES-MELLITUS; BEVERAGE INTAKE AB Consumption of foods, beverages, and packets containing low-calorie sweeteners (LCS) has increased markedly across gender, age, race/ethnicity, weight status, and socio-economic subgroups. However, well-controlled intervention studies rigorously evaluating the health effects of LCS in humans are limited. One of the key questions is whether LCS are indeed a beneficial strategy for weight management and prevention of obesity. The current review discusses several methodological considerations in the design and interpretation of these studies. Specifically, we focus on the selection of study participants, inclusion of an appropriate control, importance of considering habitual LCS exposure, selection of specific LCS, dose and route of LCS administration, choice of study outcomes, and the context and generalizability of the study findings. These critical considerations will guide the design of future studies and thus assist in understanding the health effects of LCS. C1 [Sylvetsky, Allison C.] George Washington Univ, Dept Exercise & Nutr Sci, 950 New Hampshire Ave NW, Washington, DC 20052 USA. [Sylvetsky, Allison C.; Blau, Jenny E.; Rother, Kristina I.] NIDDK, Sect Pediat Diabet & Metab, NIH, 9000 Rockville Pike,Bldg 10,Room 8C432A, Bethesda, MD 20892 USA. RP Rother, KI (reprint author), NIDDK, Sect Pediat Diabet & Metab, NIH, 9000 Rockville Pike,Bldg 10,Room 8C432A, Bethesda, MD 20892 USA. EM kristina.rother@nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health FX This work was funded in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health. NR 72 TC 1 Z9 1 U1 18 U2 18 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9155 EI 1573-2606 J9 REV ENDOCR METAB DIS JI Rev. Endocr. Metab. Disord. PD JUN PY 2016 VL 17 IS 2 BP 187 EP 194 DI 10.1007/s11154-016-9344-5 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DX7KJ UT WOS:000384565500007 PM 26936185 ER PT J AU Hoffman, HJ Rawal, S Li, CM Duffy, VB AF Hoffman, Howard J. Rawal, Shristi Li, Chuan-Ming Duffy, Valerie B. TI New chemosensory component in the US National Health and Nutrition Examination Survey (NHANES): first-year results for measured olfactory dysfunction SO REVIEWS IN ENDOCRINE & METABOLIC DISORDERS LA English DT Article DE Olfaction disorders; Epidemiology; Taste; Risk factors; Public health surveillance; Health status ID SMELL IDENTIFICATION TEST; TEST-RETEST RELIABILITY; SELF-REPORTED SMELL; QUALITY-OF-LIFE; ODOR IDENTIFICATION; OLDER-ADULTS; BITTER TASTE; GENERAL-POPULATION; UNITED-STATES; OTITIS-MEDIA AB The U.S. NHANES included chemosensory assessments in the 2011-2014 protocol. We provide an overview of this protocol and 2012 olfactory exam findings. Of the 1818 NHANES participants aged aeyen40 years, 1281 (70.5 %) completed the exam; non-participation mostly was due to time constraints. Health technicians administered an 8-item, forced-choice, odor identification task scored as normosmic (6-8 odors identified correctly) versus olfactory dysfunction, including hyposmic (4-5 correct) and anosmic/severe hyposmic (0-3 correct). Interviewers recorded self-reported smell alterations (during past year, since age 25, phantosmia), histories of sinonasal problems, xerostomia, dental extractions, head or facial trauma, and chemosensory-related treatment and changes in quality of life. Olfactory dysfunction was found in 12.4 % (13.3 million adults; 55 % males/45 % females) including 3.2 % anosmic/severe hyposmic (3.4 million; 74 % males/26 % females). Selected age-specific prevalences were 4.2 % (40-49 years), 12.7 % (60-69 years), and 39.4 % (80+ years). Among adults aeyen70 years, misidentification rates for warning odors were 20.3 % for smoke and 31.3 % for natural gas. The highest sensitivity (correctly identifying dysfunction) and specificity (correctly identifying normosmia) of self-reported olfactory alteration was among anosmics/severe hyposmics (54.4 % and 78.1 %, respectively). In age- and sex-adjusted logistic regression analysis, risk factors of olfactory dysfunction were racial/ethnic minority, income-to-poverty ratio aecurrency sign 1.1, education < high school, and heavy drinking. Moderate-to-vigorous physical activity reduced risk of impairment. Olfactory dysfunction is prevalent, particularly among older adults. Inexpensive, brief odor identification tests coupled with questions (smell problems past year, since age 25, phantosmia) could screen for marked dysfunction. Healthcare providers should be prepared to offer education on non-olfactory avoidance of hazardous events. C1 [Hoffman, Howard J.; Li, Chuan-Ming] NIDCD, Epidemiol & Stat Program, Div Sci Programs, NIH, Bethesda, MD USA. [Rawal, Shristi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD USA. [Rawal, Shristi; Duffy, Valerie B.] Univ Connecticut, Dept Allied Hlth Sci, 358 Mansfield Rd,Unit 1101, Storrs, CT 06269 USA. RP Duffy, VB (reprint author), Univ Connecticut, Dept Allied Hlth Sci, 358 Mansfield Rd,Unit 1101, Storrs, CT 06269 USA. EM valerie.duffy@uconn.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The authors wish to thank the study participants and the dedicated staff who helped organize and conduct the chemosensory (taste and smell) interview and examination components in the National Health and Nutrition Examination Survey (NHANES). We also wish to acknowledge the valuable contribution of our colleagues, Dr. Richard Doty (University of Pennsylvania), Dr. John Hayes (Pennsylvania State University), and Dr. Charles Dillon (Project Officer for the 2011-2014 NHANES Chemosensory Protocol, NCHS/CDC), as well as several experts in chemosensation science who provided critical counsel and encouragement over sustained periods, Dr. Linda Bartoshuk, Dr. Susan Coldwell, Dr. Beverly Cowart, Dr. Karen Cruickshanks, Dr. Pamela Dalton, Dr. Barry Davis [deceased], Dr. Claire Murphy, and multiple others. Also, Dr. Shristi Rawal was partially supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 101 TC 2 Z9 2 U1 4 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9155 EI 1573-2606 J9 REV ENDOCR METAB DIS JI Rev. Endocr. Metab. Disord. PD JUN PY 2016 VL 17 IS 2 BP 221 EP 240 DI 10.1007/s11154-016-9364-1 PG 20 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DX7KJ UT WOS:000384565500010 PM 27287364 ER PT J AU Sousa, ADA Johnson, KR Nicholas, R Darko, S Price, DA Douek, DC Jacobson, S Muraro, PA AF Alves Sousa, Alessandra de Paula Johnson, Kory R. Nicholas, Richard Darko, Sam Price, David A. Douek, Daniel C. Jacobson, Steven Muraro, Paolo A. TI Intrathecal T-cell clonal expansions in patients with multiple sclerosis SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article ID CEREBROSPINAL-FLUID; NERVOUS-SYSTEM; REPERTOIRE; LYMPHOCYTES; DIVERSITY; LESIONS AB Objective: Analysis of the T-cell receptor (TCR) repertoire in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) can reveal antigen-specific immune responses potentially implicated in the disease process. We applied a new unbiased deep-sequencing method for TCR repertoire analysis to accurately measure and compare receptor diversity and clonal expansions within the peripheral and CSF-trafficking T-cell populations of patients with MS and control individuals with idiopathic intracranial hypertension (IIH). Methods: Paired blood and CSF TCR beta-chain libraries from five MS patients and five IIH controls were sequenced, yielding a total of 80 million reads. Results: Although TCR repertoire diversity was greater in the blood and CSF compartments of MS patients when compared with IIH controls, it is notable that the frequency of clonal expansions was also significantly higher in both compartments of MS patients. Highly expanded T-cell clones were enriched in the CSF compartment of MS patients compared to peripheral blood, very few of them were detected in both compartments. Interpretation: Collectively, our data provide a proof of principle that private compartmentalized T-cell expansion exists in the intrathecal space of MS patients. C1 [Alves Sousa, Alessandra de Paula; Jacobson, Steven] NINDS, Neuroimmunol Branch, Viral Immunol Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Alves Sousa, Alessandra de Paula; Muraro, Paolo A.] Imperial Coll London, Div Brain Sci, Fac Med, London, England. [Johnson, Kory R.] NINDS, Bioinformat Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Nicholas, Richard] Imperial Coll Healthcare NHS Trust, London, England. [Darko, Sam; Price, David A.; Douek, Daniel C.] NINDS, Human Immunol Sect, Vaccine Res Ctr, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Price, David A.] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff, S Glam, Wales. RP Muraro, PA (reprint author), Imperial Coll London, Wolfson Neurosci Labs, Burlington Danes Bldg,160 Du Cane Rd, London W12 0NN, England.; Jacobson, S (reprint author), NINDS, Neuroimmunol Branch, Viral Immunol Sect, Clin Res Ctr, 9000 Rockville Pike,Room 5C100, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov; p.muraro@imperial.ac.uk RI Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 NR 23 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2328-9503 J9 ANN CLIN TRANSL NEUR JI Ann. Clin. Transl. Neurol. PD JUN PY 2016 VL 3 IS 6 BP 422 EP 433 DI 10.1002/acn3.310 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DX1JE UT WOS:000384122200002 ER PT J AU Azoury, SC Gilmore, RC Shukla, V AF Azoury, Said C. Gilmore, Richard C. Shukla, Vivek TI Molecularly Targeted Agents and Immunotherapy for the Treatment of Head and Neck Squamous Cell Cancer (HNSCC) SO DISCOVERY MEDICINE LA English DT Article ID PHASE-II-TRIAL; GROWTH-FACTOR RECEPTOR; PHOSPHATIDYLINOSITOL 3-KINASE INHIBITOR; CHEMOTHERAPY PLUS CETUXIMAB; COLONY-STIMULATING FACTOR; AND/OR METASTATIC HEAD; PLATINUM-BASED THERAPY; 1ST-LINE TREATMENT; OPEN-LABEL; ADVANCED MELANOMA AB Squamous cell carcinoma is one of the most frequent tumors of the head and neck and often presents at an advanced-stage. Traditionally, treatment for head and neck squamous cell carcinoma (HNSCC) has included surgery, radiation, and chemotherapy depending on both the site and stage of disease. Although the treatment approach for local disease is often standardized, the management of recurrent and advanced disease is evolving. A better understanding of the molecular mechanisms of HNSCC has led to numerous promising investigations and the push for the development of novel therapies. Similarly, over the past several decades, growing data supports the notion that an individual's immune system can be manipulated in such a way to help eradicate cancer. The success of immunotherapeutic agents such as interleukin therapy and immune checkpoint inhibitor blockade in cancer, particularly advanced-stage melanoma, has stimulated researchers to uncover similar success stories in HNSCC. Examples of immunotherapeutics that are being studied for the treatment of HNSCC include adoptive T-cell therapy, vaccines, and immune checkpoint inhibitor proteins (e.g., anti-CTLA-4, -PD-1, -PD-L1). Molecularly targeted agents of interest include inhibitors of transmembrane growth factor receptors, angiogenesis, and PI3K/AKT/mTOR and NOTCH signaling pathways. To date, cetuximab, an epidermal growth factor receptor inhibitor, is the only targeted agent for HNSCC that was approved by the Federal Food and Drug Administration (FDA) on the basis that it improves overall survival when combined with chemotherapy or radiation. Herein, the authors provide an up-to-date review of immunotherapeutic and molecularly targeted agents for the treatment of HNSCC. C1 [Azoury, Said C.; Gilmore, Richard C.] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21202 USA. [Shukla, Vivek] NCI, Thorac & Gastrointestinal Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Shukla, V (reprint author), NCI, Thorac & Gastrointestinal Oncol Branch, NIH, Bethesda, MD 20892 USA. EM vivek.shukla@nih.gov NR 78 TC 1 Z9 1 U1 5 U2 5 PU DISCOVERY MEDICINE PI TIMONIUM PA 10 GERARD AVE, STE 201, TIMONIUM, MD 21093 USA SN 1539-6509 EI 1944-7930 J9 DISCOV MED JI Discov. Med. PD JUN PY 2016 VL 21 IS 118 BP 507 EP 516 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DX2KC UT WOS:000384196800008 PM 27448787 ER PT J AU Gardner, EL Bi, GH Thakur, G Makriyannis, A Seltzman, HH He, XH Xi, ZX AF Gardner, Eliot L. Bi, Guo-Hua Thakur, Ganesh Makriyannis, Alexandros Seltzman, Herbert H. He, Xiang-Hu Xi, Zheng-Xiong TI Preclinical Evaluation of Neutral Cannabinoid CB1 Receptor Antagonists and Cannabinoid CB1 Receptor Negative Allosteric Modulators for Treating Drug Addiction SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 30th Seoul World Congress of the International-College-of-Neuropsychopharmacology (CINP) CY JUL 03-07, 2016 CL Seoul, SOUTH KOREA SP Int Coll Neuropsychopharmacol C1 [Gardner, Eliot L.; Bi, Guo-Hua; He, Xiang-Hu; Xi, Zheng-Xiong] NIDA, Baltimore, MD USA. [Thakur, Ganesh; Makriyannis, Alexandros] Northeastern Univ, Boston, MA 02115 USA. [Seltzman, Herbert H.] Res Triangle Inst, POB 12194, Res Triangle Pk, NC 27709 USA. [He, Xiang-Hu] Wuhan Univ, Zhongnan Hosp, Wuhan, Hubei, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2016 VL 19 SU 1 MA PM288 BP 152 EP 152 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DW8PI UT WOS:000383917600404 ER PT J AU Smith, AH Bolcho, U Phokaew, C Ovesen, PL Yeo, S Jensen, KP Diazgranados, N Zhao, H Farrer, LA Goldman, D Glerup, S Kranzler, HR Nykjoer, A Gelernter, J AF Smith, Andrew H. Bolcho, Ulrik Phokaew, Chureerat Ovesen, Peter L. Yeo, Seungeun Jensen, Kevin P. Diazgranados, Nancy Zhao, Hongyu Farrer, Lindsay A. Goldman, David Glerup, Simon Kranzler, Henry R. Nykjoer, Anders Gelernter, Joel TI SORCS2 regulates alcohol withdrawal severity and excitatory synaptic transmission SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 30th Seoul World Congress of the International-College-of-Neuropsychopharmacology (CINP) CY JUL 03-07, 2016 CL Seoul, SOUTH KOREA SP Int Coll Neuropsychopharmacol C1 [Smith, Andrew H.] Yale Sch Med, Interdept Neurosci Program, West Haven, CT USA. [Smith, Andrew H.] Yale Sch Med, Med Scientist Training Program, West Haven, CT USA. [Smith, Andrew H.; Phokaew, Chureerat; Jensen, Kevin P.; Gelernter, Joel] VA CT Healthcare Ctr, Dept Psychiat, Div Human Genet, New Haven, CT USA. [Smith, Andrew H.; Phokaew, Chureerat; Jensen, Kevin P.; Gelernter, Joel] Yale Sch Med, West Haven, CT USA. [Bolcho, Ulrik; Ovesen, Peter L.; Glerup, Simon; Nykjoer, Anders] Aarhus Univ, Danish Res Inst Translat Neurosci DANDRITE, Lundbeck Fdn,Res Ctr MIND, Nord EMBL Partnership Mol Med,Dept Biomed, DK-8000 Aarhus C, Denmark. [Yeo, Seungeun; Goldman, David] NIAAA, Neurogenet Lab, Bethesda, MD 20892 USA. [Diazgranados, Nancy; Goldman, David] NIAAA, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Zhao, Hongyu] Yale Sch Publ Hlth, Dept Biostat, New Haven, CT USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Med Biomed Genet, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [Kranzler, Henry R.] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Kranzler, Henry R.] Corporal Michael J Crescenz VAMC, Philadelphia, PA 19104 USA. [Nykjoer, Anders] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Gelernter, Joel] Yale Univ, Yale Sch Med, Dept Genet, New Haven, CT 06510 USA. [Gelernter, Joel] Yale Univ, Yale Sch Med, Dept Neurobiol, New Haven, CT 06510 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2016 VL 19 SU 1 MA PM296 BP 154 EP 155 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DW8PI UT WOS:000383917600412 ER EF